Multi Drug Test Kits can help detect intake of illegal drugs.
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Most multi-drug test kits from leading companies like 1st Health Products are used to check for the presence of illegal/dangerous drugs as part of a well established, ongoing random screening programme in a range of employment sectors, such as public transport, road transport, the oil and gas industries, as well as educational establishments.
Home use drug test kits are non-invasive tests and if you buy tests from reliable companies like 1st Health Products, they are accurate and reliable. The test requires a simple urine sample and produces a visual result in less than 5 minutes.
All responsible adults get concerned when hazardous drugs like ecstasy and cocaine are increasingly commonly and frequently abused by children and young people. Substances like Ecstasy (mAMP), Cocaine (COC) are among common drugs that can be detected by SELFCheck multi drug home test kits and include Opiates (including Heroin OPI), barbiturates, Methamphetamines (including Ecstasy (mAMP), Amphetamine (AMP), Cannabis (THC) and Benzodiazepines (BZO). The SELFCheck multi-drug screening test is based on a urine assay/test. It is easy to use, detecting six of the most commonly abused drugs and producing a reliable, easy to read result in 5 minutes. A simple screening test that can be carried out in privacy, ensures confidentiality as well as providing the necessary incentive needed to take further steps in terms of managing personal health and enabling earlier consultation with a healthcare professional to facilitate earlier medical intervention should further action be needed.


text:
Salyer American shuts its doors
By Larry Parsons |
The large presence of Salyer American Fresh Food in the Salinas Valley produce industry is shrinking fast.
Layoffs of hundreds of seasonal and full-time workers are expected to start this week as the cash-strapped produce company is under control of a court-appointed receiver, an attorney for SK Foods Group owner Scott Salyer said.
"Salyer American looks like it now is, unofficially, defunct," attorney Gerard Rose said.
His dire statement came hours after receiver Steve Franson — who took the financial reins of the company after three lenders said Salyer American defaulted on $34 million in loans — said the lenders wouldn"t advance funds for crops already being grown for Salyer American by Salinas Valley growers.
"While I feel sorry for the growers and employees who have been loyal to (Salyer American), I also understand the position of the lenders who stand to lose significant sums of money due to the defaults of (the company)," Franson said in a prepared statement.
Collections and assets
Franson said he will turn his attention to collecting money owed to Salyer American, selling assets that were pledged to lenders, and paying "the legitimate claims of growers" who have sold commodities to Salyer American.
Franson came to the front door of the company"s executive offices on Lower Ragsdale Drive in Monterey on Tuesday, but wouldn"t elaborate on his statement. An executive with SK Foods did not return repeated calls.
A sign on the locked front door of the company"s offices advised employees to use their key cards to enter. About a dozen cars were in the lot shortly before 5 p.m.
Avoiding losses
One grower for Salyer American said he would have to scramble to sell crops already in the ground to other shippers at a time when produce prices are very low.
"It doesn"t surprise me," said Paul Moncrief, a Salinas attorney representing several Salyer American growers who would have grown thousands of acres of crops this year for the 23-year-old company. "It would take an act of God to get them back on track."
He said growers with crops in the ground will have to hustle to find other buyers or simply plow under the crops to avoid bigger losses.
Growers on notice
The company"s shaky status became apparent in late April when Salyer American abruptly notified growers to stop planting, he said.
"It"s tough for the industry," Moncrief said. "Growers all of sudden have to go find another place for their crops, and the market, obviously, isn"t very good now."
Salyer American started in 1986 and grew to become a major player in the fresh produce industry with year-round operations in California and Arizona.
Its Monterey headquarters is home to three other companies, including SK Foods LP, a major Central Valley vegetable processor. SK Foods LP has been at the center of a yearlong federal investigation of corruption in the processed vegetable industry.
Receiver appointed
SK Foods LP filed for Chapter 11 bankruptcy protection May 7 in the face of pressure by banks and other lenders that say they loaned the company more than $130 million. That move came the same day that the court-appointed receiver arrived in Monterey to assume control of Salyer American.
Rose said the goal in the bankruptcy proceedings is to find another buyer for SK Foods LP before July 1, when the tomato canning season starts. He said the lenders in Salyer American"s case could have done the same thing.
"Instead of working with Mr. Salyer, they declared war," he said.
He said Salyer "is the unfortunate owner of a company hijacked by his banks, and the consequences of the actions taken by the banks will be substantial and enduring."
Workers laid off
Rose said Salyer American employs 700 to 1,000 seasonal workers and has a full-time staff of about 60 additional employees. Many employees will be getting layoff notices by Friday, he said.
Moncrief said some growers are in the position to press claims against Salyer American, but "whether there is going to be any money to pay those claims is another question."
In his statement, Franson said it would take several months to work through Salyer American"s receivership. He said he would not speculate on the reasons for the financial troubles at Salyer American and SK Foods LP.
Rose has blamed the firms" problems on the spotlight shone on them by the federal corruption investigation. A former broker for SK Foods, three major food company buyers and a former inventory manager for SK Foods have pleaded guilty to various charges in the prosecution.
Layoffs of Salyer American employees will probably take place during the next three to four months, he said.
"A proud and prestigious company has essentially been driven out of business," Rose said.
Larry Parsons can be reached at 646-4379 or lparsons@montereyherald.com.
Salyer American at a glance 1986: Salyer American starts operations as grower-shipper of fresh produce in the Salinas Valley. Company founder Scott Salyer is from a prominent Central Valley agricultural family. April 2008: Federal investigators search SK Foods" headquarters in Monterey as part of an ongoing corruption investigation into the processed vegetable industry. Salyer American"s sister company, SK Foods LP, is one of the biggest producers of processed tomato products. December 2008: A former SK Foods LP broker pleads guilty in federal court to charges that he bribed buyers for major food companies to purchase processed vegetables from SK Foods. April 29: Bank of the West and other lenders sue Salyer American, claiming the company owes more than $34 million. May 7: Court-appointed receiver takes over Salyer American. SK Foods LP files for Chapter 11 bankruptcy protection for banks and other lenders.
Larry Parsons

redpajama_set_name: RedPajamaCommonCrawl


text:
by: MD Team
Opiant Pharmaceuticals Licenses Novel CB-1 Receptor Antagonist for Treatment of Acute Cannabinoid Overdose from Sanofi
New Delhi: Through a press release, Opiant Pharmaceuticals recently announced that it has entered into an exclusive global licensing agreement with Sanofi for the development and commercialization of drinabant for the treatment of acute cannabinoid overdose (ACO). Opiant intends to develop drinabant, a cannabinoid CB-1 receptor antagonist, as an injectable for administration in an emergency department setting.
The release quoted, "ACO is most frequently linked to the ingestion of "edibles" containing large quantities of D9-tetrahydrocannabinol (THC) and synthetic cannabinoids ("K2" and "spice") that are more potent and less expensive than marijuana. Edibles, sold as brownies, cookies and candies, pose particular risks for children, who often consume these by accident. Based on 2014 rates from the National Emergency Department sample and United States Census Bureau figures, we estimate that ACO resulted in more than one million emergency department visits in the United States in 2016. With an increasing number of states legalizing marijuana for personal and recreational use, ACO rates are expected to rise. Symptoms of ACO produced by edibles and synthetic cannabinoids can include panic and anxiety, feelings of paranoia, agitation, visual and auditory hallucinations, and nausea. These symptoms often require emergency medical attention and can take six or more hours to resolve (Winstock, et al., J Psychopharmacology 2015). There are currently no approved treatments for ACO."
In a previous clinical study conducted by Sanofi in collaboration with the Centre for Human Drug Research, oral administration of drinabant was shown to block both subjective and objective effects of inhaled THC. However, oral drinabant's slow onset of action creates the need for an injectable version that can rapidly reverse the symptoms of ACO in an emergency situation. There is an extensive safety database with oral drinabant, generated in Sanofi's previous research and development program, including multiple Phase 1 and 2 studies.
"This agreement with Sanofi is indicative of our leadership and commitment to developing best-in-class treatments for addictions and drug overdose," said Roger Crystal, M.D., Chief Executive Officer of Opiant. "We are encouraged by both the safety profile of drinabant, as well as the potential of an injectable CB-1 antagonist to rapidly reverse the symptoms of ACO and address a growing medical need. We intend to initiate development efforts in 2019 and commence clinical studies thereafter."
Under the terms of the transaction, Opiant will pay Sanofi an upfront fee of $500,000, with any further payments contingent upon Opiant achieving certain clinical, regulatory and sales milestones. Opiant will assume all development and commercial responsibilities related to drinabant.
Also Read: Sanofi gets US FDA approval for the new paediatric vaccine
Source: self
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Below you will find MP3's of the sermon portions of our Sunday services.
For Live Streaming or to watch a service in its entirety, click here.
No church on February 24. Snow Day!
From 3/11/18: For the text on James 5:12 click here.


text:
FocusWish
Adderall Alternatives
Home/Modafinil's Half-Life - What Your Mother Never Told You/
Modafinil's Half-Life - What Your Mother Never Told You
Published 2016-11-09T11:00:00.000Z
MODAFINILHALF LIFEPHARMACOKINETICS
Contrary to what's stated elsewhere, the elimination half-life of modafinil is about 15 hours. However, some sources quote the half-life as ~13 hours.
The half-life of a drug is the amount of time it takes for the body to eliminate 50% of the drug from plasma (e.g., the bloodstream).
The half-life of modafinil has been studied extensively, but the results have not been completely uniform. Here are three sources authoritative sources that are in the same ballpark.
12-15 hours Robertson P, Hellriegel ET. Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003;42(2):123-37.
13.6 hours Darwish M, Kirby M, Hellriegel ET, Robertson P. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies. Clin Drug Investig. 2009;29(9):613-23.
15 hours AccessData.fda.gov
Note that while the mean elimination half-life of modafinil's sister drug armodafinil (Nuvigil) is roughly identical, it nevertheless has a greater AUC (area-under-the-curve) with monophasic pharmacokinetics.
See the following abstract[^1]:
Armodafinil and modafinil both had a mean single-dose terminal elimina- tion half-life of ~13 hours, with similar mean maximum plasma drug concentration (Cmax) and median time to Cmax values. After reaching Cmax, plasma concentrations appeared to decline in a monophasic manner with armodafinil, but in a biphasic manner with modafinil due to the initial rapid elimination of its S-isomer. As a result, mean area under the plasma drug concentration versus time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) and AUC from time zero to infinity (AUC¥) values were 33% and 40% higher, respectively, with armo- dafinil compared with modafinil on a milligram-to-milligram basis.
How Long Does Provigil Stay In Your System?
This answer is tricky becuase it depends on how you define "stay in your system."
After three half-lives, the remaining concentration of a drug is 12.5%. We'll treat the drug as being essentially gone at this point, even though a small amount remains.
Since the half-life of modafinil is 15 hours, three half-lives is 45 hours (3 x 15 h) or almost 2 days. So how long does Provigil stay in your system? About 2 days.
How Long Does Modafinil Take to Kick In?
The chart above that plots of pharmacokinetics of modafinil will help address this question. If you look at the red line - which represents modafinil - you'll notice that after about 1 hour we're up to plasma concentration of 3 ug/mL.
Two hours later, plasma concentrations peak at 4 ug/mL. So how long does modafinil take to kick in? It takes about 1 hour to get to 75% of the Cmax or the maximum concentration that the drug will attain.
[^1]: Darwish M, Kirby M, Hellriegel ET, Robertson P. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies. Clin Drug Investig. 2009;29(9):613-23.
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© 2017 FocusWish


text:
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What are the benefits and risks of wave-front excimer laser refractive surgery for common eye disorders?
Why is this question important?
Refractive errors are the most common cause of poor vision worldwide. People with refractive errors have trouble focusing, because of irregularities in the shape of their eyes. This causes:
- Nearsightedness (myopia), which makes far-away objects look blurry;
- Farsightedness (hyperopia), which makes nearby objects look blurry; and
- Astigmatism, which can make far-away and nearby objects look blurry or distorted.
Refractive errors can be corrected with glasses or contact lenses, or treated with surgery. Conventionally, surgeons use a computer-controlled laser that emits ultraviolet light (excimer laser refractive surgery) to correct irregularities. Newer surgical procedures use three-dimensional imaging technology to identify irregularities (wave-front modified techniques); this allows the correction of much smaller irregularities than the conventional procedure.
We reviewed the evidence from research studies to compare the benefits and risks of:
- conventional excimer laser refractive surgery versus wavefront-modified techniques; and
- different wavefront-modified techniques.
How did we identify and evaluate the evidence?
First, we searched for randomized controlled studies (clinical studies where people are randomly put into one of two or more treatment groups), because these studies provide the most robust evidence about the effects of a treatment. We then compared the results, and summarized the evidence from all the studies. Finally, we rated our confidence in the evidence, based on factors such as study methods and sizes, and the consistency of findings across studies.
What did we find?
We found 33 studies that involved a total of 1499 people aged 18 years or older. These studies were conducted in Asia, Europe and the USA, and followed people for between one month and one year. Most people in the studies were women, and most people were near-sighted.
Twelve studies reported their source of funding: two studies were funded by the US government, three studies were industry-funded and seven studies did not receive any specific funding.
Few studies provided information about the main effects that interested us:
- improvement in vision one year after surgery; and
- the occurrence of unwanted (adverse) effects such as significant vision loss, halos (seeing bright circles around light sources) or glare (discomfort caused by intense light).
We have little to very little confidence in the evidence from the studies we found, mainly because the studies:
- produced imprecise and inconsistent results; and
- were designed or conducted in ways that could introduce error into their results.
Conventional excimer laser refractive surgery versus wavefront-modified techniques
In procedures where the surgeon removes the outer layer of the front of the eye to access the treatment area (photorefractive keratectomy, PRK), there may be little to no difference between conventional and wavefront-modified techniques in vision improvement one year after surgery (one study).
No studies investigated conventional surgery versus wavefront-modified techniques in procedures where the surgeon creates a small flap in the front of the eye to access the treatment area (laser-assisted in-situ keratomileusis, LASIK).
Comparisons between different wavefront-modified techniques
There may be little to no difference between wavefront-optimized and wavefront-guided procedures (two different types of wavefront-modified technique) in vision improvement one year after surgery (six studies).
Our confidence in the evidence is too low to determine whether there is any difference in effect between wavefront-guided PRK and wavefront-guided LASIK (one study).
Fewer studies that reported information on unwanted effects suggest that there may be little or no differences between the procedures that were compared in terms of unwanted effects.
There may be little to no difference in improvement of vision between:
- conventional excimer laser refractive surgery and wavefront-modified techniques when using PRK;
- wavefront-optimized and wavefront-guided procedures.
We do not know which procedures are associated with fewer unwanted effects, because of limited evidence.
More, large and well-conducted studies are needed to improve the evidence and provide information about unwanted effects.
How-up-to date is this review?
The evidence in this Cochrane Review is current to August 2019.
Authors' conclusions:
This review suggests that at 12 months and six months postoperatively, there was no important difference between wavefront versus conventional refractive surgery or between wavefront-optimized versus wavefront-guided surgery in the clinical outcomes analyzed. The low certainty of the cumulative evidence reported to date suggests that further randomized comparisons of these surgical approaches would provide more precise estimates of effects but are unlikely to modify our conclusions. Future trials may elect to focus on participant-reported outcomes such as satisfaction with vision before and after surgery and effects of remaining visual aberrations, in addition to contrast sensitivity and clinical outcomes analyzed in this review.
Read the full abstract...
Refractive errors (conditions in which the eye fails to focus objects accurately on the retina due to defects in the refractive system), are the most common cause of visual impairment. Myopia, hyperopia, and astigmatism are low-order aberrations, usually corrected with spectacles, contact lenses, or conventional refractive surgery. Higher-order aberrations (HOAs) can be quantified with wavefront aberration instruments and corrected using wavefront-guided or wavefront-optimized laser surgery. Wavefront-guided ablations are based on preoperative measurements of HOAs; wavefront-optimized ablations are designed to minimize induction of new HOAs while preserving naturally occurring aberrations. Two wavefront procedures are expected to produce better visual acuity than conventional procedures.
The primary objective was to compare effectiveness and safety of wavefront procedures, laser-assisted in-situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) or laser epithelial keratomileusis (LASEK) versus corresponding conventional procedures, for correcting refractive errors in adults for postoperative uncorrected visual acuity, residual refractive errors, and residual HOAs. The secondary objective was to compare two wavefront procedures.
Search strategy:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, which contains the Cochrane Eyes and Vision Trials Register; 2019, Issue 8); Ovid MEDLINE; Ovid Embase; Latin American and Caribbean Health Sciences (LILACS); the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 6 August 2019. We imposed no restrictions by language or year of publication. We used the Science Citation Index (September 2013) and searched the reference lists of included trials to identify additional relevant trials.
We included randomized controlled trials (RCTs) comparing either wavefront modified with conventional refractive surgery or wavefront-optimized with wavefront-guided refractive surgery in participants aged ⪰ 18 years with refractive errors.
Data collection and analysis:
We used standard Cochrane methodology.
Main results:
We identified 33 RCTs conducted in Asia, Europe and United States, totaling 1499 participants (2797 eyes). Participants had refractive errors ranging from high myopia to low hyperopia. Studies reported at least one of the following review-specific outcomes based on proportions of eyes: with uncorrected visual acuity (UCVA) of 20/20 or better, without loss of one or more lines of best spectacle-corrected visual acuity (BSCVA), within ± 0.50 diopters (D) of target refraction, with HOAs and adverse events.
Study characteristics and risk of bias
Participants were mostly women, mean age 29 and 53 years, and without previous refractive surgery, ocular pathology or systemic comorbidity. We could not judge risks of bias for most domains of most studies. Most studies in which both eyes of a participant were analyzed failed to account for correlations between two eyes in the analysis and reporting of outcomes.
For the primary comparison between wavefront (PRK or LASIK or LASEK) and corresponding conventional procedures, 12-month outcome data were available from only one study of PRK with 70 participants. No evidence of more favorable outcomes of wavefront PRK on proportion of eyes: with UCVA of 20/20 or better (risk ratio [RR] 1.03, 95% confidence interval (CI) 0.86 to 1.24); without loss of one or more lines of BSCVA (RR 0.94, 95% CI 0.81 to 1.09); within ± 0.5 D of target refraction (RR 1.03, 95% CI 0.86 to 1.24); and mean spherical equivalent (mean difference [MD] 0.04, 95% CI −0.11 to 0.18). The evidence for each effect estimate was of low certainty. No study reported HOAs at 12 months.
At six months, the findings of two to eight studies showed that overall effect estimates and estimates by subgroup of PRK or LASIK or LASEK were consistent with those for PRK at 12 month, and suggest no difference in all outcomes. The certainty of evidence for each outcome was low.
For the comparison between wavefront-optimized and wavefront-guided procedures at 12 months, the overall effect estimates for proportion of eyes: with UCVA of 20/20 or better (RR 1.00, 95% CI 0.99 to 1.02; 5 studies, 618 participants); without loss of one or more lines of BSCVA (RR 0.99, 95% CI 0.96 to 1.02; I2 = 0%; 5 studies, 622 participants); within ± 0.5 diopters of target refraction (RR 1.02, 95% CI 0.95 to 1.09; I2 = 33%; 4 studies, 480 participants) and mean HOAs (MD 0.03, 95% CI −0.01 to 0.07; I2 = 41%; 5 studies, 622 participants) showed no evidence of a difference between the two groups. Owing to substantial heterogeneity, we did not calculate an overall effect estimate for mean spherical equivalent at 12 months, but point estimates consistently suggested no difference between wavefront-optimized PRK versus wavefront-guided PRK. However, wavefront-optimized LASIK compared with wavefront-guided LASIK may improve mean spherical equivalent (MD −0.14 D, 95% CI −0.19 to −0.09; 4 studies, 472 participants). All effect estimates were of low certainty of evidence.
At six months, the results were consistent with those at 12 months based on two to six studies. The findings suggest no difference between two wavefront procedures for any of the outcomes assessed, except for the subgroup of wavefront-optimized LASIK which showed probable improvement in mean spherical equivalent (MD −0.12 D, 95% CI −0.19 to −0.05; I2 = 0%; 3 studies, 280 participants; low certainty of evidence) relative to wavefront-guided LASIK.
We found a single study comparing wavefront-guided LASIK versus wavefront-guided PRK at six and 12 months. At both time points, effect estimates consistently supported no difference between two procedures . The certain of evidence was very low for all estimates.
Significant visual loss or optical side effects that were reported were similar between groups.
Health topics:
Eyes & vision > Refractive error
Li S-M, Kang M-T, Wang N-L, Abariga SA
Primary Review Group:
Eyes and Vision Group
See the full Review on
the Cochrane Library
Li S-M, Kang M-T, Wang N-L, Abariga SA. Wavefront excimer laser refractive surgery for adults with refractive errors. Cochrane Database of Systematic Reviews 2020, Issue 12. Art. No.: CD012687. DOI: 10.1002/14651858.CD012687.pub2.
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text:
Self-portraiture
How would I describe my character?
Oliver Sacks	Scientist
341. Correspondence and 2am phone calls with Richard Gregory 173 01:04
342. Richard Gregory's Exploratory 131 01:04
343. Richard Gregory's illusions 140 01:09
344. A tribute to Richard Gregory 142 03:01
345. Studs Terkel 179 02:59
346. Believing in angels 1 246 01:05
347. How would I describe my character? 1 310 01:00
348. Self-portraiture 261 00:24
349. Experiencing my brother's teenage schizophrenia 774 01:21
350. My brother's life with schizophrenia and treatment for it 1689 03:53
There is a book called Flaubert's Parrot, which has parallel columns, Flaubert trying to define himself and say who he is, first in the most negative, self-deprecatory mode, then in a rather positive, vainglorious mode, and somewhere in the middle. I... I am shy, I am curious, I am tenacious, I am ravenous sometimes for information, but also, as you saw yesterday, a dangerous eater at the dinner table, things have to be removed from me. I am… no, I... I can't give a portrait of myself, it's up to other people to give their portraits.
Oliver Sacks (1933-2015) was born in England. Having obtained his medical degree at Oxford University, he moved to the USA. There he worked as a consultant neurologist at Beth Abraham Hospital where in 1966, he encountered a group of survivors of the global sleepy sickness of 1916-1927. Sacks treated these patients with the then-experimental drug L-Dopa producing astounding results which he described in his book Awakenings. Further cases of neurological disorders were described by Sacks with exceptional sympathy in another major book entitled The Man Who Mistook His Wife For A Hat which became an instant best seller on its publication in 1985. His other books drew on his rich experiences as a neurologist gleaned over almost five decades of professional practice. Sacks's work was recognized by prestigious institutions which awarded him numerous honours and prizes. These included the Lewis Thomas Prize given by Rockefeller University, which recognizes the scientist as poet. He was an honorary fellow of both the American Academy of Arts and Letters and the American Academy of Arts and Sciences, and held honorary degrees from many universities, including Oxford, the Karolinska Institute, Georgetown, Bard, Gallaudet, Tufts, and the Catholic University of Peru.
Title: How would I describe my character?
Listeners: Kate Edgar
Kate Edgar, previously Managing Editor at the Summit Books division of Simon and Schuster, began working with Oliver Sacks in 1983. She has served as editor and researcher on all of his books, and has been closely involved with various films and adaptations based on his work. As friend, assistant, and collaborator, she has accompanied Dr Sacks on many adventures around the world, clinical and otherwise.
Tags: Flaubert's Parrot, Julian Barnes


text:
Mashantucket Pequot Tribal Member Among WW II Veterans on Washington D.C. Day of Honor Trip
WW II veteran Earl Colebut (center) and his grandson Roy Colebut-Ingram (left) shown with a fellow member of the Mashantucket Pequot Tribal Nation at Bradley Airport April 27.
Story & Photos by Jacqueline Bennett newsandviewsjb
Looking dapper in a black suit and dark blue shirt accented by a bolo tie, World War II veteran Earl Colebut was welcomed back at Bradley International Airport last Saturday night by about thirty fellow members of the Mashantucket Pequot Tribal Nation. Family and friends turned out to greet Colebut who was among 100 veterans, who took a Day of Honor trip on April 27 to visit the WW II Memorial and other monuments in Washington, D.C.
The soft-spoken Colebut said he served in Germany during the war. As is typical of veterans of his era, rather than elaborating on his wartime experience, Colebut described himself as a man of peace not violence and spoke of the senselessness of the recent bombings at the Boston Marathon.
For Colebut's grandson, Roy Colebut-Ingram, a Tribal Councilor, his grandfather's service is clearly a source of tremendous pride.
"This is a really proud moment, not only for me personally but for our history as well," said Colebut-Ingram.
The Day of Honor trip was sponsored by the American Warrior project which was founded circa 2006 by Christopher Coutu of Norwich after a visit he made to the WW II memorial. While there Coutu said he noticed the absence of the veterans the memorial was built to honor. A member of the Connecticut Army National Guard himself and inspired by seven of his own family members who served in WW II, including his Great Uncle Edward who at that time was still living, Coutu returned home determined to help the warriors from America's "greatest generation" visit their memorial, built sixty years after the war.
So dedicated to that mission was Coutu that he withdrew the last $10,000 from his savings account to pay for the first trip when funding fell short. He has since recouped that money.
"I promised them this trip and so I put everything on the line," said Coutu, who joined the veterans on the Day of Honor trip.
American Warrior Founder Chris Coutu and his assistant Sue Ponder shown with WW II veterans who took the April 27, 2013 Day of Honor trip.
The daylong trip on a chartered aircraft departed from BIA early Saturday morning. In addition to the WW II Memorial, the veterans, 99 from WW II and one from the Korean War, were scheduled to see the Korean, Air Force, SeeBee, Vietnam, Marine, Navy and Women's Memorials. The American Warrior project pays the trip cost for the veterans who are accompanied by guardians that pay their own $300 fare. Guardians are often next generation family members or volunteers there to escort and care for the veterans, some of whom are in wheelchairs.
They returned to a glorious patriotic welcome at Bradley Airport of family, friends and the Glamour Girls belting out popular tunes from the 1940s, such as "Sincerely", " Don't Sit Under the Apple Tree (With Anyone Else But Me)" and the "Boogie Woogie Bugle Boy." BIA Marketing Coordinator Stacey Doan grabbed a sailor out of the welcoming crowd and proceeded to dance up a storm with Seaman Cameron Slate of Knoxville, Illinois. Slate and his buddies, who are studying at the Naval Submarine Base located in Groton, drove up to the airport to greet the returning veterans.
As part of a patriotic welcome home for the WW II veterans, the Glamour Girls sang tunes from the 1940s.
Seaman Cameron Slate of Knoxville, Illinois, dances with Bradley Airport Marketing Coordinator Stacey Doan.
To date, thanks to Coutu 930 WW II veterans have been on Day of Honor trips. According to information provided by American Warrior, over 16 million served. Of that number, 400,000 died in the war. Presently, the average age of the surviving veterans is 85 but their ranks are dwindling – some 1.200 pass away daily. Thus far, Coutu has only a few WW II veterans signed up for the Day of Honor trip expected to take place in the spring of 2014. But he hopes more sign on. According to Coutu, his next mission will be to bring Korean War veterans on Day of Honor trips.
For more information about American Warrior and how to donate to the project go to: WWW.AMERICAN WARRIOR.US
Categories: American history, NEWS, war memorials, WW II
Tagged: American Warrior, Christopher Coutu, Day of Honor, Glamour Girls, Jacqueline Bennett, Mashantucket Pequots, Roy Colebut-Ingram, WW II veterans
« Changes On Tap For newsandviewsjb "And If You're Very Lucky, You Find Someone Willing To Stand With You" »


text:
describe TicTacToe::Player do
  let :board do
    TicTacToe::Board.new
  end

  let :player do
    described_class.new(board, TicTacToe::Markers::X, driver_double)
  end

  describe '#mark_board!' do
    context 'performing the driver' do
      before do
        player.perform_driver!
        player.mark_board!
      end

      it 'mark a cell on board' do
        expect(board.cells[0].value).to eq(TicTacToe::Markers::X)
      end
    end

    context 'without performing the driver' do
      before do
        player.mark_board!
      end

      it 'dont mark any cell on board' do
        expect(board.cells).to all(be_empty)
      end
    end
  end
end

redpajama_set_name: RedPajamaGithub


Waiting for him, however, is Robert Mueller, the widely respected Special Counsel who has assumed the roles which Archibald Cox and Leon Jaworski assumed in the prosecution of Richard Nixon's hubris. Mueller is investigating Russia's interference in our presidential election and Russia's ties to Trump's campaign.
Associate solitary reporter Susanna Sherman, who covers issues involving the Justice Department and our justice system for us, called us moments ago to tell us that Mueller has hired Allan Lichtman, the award-winning American University professor who wrote The Case For Impeachment. Prof. Lichtman's book is, essentially, a strategy for making Mike Pence our next president. It was Lichtman who predicted, before November 8, that Hillary Clinton would lose the election, so Trump wrote Lichtman a note congratulating him on his prediction, ignoring the fact that Lichtman also predicted that Trump would, yes, win the election, but that he would also be impeached. The Donald did not congratulate him for that, but our team of ace reporters here at AP did.
Sherman also reminded us that the case for impeachment grows stronger every day, now that the whole world knows that Trump asked former GOP Sen. Dan Coats, his Director of National Intelligence, and Admiral Mike Rogers, his Director of the NSA, to deny evidence of Russia's collusion with his ruthless campaign to become, initially, the Leader of the Free World, and then its Dictator.


Deposition Author(s): Song, G., Springer, T.A.
Structures of the Toxoplasma gliding motility adhesin.
Program in Cellular and Molecular Medicine and Division of Hematology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115.


text:
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Garth Brooks Tribute Show
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text:
Stratification of ovarian tumor pathology by expression of programmed cell death-1 (PD-1) and PD-ligand- 1 (PD-L1) in ovarian cancer
Maureen L. Drakes1Email author,
Swati Mehrotra2,
Monica Aldulescu2,
Ronald K. Potkul3,
Yueying Liu4,
Anne Grisoli4,
Cara Joyce5,
Timothy E. O'Brien6,
M. Sharon Stack4 and
Patrick J. Stiff1
https://doi.org/10.1186/s13048-018-0414-z
Accepted: 9 May 2018
Ovarian cancer is the major cause of death among gynecologic cancers with 75% of patients diagnosed with advanced disease, and only 20% of these patients having a survival duration of five years. Treatments blocking immune checkpoint molecules, programmed cell death (PD-1) or its ligand PD-ligand- I (PD-L1) have produced a beneficial and prolonged effect in a subgroup of these patients. However, there is debate in the literature concerning the prognostic value of the expression of these molecules in tumors, with immunotherapy responsiveness, and survival.
We evaluated the immune landscape of the ovarian tumor microenvironment of patients, by measuring the impact of the expression of tumor PD-1, PD-L1 and infiltrating lymphocytes on stage and grade of tumors and survival, in a cohort of 55 patients with gynecologic malignancies. Most patients under study were diagnosed with advanced disease ovarian cancer.
Our studies revealed that a low density of PD-1 and of PD-L1 expressing cells in tumor tissue were significantly associated with advanced disease (P = 0.028 and P = 0.033, respectively). Moreover, PD-L1 was expressed significantly more often in high grade tumors (41.5%) than in low grade tumors of patients (7.7%) (P = 0.040). The presence of CD3 or of FoxP3 infiltrating cells with PD-L1 in patient tumors did not impact the significance of the association of PD-L1 with high grade tumors (P = 0.040), and our analyses did not show an association between the presence of PD-1 or PD-L1 and survival.
We conclude that a subgroup of advanced disease ovarian cancer patients with high grade tumors, expressing PD-L1, may be prime candidates for immunotherapy targeting PD-1 signaling.
Programmed cell death-1
Programmed cell death-1 ligand
High grade disease
The early signs of ovarian cancer are asymptomatic and thus approximately 75 % of cases are detected in the advanced metastatic stages. Conventional management strategies for advanced disease include cytoreductive surgery and chemotherapy. Most current treatments are not curative for patients with advanced disease and hence survival for this category of patients is low [1]. It is estimated that in 2017 there will be 22,440 new cases of ovarian cancer in the Unites States, and that 14,080 patients will die due to this disease [2]. Approximately 80 % of patients diagnosed with late stage ovarian cancer die within five years.
To provide more effective treatment options for patients, several clinical trials are ongoing using novel single and combination regimens to improve survival. For cancer therapy, there have been several distinct landmarks in the development of new therapies and FDA approved treatments over the last decade [3]. However, even with the current treatment options a considerable number of patients are not yet receiving adequate therapy for the management of advanced stage ovarian cancer and other malignancies.
The development and optimization of the use of novel therapies such as immunotherapy, requires an in-depth understanding of specific target molecules and cellular interactions in tumors. Early efforts in immunotherapy can be traced to 1891, in which administration of intra-tumoral injections of bacteria led to a shrinkage of patients' tumor [4, 5]. Since then, significant progress has been made in the field [6]. One of the recent highlights in novel treatment options for cancer has been the targeting of immune checkpoint inhibitory molecules [7–9]. Immune checkpoints are critically important in health and disease. They represent co-signaling pathways which are either costimulatory or coinhibitory. In the body, linkage of coinhibitory receptor and ligand suppresses T cell receptor signaling, and limits immune responses. Whereas this function of checkpoint inhibitory molecules is beneficial during resolution of infection, or in the development of self tolerance to prevent autoimmune conditions [10–12], ligation of checkpoint inhibitory molecules can be a powerful and unwanted mechanism of immunosuppression in cancer [13–15]. Since the successful introduction and FDA approved use of an antibody targeting checkpoint inhibitory molecule cytotoxic T lymphocyte associated-4 (CTLA-4) (Ipilimumab; Yervoy®) in patients with unresectable or metastatic melanoma in 2011 [16], this agent is now in use in over 40 countries. Attention has more recently focused on another checkpoint inhibitory molecule programmed cell death-1 (PD-1) and its ligand programmed cell death-1 ligand (PD-L1) [17–19].
Antibodies inhibiting PD-1 and PD-L1 have recently been FDA approved for the treatment of cancer. For example, the agent nivolumab (Opdivo®) is approved for unresectable or metastatic melanoma, non-small cell lung cancer (NSCLC), Hodgkin's lymphoma and renal cell carcinoma. Pembrolizumab (Keytruda®) is FDA approved for melanoma and NSCLC, and a blocking anti-PD-L1 antibody Atezolizumab (Tecentriq®) is also FDA approved for unresectable bladder cancer and for NSCLC. Blockade of this pathway is particularly useful in patients as it is applicable to a wide range of cancers, and because it induces anti-tumor immune responses capable of targeting mutated proteins [20]. Importantly, treatment targeting PD-1 signaling has fewer high grade toxicities than other immunotherapies [13, 21].
Medical centers are currently utilizing these agents in ongoing clinical trials for various cancers, including ovarian cancer [7, 22, 23]. Initial reports of some trials show promising objective response rates (ORR) for the treatment of ovarian cancer with anti-PD-1 antibody nivolumab (ORR of 15%, n = 20 patients), and pembrolizumab (ORR 11.5%, n = 49), or an anti-PD-L1 antibody avelumab (ORR 10%, n = 124) [3, 24]. Those responding often had durable responses, suggesting that if we could identify the subgroup that might typically respond, we could advance the therapeutic options in this subgroup of ovarian cancer patients.
PD-1 is primarily expressed on CD4+ and CD8+ T cells and is associated with T cell exhaustion [11, 12, 14]. PD-L1 is expressed on many cell types including tumor cells and macrophages, including those with an immunosuppressive phenotype [12, 25, 26]. Ligation of PD-L1 on tumor cells with PD-1 on T cells, for example, abrogates T cell proliferation, diminishes T cell activation and leads to a predominance of a T helper 2 (Th2) cytokine tumor microenvironment, with a pro-tumor propensity. Antibody blocking of PD-1 or PD-L1 restores T cell proliferative and cytotoxic functions, and induces a T-helper 1 (Th1) phenotype, thereby re-invigorating T cells, with resulting potent anti-tumor capacity [14, 27, 28].
The immune mechanisms of disease improvement with administration of checkpoint inhibitory molecules are not well understood. Clinically, there is also ongoing debate over which patients will benefit from this therapy, whether patients who respond initially will continue to show complete responses (CR) or partial responses (PR), and whether patients' tumors need to express PD-1 and/ or PD-L1 in abundance, to predict beneficial responses to checkpoint inhibitory molecule blocking therapy targeting these molecules. At the present time, there are more questions than answers.
As a study of the immune microenvironment of ovarian cancer patient tumors offers insight into the baseline immune landscape associated with patient survival and tumor pathology, and implicates broader scope for targeting these molecules in combination studies with conventional therapy and with other novel therapies, we undertook these present investigations. We primarily selected advanced disease ovarian cancer patients for study, since this group typically have poor outcome with standard therapy, and our future goal in translational medicine is to address the need for novel alternative treatment options in this patient sector. We evaluated the expression and localization of PD-1 and PD-L1 in a cohort of ovarian cancer formalin fixed paraffin embedded (FFPE) tumor sections, and investigated whether the relative expression levels of these molecules can be relevant patient prognostic indicators. We also studied the impact of tumor infiltrating lymphocytes (TILS) along with these checkpoint molecules, on patient status including tumor grade, disease stage and survival post diagnosis.
Patients underwent surgery between 2003 and 2006 at Loyola University Medical Center (LUMC) for ovarian and other gynecologic associated cancers. Tissues were embedded in paraffin blocks for patient diagnosis to characterize stage and grade of cancer in tissue sections, and blocks were stored in the Department of Pathology, LUMC. After receiving approval by the Institutional Review Board (IRB) for the Protection of Human Subjects, we selected a cohort of 55 patients for study, most of whom were diagnosed with advanced disease ovarian cancer (Table 1). Patient histories in the LUMC medical records were evaluated by two investigators and data collected for parameters including: age, date of birth, date of diagnosis, pre-treatment status before surgery, cancer stage, tumor grade, date of last encounter, and whether the patient was alive or deceased. Dates of death were retrieved from the patients' medical records when this date was available, or found by a search on a website such as http://www.dobsearch.com/death-records/.
Categories of patient tumors
Tumor type
Histological subtype
No. of patients
Low (I/ II)
papillary mucinous cystadenocarcinoma
mixed adenocarcinoma, serous and endometroid
papillary serous adenocarcinoma
papillary serous carcinoma
serous carcinoma
High (III/ IV)
poorly differentiated serous carcinoma
aTumor stage reflects the International Federation of Gynecology and Obstetrics (FIGO) classification
Antigen revealing
Formalin fixed paraffin embedded (FFPE) tissue sections (4 μm) were adhered to glass slides using tissue from a single patient on each slide for detection of PD-L1, PD-1, CD3 and CD8 by immunohistochemistry (IHC). For staining of FoxP3 on T cells, patient tissue arrays were constructed from the paraffin embedded blocks and adhered on a total of 2 glass slides with a core of tissue from each of 27 or 28 patients, as well as control tissues. Positive control thymus tissue highly expressed the molecules/ markers under study. Negative control tissue was sections of benign ovarian disease such as polycystic ovarian disease. Sections on slides were de-paraffinized in xylene and then rehydrated in a series of decreasing concentrations of alcohols. Antigen retrieval for PD-L1 and PD-1 was performed by boiling slides in a pressure cooker for 5 min in Universal HIER retrieval agent (ab 208,572, Abcam, Cambridge, MA) at a 1X concentration. Sections were washed in 0.1% tween in Dulbecco's phosphate buffered saline (DPBS; 1X, Lonza, Walkersville, MD) and then blocked in 0.4% hydrogen peroxide in DPBS, followed by blocking in 10% goat serum (S1000, Vector Laboratories, Burlingame, CA) for 1 h.
Antigen retrieval for FoxP3, CD3 and CD8 was performed by boiling sections in a pressure cooker for 5 min in Reveal Decloaker (RV1000G1, Biocare Medical, Concord, CA). After washing in DPBS, sections were blocked in 0.4% hydrogen peroxide in DPBS for 20 min, 10% goat serum or 10% horse serum (S1000 or S2000 respectively, Vector Laboratories) for 20 min, and then in Avidin/ Biotin blocking reagents (SP 2001, Vector Laboratories) to further reduce non-specific staining of primary antibody (FoxP3, CD3, or CD8).
Identification and assessment of antigens in patient sections
Tissue sections were incubated overnight in 5% blocking serum with or without primary antibody at a pre-determined and optimized dilution. PD-1 (ab137132, Abcam) and PD-L1 (ab205921, Abcam) were used at 1:500 dilution for IHC staining. The next day sections were washed in 0.1% tween in DPBS, and an amplifier polymer detection system specific for rabbit anti-human primary antibodies (ab 20,901, Rabbit specific IHC polymer detection kit; HRP/ DAB) added according to the manufacturers' guidance.Tissue was also stained overnight with primary antibodies for FoxP3 (236A/E7; ab 20,034, 1:1600 dilution, Abcam), CD8 (C8/144B; 1:100 dilution, Cell Marque, Rocklin, CA 1:1000 dilution) and CD3 (F7.2.38; 1:1000 dilution, Dako, Glostrup, Denmark). Sections were washed in DPBS and a biotinylated secondary antibody for peroxidase (PK 6102, Vector Laboratories) added for 30 min, followed by an avidin-biotin peroxidase complex and enzyme reagent (ABC, Vector laboratories). All sections were washed in DPBS and developed in Vector NovaRED (SK4800) or diaminobenzidine (DAB; SK4100, Vector Laboratories). Sections were counterstained in hematoxylin and rehydrated in xylene, followed by alcohol, then mounted in Vectamount H-5000 (Vector Laboratories).
Tumor sections were examined by pathologists SM and MA to investigate the frequency of occurrence of markers, the degree of staining intensity and location of tumor cells or lymphocytes expressing each molecule. A customized scoring system was developed by the abovementioned pathologists to obtain a numerical score to represent the average frequency of antigens as visualized over 7–10 high power fields (hpf) of IHC stained tissue sections (Table 2), where "0" was the lack of expression, and "4" represented the highest frequency of expression of molecules in sections. In addition to the scoring pattern shown in Table 2, in statistical analysis, combined PD-1 was assigned as a mathematical score which was derived by adding the observed pathology scores (0–2) for T-PD-1 and S-PD-1 in each patient section.
Pathological interpretation of IHC stained tissue
Scoring criteria based on cells/ high power fieldsa
T-PD-1
0 = < 1; 1 = 1–10, 2= > 10–50 and 3= > 50
S-PD-1
0 = < 1, 1 = 1–25; 2= > 25–50 and 3= > 50
PD-L1
0 = < 1, 1= > 1–5, 2= > 5–10 and 3= > 10
0 = < 5, 1 = 5–15, 2= > 15–25, 3= > 25–40 and 4= > 40
0 = < 1, 1 = 1–25, 2= > 25–50 and 3= > 50
FoxP3
0 = < 1, 1 = 1–5, 2= > 5–15, 3= > 15–25 and 4= > 25 cells/ hpf
aBased on the known frequency of each marker in various cancer tissues, each stained section was observed over 7–10 hpf and given an average numerical value to represent the scoring frequency based on the categorization in Table 2. PD-1 was assigned 2 different scores to reflect the observed localization of this molecule in tumor tissue. The percentage of PD-1 stained TILs completely enclosed by tumor epithelial cells was termed tumor-PD-1 (T-PD-1). PD-1 stained lymphocytes in the stromal compartment were classified as stromal-PD-1 (S-PD-1)
In some statistical analysis PD-1 and PD-L1 expression was classified as low (score of 1) or high frequency (score of 2–4) to decipher correlations between the levels of expression of these molecules and parameters studied.
Patient O/S was displayed visually in Kaplan Meier plots and significance of differences by strata were determined with Log Rank tests. The frequency of occurrence of each marker was graded on a scale from 0 to 4 (Table 2), and Cochran Armitage tests used to determine the statistical significance of trends by patient characteristics including age, cancer stage and tumor grade. Associations between the presence of PD-1, PD-L1, CD3, CD8 and FoxP3 positive cells with patient age at the time of diagnosis, cancer stage, or tumor grade were determined with chi-square or Fisher's exact tests as appropriate. Hazard ratios for overall survival (O/S) were determined from univariable Cox proportional hazard regression models for each patient characteristic and each marker. Analyses were performed using SAS 9.4 (SAS Institute, Cary, NC).
The cohort consisted of 55 patients as follows: ovarian (45 patients), fallopian tube (1 patient), peritoneum (5 patients), endometrium (2 patients) and omentum (2 patients) cancer tissue blocks. Patients were diagnosed as stage I or stage II (stage 1 or 2, low/ early stage; 9 patients) and stage III or IV (stage 3 or 4, high stage or advanced; 46 patients) disease (Table 1). One patient did not have known cancer grade, and of the remaining, about three quarters of patients had tumor grade 3 (n = 41, 75.9%).The mean age of patients at the time of diagnosis was 61 years (standard deviation = 12), with a range of 26 to 85 years. At the time of last follow up, 6 patients were alive, 9 patients were lost to follow up (3 of whom were deceased at an unknown date), and 40 other patients had recorded dates of death, 38 of whom had died as a cause of ovarian cancer. The median length of survival time for all patients was 3.10 years (95% confidence interval (CI): 2.24–5.19).
Localization of checkpoint inhibitory molecules in ovarian cancer tissue
We studied the distribution of PD-1 and PD-L1 in ovarian cancer tissue sections by IHC staining. Sections were visualized and staining evaluated by methods as outlined in Table 2. Results showed that PD-1 in ovarian cancer tissue was localized primarily to cell membranes. PD-1 stained cells appeared to be primarily tumor infiltrating lymphocytes (TILs), with varying degrees of intensity of staining and frequency of occurrence of these cells. Additionally, this staining was strikingly evident in two separate compartments of the tumor microenvironment, thus we scored this stain in two different categories. Intraepithelial TILs completely enclosed by tumor epithelial cells and positive for PD-1 were designated as tumor PD-1 cells (T-PD-1). These cells were either clustered (Fig. 1a), or scattered in a less dense pattern in the tumor epithelium (Fig. 1b). Cells which stained positive for PD-1 in the stromal compartment were termed stromal PD-1 (S-PD-1). In the stroma, there were aggregates of cells staining positive for PD-1 (Fig. 1c), or regions of fewer cells staining for this molecule (Fig. 1d). Table 3 shows a summary of scores for each PD-1 classification as well as the frequency of PD-1 observations in tissue in the cohort of 55 patients studied. A total of 48 (87%) patients expressed PD-1 on cells, whilst 40 (73%) patients expressed PD-1 in both the epithelial (T-PD-1) and stromal (S-PD-1) compartments (data not shown).
Distinct IHC staining patterns of PD-1 positive cells in the stroma and epithelium of tissue. In ovarian cancer tissue sections, tumor infiltrating lymphocytes (TILS) exhibiting strong membranous and cytoplasmic staining for PD-1 are apparent as clusters (a) or single scattered cells (b). TILS are also seen in aggregates (c) and as single cells (d) in the reactive stroma associated with tumor
Occurrence of checkpoint inhibitory molecules and TILS in tumors
Molecules in tumor sectionsa
Total patients positive
aTumor sections of 55 ovarian and related cancers were IHC stained for molecules as indicated. Sections were visualized by microscopy and a pathological score assigned from 0 to 4, based on the frequency of expression of each molecule, where "0" indicates the absence and "4" the highest frequency of expression
In tissue sections, PD-L1 was localized to the cell membrane. In lesions of some patients there were solid tumor aggregates with diffuse membranous staining of these cells for this marker (Fig. 2a). PD-L1 was also identified in scattered tumor cells with focal strong membranous staining (Fig. 2b). Additionally, in some sections PD-L1 staining was observed in cells with the morphology of immune cells (not shown). Staining for this marker was positive in approximately one-third (18 of 55, 33%) of patients with ovarian cancer.
Membranous staining of PD-L1 positive cells in ovarian tumors. Diffuse membranous staining of almost all ovarian cancer cells (a) versus focal strong membranous staining in a few scattered tumor cells positive for PDL1 (b)
Variable expression of tumor infiltrating lymphocytes in ovarian cancer
Immunocompetent TILS and FoxP3 T regulatory cells, are strategically located in ovarian cancer tissue. We sought to determine whether the levels of CD3, CD8 and/ or FoxP3 T cells in the tumors of patients would alter the potential role of checkpoint inhibitory molecules as predictors of disease pathology or of outcome. In FFPE tissue sections, of all T cells, CD3 positive T cells were found in highest frequency, as expected (Table 3), sometimes staining intensely. Some patients had an abundance of these cells, while other cases showed a scattered arrangement (Fig. 3a and b respectively). Staining for CD8 T cells was widely observed in patient sections as membranous reactivity, either with a dense distribution, or with lower frequency (Fig. 3c and d respectively). FoxP3 staining of cells was revealed as strong nuclear reactivity, either in clustered foci in some patient sections (Fig. 4a), or scattered in the tumor stroma in other cases (Fig. 4b). FoxP3 positive cells were present in 48 of 55 patients.
High and low density of TILs in ovarian tumors. IHC staining of T cell subsets in patients' FFPE tissue sections. CD3 exhibiting diffuse strong staining in clusters of tumor infiltrating lymphocytes (a) versus focal staining in scattered TILs in less dense areas (b). Distribution of CD8 T cells in clusters and as single cells is apparent in c and d respectively
Distribution of FoxP3 expressing T regulatory cells in ovarian tumors. Intense nuclear staining of FoxP3 positive lymphocytes in a focal arrangement (a). Other cases (b) showed nuclear staining of fewer cells positive for this marker
Clinical parameters as predictors of patient prognosis
We examined trends between age of patients at the time of diagnosis, tumor grade or tumor stage with overall survival. Significant parameters for these associations are represented in Kaplan Meier plots (Additional file 1: Figure S1). We found that patients diagnosed with ovarian cancer when over 60 years of age had a higher hazard of death (HR: 2.63, 95% CI: 1.34–5.16) and were significantly more likely to die as a cause of disease than patients diagnosed at a younger age (P = 0.005), (Additional file 2: Table S1). Additionally, patients diagnosed with advanced disease (stage III or IV) had a higher hazard of death (HR: 3.70, 95% CI: 1.28–10.76) and were significantly more likely to die than patients diagnosed in the early stages of the disease (P = 0.016). Tumor grade had no significant association with patient survival (Additional file 2: Table S1).
Similar analysis was performed to determine survival estimates as a function of the expression of each marker. It was found that while survival was similar in the first few years of follow-up for those with or without PD-L1, those with PD-L1 present in tissue sections appeared to have a survival advantage with increased time after diagnosis, even though this trend was not statistically significant (Additional file 3: Figure S2A). The presence of PD-1 and of CD3 showed modest but insignificant trends toward improved survival (Additional file 3: Figure S2 B and C). CD8 or FoxP3 did not show a significant association with survival, even though for high expression of FoxP3 there was a trend towards decreased survival (data not shown).
The presence of PD-L1 is positively associated with high grade tumors
We undertook detailed analysis to determine how the presence of checkpoint inhibitor molecules, PD-1 or PD-L1 correlated with patient history. We did not find any significant associations between the presence of PD-1, with patient age at the time of diagnosis, stage of cancer or tumor grade (Table 4).
Patient history and presence of PD-1 and PD-L1
combined PD-1a
No. Patients
Age at diagnosis
< 60
Stage of cancer
I-II
9 (100.0)
Tumor grade
aThe presence of PD-1 in the tumor epithelial or stromal compartment (combined PD-1), and PD-L1 was defined as the occurrence of these molecules (scores 1, 2, 3, or 4) in tissue sections. Tumor grade was unknown for one patient. Significant P-values are indicated in italics
Only one patient with low tumor grade expressed PD-L1, thus 17/18 (94%) patients who expressed PD-L1 in their ovarian tumors had a tumor grade of 3. Thus PD-L1 was expressed significantly more often in patients with high grade tumor than in those with low grade tumor (n = 54; 41.5% versus 7.7%, P = 0.040) (Table 4). We did not observe any other significant associations with the presence of any other molecules studied as single predictors, with age at the time of diagnosis, stage of disease or tumor pathology.
Further analysis of data showed that the presence of CD3 or of FoxP3 infiltrating cells together with PD-L1 in patient tumors did not impact the significance of the association of PD-L1 with high grade tumors (P = 0.040) (Table 5). There was borderline significant association between the presence of S-PD-1 cells together with FoxP3 positive cells in tumors with high grade (P = 0.075). The presence of TILs and of cells expressing PD-1 or PD-L1 occurring together in ovarian tumors had no impact on disease stage (Table 5), or on survival (data not shown).
Association with immune markers, grade and stage
n (%) with stage III-IV
n (%) with grade 3
41/54 (75.9)
aPresence with CD3
T-PD-1 + CD3
S-PD-1 + CD3
Combined PD-1 + CD3
PD-L1 + CD3
Presence with FoxP3
T-PD-1 + FoxP3
S-PD-1 + FoxP3
Combined PD-1 + FoxP3
PD-L1 + FoxP3
aEvaluation of the association of the presence of PD-1 or PD-L1 together with CD3 and FoxP3 T cells on advanced disease and on high grade tumors. Significant P-values are indicated in italics
Low frequency of expression of PD-1 and of PD-L1 correlates with advanced ovarian cancer
We further investigated whether high or low frequency of expression of PD-1 correlated with the stage or grade of cancer. Based on our scoring pattern for the occurrence of PD-1 in the tumor epithelium (T-PD-1) or in the stroma (S-PD-1), we initially analyzed observations in these compartments separately. As expected, the frequency of PD-1 expressing cells in tumor tissue was in general not as high as those expressing CD3 or CD8 (Table 3). A higher percentage of patients with early stage cancer were more likely to have a higher frequency of expression (pathology score of 2) of T-PD-1 than in patients with advanced disease, but this difference was not significant (P = 0.13, data not shown). In the case of S-PD-1, a higher percentage of patients with early stage cancer had higher levels (frequency score of 2, 22%) of S-PD-1 than for advanced disease patients (frequency score of 2, 2%) (P = 0.033) (Additional file 4: Table S2).
A significantly higher percentage (33%) of early stage patients had a higher frequency (score 3 and 4) of combined PD-1 (PD-1 in the tumor epithelium and/or stroma) than those with advanced disease (17%) (P = 0.028, Table 6). Thus, a high density of PD-1 was significantly associated with early stage disease diagnosis, and a low PD-1 density was associated with advanced disease.
Patient tumor and combined frequency of PD-1 expression
aCombined PD-1 Level, n (%)
aCombined PD-1 was derived by adding the observed pathology scores for tumor PD-1 (T-PD-1) and S-PD-1 in each patient tumor section. Significant P-value in table is indicated in italics
PD-L1 was expressed in 33% of the patient cohort. Scoring for PD-L1 was performed by scoring regions of intense or moderate staining for PD-L1 in either stromal or tumor epithelial compartment, and an average of cells stained over 7 hpfs taken into account. Most patients (5/9; 56%) with early stage disease expressed PD-L1. A lower percentage of patients with advanced disease expressed PD-L1 (13/46; 28%) (Table 7). Most patients (11/13; 85%) with advanced disease who expressed PD-L1, expressed this molecule in tumors with a score of 1 (on a scale of 0–3). A higher percentage of patients with early stage disease (22%) expressed high levels of PD-L1 (frequency score 2 or 3) in comparison with patients with advanced disease (4.3%) (Table 7). There were no significant trends in frequencies of CD3, CD8 or FoxP3 with age at the time of diagnosis, stage of disease, or tumor grade (data not shown).
Patient tumor characteristics and frequency of PD-L1 expression
PD-L1 Level, n (%)
Significant P- values in table are indicated in italics
Ovarian cancer is usually diagnosed in the advanced metastatic stages. Treatment of advanced stage disease with conventional therapies is only sufficiently effective in a limited number of patients, thus in about 80 % of these patients there is disease progression or disease recurrence and death, within five years of diagnosis. In many cancers, investigators are focusing on the development of novel therapies as alternative and more robust options to existing therapies. Whereas conventional therapies primarily focus on the destruction of tumor cells, many novel therapies are designed to stimulate immune cells to elaborate augmented anti-tumor immune responses. In this respect, checkpoint immune inhibitory molecules have come full circle over the last decade for cancer immunotherapy.
In a normal functioning immune system, T cell activating and inhibitory receptors balance immune tolerance, and the amplification of immune responses. In the body, immune checkpoints are designed to reduce autoimmune responses, or to attenuate immune responses which were elaborated after infections [10–12, 14, 27, 28]. In cancer, blocking of immune checkpoint molecules with antibodies is a novel and promising therapy, as it potentiates anti-tumor immune responses in patients [9, 13, 15, 19].
The first of these checkpoint inhibitory molecules to be targeted for blocking in therapy, and is now FDA approved for cancer therapy, is CTLA-4 [16, 17]. Therapy design is based on the following principle. Binding of costimulatory molecules CD80 or CD86 on antigen presenting cells to CD28 on T cells delivers a positive costimulatory signal contributing to T cell activation. On the contrary, linkage of CD80 or CD86 to CTLA-4 (a molecule closely related to CD28) results in inhibition of immune responses, and exhausted T cells, which are less able to proliferate or to secrete T helper 1 (Th1) cytokines [29] . Blocking of this inhibitory pathway with anti-CTLA-4 antibodies, results in re-invigorated T cells with greater proliferative function, and durable anti-tumor potency [30, 31]. By similar rationale, there are several other immune checkpoints in the immune system, which are now being targeted in cancer clinical trials. In the case of blocking PD-1 signaling, there are currently about nine different antibodies in cancer clinical trials targeting the PD-1/ PD-L1 pathway [3, 17].
This study was designed to better understand the ovarian cancer tumor microenvironment (TME) with relation to the localization and frequency of PD-1, PD-L1 and TILS in the tumors of ovarian or related cancer patients, diagnosed with advanced disease. Firstly, results showed that patients' age was an independent prognostic factor in survival, with patients over 60 years of age more likely to die than those diagnosed when younger than 60 years. This may be due to the fact that younger patients can tolerate more aggressive surgery and chemotherapy than older patients. Additionally, as expected, disease stage was also an independent prognostic factor in outcome, such that patients diagnosed with advanced disease had a lower median survival than patients diagnosed with early stage disease. These findings are in agreement with those of other investigators [32].
To shed light on the relevance of PD-1 and PD-L1 in ovarian cancer outcome, we studied the abundance of these molecules in the TME. PD-1 was compartmentalized in the stroma and in the tumor epithelium, and this molecule was expressed in 87% of tumors. PD-L1 was only present in the tumors of 33% of patients. Patients who expressed PD-L1 had a trend towards survival, as did those expressing PD-1 or CD3, even though these trends were not significant. In our cohort we did not find a significant association with FoxP3 and survival. The presence of PD-L1 and FoxP3 together in high grade tumors showed the same level of association as the presence of PD-L1 alone. Some studies have reported that FoxP3 positive cells in ovarian tumors is negatively associated with outcome, however a meta-analysis of 7 ovarian cancer studies with a total of 869 patients, did not find FoxP3 TILS in ovarian cancer to be a significant prognostic indicator [33].
In cancer there are conflicting reports concerning the expression patterns of PD-1 in patients' tumors and the association with survival, with either positive or a negative association [34–36]. One recent report found that PD-1 positive TILS and /or PD-L1 positive tumor cells had a positive association with survival of ovarian cancer patients [37].
The expression of PD-L1 in tumors was shown to be positively associated with survival in NSCLC [38] and in ovarian cancer [37]. On the contrary, others report a negative prognostic impact of PD-L1 expression in ovarian cancer [39, 40] and breast cancer [41]. In a review and meta-analysis of 17 studies using data of 2869 head and neck cancer (HNC) patients, authors found that there was no significant association between the expression of PD-L1 on survival in HNC patients [42]. Additionally, similar analysis of reports with NSCLC patients also did not show a significant association with PD-L1 expression and survival [43]. Taken together, this indicates that the prognostic impact of PD-1/ PD-L1 expression in tumors is not yet established. Here, our studies did not find a significant association between survival and PD-1 or PD-L1 expression in ovarian cancer.
Differences in reports of the expression of these molecules and associations with survival may be attributed to several reasons. Firstly, it is possible that there may be different survival outcomes due to the site of cancer. For example, Paulsen and colleagues [38] found that whereas in a cohort of patients a high density of PD-1 and PD-L1 had a favorable impact on NSCLC, this association was not present when these molecules were studied at metastatic sites such as lymph nodes of the same patients. This is highly likely because each cancer site has a different immune landscape, and levels of soluble molecules such as IFN-γ which is a strong regulator of PD-L1 expression [44, 45].
Secondly, differences in reports may be due to variations in staining protocols across individual laboratories. Many investigators report difficulty in IHC staining for PD-L1. In these present investigations, we initially used tumor arrays to study the expression of PD-L1 and PD-1 in tumors. When optimizing our staining protocol, we found that it was difficult to select cores which had a good representation of tumor and stromal areas for accurate visualization of the density of these molecules in tissue arrays. Therefore, in this study we used whole tumor sections for the identification of these molecules, as is done for patient diagnosis. For molecules such as PD-L1 especially, which is not widely expressed in tumor tissues, reports in which IHC staining was performed using tumor cores may give different findings than reports from other laboratories in which staining was performed using whole tissue sections.
Thirdly, the use of different primary antibody clones to identify PD-1 or PD-L1 in tumor tissue in each laboratory, may also lead to variability in staining of sections and in interpretation. Finally, manual staining protocols in comparison with automated staining may further contribute to variations in staining interpretation.
Finally, additional parameters which may alter the expression of these molecules in tumors, is the administration of treatments such as chemotherapy to patients prior to surgery. However, at our center, for patients diagnosed with ovarian and related gynecologic cancer, the primary treatment is most often surgery for removal of tumors. Patients then undergo courses of standard therapy such as chemotherapy. Consistent with this practice, we found that a study of our patient cohort treatment plans revealed that only 3 of 55 (5.5%) patients had chemotherapy in the interval before surgery.
A low frequency of PD-1 in tumors was associated with advanced disease. This association between low PD-1 density and advanced disease was only significant when measuring S-PD-1 or combined PD-1, whereas low T-PD-1 density alone was not associated with advanced disease. Although beyond the scope of this study, this finding raises the possibility that T-PD-1 and S-PD-1 positive cells may perform unique immunosuppressive roles in the ovarian TME.
PD-L1 expression was almost exclusively restricted to high grade tumors, such that there was a positive and significant association between PD-L1 and high grade tumors. This finding may be of translational significance in selecting patients for therapy blocking PD-1/ PD-L1 signaling, and we suggest that patients with high grade tumors, with pre-existing PD-L1 expression might be excellent candidates for therapy blocking this pathway. In support of this idea, a recent report shows that in an ongoing study of urothelial bladder cancer patients, treatment with durvalumab (MED14736; an anti-PD-L1 antibody) resulted in improved outcome in PD-L1 tumor positive patients. In pre-treatment tumor biopsies patients, 40 patients were PD-L1 positive and 21 patients negative for PD-L1. In 42 evaluable patients, the ORR was 31.0% (95% CI, 17.6 to 47.1), the ORR was 46.4% (95%CI, 27.5 to 66.1) in the PD-L1 positive patient subgroup, and 0% (95% CI, 0.0 to 23.2) in patients negative for PD-L1 [46].
We suggest that due to the conflicting reports concerning the impact of PD-1 and PD-L1 on survival in cancer patients, a future larger study is needed investigating these molecules in ovarian tissue, with standardized protocols and defined cut off points for positive staining and scoring criteria across centers, to minimize study variations. Even so, the potency of patient responses to PD-1/ PD-L1 blocking antibody therapy may be influenced by the density of other pre-existing or emerging checkpoint molecules in tumors, including T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3) and V-domain Ig suppressor of T cell activation (VISTA). Other parameters such as the presence of myeloid derived suppressor cells, levels of Th2 cytokines (for example IL-10) and of indoleamine 2,3-dioxygenase (IDO) can also limit anti-cancer immune responses to therapy blocking PD-1/ PD-L1 [19, 47, 48]. Furthermore, genetic alterations within the tumor (including DNA rearrangements, mutations, deletions and insertions) alter tumor mutational loads, and it is reported that tumors with high mutational loads have the greatest response to checkpoint inhibitory blockade therapy [17, 49, 50].
Finally, due to the multiplicity of factors regulating ORR, we believe that antibody therapy targeting the PD-1/ PD-L1 pathway in ovarian cancer will be of maximum efficacy when used in combination with other treatment regimens. Such treatments include standard therapy, immunotherapy blocking other checkpoint inhibitory molecules, dendritic cell vaccines, chimeric antigen receptor (CAR) T cell therapy, or targeted therapy, all of which can downregulate other immune suppressive mechanisms in patients, concomitantly.
Treatments inhibiting PD-1 and PD-L1 are beneficial only in some ovarian cancer patients. Our studies reveal that a low density of PD-1 and of PD-L1 expressing cells in tumor tissue are significantly associated with advanced disease, and that PD-L1 is expressed significantly more in high grade tumors than in low grade tumors. We conclude that a subgroup of advanced disease ovarian cancer patients with high grade tumors, bearing PD-L1, may be the best candidates for immunotherapy targeting PD-1 and/ or PD-L1.
complete response
CTLA-4:
cytotoxic T lymphocyte associated-4
formalin fixed paraffin embedded
HNC:
hpf:
high power fields
NSCLC:
non-small cell lung cancer
O/S:
overall survival
ORR:
objective response rate
PD-1:
PD-L1:
partial response
S-PD-1:
stromal PD-1
Th1:
T helper-1
TILS:
tumor infiltrating lymphocytes
TME:
T-PD-1:
Tumor PD-1
This research was supported by a joint research award offered by the Cardinal Bernardin Cancer Center, Loyola University (to M.L.D.), and the Harper Cancer Research Institute, University of Notre Dame (to M.S.S.), made possible by funds from the Cronk Foundation. Additional support was from the Perritt Charitable Foundation (to P.J.S.). Funding agencies did not participate in the design of the study, collection, analysis or interpretation of data, or in writing the manuscript.
All data generated or analyzed during this study are included in this published article (and its additional information files).
MLD Conceptualization, investigation, patient history data, data analysis, writing- original draft, review and editing, and project administration. SM Pathology grading and scoring, writing- review and editing. MA Pathology grading and scoring, patient history data, writing- review and editing. RP Patient surgery, writing- review and editing. YL Investigation, writing- review. AG Investigation, writing- review. CJ Statistical analysis. Writing- statistical writing, review and editing. TO Statistical analysis, writing- review. MSS Conceptualization, investigation, data analysis, writing- review and editing, and project administration. PJS Investigation, writing- review and editing, and project administration. All authors read and approved the final manuscript.
Investigators received approval by the Institutional Review Board (IRB) for the Protection of Human Subjects at Loyola University Medical Center for the use of the cohort of patients in study.
Additional file 1: Figure S1. Survival estimates by patient age and tumor grade. Kaplan Meier survival analysis to estimate overall survival in patients as a function of age (A) or tumor stage (B). Patient survival was displayed visually in Kaplan Meier plots and significance of differences determined with Log Rank tests. (PPTX 427 kb)
Additional file 2: Table S1. Univariable hazard ratios for Cox proportional hazards models (DOCX 25 kb)
Additional file 3: Figure S2. Survival estimates by expression of immune molecules. Kaplan Meier survival analysis to estimate overall survival in patients expressing PD-L1 (A), PD-1 (B) and CD3 (C) in tumor sections. (PPTX 456 kb)
Additional file 4: Table S2. Patient tumor and frequency of S-PD-1 expression (DOCX 25 kb)
Cardinal Bernardin Cancer Center, Oncology Research Institute, Department of Medicine, Loyola University Chicago, Bldg. 112, Room 232, 2160 South First Avenue, Maywood, IL 60153, USA
Department of Pathology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
Department of Obstetrics and Gynecology, Loyola University Chicago, Maywood, IL, USA
Department of Chemistry & Biochemistry, Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA
Department of Public Health Sciences, Loyola University Chicago, Maywood, IL, USA
Department of Mathematics & Statistics, and Institute of Environmental Sustainability, Loyola University Chicago, Chicago, IL, USA
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