In celebration of the American Library Association's National Library Week running from April 7 – 13, I thought I would break out this book tag I've been hanging on to. I don't recall where I found it, but I've been very eager to get it posted. Many thanks to the original creator.
1. How often do you visit your local library?
Physically not very often, but I frequently browse the online catalogue to make sure I have plenty of ebooks ready to go at a moment's notice! When my son was younger I would go to a weekly storytime session with him every Saturday, but he kind of lost interest in that (he still loves being read to though!).
2. Are you the type of person who checks out more books than you can read or are you someone who checks out the exact amount of books you intend to read before they are due?
I'm usually pretty good about only having the book I am currently reading checked out at any one time. Where I run into trouble, however, is when things I've had on hold long-term come through either while I'm already in the middle of a book or at the same time. At that point the race is on to finish them before they auto-return!
Probably 5 or 6. I was fortunate in that I grew up in a town with a great public library that my parents took full advantage of. Some ten years later, I would also have my first job working at that library!
4. Do you go to your library for a particular book or do you check out anything that piques your interest?
It depends on my mood, but more often than not I am looking for a specific title or author.
5. Do you only check out books or do you also get DVDs, audiobooks, etc.?
Probably 98% of my library check-outs from the past year have been ebooks. It's just so convenient being able to download them directly to my phone and/or Kindle.
6. From what section of the library do you check out most of your books?
Science Fiction/Fantasy followed by General Fiction.
The easy answer is free books, but I also like the idea of supporting a community resource that is centered around the idea of making reading and research generally available to all who seek it out. It's such an important service that everyone who can really ought to take advantage of. Discounted museum passes are also a pretty nice perk, too.
Hello and welcome to my Second Annual BeerRantsAndBooks Blogger's Choice Book Awards! In preparing for this post I've gone through my notes on all the books I reviewed this past year and compiled a list of my favorite characters and stories. I'm quite pleased with how strong all the nominees were this year, though that did mean making my final decisions was no easy task!
To note, I considered for these awards any book I read in 2018, regardless of when it was initially published. As much as I'd like to, I simply don't have the time to focus solely upon new releases. With that said, bring on the nominees!
Dalinar Kholin (Oathbringer, by Brandon Sanderson – Book Three in the Stormlight Archive): Oathbringer was Dalinar's turn to take center stage in the Stormlight Archive and he certainly made good use of his time. In this book he emerged not only as a leader capable of uniting humanity, but also someone who may have the potential to stand up to Cosmere bad guy Odium as well.
Hadi (Frankenstein in Baghdad, by Ahmed Saadawi): Hadi stands out on this list in that unlike the other characters here, he is not a fantasy hero. Instead, he's a junk trader with a drinking problem who has spent months morning the loss of a friend who died in a suicide bombing. To find purpose in his grief, he begins the grim task of collecting body parts and sewing them together in the hopes that a completed corpse can get a dignified burial in honor of his friend.
Kvothe (The Name of the Wind, by Patrick Rothfuss – Book One in the Kingkiller Chronicles): Although Kvothe was the star of two books I read this past year, I am nominating only his performance in The Name of the Wind as it was his most likeable. In this book we are told (by him) about how his seemingly exceptional skills, determination, and wit enabled him to rise from an orphan living in poverty to a gifted aspiring arcanist.
Roaden (Elantris, by Brandon Sanderson): The Prince of Arelon, Roaden is an idealistic, charismatic young man who pushes his father to implement economic and social reforms their kingdom desperately needs. On the eve of his wedding, however, he is afflicted by a disease called the Shaod and exiled with others like him to the city of Elantris. On the verge of giving up, he instead finds a new purpose in organizing his fellow outcasts.
Winner: I went back and forth on all of these characters, but ultimately my decision is Roaden. I found him very likeable and thought his selfless desire to constantly work for the betterment of others helped push him past the often arrogant Kvothe.
Adda Karpe (Barbary Station, by R.E. Stearns): Adda was truly a joy to meet. An extremely talented programmer/hacker and aspiring space pirate, she was also an extreme introvert (like myself!) who finds the energy and motivation to get through the day by cuddling her girlfriend and harvesting the hallucinogenic mushrooms she uses to help focus on work.
Lisette Toutournier (Everfair, by Nisi Shawl): A free-spirited French woman who rises to a highly influential position in the fictional African nation of Everfair. In addition to her diplomatic skills, her keen intellect and life-long fascination with machines put her right at home in her new surroundings. Through the course of the book, her duties and obligations push her to confront both her identity as a woman of mixed race and the dynamics of her decades spanning relationship with the ex-wife of her former lover.
Sarene (Elantris, by Brandon Sanderson): After learning of her husband-to-be's suspicious death upon arriving in a foreign land, this cunning, sharp-tongued princess wasted little time establishing herself in her new home. Between inserting herself in local politics, training the previously idle court ladies in fighting techniques, and providing humanitarian aid to the outcast people of Elantris, she becomes a force for good in an otherwise stagnant kingdom.
Shallan Davar (Oathbringer, by Brandon Sanderson – Book Three in the Stormlight Archive): Shallan overcame a lot in this story; she came to grips with her multiple personalities, confronted her past family traumas, resolved a love triangle (further complicated by the aforementioned multiple personalities), and stepped into her powers as a Radiant. She also played a pivotal role in some very key situations, cementing her position as a key player in the fight against Odium.
Winner: I honestly could (and even did) make a case for each of these women and indeed went back and forth on my final decision multiple times. Upon my final review, however, I found Lisette to be the best choice. She was a deep, multifaceted character whose story exposed me to a fresh perspective that really made me think.
Bast (The Wise Man's Fear, by Patrick Rothfuss – Book Two in the Kingkiller Chronicles): Companion to an older Kvothe in his guise as an innkeeper, Bast is certainly more than meets the eye. Not only is he a fae/demon of some kind, but underneath his often laid-back and jovial exterior lies a ruthless desire to see his tutor restored to his former glory.
Da Shi (The Three Body Problem, by Liu Cixin – Book One of Remembrance of Earth's Past Trilogy): I'm pretty sure you're not sure you're supposed to like him, but this detective had a certain vulgar charm and ruthless cunning that made him stand out for me.
Kiin (Elantris, by Brandon Sanderson): Sarene's uncle and political exile, Kiin was a kindly family man, excellent cook, and former pirate who provided his niece with some much-needed support in her new home.
Winner: This one goes to Bast. He was just such an interesting character and I feel like we've only scratched the surface of what is going on with him. I can't wait to learn more of his backstory and see what inspires his a actions. Assuming, of course, that this series ever gets finished.
Devi (The Wise Man's Fear, by Patrick Rothfuss – Book Two in the Kingkiller Chronicles): An underground money-lender who despite her pixie-like appearance and flirtatious nature has by all accounts earned her nickname "Demon Devi." She also turns out to be an extremely gifted alchemist and sympathist who enjoys collecting favors from interesting people.
Lift (Oathbringer, by Brandon Sanderson – Book Three in the Stormlight Archive): Lift used her "awesomeness" to steal more than a few scenes in this book, most notably by crashing the private visions of a minor deity and later on by playing a key role in foiling the plans of a considerably larger one. She also managed to keep her irreverent, and hungry, outlook on the world despite having matured a bit since her previous appearance.
Sam (The Last Days of New Paris, by China Mieville): A mysterious photographer/secret agent who joins forces with the main character Thibaut to navigate the Nazi and demon infested streets of Paris. Her true intentions, however, remain something of a mystery.
Winner: As much as I gave some serious last-minute consideration to Devi, it felt wrong to not choose Lift. She's such a fun character to have around in any situation. She's also the nominee I'd most want to hang out with; maybe hit up an all you can eat buffet to chat about life, the universe, and everything before she runs off.
Exquisite Corpse (The Last Days of New Paris, by China Mieville): The physical manifestation of a surrealist art exercise, it didn't speak at all but its presence certainly loomed large throughout the story. It's fascination with, and protectiveness of, Thibaut brought an added curiosity to an already weird tale.
Wyndle (Edgedancer, by Brandon Sanderson – Book 2.5 in the Stormlight Archive): Lift's vine-like spren companion and proud owner of a chair garden in the Cognitive Realm. For as impulsive and capricious as his partner may be, Wyndle is equally level-headed and logical. Often a voice of sense and reason, his kindly advice and dry humor brings a balance to the duo that makes them quite a team.
Whatsitsname (Frankenstein in Baghdad, by Ahmed Saadawi): A corpse sewn together from human remains collected at bomb scenes throughout downtown Baghdad, the Whatitsname came to life when entered by the soul of a slain security guard. Initially seeking revenge for each of its parts, it ultimately comes to question the righteousness of its quest.
Winner: The tough part about this category was that not was each character so different, but the stories they came from were all very different as well. After some deliberation, the winner here is Whatsitsname, on account of the questions it raised about the roles of justice, vengeance, and order in a society racked by violence.
Ancillary Justice, by Ann Leckie (Book One of the Imperial Radch Trilogy): Simplified greatly, this was the story of a once-sprawling troop ship AI now confined to a single, human body through a complicated series of political maneuverings and betrayals. Seeking revenge for its lost lives, our main character pins her hopes on locating a lost relic from a conquered civilization.
Persepolis Rising, by James S.A. Corey (Book Seven of the Expanse Series): While the old powers in the Solar System have been slowly rebuilding their strength following the cataclysmic events of the previous novel, new forces emerge from beyond the ring gates seeking to expand their reach.
The Three Body Problem, by Liu Cixin (Book One of Remembrance of Earth's Past Trilogy): The story of a modern-day Chinese research scientist who stumbles upon a Cultural Revolution-era conspiracy involving contact with alien life.
Winner: This really came down to Ancillary Justice and The Three Body Problem, and I really had to think hard about which story I liked more. I put myself in a tough position on this one, so I am going with my gut answer and deciding upon Ancillary Justice. As much as a I loved the harder sci-fi angle of the Three Body Problem, I got into the story of Ancillary Justice in a way that made it very hard to pick against. Moving on before I change my mind.
Name of the Wind, by Patrick Rothfuss (Book One of the Kingkiller Chronicles): This story began the journey of the prodigy Kvothe. After escaping from a group of demons that murdered his parents and traveling companions as a child, Kvothe overcame being a penniless orphan to enlist in a prestigious University to study the magical arts. Along the way, he makes a rather impressive and memorable list of friends and foes.
Elantris, by Brandon Sanderson: Once a beacon of progress, the city of Elantris has fallen into ruin after magic system supporting it has faltered. In its shadow, the Kingdom of Arelon is desperately seeking to secure its borders against the rapidly expanding Fjorden Empire.
Winner: There is now way I can't pick Oathbringer. I don't know if that's entirely fair given where it occurs in its series, but my expectations for this going in were sky-high and the book more than delivered. It was a very long book, but still felt packed full of action, world building, and character development that culminated in one epic battle.
Radio Free Boston – The Rise and Fall of WBCN, by Carter Allen: A behind-the-scenes look at Boston's WBCN radio station from its founding in 1968 to its eventual demise in 2009, told by the people who worked there.
Barrel Aged Stout and Selling Out: Goose Island, Anheuser-Busch, and How Craft Beer Became Big Business, by Josh Noel: The story of how Chicago's Goose Island Brewing Company rose to become one of the early champions of "craft beer" in the United States and how its sale to the multinational conglomerate known as AB-Inbev changed the American beer industry.
Summer of '68, by Tim Wendell: An examination of the 1968 baseball season and how the World Series matchup between the Detroit Tigers and St. Louis Cardinals reflected the social unrest going on at the time.
Winner: I'm going for the nostalgic pick here and selecting Radio Free Boston. It was a fun and informative look at my favorite radio station growing up.
Well, that rounds out my 2018 awards. It was a great year for reading and I look forward to seeing what 2019 has in store. See you all in the new year!
With Halloween right around the corner, I went searching for ideas on how to mix up my anticipatory posts. That quest led me to this fun tag, which I found on another blogger's page (thank you Madame Writer). This is a long one, but it sure did get me ready for tomorrow night!
It's really hard to pick just one, so why don't I refer you to the Halloween music post I did yesterday? Gut answer is probably Black No. 1 by Type O Negative, but I reserve the right to change my mind a few times.
I suppose any number of things would fit here. I'd hate to run into a murder-hobo or something like that in either location, nor would I especially like to come across a bear while hiking.
Nope. If taken as a game, it's always seemed pointless to me. If taken as something more intense/serious than that, WHY DO THAT!?
I'm going to confess now that I'm not all that into horror so picking a favorite is hard. I was really into monster movies as a kid, though, so does Godzilla qualify? If not maybe I'll pick the Shrike from the Hyperion novels.
I've seen some weird/crazy stuff in my younger days, though most if not all of the truly creepy or weird can be attributed to my, er, state of mind at the time. Setting those experiences aside, in everyday life I really have only had more run-of-the-mill random house noises or centipede in the basement type things happen.
No, I'd probably psych myself out about it. That said, I have spent the night in a few hotels that are supposed to be haunted (though I have no ghost stories to report).
Yes, but more in the idiosyncratic sort of way. Maintaining certain rituals during sports games, not mentioning certain things or events I want to happen, things of that nature.
Nothing more menacing than the usual tricks of the eye. I also wear glasses, so that may have an impact as well.
Thrillers. I'm generally not a fan of gore and that is probably the number one reason I never got into the horror genre.
Yes. I don't necessarily think that we can interact with them without extraordinary cosmic upheaval or technology WAY beyond or current capabilities, but I do believe they exist.
Sure, if you count mixed drinks.
Yeah, probably. I'm not necessarily proud to admit this but that's my honest answer.
Nope. Seemed pointless to me as a kid and I'm not about to start doing it as an adult.
No, though I suppose I could also be called somewhat agnostic on the issue. I'm not exactly sold on the idea of their counterparts either, at least in any mainstream sort of way.
Assume it's from next door or outside most likely. I'd probably be more weirded out in a strange setting, like an Airbnb though.
This doesn't really sound like my idea of a good time, but I wouldn't mind hanging out with Bill Murray in Zombieland I guess.
My Flava-Flav inspired steampunk suit. Basically I wear black dress pants and shirt, a knee-length men's black dress jacket, a top-hat with gears on it, big silver goggles, and a bronze wind-up clock around my neck on a thick chain. Usually a cane completes the ensemble.
Absolutely. There are some very nice cemeteries in my area and I find evening strolls in them very relaxing.
Practical answer is probably a machete since it doesn't rely on expendable ammunition and can serve other uses. My purely fictional, and likely impractical, answer is shotgun with a pitchfork bayonet.
My likely answer is party, but that might change after taking my son out for his first trick-or-treat this year (at least until he gets too old to want his parents around).
Well, for starters I'm a guy but in keeping with the spirit of the question I'd probably be the skeptic. I give myself even odds of living.
Not necessarily, but a little decompressing by doing something mindless isn't out of the question.
24. Whilst watching scary movies, are you the type who yells at the characters, the person with their eyes covered the whole time, or the person who falls asleep?
Who says I can't be all of the above?
It's a pretty even mix in my house. I've gotten my wife pretty good over the years, but she never fails to return the favor. Our two-year old seems to be trying to get in on the action, a prospect that is both adorable and concerning.
Uh-oh. Um, I don't really read scary books! I've already mentioned Hyperion in this post which has some scary/horror elements to it, but I don't know if it quite fits what this prompt was going for. I also enjoyed the Lovecraft collection I read earlier this month, though I can't really say that it scared me.
Grade school probably. I recall for sure seeing Ernest Scared Stupid in the theater at roughly 9 years old so I'll go with that. Truly a horror classic.
I don't know for sure, but the first one I remember is a light blue felt stegosaurus suit. I loved that thing!
My official costume is Vampire. My son has been really excited for over a month about being a vampire for Halloween, so that is what the whole family is doing. How/if he knew what a vampire was at the time he asked for this is a mystery.
My unofficial costume that I'll wear to work or more minor Halloween outings is MegaMan from the series of NES games. It's nothing crazy, just a hoodie designed to look like him and a stuffy of his robot dog, Rush, pinned to my shoulder.
Black cat all the way! I actually had one as a teenager named Edgar (after Edgar Allen Poe) and we had a special bond, probably due to our mutual love of food and extreme introversion. I'd love to have a cat now as an adult, but my wife and I are now both terribly allergic.
It's been awhile since I last took on a book tag and this was definitely one of the more intriguing options I had lying around in my notes. I like to think that I am fairly inclusive and open-minded in my readings, so, to the extent possible, I am limiting my selections to books I've reviewed here.
I had to think about this one for a bit, but I eventually decided that I am going with Colleen McCollough on this one. I absolutely love her Masters of Rome series and consider it the absolute standard against which I will forever judge all works of historical fiction. I know she has written other things that are bit different from these books (and with which I am entirely unfamiliar), but it was hard to pick against her after so thoroughly enjoying seven books and nearly 6,500 pages of her work.
Ugh, another favorite question! I'm calling this one a toss-up because I couldn't decide. It's either Darwi Odrade from Heretics of Dune and Chapterhouse: Dune or Vin from the first era Mistborn trilogy.
After spending a pretty good amount of time thinking about this what would make a novel feminist, I decided upon Everfair, by Nisi Shawl. I did so because it features two prominent female characters who challenge conventions with their political activism, academic/scientific interests, and sexuality. A quick read of the author's bio reveals that these are all topics near and dear to her own heart, as her academic and literary focus is on Sci-Fi and Fantasy works that look at, among other things, issues of race, gender, sexual orientation, and socio-economic status.
Not sure that cover art is necessarily a sign of feminism, but Brandon Sanderson's Oathbringer, one of my favorite books from this year, has a rather striking depiction of Jasnah Kholin on the cover.
While I certainly wouldn't call them "girls," I'll pick the all-woman cast of The Stars are Legion, by Kameron Hurley – a female author who strongly identifies as a feminist. Digging a bit deeper here, I read an interesting review after finishing this book that touched upon the issue of gender in this universe where men simply do not exist even as a concept (at least in the scope of the story thus far).
It just so happens that I've read two books so far this year starring main characters that fall within this category. The first was Barbary Station, by R.E. Stearns, in which engineer/programmer Adda Karpe and her girlfriend Iridian try to join a band of space pirates. The second book was the aforementioned Everfair, in which a young biracial French woman named Lisette enters into a polyamorous relationship with an Englishman only to find a more lasting love with his (former) wife Daisy.
Different is a bit ambiguous here, but easily the most atypical female POV I can readily recall is Purga from Stephen Baxter's Evolution. She is a small mammal living roughly 65 million years ago in the late Jurassic era.
I'll go with Soon I Will be Invincible, by Austin Grossman for this one though I won't spoil which of the novel's superheroines ultimately saves the day.
All the books in the The Expanse series featuring Bobbie Draper. It's no contest between her and James Holden, or any of the other Rocinante crew members for that matter. Needless to say, certain events that happen early on in Persepolis Rising made me very happy.
I'm going to assume this meant to say female main character. Um, lots? Sarene from Brandon Sanderson's Elantris is one of my favorite new (to me) characters of the year thus far and she would probably embrace being called a feminist to boot.
Here we go with another fun book tag I unearthed. Who doesn't want to assemble characters from their favorite books into a zombie apocalypse survival group? Let's see who I wind up with.
Uh-oh, not a redshirt in the bunch. This might get painful. On paper, though, I couldn't have asked for a much better crew.
James Holden (Persepolis Rising). Eh, maybe this isn't such a bad thing. Holden has a tendency to draw a lot of attention to himself that greatly complicates life for those in his wake. I could see him getting the group killed or worse in the zombie apocalypse.
Naomi Nagata (Persepolis Rising). I feel bad about this one, but let me try to rationalize. Naomi's expertise is in advanced computing and engineering which probably won't be needed in the zombie apocalypse. More importantly, her physical inability to handle Earth's gravity after a lifetime in space would make her a huge liability.
Kelsier (Mistborn: The Final Empire). I'd like to think that it was a situation where it was either him or me, or perhaps karmic retribution for Naomi, but I can kind of see this one. Especially if I hadn't proven my usefulness to the group at that point.
Vin (Mistborn: The Final Empire). Ouch. That's a significant blow to our survival chances right there. Not only do we lose her formidable fighting and scouting abilities, but we also lose her experience as a scavenger and thief. This one hurts folks, but I'm sure she went out a hero.
Darwi Odrade (Heretics of Dune). If she is the idiot, the rest of the team must be exceptionally intelligent. The only way I believe this is if you factor in melange withdrawal.
Alma Mavis Taraza (Heretics of Dune). Seems highly likely. Taraza has a formidable intelligence along with superior skills in leadership, tactics, and leveraging social and political influences. Melange withdrawal is again a concern though.
Bilbo Baggins (The Return of the King). We might be in trouble here unless old Bilbo has some tricks up his sleeve. I hope pipe weed and ale have medicinal powers way beyond what I am aware of.
Frodo Baggins (The Return of the King). Frodo is one brave and resourceful Hobbit, but he wasn't exactly a fighter. Fortunately this is a pretty veteran group that doesn't need much advice on weaponry.
Severus Snape (Harry Potter and the Prisoner of Azkaban). Yeah, I can get behind this choice. Especially with Vin out of commission and Kelsier busy tripping me. No chance he beats either Odrade or Taraza in a duel, but there's no doubt he's suited to this role.
Hermione Granger (Harry Potter and the Prisoner of Azkaban). Feeling pretty confident with Hermione as team leader. I can only imagine how badass she'd turn out with both Odrade and Taraza around to guide her.
Keeping things going with another fun book tag I came across while looking for things to write about. This one gives you a peek at some of the inner workings of how things get done here over here at BeerRantsandBooks. I don't really like playing the tagging game, so I again offer my apologies if not doing so is some sort of no-no around here. No disrespect is intended to the tag's creators.
Wherever I can. Usually that means my couch or dining room table, though I often write in bed, at work during lunch, and on the subway as well. I'm currently sitting on my back deck and writing which is a trend I'd like to continue in the coming months.
Depends on the book, how much I want to say, and how busy I am with work and childcare. Anywhere from a few days to a few weeks though I've had some linger on for longer.
I started my blog back in November 2014, though it wasn't until December 8th of that year that I got my first book review up.
Accepting my limitations as a writer/reviewer. Despite being an otherwise fairly intelligent and capable individual, writing, even informally, has always been a bit of a process for me. I often have difficulty pulling all the ideas out of my head and then getting them organized on a page. I like to think that I've improved over the years of plugging away here, but I'm still not as efficient at it as I would like to be.
Going back to the previous question, I like having a book blog because it pushes me to write more. This has on occasion been a source of frustration, but in the end I find it worthwhile as it gives me a creative outlet through which to voice my thoughts while at the same time encouraging me to constantly seek out new reading material.
Lately I've been having a lot of fun searching out and writing book tags as it gives my blog more a personal touch that it hasn't really had until recently. Beyond that, I've really enjoyed my beer reviews that include mini photo shoots. Anytime I'm able to combine a beverage with some kind of prop (usually an on-theme book or Star Wars Lego) I'm having fun.
My most rewarding post, however, is one I wrote back in November 2015 about going through my old baseball cards. Not only did looking at them bring back a ton of childhood memories, but the post ended up getting linked to on Major League Baseball's Around the Horn blog. That is without a doubt my proudest moment as a blogger and it always makes me happy when I see it get hits.
I'm not sure I really have a favorite since what I'm into posting so often depends more on my mood and what subject matter I have to work with.
Usually either in the morning on my subway ride into work or in the evening after I have gotten my son to bed. Time has been at a premium for me lately so I try to get my writing in whenever and wherever I can.
For the most part. There have been a few I've skipped for a variety of reasons, but on the whole I am very selective when picking up books and enjoy writing about my thoughts on them.
This may sound crazy, but here goes. I typically type up a draft on my phone whenever and wherever I can; on the subway, in bed, sitting on the couch, etc. I then print that to (*gasp*) paper and make revisions in any and all of the locations listed previously. I do final draft either on my laptop or sitting at desk. Thank you wireless printer and Google docs!
I usually start drafting my reviews within a day of finishing the book, but depending upon my schedule it can sometimes take a few weeks for me to finish. I do always like to at least get my thoughts outlined while the book is still fresh in my head.
I generally post 2-3 times per week. Lately I started alternating weeks were I post Monday/ Wednesday/Friday and those where I post Tuesday/Thursday and I like how that has been going. I'm jealous of the people I see with dedicated posting schedules and thematic days, but I know that I would never be able to keep up with that and just end up getting overwhelmed or stressed in try to.
I've decided to try out another book tag for today. Since I've having fun with these lately, look for them to become a new feature here. I'm not really into tagging, so I'm just searching and grabbing the ones I like most. Apologies if this is some kind of major WordPress faux pas or breach of etiquette.
I find the majority of my new books/authors by either skimming through library listings, the Tor Publishing newsletter, or the ARC piles featured over at Whatever.
How has your taste in books changed since you got older?
I'd like to think my taste has gotten more refined over the years. I also used to read a lot of political non-fiction as a teenager and I haven't really been as into that since university.
Rarely. I probably only buy 2-3 a year, if that. I am fortunate enough to live in an area with an excellent library network, giving my library card quite the workout.
A few years back I was looking for a hobby or some kind of creative outlet and after brainstorming ideas (and realizing I didn't have sufficient time or space for home brewing), I decided upon a blog. Blogging had the added benefit of forcing me to write more frequently, something that doesn't always come easy to me. I initially had some trouble deciding on a theme, but here I am nearly three and a half years later still posting about beer and books. Not sure I really fit into either the beer blogger or the book blogger world, but I'm having fun doing my thing which was exactly the point.
Usually just feel a bit disappointed. I suppose I have on occasion taken my frustrations to the internet, but what else can you do?
How often do you sneak peek at the ending to see if there is a happy ending?
Never! Is this a thing?!?!
I've seen this tag making the rounds lately and thought it would be fun to play along. Hopefully I'm not too late to the party.
Generally speaking I feel like if you're going beyond a trilogy, there should be both a compelling reason to do so and a plan for where the series is going. There are a few longer running series that I love, but what they all have in common is that they clearly have a destination in mind.
They're fine so long as the author intends to keep the series going in a timely manner.
The last few years I've been doing almost all my reading via Kindle and switching between the actual device and the app on my phone. I really love the portability and convenience of being able to borrow ebooks from my local library.
What kind of sick tag asks a reader to make a choice like this? There are so many books I like for so many different reasons that I'm not sure I could choose. Gun to my head answer: Children of Dune. Don't ask how often I changed that before hitting publish.
Another tough choice. I tend not to remember the bad ones, but I do recall particularly disliking Ethan Frome and Tuesdays with Morrie. Both of these I had to read for school, though. The former was forced upon me as a seventh grader and the latter upon entering university so I do take that into account. With the exception of Upton Sinclair's The Jungle I think I've disliked nearly every book I've had to read. This is some kind of unwritten rule, right?
If they fit the story, fine I guess. The trope doesn't really do anything for me either way. Just don't add it for the sole purpose of selling the book.
I'm pretty selective, so this doesn't happen often. My last DNF was First and Last Men, by Olaf Stapledon but that was a few years ago. It was a very dense hard sci-fi novel written in the early 1930s that I just couldn't get into. Ernest Cline's Armada recently came very, very close.
Currently reading Elantris, by Brandon Sanderson. I'm absolutely hooked on his Cosmere universe, so I'll be reading a lot from him.
Frankenstein in Baghdad, by Ahmed Saadawi. Consider it recommended again.
Depends on how we're treating translations. It's Homer's Odyssey if we're going with the date of the original and probably Dune (1965) if not.
Again, it depends on how we're dealing with translations. It's either Frankenstein in Baghdad (English language translation published January, 2018) or Collapsing Empire, by John Scalzi (March, 2017).
Gut answer: Haruki Murakami. Moving on before I change it.
Borrow. My library card gets a real workout, especially since I can use it for ebooks.
American Gods, by Neil Gaimon. So many people whose opinions I value spoke highly of this, but I just never really got into it. Perhaps it was a victim of hype.
I've been known to do both, as place savers and as a means to keep track of passages I particularly like. Depends on the book and what I happen to have handy to use as a bookmark. Some of the most well loved books in my library have extensive dog-earing while others have multiple bookmarks.
A BOOK YOU CAN ALWAYS REREAD?
There are a few books I reread with some regularity, most notably Frank Herbert's Dune series and Hunter S. Thompson's Fear and Loathing on the Campaign Trail '72, but those depend highly upon my mood. For an anytime reread I would have to pick The Hitchhiker's Guide to the Galaxy.
I do a lot of reading on the subway so I'm pretty good at phasing out background noise, but I don't think I could purposefully listen to music and be able to focus on reading.
Really depends on the book and the author. Both are fine in the proper context.
Multiple days. I no longer have the luxury of sufficient time to finish a book in one day.
ONE BOOK YOU READ BECAUSE OF THE COVER.
Hyperion, by Dan Simmons and it turned out to be one of my favorites. The image of the sunset gleaming off the Shrike as it stares out across an alien landscape captivated me for years before I even read the book.


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ZEPTER INTERNATIONAL s.r.o.
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Centropen has been producing high quality writing and drawing utensils for a broad range of uses for over 70 years now.
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It is a major football club, founded in 1958, by merging Jiskra with Slavoj – two Liberec clubs that followed the local football tradition.
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It is a Czech manufacturer of clothing accessories with twenty years of experience. Its ties, bowties, scarves and other goods are mostly made of polyester and silk.
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RAVEO s.r.o. is a dynamic company offering components and complete solutions in the area of motion technology. They focus on industrial applications requiring motion and positioning.
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Company For Baby, spol. s r.o. was founded in February 1998 as a small private company with their goal being to bring high quality products for parents and babies to the market.
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A generous spoonful of Dulce de Leche sauce.
Dulce de Leche is a traditional Argentinian dessert accompaniment. Translated, the term means "candy of milk." It has a creamy, smooth texture that is a delicious topping for any dessert you can dream up, from simple to more complex.
Ice cream sundae with Dulce de Leche sauce. YUM!
Here are the only ingredients needed.
Empty one can of sweetened condensed milk into an oven-proof dish.
Sprinkle with a pinch of Kosher salt. Do not stir.
Cover this dish with foil very tightly.
Place the covered dish into a larger roasting pan or casserole dish and pour water into the larger dish (creating a water bath) until it reaches 3/4 of the way up the sides of the dish of sweetened condensed milk.
Bake for 60-90 minutes, checking frequently on the water level and adding hot water if needed, being careful not to get it into the milk mixture.
Once the mix takes on a caramel color, remove water bath from the oven and remove the Dulce de Leche from the water bath.
Whisk the mixture to smoothness and allow to cool before using. This may be put in a glass jar and stored in the refrigerator for later use. It will keep for up to two weeks, longer if frozen.
This Dulce de Leche sauce can be used for dipping fruit as well as for ice cream topping. If you love the flavor of caramel, this sauce is a sure thing for you!
These tulip sundae dishes are a festive way to serve your ice cream with Dulce de Leche sauce.
Dipping frozen ice cream can be a tough job, but not if you've got this ice cream scoop. OXO Good Grips make it easy on the hands to grip, and the sharp point of the dipper makes it easier to scoop that frozen goodness.
This is a good baking dish to pour that sweetened, condensed milk into for baking in the oven. Glass baking dishes seem to release their contents easier than metal ones for me.
If you plan to eat your Dulce de Leche sauce on ice cream in one of the tulip shaped sundae dishes shown above, you'll need some long handled spoons to reach the bottom of the dish. I recommend these, not expensive, and perfectly shaped to reach the last yummy bit of ice cream and sauce.


Home » Glossary » What is Employee ROI?
Employee ROI (Return On Investment) is a performance measure used by business organizations to evaluate the efficiency of their financial resources invested in their workforce, or to compare two or more employee investment opportunities with each other. It proves how good employed people are and whether the invested resources are fully covered by the benefits produced by the employees.
By using this formula, a business organization can figure out whether to invest in a given employee opportunity or not. If the ROI is negative (that's the cost is higher than the gains), then obviously the organization should not take the opportunity.
The measure is often used to make a preliminary assessment of employee investment opportunities, so that a business organization has a better way for ensuring that it gets great quality of hire, engaged workforce, and low attrition rates.


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Russian 9S932-1 intelligence and control modules with 1L122-1E radar from Barnaul-T command system found by Ukrainian army
Ukraine - Russia conflict war 2022
As largely documented by countless pictures and videos posted on many social networks, Ukrainian forces continue to capture, or at least stumble across, numerous examples of some of Russia's most sophisticated ground combat hardware, on top of impressive numbers of common tanks, armored and soft-skin vehicles, often completely destroyed by anti-tank missiles fired from the ground or by attack drones, if not by artillery and tank fires.
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Russian 9S932-1 MRU-B radar-equipped air defense command post vehicle, part of a larger system known as Barnaul-T, found by Ukrainian soldiers (Picture source: Twitter)
Last weekend, pictures emerged online showing a Russian radar-equipped air defense command post vehicle, part of a larger system known as Barnaul-T, that Ukrainian troops found during a counteroffensive in the northeastern Kharkiv region, Joseph Trevithick publishes in The War Zone, echoing various tweets from Ukrainians. The fact that this vehicle is intended to serve as a sensor, command and control, and communications node all rolled into one could make it a particularly invaluable source of intelligence for Ukrainian and foreign governments, as well as be a significant operational loss for Russian forces, Joseph Trevithick comments.
A Ukrainian unit reportedly found this vehicle relatively intact, also known by the nomenclature 9S932-1 and the acronym MRU-B, among other Russian vehicles and artillery pieces, in the town of Husarivka. The 9S932-1 is most readily identifiable by its 1L122 surveillance and target acquisition radar, which is mounted on the top rear portion of the hull and is folded down during transit. There was also a TZM-T dedicated reloading vehicle for the TOS-1A thermobaric artillery rocket launch system, another uncommon find.
Ukrainian forces appear to come across at least three examples of this particular component of the Barnaul-T system in the course of what has now been nearly five weeks of fighting. What looks to have been a second 9S932-1 was found in relatively good condition in the Kharkiv region sometime around March 12. A third one was captured near the capital Kyiv on or about March 3 and was apparently so pristine that it was then pressed into Ukrainian service in an unclear capacity, Joseph Trevithick reports.
Russian radar-equipped 9S932-1 MRU-B air defense command post vehicle, part of a larger system known as Barnaul-T, found by Ukrainian soldiers (Picture source: Twitter)
9S932-1 intelligence and control module with 1L122-1E radar from Barnaul-T command system (Picture source: Vitaly Kuzmin)


what do you mean how many times? every time i could for the last twenty five years ok?
"Even the rare bishops who policed their own dioceses and punished the predators and protected their flocks were guilty of not doing more to stop what they knew was going on in other dioceses."
there is a limit to how much one can do before compromising whatever good one can achieve or even putting themselves in harms way.
Thank you, B. Thank you, Icarus. Glad you liked the post. And Icarus makes a very good point. One of those rare bishops is mentioned in Spotlight. John D'Arcy. He was an auxiliary bishop in Boston and tried to get Cardinal Law to take action and got himself promoted for his trouble. Wound up the bishop in Fort Wayne, Indiana, arriving there at about the same time as Mrs M and I did. It appears he kept a good watch there. On the other hand, he kept quiet even after the stories broke and the only times he made the national news through his own initiative were when he tried to get Patrick Moynihan and then Barack Obama dis-invited from speaking at Notre Dame because they were pro-choice.


Public Service Enterprise Group Incorporated, through its subsidiaries, operates as an energy company primarily in the Northeastern and Mid- Atlantic United States. It operates through two segments, PSE&G and Power. The PSE&G segment transmits electricity; and distributes electricity and gas to residential, commercial, and industrial customers, as well as invests in solar generation projects, and energy efficiency and related programs; and offers appliance services and repairs to customers. As of December 31, 2017, it had electric transmission and distribution system of 24,000 circuit miles and 853,000 poles; and 18,000 miles of gas mains, 12 gas distribution headquarters, 2 sub-headquarters, and 1 meter shop. The Power segment operates nuclear, coal, gas, oil-fired, solar, and renewable generation facilities. As of December 31, 2017, it had an installed fossil and nuclear generating capacity of approximately 10,562 megawatts. Public Service Enterprise Group Incorporated was founded in 1985 and is headquartered in Newark, New Jersey.
The company reported Net Income for the third quarter of 2018 of $412 million, or $0.81 per share as compared to Net Income of $395 million, or $0.78 per share, in the third quarter of 2017.
Public Service Enterprise Group's recent inclusion on the Dow Jones Sustainability Index (DJSI) for North America for the 11th year in a row is the latest confirmation of the company's commitment to sustainable and ethical practices.
PEG's strengths can be seen in its better profitability and better solvency compared with its peers. Technical indicators signal the bullish signs, as there is a bullish crossover in Stochastic oscillator, the RSI is strong in the bullish zone and the MACD is trying to cross back up. We rate Public Service Enterprise Group Incorporated (PEG) a STRONG BUY.


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Creating a Revolution in Fitness – Grandmaster Adam Nguyen is Reinventing the Hamster Wheel!
This morning, one of Grandmaster Adam's students came to his class, and said she went to a stretch and exercise class this week at a local gym, and asked "is this all there is?" The class wasn't constructive or beneficial. Adam nodded. It resonated with his thoughts. He recognized this situation throughout the years. He has seen hundreds of programs come and go. A lot of them do more harm than good. That's why they don't last. It's a hamster wheel of fitness – a lot of running around, but you get nowhere.
When Adam came to America in 1971, he was 19-years-old, and had already been assisting his Grandmaster Ly Xuan Cuong in teaching for four years. Wherever Adam traveled, Utah, Washington, DC, Maryland, and Virginia people would marvel at his practice of Yoga, Karate-do, and Zen Meditation. They would inevitably ask what he was doing, and ask him to demonstrate more. Even though Adam was a college student himself, they would ask him to teach them. He was only too happy to share what his family had been teaching first to the Royal Families, and top officials of Vietnam for hundreds of years. What Adam teaches to this day is a unique brand of wellness. The foundation is Yoga, but much more elaborate and intense. Adam has a poster where he is holding 222 Yoga poses. Most people are impressed by not only the poses, but the beauty of the proper form – the depth of the execution. Adam waves this off. "We have more than 10,000 variations and combinations of technique and sequences." That's the difference he insists.
So Adam showed up on my doorstep this morning, very excited for such a peaceful Master. "We are going to create a revolution," he said. "There is a hamster wheel of exercise programs out there. People are stuck, but we are going to make them healthy. If they practice the right way they can improve their health, and move well, feel great. They will function well until their very last days."
It's difficult to explain to someone younger who has not nursed an aging parent; someone who feels invincible in their youth how important it is to be able to stand straight, tall, and strong, and be able to walk on their own power. Once you see how difficult it is for your own parents to make it up a flight of stairs – you understand. It's equally difficult to explain to someone in their sixties that it is not too late improve, and return to a more youthful condition. Grandmaster Adam has already proved this to be the case with many of his senior students!
How does Adam do it? He takes proper time to work the whole body; head to toe; the senses, the mind, the nervous, lymphatic, immune, and all other systems. It's stretching, loosening, straightening, balancing and stabilizing the body. He helps you create energy by invigorating the internal organs and glands. You work on breath -so important. All the joints become properly aligned and lubricated. He works on straightening and strengthening tendons, ligaments, and muscles. Whereas weightlifting might tighten and tear, his way of practice restores and rejuvenates.
So, let the peaceful revolution begin. If Master Adam has his way he will teach millions of students to live happier healthier lives. Maybe one of them will be you.
Within You Without You
"Sometimes we explore the Earth to discover a dormant world inside ourselves." -Ethan Marten https://t.co/O7wNa8CKfH Photo by @ianskellett pic.twitter.com/iicmSnirNR
— Ethan Marten (@ethanmarten) October 7, 2016
With Apologies to John Lennon – Reel Love
Thank you for watching, and showing me some Reel Love. I've been remiss about putting out a reel for years so I've compiled some quick clips from various films and television appearances. Hope you enjoy it. Clips are from Eyes of the Roshi; The Dream Machine; Chasing Laughter; Alfred from Ghost Stories; Broken; The Son; Mercy; and, The Alcoholic. Too many fun things to choose from, and wanted to keep it under two minutes. All the Best, Ethan.
Actors impossible dream. To follow that star,
No matter how hopeless, no matter how far https://t.co/ld38yX1uk3 #DemoReel #Actorslife pic.twitter.com/QHIrgkHexg


Plant Electrosila (St. Petersburg) - a largemachine-building enterprise. He was and remains one of the world leaders in the production of equipment for hydroelectric power plants, nuclear and thermal power plants. The plant supplies to Europe, Africa, and Asia. The whole geography of cooperation counts 87 countries of the world.
To date, nuclear power plants in the territory of the CIS are equipped with generators of this enterprise. Also the equipment is mounted on 70% of hydraulic and 60% of heat stations.
The first factory, engaged in the production of electricmachines for industrial enterprises, was named "Siemens-Shukkert." It was founded in 1853. In fact, it was a branch of a German company opened on Vasilievsky Island in response to large orders from the Russian government. In 1898 the factory became a part of the Russian joint-stock company "Siemens and Galske", and from this moment the history of the enterprise is counted.
After the revolution, the enterprise wasnationalized. Its real name was Electrosila Plant in 1922. During this period, the company's specialists took part in the development and implementation of the state electrification plan for Russia (GOELRO). Design Bureau was designed the first in the history of the country's electric generators. They were delivered to the Volkhov HPP, Gomel and Omsk TPPs.
In the thirties, the Elektrosila plant representeda well-developed industrial structure with advanced engineering technologies. At the production facilities, new types of machines and demanded structures were designed and manufactured. The company supplied products to domestic and foreign markets, exported technology, shared experience.
Specialists of this enterprise in the early thirtiesyears have created a unique hydrogenerator with a capacity of 62 MW, which breathed life into DnieproGES, and the plant made it the industry leader. In 1937, a turbine-type generator with a capacity of 100 MW was designed and built by the staff. At that time it was a world-class technological breakthrough.
Postwar time posed new challenges,there were projects of using atomic energy for peaceful purposes. The Electrosila plant took an active part in the development of the technological part of future nuclear power plants. The design bureau was created at the enterprise, the main tasks of which was the design of electromagnetic converters.
In the period of 60-70-s the factory equippedgenerators with a capacity of 500 MW Krasnoyarsk HPP, and for the Sayano-Shushenskaya station machines were created in 640 MW. In 1980, the employees of the enterprise were supplied with another professional record, and a technological breakthrough was made. The company has created the world's largest high-speed turbo-generator, whose capacity is 1200 MW. The place of his work was Kostromskaya GRES.
One of the greatest achievementsthe plant "Electrosila" was proud of, the design and manufacture of explosion-proof turbine generators for nuclear power plants became. Such machines have no analogues in the world engineering market. In addition to providing power plants, the company produces electric cars in demand in shipbuilding, chemical, mining, and metallurgy. Most enterprises use products with the stamp of the Electrosila plant.
In 1996, the company Elektrosila becamejoint-stock company, and having completed the procedure for changing the form of ownership in 2000, it became part of the concern of OJSC Power Machines. Companies that worked in engineering, aimed at producing equipment for generating electricity, heat, etc. joined the association. The concentration of one branch of engineering under a single jurisdiction increases the country's chances of successful competition in the globalizing economic process.
It is believed that by 2020, the world'selectricity will increase to 22 trillion kWh, and only those enterprises that will be able to provide the customer with a full range of services will be able to successfully operate in this production segment. Such an opportunity is available only to large enterprises that meet the toughened world standards.
In the structure of OJSC "Power Machines" the enterpriseElectrosila is engaged in the production of equipment for Russian cascade projects at Bureyskiye HPPs, Boguchanskaya HPP, Indian TPPs (Sipat, Varkh), Mexican HPP El Kahon and many others.
Products of OJSC "Power Machines"
Nuclear power. On the basis of the plant "Electrosila" steam turbines, turbine islands, drive turbines, turbogenerators, control and automation systems are produced.
Thermal power engineering. Boiler and turbine islands are produced, equipment for boiler houses, excitation systems, steam generators, starting devices, turbogenerators.
Hydropower engineering. Hydro turbines, hydrogenerators, excitation systems, pre-turbine gates, launch systems, etc. are produced.
Industrial, transport equipment. The output of AC generators, complete devices for alternating and direct current electric generators, electric drives of AC and DC devices, traction electric drives, electric motors, synchronous generators and steam turbines for the needs of the shipbuilding industry is established.
Electric grid production. The company produces transformer complexes, and also deals with their design and installation.
The enterprise pays much attention tosocial security of personnel, labor safety and ensuring a decent level of wages. There are social facilities on the territory of the plant, such as dining rooms, medical centers, libraries, etc. Each employee can count on preferential purchase of sanatorium vouchers, as well as preferences when purchasing permits for houses and recreation centers, children's camps. The corporation provides all specialists with working conditions in accordance with the Labor Code of the Russian Federation.
Annually for the employees of the enterprise, workwhich is associated with increased health risks, medical examinations are conducted on the basis of medical institutions. The company issues a corporate edition of "Megawatt", which reflects the latest news of the concern, highlights the events within the team, also operates corporate television, Internet sites, regularly conducted radio broadcasts.
Director of the company Elektrosila - RabchenyaVladimir Nikolayevich. He received a profile education at the Mogilev Machine-Building Institute, after which he was sent to the plant for distribution. He began his career as a master.
Received a second higher education in LeningradEngineering and Economics Institute, where he mastered the economic aspects of the engineering industry. In 1997 he deservedly received the post of director for the production of the plant "Elecrosila", and in 2011 became the director of the enterprise.
Plant "Elecrosila" is one of sixworld leaders in the construction of hydroelectric generators. He successfully competes with Hitachi, General Electric, Alsthom, Siemens, ABB. Where is the plant "Electrosila"? The address of the company: St. Petersburg, Moskovsky prospect, building 139.
After pouring the plant into the concern "Power Machines"part of its territory (7.2 hectares) on the odd side of Moscow Avenue was given for building. The beginning of construction is planned for 2017. At this stage, the production capacity is withdrawn from the zone.
Angry Birds Park is now also in St. Petersburg!
Pikabolo: a mirror labyrinth in St. Petersburg, which will give a lot of positive emotions!


IL-17A is a pro-inflammatory cytokine that is normally associated with autoimmune arthritis and other pro-inflammatory conditions. Recently, IL-17A has emerged as a critical factor in enhancing breast cancer (BC)-associated metastases. We generated immune competent arthritic mouse models that develop spontaneous BC-associated bone and lung metastasis. Using these models, we have previously shown that neutralization of IL-17A resulted in significant reduction in metastasis. However, the underlying mechanism/s remains unknown.
We have utilized two previously published mouse models for this study: 1) the pro-arthritic mouse model (designated SKG) injected with metastatic BC cell line (4T1) in the mammary fat pad, and 2) the PyV MT mice that develop spontaneous mammary gland tumors injected with type II collagen to induce autoimmune arthritis. Mice were treated with anti-IL-17A neutralizing antibody and monitored for metastasis and assessed for pro-inflammatory cytokines and chemokines associated with BC-associated metastasis.
We first corroborate our previous finding that in vivo neutralization of IL-17A significantly reduced metastasis to the bones and lungs in both models. Next, we report that treatment with anti-IL17A antibody significantly reduced the expression of a key chemokine, CXCL12 (also known as stromal derived factor-1 (SDF - 1)) in the bones and lungs of treated mice. CXCL12 is a ligand for CXCR4 (expressed on BC cells) and their interaction is known to be critical for metastasis. Interestingly, levels of CXCR4 in the tumor remained unchanged with treatment. Consequently, protein lysates derived from the bones and lungs of treated mice were significantly less chemotactic for the BC cells than lysates from untreated mice; and addition of exogenous SDF-1 to the lysates from treated mice completely restored BC cell migration. In addition, cytokines such as IL-6 and M-CSF were significantly reduced in the lung and bone lysates following treatment. The data presented suggests that systemic neutralization of IL-17A can block the CXCR4/SDF-1 signaling pathway by reducing the expression of SDF-1 in the metastatic niches and significantly reducing metastasis in both mouse models.
In our model, neutralization of IL-17A regulates SDF-1 expression in the metastatic niches either directly or indirectly via reducing levels of IL-6 and M-CSF.
By the year 2013, an estimated 750,000 women will die from breast cancer (BC) worldwide. Ninety percent of these deaths will be due to metastatic disease . The most common site of metastasis is the bones and the lungs. Metastatic BC especially bone disseminated BC remains incurable . Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the host microenvironment. Several studies have demonstrated that sites of chronic inflammation are often associated with establishment and growth of various types of malignancies [2, 3]. A common inflammatory condition in humans is autoimmune arthritis (AA) with inflammation and deformity of the joints and increased cellular infiltration and inflammation in the lungs . Several underlying molecular processes that characterize AA are also associated with cancer progression and metastasis. Epidemiologic studies indicate that BC patients with AA have poor prognosis and higher mortality rate compared to BC patients without AA . To understand the molecular mechanisms and factors that facilitate BC-associated metastasis in arthritic conditions we have generated couple of models: one in which the mice are pro-arthritic and are later challenged to develop metastatic BC; and second in which the mice develop spontaneous BC first and then induced to develop arthritis [6–8]. Both mouse models are immune competent and develop significant levels of bone and lung metastasis. It is important to note here that without arthritis, very few mice develop lung and bone metastasis. Thus, these mice are ideally suited to study bone and lung metastasis that develops from the primary mammary gland tumors.
Using these models, we have previously reported that the inflammatory microenvironment caused by AA serves as a chemo attractant for recruitment, retention, and proliferation of BC cells in the bones and lungs [6–8]. We have identified interleukin-17A (IL-17A) as one of the critical pro-inflammatory cytokines within the metastatic niche and in the circulation, contributing to the enhanced metastasis. IL-17A mediates its pro-inflammatory effects by stimulating the release of multiple other cytokines such as IL-6, IL-8, and G-CSFs from epithelial, endothelial, and fibroblastic cells . IL-17A is also associated with increased angiogenesis, proliferation, and metastasis in breast and other cancers [6, 7, 10]. Blocking IL-17A with a neutralizing antibody significantly reduced BC associated metastasis in both models [6, 7].
In this study, we investigated the underlying mechanism/s of how systemic neutralization of IL17A inhibits/reduces metastasis. We report that IL-17A neutralization is highly effective in down- regulating the expression of CXCL12/SDF-1 in the metastatic niches. This in turn blocks the migration of the CXCR4-positive BC cells towards the metastatic niches. Data presented here shows that treatment with anti-IL-17A antibody significantly reduces metastasis to the bone and lungs in the two arthritic-BC mouse models by regulating the CXCR4/SDF-1 axis necessary for metastases. The study is of high significance since therapeutic strategies to block the CXCR4/SDF-1 interaction is being actively pursued [11–13].
All experimental procedures were conducted according to Institutional Animal Care and Use Committee (IACUC) guidelines and the IACUC Committee of University of North Carolina at Charlotte (UNCC) has specifically approved this study (IACUC ID: 08–036.0 and 11–015.0). All mice were bred and maintained in specific pathogen-free conditions.
The 4 T1 cells were purchased from The American Type Cell Culture Collection (Manassas, VA). Cells were maintained in complete RPMI . The 4 T1 cells had stable expression of green fluorescent protein (4 T1-GFP). 4 T1 tumors is known to resemble human late stage metastatic BC [14–16]. The PyV MT cell lines were generated from PyV MT tumors and cultured as previously described in complete DMEM .
SKG mice have been established from a closed breeding colony of Balb/C mice [17, 18]. To test the efficacy of anti-IL-17A antibody treatment on BC associated metastasis, three month old SKG mice were injected with 1 × 105 4 T1-GFP cells (in 100 μl of PBS) in the mammary fat pad. When the tumors were ~5 mm in size (post ~6 days of 4 T1 injections), four intraperitoneal (ip) injections of 5 μg/ml of anti-IL17 antibody (Cat#560268; BD Pharmingen, San Diego, CA, USA;) or rat IgG isotype control antibody (Cat# 554682, BD Pharmingen) was administered once a week. 1XPBS was used as the solvent. Untreated 4 T1-tumor bearing SKG mice served as controls. The mice were euthanized 24 hours after the last injections at ~35 days post tumor challenge.
PyV MT oncogenic mice were originally a gift from Dr. W. J. Muller (McGill University, Toronto, Canada) . The PyV MT mice were bred to be congenic on the C57BL/6 background and have been used in several of our prior publications [7, 20–23]. At 12 weeks of age, PyV MT mice were injected intradermally with 50 uls of 2 mg/ml CII (Cat#804002-Lyo, MD Biosciences, St. Paul, MN, USA) in CFA (Difco laboratories, Michigan, USA) approximately 1.5cms distal from the base of the tail. Approximately 60% of mice develop arthritis within 15–30 days post collagen injection [24, 25]. Four weeks post CII injection (at 16-weeks of age), four i.p injections of 5 μg/ml of anti-IL17 antibody or control IgG antibody (Cat#560268; BD Pharmingen, San Diego, CA) once every two weeks was administered. The mice were euthanized 24 hours after the last injections at ~23 weeks of age. Thus, mice received a total of 4 injections of the antibody. Untreated PyV MT mice served as controls.
SDF-1/CXCL12 levels were measured in the lung and bone lysates by a specific mouse Elisa kit (Cat# CKM061, Cell Sciences, Canton, MA). IL-17A levels were determined using a specific mouse Elisa kit (Cat#88-7371; eBioscience, San Diego, CA, USA). The limit of detection for the mouse CXCL12/SDF-1 Elisa kit from Cell Sciences, Cat#CKM061 is 9.38 pg/ml to 600 pg/ml. The limit of detection for the mouse IL17A ELISA kit from eBiosciences, Cat#88-7371 is 4 pg/ml to 500 pg/ml. 300 ug of tumor, lung and bone whole tissue lysates were used and manufacturer recommended protocols were followed. Results are expressed as picograms/ml. Lysate preparation: Briefly, lung tissue was collected in complete lysis buffer (20 mmol/L HEPES, 150 mmol/L NaCl, 1%Triton X100, and 2 mmol/L EDTA) supplemented with serine protease inhibitor (Complete inhibitor cocktail; Roche, Indianapolis, IN) and phosphatase inhibitor cocktail (Sigma-Aldrich,Missouri, USA). The tissues were homogenized using the IKA T25 digital ultra Turrax homogenizer (IKA, Wilmington, USA). After centrifugation, the supernatant was collected and used as the source of the protein lysate. Bones were collected in the same buffer and stored at -80°C. When ready to isolate protein, bones were placed on dry ice, cleared of all surrounding soft tissue and pulverized in liquid nitrogen using a mortar and pestle. The powdered bone was further homogenized in complete lysis buffer, centrifuged at 13000 rpm for 10 minutes and supernatant collected. A standard BCA assay was used to determine protein concentration (Cat#23225, Pierce BCA protein assay kit, Thermo Scientific, Rockford, USA).
CXCR4 antibody was used at a concentration of 1ug/ml (Cat#ab2074, Abcam, Cambridge, MA 02139) and secondary donkey anti-rabbit IgG HRP at 1:5000 dilution (Cat#sc-2313, Santa Cruz Biotechnology, Santa Cruz, CA). β-actin (Cat#sc-47778) antibody was used at 1:500 dilution and secondary anti-mouse IgG HRP (Cat#sc-2314) at 1:2000 dilution (Santa Cruz Biotechnology, Santa Cruz, CA). β-actin expression was used to confirm equal protein loading on the SDS-PAGE gels.
Lung and bone sections were processed as previously described [6, 7]. Paraffin embedded blocks were prepared and 4-micron thick sections were cut for hematoxylin eosin (H&E), SDF-1, and pancytokeratin staining. The SDF-1 (Cat#sc-74271) and pancytokeratin antibodies were purchased from Santa Cruz Biotechnology and used at 1:50 dilution following the same protocol as described in our previous publications [6, 7] followed by DAKO anti-mouse secondary antibody (Cat# P0447, 1:100 dilution; Dako North America, Carpinteria, CA, USA).
All bright field images were taken using the Olympus DP71 light microscopy with Olympus BX60 camera (U-ND25-2, Olympus; Melville, NY) at magnifications shown in the figure legend. The images were analyzed by Caresbio Laboratory, Shelton, CT, USA. Image analysis algorithms were applied to the images generated from microscopic slides of tissues stained with DAB and hematoxylin. An algorithm was applied to the Red-Green-Blue (RGB)-filtered grayscale values from images. Images were analyzed using the image analysis software, MATLAB (R2011b, MathWorks). This provides the option for separation of DAB only- and double-stained areas from hematoxylin only- stained areas by means of subject specific thresholding. A good separation of DAB- and double-stained pixels from hematoxylin-stained pixels was achieved. Automatic background subtraction was performed applying median filters only. Significant differences in relative areas stained and mean specific intensity for the stains between control and treatment groups in mouse tissue were calculated.
4 T1 or PyV MT cells in serum free media (50,000 cells) were plated over transwell inserts (BD Biosciences, San Jose, CA), pre-coated with reduced growth factor matrigel (BD Biosciences, San Jose, CA, USA) and were permitted to invade towards lung and bone lysates (500 ug protein) contained in the bottom chamber for 24 hours. Percent invasion was calculated as absorbance of samples/absorbance of controls × 100 [6, 7, 26, 27]. We added neutralizing anti-CXCR4 antibody (Cat#247506, R&D Systems, Minneapolis, MN) to tumor cells at 10ug/ml or recombinant mouse SDF-1 to the lower chamber at 0.6 ng/ml (Cat#460-SD, R&D Systems, Minneapolis, MN) and analyzed the invasion of BC cells.
The Pix array 100 x-ray machine (Bi Optic Inc, Santa Clara, CA, USA) was used for bone imaging as previously described [6–8, 28].
The RayBio® Custom Mouse Cytokines Antibody Array kit was purchased from Ray Biotech (Norcross, GA, USA) and used according to the manufacturer's instructions. This is an immunoblot-based kit. The array of cytokines included in the study template was: IL-17A, IL-6, M-CSF, TNF-α, IGF-II, IL-4, IL-1B, Pro-MMP9, VEGF and osteoprotegerin. To measure the cytokines in the lung and bone microenvironment, 300ug of protein lysate was used. The densitometric analyses of immunoblots were performed using NIH Image J software (obtained from the NIH Web site: http://rsb.info.nih.gov/nih-image). Results are presented as mean values of arbitrary densitometric units corrected for background intensity and normalized using pre-determined controls (provided by the manufacturer).
Data were analyzed using the GraphPad software. Results are expressed as mean ± s.e.m and are representative of greater than or equal to 3 replicate experiments. We used a one-way ANOVA with Tukey to compare all groups to each other. Comparison of groups was done by using 2-way ANOVA followed by the Bonferroni posttest for multiple comparisons. Student's t-test was used for comparing the level of significance between two experimental groups.
For Figure 1A and C and Figure 2A and B, Minitab was used to conduct the statistical test based on a normal approximation for percentage differences.
Treatment with anti-IL17A significantly reduced lung and bone metastasis in SKG mice orthotopically injected with GFP positive 4 T1 BC cells. A: Percentage of lung metastasis in 4 T1 tumor-bearing SKG mice ± treatment and in 4 T1 tumor-bearing non-arthritic Balb/C mice. Statistical test based on a normal approximation: The difference between untreated and IgG treated versus anti-IL-17 treated is significant (*p = 0.006) and difference between untreated SKG + 4 T1 versus Balb/C + 4 T1 is also significant (**p = 0.001). Bi-iii: Representative images of GFP positive 4 T1 cells in lungs with no treatment (i), control IgG antibody treatment (ii) or anti-IL17A antibody treatment (iii). C: Percentage of bone metastasis in 4 T1 tumor-bearing SKG mice ± treatment and in 4 T1 tumor-bearing non-arthritic Balb/C mice. Assuming normal approximation, the difference between IgG control and anti- IL-17 treated group is significant (*p = 0.03) and difference between untreated SKG + 4 T1 and Balb/C + 4 T1 is also significant (**p = 0.001). Significance was not reached between untreated SKG + 4 T1 and IL-17A treated group although lower numbers of mice developed bone metastasis with anti-IL-17A antibody treatment. Di-iii: Representative X-ray images of metastatic bone lesions in 4 T1 tumor bearing SKG mice with no treatment (i) 4 T1 tumor bearing SKG mice treated with control IgG antibody (ii) or anti-IL-17A antibody treatment (iii) Arrows point to a metastatic site in the proximal humerus; note the prominent lucency in the proximal region, reflecting extensive bone loss at this site . (A-D: N = 10 mice). Ei-iii: Representative images of pancytokeratin staining of bone tissue to confirm metastasis in 4 T1 tumor bearing SKG mice with no treatment (i) 4 T1 tumor bearing SKG mice treated with control IgG antibody (ii) or anti-IL-17A antibody treatment (iii).
Diminution of lung and bone metastasis in arthritic PyV MT mice treated with anti-IL-17A antibody. A and B: Percentage of lung (A) and bone (B) metastasis in PyV MT mice Statistics: The difference in lung metastasis between untreated and IgG treated versus anti-IL-17 treated is significant (*p = 0.006) and difference between untreated PyV MT + AA versus PyV MT with no AA is also significant (**p = 0.001). Although fewer animals developed bone metastasis with anti-IL-17 antibody treatment, significance was not reached. However there was a significant difference in bone metastasis between PyVMT mice with no AA versus PyVMT mice with AA (*p = 0.002) C: Representative images of H& E (200x magnification) of lungs to confirm metastasis in PyV MT mice with no AA (i), PyV MT mice with AA treated with control IgG antibody (ii) or with anti-IL-17A antibody (iii). D: Representative X-ray images of metastatic bone lesions in PyV MT mice with no AA (i); arthritic PyV MT model treated with control antibody (ii) or anti-IL-17A antibody (iii) (A-D: N = 6–8 mice) Arrows point to a metastatic site in the proximal humerus; note the prominent lucency in the proximal region, reflecting extensive bone loss at this site. Ei-iii: Representative images of pancytokeratin staining of bone tissue to confirm metastasis in PyV MT mice with no AA (i), PyV MT mice with AA treated with control IgG antibody (ii) or with anti-IL-17A antibody (iii).
We selected two models to test the efficacy of the anti-IL-17A antibody treatment on BC-associated bone and lung metastasis: 1) the SKG mice challenged with 4 T1 tumors and 2) the PyV MT mice induced with CII. We selected only the arthritic models because very few non-arthritic tumor-bearing mice (0–3 mice out of 10) develop bone or lung metastasis as compared to their arthritic counterparts (5–9 mice out of 10) (Figures 1A and B & 2A and B).
In the 4 T1-tumor bearing SKG mice, data demonstrates a significant reduction in the percent of mice that develop bone and lung metastasis when treated with anti-IL17A antibody compared to control mice (80-90% of control mice develop metastasis versus only 40-50% of treated mice develop metastasis) (Figure 1A and C). Also shown are representative images of a) GFP positive lesions in the lungs (Figure 1B (i-iii)), b) radiographic metastatic lesions in the bone (Figure 1D (i-iii)), and c) pancytokeratin brown staining representing epithelial cell lesions in sections of bone confirming metastasis (Figure 1E (i-iii)). In addition, densitometric analysis was performed for pancytokeratin IHC images and the data is tabulated in Table 1. Arrows in Figure 1D (i and ii) point to a metastatic site in the proximal humerus; note the prominent lucency in the proximal region, reflecting extensive bone loss at this site.
The effect of the anti-IL-17A antibody treatment on primary tumors showed a small but significant reduction in tumor size as previously published  and shown as Additional file 1: Figure S1A.
In the arthritic PyV MT mice, similar results were observed. Treatment with anti-IL-17A showed a significant decrease in the percent of mice that developed metastasis (Figure 2A and B). Data shows that ~70% (7 out of 10) of control mice developed lung metastasis and 50% (5 out of 10) developed bone metastasis (Figure 2A and B). When treated with anti-IL-17A antibody, only 40% (4 out 10) and 30% (3 out of 10) developed lung and bone metastasis respectively (Figure 2A and B). Representative H&E staining confirming metastatic lesion in the lung is shown in Figure 2Ci-iii while representative radiographic images of the bone lesions and pancytokeratin staining confirming metastasis in sections of the bone is shown in Figure 2Di-iii and Figure 2Ei-iii (for lung) and 4 (for bone). In addition, densitometric analysis was performed for pancytokeratin IHC images and the data is tabulated in Table 2.
(i) PyV MT mice with no AA; (ii) PyV MT mice with AA treated with control IgG antibody or (iii) with anti-IL-17A antibody. (*P < 0.01: PyV MT and PyV MT + CII + anti-IL-17A against PyV MT + CII + IgG).
Treatment with anti-IL-17A antibody had no effect on the primary tumor burden in the arthritic PyV MT mice (Additional file 1: Figure S1B). Thus, the study focused on the effect of anti-IL-17A antibody treatment on metastasis.
To determine if treatment reduced IL-17A levels within the tumor and metastatic niches, we evaluated the levels of IL-17A using an ELISA. Compared to the control group, the level of IL-17A in the tumor of SKG mice treated with anti-IL-17A antibody was significantly lower (Figure 3A). Level of IL-17A in the lungs and bones was also significantly reduced as compared to control mice (Figure 3B and C respectively) with levels as low as seen in SKG mice with no tumors (Figure 3B and C). Similarly, we observed a significant decrease in IL-17A levels in the tumors, lungs and bones of the PyV MT mice treated with anti-IL-17A antibody compared to the control groups (Figure 3D, E and F respectively). Non-arthritic PyV MT mice served as another control.
Anti-IL17A treatment down regulates pro-inflammatory cytokines associated with IL-17A expression. A-C: Levels of IL-17A (pgs/ml) by ELISA in the tumor, lung and bone protein lysates of SKG mice (*P < 0.05;**P < 0.01). D-F: Levels of IL-17A by ELISA in the tumor, lung and bone of PyV MT mice (**P < 0.01; *P < 0.05). The limit of detection for mouse IL-17A is 4 pg/ml to 500 pg/ml. G-J: Ray Biotech cytokine array densitometry values: G and H: 4 T1 tumor bearing SKG mice. I and J: Arthritic PyV MT mice (*P <0.05, **P < 0.01, ***P < 0.001). N = 4 mice.
Since IL-17A mediates its downstream effects by stimulating the release of multiple other cytokines , we examined which factors in the bone and lung may be influenced by anti-IL-17A antibody treatment. In both the SKG and PyV MT mice, multiple cytokine array analyses showed a significant reduction in the levels of IL-6 and M-CSF in addition to reduction in IL-17A levels in treated versus control mice (Figure 3G and H for SKG mice and Figure 3I and J for PyV MT mice). The array of cytokines included IL-17A, IL-6, M-CSF, TNF-α, IGF-II, IL-4, IL-1B, Pro-MMP9, VEGF and osteoporotegerin. None of the other cytokines showed significant differences.
BC metastasis is known to be facilitated by the interaction of the chemokine SDF - 1/CXCL12 with its ligand CXCR4 . Thus, we first investigated if anti-IL-17A antibody treatment affects the expression of SDF-1 in the metastatic niches. We observed a significant reduction in SDF-1 levels by specific ELISA in the lung and bone lysates of the treated versus control mice (Figure 4A and B respectively). Non-tumor bearing SKG mice were included in the study as control. Data clearly suggests that when SKG mice were induced to develop tumors, the level of SDF-1 significantly increased in the lungs and that treatment with anti-IL-17A antibody brought the levels back down to the non-tumor bearing levels (Figure 4A). Similarly, in the bones, the level of SDF-1 was significantly decreased with anti-IL-17A treatment (Figure 4B). Control non-arthritic Balb/C mice have low levels of SDF-1 (data not shown: 26.8 pg/ml and 64.11 pg/ml in the bone and lung lysate respectively). The data was further confirmed by immunohistochemistry (IHC) staining of lung and bone tissue sections. Representative images of lung and bone sections are shown in Figures 4 Ci-iii and Di-iii respectively. In addition, densitometric analysis was performed for all IHC images and the data is tabulated in Table 3 (for lung) and Table 4 (for bone). It is apparent from the data that non-arthritic Balb/C mice have low expression of SDF-1 (Figure 4Cii and Dii) while SKG mice without any tumor have elevated levels of SDF-1 as noted by ELISA (Figure 4A&B) and by IHC (Figure 4Ciii and Diii and Table 3). This suggests that SDF-1 expression increases with induction of arthritis prior to tumor development.
Significant down-regulation of SDF-1 (CXCL12) expression in the metastatic niches. A and B: Levels of SDF-1 by ELISA in the lung (A) and bone (B) lysate of SKG with no tumor, 4 T1 tumor bearing SKG mice treated with control or anti-IL-17A antibody (*P < 0.05) (N = 3 mice). The limit of detection for mouse SDF-1 is 9.38 pg/ml to 600 pg/ml. C and D: Representative images of SDF-1 expression by IHC in lung (C) and bone (D) (N = 6 mice), (i) Secondary antibody only; (ii) Balb/C with no tumor or AA (iii) SKG with no tumor; (iv) 4 T1 tumor bearing SKG mice treated with control IgG antibody or (v) with anti-IL-17A antibody. Brown staining represents SDF-1 localization (Bone at 400X magnification and Lung at 600X magnification). E and F: Levels of SDF-1 by ELISA in the lung (E) and bone (F) lysate of PyV MT mice with no AA and PyV MT + AA with control or anti-IL-17A antibody treatment (*P < 0.05) (N = 3 mice).
(i) Secondary antibody only; (ii) Balb/C with no tumor and no AA; (iii) SKG with no tumor; (iv) 4 T1 tumor bearing SKG mice treated with control IgG antibody or with anti-IL-17A antibody (v) (*P < 0.05: Balb/C, SKG, SKG + BC + anti-IL-17A against SKG + BC + IgG; **P < 0.01: Secondary antibody against all other groups).
(i) Secondary antibody only; (ii) Balb/C with no tumor and no AA; (iii) SKG with no tumor; (iv) 4 T1 tumor bearing SKG mice treated with control IgG antibody or with anti-IL-17A antibody (v). (*P < 0.05: all groups against SKG + BC + IgG).
Similar results were observed in the PyV MT mice where the level of SDF-1 was significantly increased when mice were induced with CII to develop arthritis (Figure 4E and F). However, treatment with anti-IL-17A antibody completely reversed the effect of CII and reduced the level of SDF-1 to that of non-arthritic mice in the lung and bone (Figures 4E and F respectively).
To reconfirm that anti-IL-17A treatment indeed reduces the level of SDF-1 in the arthritic mice prior to the development of tumor, we treated non-tumor bearing arthritic mice (C57BL/6 mice injected with CII) with the anti-IL-17A antibody. We found that anti-IL-17A antibody treatment indeed reduces the CII-induced SDF-1 levels in the bone and lung prior to tumor development (Additional file 2: Table S1). The data therefore suggests that treatment with anti-IL-17A antibody reduces the level of SDF-1 first which subsequently reduces the migration of the CXCR4+ BC cells to the bones and lungs.
Next, we assessed the expression of CXCR4 on the tumors dissected from the control and treated mice by western blotting. No change in the CXCR4 expression was observed in the 4 T1 or the PyV MT tumors with treatment (Figure 5A and B respectively). N = tumors from 3 individual mice are shown. We have also shown as Additional file 3: Figure S2, the entire western blot image of CXCR4 expression in tumors from Figure 5A and B. The appropriate size for CXCR4 is 43 KD shown in Figure 5.
Bone and lung lysates from mice treated with anti-IL-17A antibody are less chemotactic than their control antibody treated counterparts. A and B) Western blotting showing the presence of CXCR4 on the tumors derived from A) 4 T1 tumor bearing SKG mice and B) PyV MT-arthritic mice treated with control or anti-IL-17A antibody (N = 3 tumors). C and D: In vitro trans-well invasion assay using 4 T1 cells in the upper chamber and lung (C) or bone (D) lysate from 4 T1 tumor bearing SKG mice treated with control or anti-IL-17A antibody in the lower chamber. E and F: In vitro trans-well invasion assay using PyV MT tumor cells in the upper chamber and lung (E) or bone (F) lysate from arthritic PyV MT mice treated with control or anti-IL-17A antibody in the lower chamber. Various treatment groups and significance are shown in the figure. *P < 0.05, **P < 0.01, ***P < 0.001 (N = 5 mice). We used a one way ANOVA with Tukey to compare all groups to each other.
It is well established that CXCR4+ cancers metastasize to the distant organs in a CXCL12/SDF-1-dependent manner [29–31]. Since we observed that the level of SDF-1 was significantly reduced with anti-IL-17A antibody treatment, we conducted an in vitro trans-well Boyden chamber assay with the bone or lung lysate in the bottom chamber and the 4 T1 or PyV MT tumor cells in the top chamber. There was a significant decrease in the migration of 4 T1 cells towards the lung (Figure 5C) and bone (Figure 5D) lysates derived from treated mice (Figure 5C and D bar# 3) as compared to the lysates derived from control mice (Figure 5C and D bar# 1). Similarly, migration of PyV MT tumor cells towards the lung (Figure 5E) and bone (Figure 5F) lysates from treated mice was significantly lower compared to migration towards control lysate (Figure 5E and F bar# 3 compared to bar #1).
Further, we demonstrate that addition of recombinant SDF-1 to the lung and bone lysates in the lower chamber reversed the effect of anti-IL-17A treatment and significantly increased the migration of the 4 T1 and PyV MT tumor cells towards the lower chamber (compare bar# 3 to bar# 4 in Figures 5C-F). Finally, we tested if blocking CXCR4 would have a similar effect. Data demonstrates that adding anti-CXCR4 neutralizing antibody to the 4 T1 and PyV MT tumor cells in the upper chamber had some effect on % migration, but in most instances the difference did not reach statistical significance (Figures 5C-E bar# 1 versus bar# 5, and Figures 5C-F bar# 3 versus bar# 6). However, in one instance, with PyV MT tumor cells treated with anti-CXCR4 antibody, there was a significant drop in % invasion towards bone lysate. (Figure 5F bar# 1 versus bar# 5).
Taken together our data suggests that in arthritic condition, IL-17A blockade reduces BC-associated metastasis by specifically reducing SDF-1 levels in the metastatic niches and thereby affecting their chemotactic potential.
Previously we established that the PyV MT mice that develop spontaneous mammary gland tumors develop severe bone and lung metastasis when induced with CII. If not induced with CII, these mice do not develop bone metastasis while 50% of CII induced PyV MT mice develop bone metastasis [6–8] and Figure 2B). Similarly, only 20-30% of PyV MT mice without CII develop lung metastasis but when induced with CII, ~80% of the mice present with lung metastasis [6–8] and Figure 2A. The primary tumors are also larger in the arthritic PyV MT mice . Correspondingly, in the pro-arthritic SKG mice (which is in the Balb/C background), establishment of the 4 T1 tumors in the mammary fat pad gives rise to bone metastasis in 80-90% of the mice [6, 8] and Figure 1B. In contrast, 30% of the Balb/C mice (which are not pro-arthritic) bearing the 4 T1 tumors develop bone metastasis [6, 8] and Figure 1B. With regards to lung metastasis, 30% of 4 T1 tumor-bearing Balb/C mice develop lung metastasis while the same 4 T1 tumors generate lung metastasis in 90% of pro-arthritic SKG mice [6, 8] and Figure 1A. The primary 4 T1 tumors are also larger in the SKG mice [6, 8].
Using these unique arthritic models of BC metastasis, we previously established that neutralizing IL-17A can significantly reduce both bone and lung metastasis [6, 7] and Figures 1 and 2. However, the underlying mechanism of action of IL-17A remained unknown.
Data clearly demonstrate that treatment with the anti-IL-17A antibody reduced the expression of SDF-1/CXCL12 in the bones and lungs (Figure 4). SDF-1 plays a critical role in the mobilization and recruitment of CXCR4+ BC cells to the neo-angiogenic niches supporting tumor growth and metastasis [32, 33]. It is known that malignant primary BC cells express high levels of chemokine receptor CXCR4. When these cells pass through the organs that express large amounts of the chemokine SDF-1/CXCL12, the cells leave the circulation and enter the organs [11, 34]. The CXCL12/CXCR4 axis is known to be involved in several aspects of tumor progression including angiogenesis, metastasis, and survival . Our data is the first to show that in arthritic condition, blockade of IL-17A can disrupt this critical interaction of CXCR4 with SDF-1 by significantly reducing the SDF-1 levels in the bones and lungs and thus inhibiting the migration of the CXCR4+ BC cells towards the metastatic niches. Furthermore, inhibition of migration of BC cells was completely reversed by exogenously adding SDF-1 to the bone and lung lysate in an in vitro migration assay (Figure 5C - F). This suggests that the SDF-1 expression is critical for mobilizing the tumor cells to migrate.
It is also of interest that the downstream effect of IL-17A neutralization was a reduction in IL-6 and M-CSF (Figure 3G - J). This was to be expected as IL-17 is known to a) directly activate other immune cells to produce IL-6, IL-8, and PGE2. and b) indirectly activate the anti-inflammatory Th2 type cytokines including IL-10 and IL-13 that are known to reduce levels of IL-6 and M-CSF . M-CSF is a cytokine involved in the development and proliferation of the monocyte/macrophage lineage cells and is reported to participate in the induction of osteoclasts, which is important in the destruction of bone and cartilage . Thus, reduction of M-CSF with the anti-IL-17A antibody treatment supports the hypothesis that bone destruction due to arthritis creates a supportive milieu for BC cells to metastasize. Indeed in our previous publications, we have shown that BC-associated metastasis is significantly augmented in mice with arthritis and that IL-17A, IL-6, COX-2, VEGF, MMP-9, IGF-II, M-CSF and TNF-α are all major players [6, 7]. These cytokines not only play an imperative role in arthritis but also cancer development and progression [37–48].
The emergence of IL-17A blockade as a future therapy in AA is already reported and initial observations from phase I trials show that signs and symptoms of AA are significantly suppressed following treatment with anti-IL-17A antibodies, without notable adverse effect . Thus, we focused on IL-17A blockade and in understanding the underlying mechanism by which IL-17A blockade inhibits metastasis.
The experiments and the unique mouse models utilized in this study implicate the importance of targeting IL-17A for preventing metastasis associated with metastatic BC. Whether IL-17A blockade directly or indirectly (via reducing M-CSF and IL-6) regulates the SDF-1 levels needs to be deciphered and will be the focus of our next study. Nevertheless, data provides a rationale for designing potential therapies that may utilize IL-17A blockade in combination with conventional treatment regimen for patients with metastatic BC that also present with arthritis.
We recognize that other BC-bone metastasis models that do not have any arthritis should be tested in the future. However, to the best of our knowledge, there is currently no immune competent spontaneous BC-bone metastasis model available.
We conclude that in our model, neutralization of IL-17A regulates SDF-1 expression in the metastatic niches either directly or indirectly via reducing levels of IL-6 and M-CSF.
Pinku Mukherjee, PhD, Irwin Belk Distinguished Professor of Cancer Research, Department of Biology, University of North Carolina, Charlotte, NC. Dr Mukherjee has worked on Breast Cancer for the past 22 years.
Lopamudra Das Roy, PhD, Research Director, CanDiag Inc and Adjunct Assistant professor, Department of Biology, University of North Carolina, Charlotte, NC. Dr Das Roy has received funding for her work in Breast Cancer Research from the US Department of Defense. Dr Das Roy has immense experience on research with Breast Cancer and Arthritis and received press releases determining the association between arthritis and Breast Cancer associated metastasis.
Mahnaz Sahraei, PhD, Post doctoral fellow, Department of Pharmacology, Yale University . Dr Sahraei graduated from University of North Carolina, Charlotte, NC under the mentorship of Dr Pinku Mukherjee.
Jorge L. Schettini, PhD, is a trained immunologist and worked with Dr Mukherjee for three years. Currently, he is working as a Research Scientist at Caris Life Sciences, Phoenix, AZ.
Dahlia M Besmer, PhD, graduated from Department of Biology, University of North Carolina, Charlotte, NC. DMB has received funding for her work on Breast Cancer from the US Department of Defense.
Helen E. Gruber, PhD, Director, Biology Division, Department of Orthopedic Surgery, Carolinas Medical Center, Charlotte, NC. Dr Gruber has over 28 years of experience in the area of bone pathology and osteoarthritis and bone metastasis.
We are thankful to all personnel in the UNCC Animal Facility for their help and Natalia Zinchenko for help with bone imaging. We are thankful to Dr Jennifer Curry for reviewing the manuscript.
LDR designed and carried out all the experiments, and wrote the manuscript. MS, JLS and DMB helped with the endpoints. MS helped with the ELISAs. HEG interpreted the x-ray imaging. PM is the principal investigator of the laboratory in which the research was performed and contributed to the interpretation of the data and writing of the manuscript. All of the authors have read and have approved the final manuscript.


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Q: Many-to-many Files Vlookup or Index-Match basic on specified cell value I am trying a vlookup to a closed workbook; however, it will not always be the same workbook. I was hoping I could reference the file name to a particular cell value and locate it from there. Here is the code I have.
Sub Vlookup()
Dim FileName As String
Dim Path As String
Dim Formula As String

Path = "C:\Users\Jwbeauch\Desktop\Schools\Chart of Accounts\["
FileName = Range("B1").Value & ".xlsx]COA'!"
Formula = "Vlookup(D3," & Path & FileName & Range("$B$15:$C$1000") & ", 2, 0)"
ActiveCell.Formula = Formula

End Sub

A: Sub Vlookup()

Dim FileName As String
Dim Path As String
Dim Formula As String
Dim SheetName As String

Path = "C:\Users\Jwbeauch\Desktop\Schools\Chart of Accounts\"
FileName = "[" & Range("B1").Value & ".xlsx]"
SheetName = "COA" ' Need to enter sheet name you are looking up

Formula = "=VLOOKUP(D3,'" & Path & FileName & SheetName & "'!" & ("$B$15:$C$1000") & ",2,0)"
ActiveCell.Formula = Formula

End Sub

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