The world has never been more connected. Companies have laid millions of miles of fiber optics and shot satellites into space so that people can communicate with each other. People all around the world are texting each other on smart phones. Yet people feel more and more disconnected. We don't feel nearly as connected to each other as people did a generation ago.
We were created for Relationship - In fact the first thing God said was, "It's not good for man to be alone." God said that humans were not made for isolation. We were made for connection. Why? We were created in the image of God. The Bible says God is love. And to love, you've got to have somebody to love.
We're built like a Building - "In Christ you are built together spiritually into a dwelling place for God" (Ephesians 2:22 NRSV). We are meant to fit together like bricks in a new building. It's essential that the parts of a building fit together. You aren't safe otherwise because there's no support. Likewise, those who aren't connected to a church family in any meaningful way have no support. Life is tough. We all need the support of people who care about us.
We're joined in a Body - "Just as there are many parts to our bodies, so it is with Christ's Body. We are all parts of it, and it takes every one of us to make it complete, for we each have different work to do. So we belong to each other, and each of us needs all the others" (Romans 12: 4-5 TLB). What Jesus Christ did when he was here in his physical body, he wants to do today through the church. We are the body of Christ on Earth. We are his hands. We are his feet. All of us have to play our part. Being part of the body of Christ means we are a part of something bigger than ourselves, and if we don't play our specific part, the mission of the church is impacted.
We're born into a Family - "I want you to know how people who are members of God's family must live. God's family is the church…" (1 Timothy 3:15 GW). This is my favorite metaphor for the church. Most people think that Christianity is a belief system. There are beliefs in Christianity, but it's so much more. Christianity is a belong system. The Bible says we were born again into God's family when we became a follower of Jesus. It also says that we've been adopted into God's family. Because we are part of God's family, we should accept one another and love one another.
We're attached to a Vine - "Live in me, and I will live in you. A branch cannot produce any fruit by itself. It has to stay attached to the vine. In the same way, you cannot produce fruit unless you live in me" (John 15:4 GW). Being connected isn't just a horizontal issue. It's a vertical one as well. We need to be connected to God himself. Jesus says when we are connected to him it's like being attached to a vine. Fruit not connected to a vine dies. It's that simple.
Two new opportunities for getting connected are starting this month at APC.
1. Purpose Driven Life Bible Study Starting July 9th at 6:30 pm we will begin a study on the book - "The Purpose Driven Life". I will be teaching the study which will help us discover what God's purposes are for our lives.
2. Sit and Sew On July 19th starting at 9 am - Sit and Sew will be meeting in the Manse Hall. This is an opportunity to meet with others and work on your crafts or learn a new one. Quilting, Scrap-Booking, Knitting are just some of the crafts that you might want to share.
Let's work together to stay connected.


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Home > Finance > 3 Stocks Flashing Signs of Strong Insider Buying
3 Stocks Flashing Signs of Strong Insider Buying
Every investor wants an 'in,' some hint that will tell exactly what a stock is going to do, and when. The kind of signal that will cut through the market's noise, and makes sense of the deluge of raw data that every company generates. Multiply that data by 10,000 publicly traded stocks, and you'll have some idea of just how daunting the markets can be.
It's tempting to follow an expert: a Wall Street analyst, or a trading guru. They all have important contributions to make. But here, we'll take a look at some corporate insiders. These are names you likely haven't heard, because they have a lower profile. They are company officers, with close insight to their own companies and business niches.
Insiders know what's in store for their companies, based on their positions of corporate responsibility – responsibility to Directors and shareholders, for bringing in profits and returns. Which makes their trades a sound place to start looking for solid buys.
TipRanks' Insiders' Hot Stocks tool offers investors a range of ways to follow insiders, and data filters that make search results easy to parse. We've picked three stocks with recent informative buys to show how the data works for you.
Nicolet Bankshares (NCBS)
We'll start with Nicolet Bankshares, a small-cap regional bank holding company based in Wisconsin. The subsidiary company, Nicolet National Bank, operates 30 branches in Wisconsin and Upper Michigan, offering a full range of personal and business banking solutions, ranging from checking accounts and savings deposits to mortgages, wealth management, and retirement services.
The company has seen sound revenue and earnings through the last 5 quarters, which continued in its latest quarterly statement. Nicolet reported EPS of $1.77 per share in 2Q21, based on $18.2 million in net earnings. The net was up 34% year-over-year, with the EPS gaining 38% – and beating consensus by over 8%. Revenue also came in ahead of the Street's forecast, increasing by 13.8% from the same period a year ago to reach $55.75 million, a $19.62 million beat. The company finished the first half of the year with $4.6 billion in total assets, of which $792 million was cash or cash equivalents.
Management boasts that Nicolet has the most active acquisition record among Wisconsin banks – and in 1H21, the company made two relevant announcements. First, in April, Nicolet reached a firm agreement to acquire Mackinac Financial, a regional bank with $1.5 billion in assets. The deal will close in 3Q21, pending shareholder approval; regulatory approval has already been obtained.
Second, Nicolet entered an agreement to acquire County Bancorp, a major agricultural lender in Wisconsin. County will also bring $1.5 billion in assets to the company, and the merger is expected to close in 4Q21. Both companies are now seeking shareholder and regulatory approval.
Turning to the insiders, we find that the company's CFO, Hubert Moore, and a Board member, Robert Weyers, have both made informative buys in recent days. Moore spent over $510,000 buying up 7,000 shares, while Weyers' buy was smaller, $253,000 for 3,500 shares.
Writing for Maxim, 5-star analyst Michael Diana sees the company's acquisition activity as key.
"We believe that NCBS deserves a premium due to its record of making accretive acquisitions, the most recent of which was announced last month…. Since 2016, NCBS has acquired Baylake Corp, First Menasha Bancshares, and Choice Bancorp to become the leading independent bank in the demographically attractive areas of Green Bay and the Fox Valley. Its recently-announced acquisitions of MFNC [Mackinac] and ICBK [County] should continue NCBS' streak of successful acquisitions, in our view," Diana wrote.
Diana gives the stock a Buy rating and $94 price target that suggests room for 30% share appreciation in the year ahead. (To watch Diana's track record, click here)
This small-cap banking company has picked up 3 recent reviews from Wall Street – and they all agree that it's a stock to Buy, making the consensus a unanimous Strong Buy. The shares are priced at $72.33 and their $89.33 average price target implies a 23.5% one-year upside potential. (See NCBS stock analysis on TipRanks)
Glacier Bancorp (GBCI)
The second stock on our list is another bank holding company, this time the parent corporation of Montana-based Glacier Bank. The company has banking locations across 8 states, including Montana, Idaho, Wyoming, Colorado, Utah, and Arizona, Washington and Nevada. Glacier Bancorp is another of the many regional mid-cap banking companies, and its subsidiary offers the usual range of banking services to individual and commercial clients, in both brick-and-mortar locations and online.
Glacier boasts over 190 locations, total assets of $20.5 billion, deposits of $16.8 billion, and loans of $11.2 billion. The company's year-to-date net income is given as $158.4 million. Second quarter income was $76.2 million, up $14.2 million year-over-year, or 22%. EPS came in at 81 cents, gaining 21% yoy and beating the forecast of 73 cents by over 10%. Excluding the PPP (payroll protection program) activity from the government during the corona crisis, the company reported a 10% annualized increase in loan activity, mainly in commercial lending, a gain of $249 million in the quarter.
Like Nicolet above, Glacier is active in acquisition activity, and announced a merger with Altabancorp during the quarter. This Utah-based company will bring assets worth $3.52 billion to the table, once the merger receives shareholder and regulatory approval.
On the insider front, the 'informative buy' here was made by Craig Langel, Director and Chairman of the Board at Glacier Bancorp. Langel spent $773,250 on 15,000 shares of GBCI.
Brandon King, covering Glacier for Truist, writes: "We view GBCI as a preferred acquirer in a footprint with limited competition and attractive demographic trends. The company has a disciplined credit culture and was able to resolve a higher than peer level of problem assets a few years ago. Moreover, the company has one of the best deposit bases in the country, which should provide greater NIM support in a higher rate environment. In our view, GBCI will likely continue to augment organic growth with digestible acquisitions given its strong currency."
King rates GBCI a Buy, and sets a $60 price target, implying an upside of 17% in the next 12 months. (To watch King's track record, click here)
Overall, Glacier's shares get a Moderate Buy from the analyst consensus, based on 2 Holds and 1 Buy. The shares are priced at $51.18 and their $58 average price target suggests an 11% upside from that level. (See GBCI stock analysis on TipRanks)
IMARA (IMRA)
Last but not least is IMARA, a clinical stage biopharmaceutical firm, engaged in research on Hemoglobinopathies. Specifically, the company has a drug candidate in the pipeline as a treatment for sickle cell disease and beta thalassemia. These are two blood disorders – both sets of related diseases – that cause anemic symptoms; sickle cell disease is a genetic disorder that causes misshapen red blood cells and can lead to serious quality-of-life issues and shortened life span, while beta thalassemia is a hemoglobin disorder, also inherited, that reduces the blood's ability to carry oxygen. Neither set of diseases currently has a fully effective treatment.
The chief drug candidate in IMARA's pipeline, IMR-687, is a selective and potent small molecule that inhibits PDE9. PDE9, in turn, plays a part in lowering levels of cGMP in blood-disorder patients, with associated inflammation, reduced blood flow, and other symptoms. Blocking PDE9 has been associated with reactivation of fetal hemoglobin – with consequent reduction of symptoms.
In June, IMARA reported final data from a Phase 2a clinical trial of IMR-687 in sickle cell disease which showed a significantly lower annualized rate of vaso-occlusive (blood flow blocking) crises (VOCs) in patients. New patients started on the drug also showed a longer time to the first VOC. IMR-687 was also well-tolerated by patients, both as a monotherapy and in combination with hydroxyurea.
In insider trades, the key transaction from an investor perspective was made at the end of July by Board member Mark Chin. Chin bought 1.333 million shares for nearly $8 million. Chin's stake in the company now totals over $13.5 million.
Leerink analyst Joseph Schwartz is bullish on IMRA, and takes the long-term view when assessing the company's prospects.
"Although IMRA shares have been under pressure this year, we believe encouraging Ph.2a VOC data should give the stock some lift today ahead of Ph.2b interim data expected in 2H21… Ahead of interim Ph.2b ARDENT and FORTE data in 2H21, we reiterate our OP rating on IMRA," Schwartz wrote.
The analyst added, "We currently estimate gross peak sales of ~$2.8B (2035E), and ~$290M (2035E) for IMR-687 in SCD and β-thalassemia, respectively. We account for clinical and regulatory risks in our probability of success (PoS) estimates, which range from 60%/40% in SCD (US/EU) to 40%/20% in βthalassemia (US/EU)."
To this end, Schwartz gives IMRA shares a $42 price target – indicating true confidence, and an impressive 661% upside potential from the current share price. (To watch Schwartz's track record, click here)
Overall, IMRA has received two recent Buy recommendations from the analysts, for a Moderate Buy consensus rating. (See IMRA stock analysis on TipRanks)
To find good ideas for stocks trading at attractive valuations, visit TipRanks' Best Stocks to Buy, a newly launched tool that unites all of TipRanks' equity insights.
Disclaimer: The opinions expressed in this article are solely those of the featured analysts. The content is intended to be used for informational purposes only. It is very important to do your own analysis before making any investment.
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redpajama_set_name: RedPajamaCommonCrawl


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Gene Therapy of the Hemoglobinopathies : HemaSphere
Cell and Gene Therapies
Hematopoiesis
Lymphoid Malignancies
Myeloid Malignancies
Red Cell and Iron Metabolism
Thrombosis and Hemostasis
Reviews & Controversies
HemaTopics
HemaBites
EHA Research Roadmap
CAR T-Cell
Benefits for Authors
Editorial, Legal, and Ethical Policies
Affiliated Society
October 2020 - Volume 4 - Issue 5
Thought you might appreciate this item(s) I saw in HemaSphere.
Gene Therapy of the Hemoglobinopathies
Kunz, Joachim B.; Kulozik, Andreas E.
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Hopp – Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Correspondence: Andreas E. Kulozik (e-mail: [email protected], [email protected]).
This review is dedicated to the late Sir David Weatherall.
Disclosures: AEK: Consultancy (bluebird bio, Novartis), JBK: Consultancy (Novartis).
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0
HemaSphere 4(5):p e479, October 2020. | DOI: 10.1097/HS9.0000000000000479
Sickle cell disease and the ß-thalassemias are caused by mutations of the ß-globin gene and represent the most frequent single gene disorders worldwide. Even in European countries with a previous low frequency of these conditions the prevalence has substantially increased following large scale migration from Africa and the Middle East to Europe. The hemoglobin diseases severely limit both, life expectancy and quality of life and require either life-long supportive therapy if cure cannot be achieved by allogeneic stem cell transplantation. Strategies for ex vivo gene therapy aiming at either re-establishing normal ß-globin chain synthesis or at re-activating fetal γ-globin chain and HbF expression are currently in clinical development. The European Medicine Agency (EMA) conditionally licensed gene addition therapy based on lentiviral transduction of hematopoietic stem cells in 2019 for a selected group of patients with transfusion dependent non-ß° thalassemia major without a suitable stem cell donor. Gene therapy thus offers a relevant chance to this group of patients for whom cure has previously not been on the horizon. In this review, we discuss the potential and the challenges of gene addition and gene editing strategies for the hemoglobin diseases.
The clinical challenges of hemoglobinopathies
Hemoglobinopathies, most importantly sickle cell disease (SCD) and ß-thalassemia, are the most prevalent genetic disorders globally.1,2 Migration from regions of high prevalence has resulted and will likely continue to result in a rise of patient numbers in Europe.3,4
Thalassemia mutations either completely abolish (ß0) or substantially reduce (ß+) the expression of the hemoglobin ß-chain, resulting in an imbalance of the hemoglobin α- and ß-chains. This imbalance causes hyperplastic but ineffective erythropoiesis and can result in extramedullary hematopoiesis.5 While the ß-thalassemias are genetically diverse with various mutations being prevalent among different ethnic groups, the clinical phenotype in most patients with biallelic inactivation of the ß-globin gene is that of thalassemia major, characterized by the need for life-long regular red blood cell transfusions from early childhood (TDT, "transfusion dependent thalassemia"). Approximately 10% to 15% of patients who carry either mutations allowing for relevant residual expression of ß-globin, who carry genetic modifiers boosting the expression of γ-globin and fetal hemoglobin (HbF) beyond infancy or who have co-inherited α-thalassemia mutations present with the phenotype of thalassemia intermedia. These patients may require red blood cell transfusions only occasionally, but typically develop skeletal changes and iron overload later in life because of marked erythroid hyperplasia. Recently, this clinical phenotype has also been referred to, probably inappropriately, as "non-transfusion dependent thalassemia" (NTDT).6
The mainstay of thalassemia treatment is red blood cell transfusion, accompanied by intensive iron chelation. While most patients will reach adulthood if well treated, both, quality of life and life expectancy are severely impaired by the complications of iron overload.7–9 If an HLA-matched stem cell donor is available, allogeneic stem cell transplantation as soon as possible and before iron overload develops is considered advisable.10–12 The economic burden of thalassemia is substantial especially in countries of high prevalence. The expenses for red blood cell transfusions and for iron chelation are estimated to exceed €30,000 annually for an adult patient.8,13
Patients with SCD always carry the HbS allele that codes for a valine instead of a glutamic acid residue at position 6 of ß-globin, either in a homozygous or a compound heterozygous state, and consequently express exclusively or predominantly sickle cell hemoglobin, HbS. Valine, a hydrophobic amino acid, at position 6 favors the polymerization of deoxygenated HbS and the formation of sickle-shaped erythrocytes. After the hemoglobin switch, when HbF is replaced by HbS during infancy, patients present with chronic hemolysis, acute vasoocclusive crises and a chronic vasculopathy that affects all organs.14 As is the case for ß-thalassemia, the severity of SCD is modulated by the expression of HbF and the co-inheritance of α-thalassemia. This modulation is most obvious in patients who carry, besides HbS, one allele of the ß-globin gene cluster that does not turn off the expression of HbF during infancy ("hereditary persistence of fetal hemoglobin", HPFH).15 As HbF efficiently interferes with the polymerization of HbS, these patients can show few or no symptoms of SCD.16 Further, pharmacologic induction of HbF is known to reduce the severity of SCD.17,18 However, it must be noted that even high levels of HbF do not consistently improve all complications of SCD.16,19
Without adequate medical care, most patients with SCD die during early childhood.20,21 With the use of prophylactic antibiotics, vaccinations, parent education, assessment for risk of stroke by transcranial Doppler ultrasound, red blood cell transfusions and hydroxycarbamide, more than 95% of patients reach adulthood.22,23 Nevertheless, the quality of life is severely impaired by painful vasoocclusive crises and chronic organ damage. Life expectancy, even with optimal care, is shortened by approximately two decades.24–28 During recent years, pharmacologic treatments targeting several pathophysiologic mechanisms of SCD have been developed and show clinically relevant effects.29–33 Although combinations of these drugs can potentially offer a chance for a meaningful reduction of SCD symptoms in many patients, they do not offer cure and need to be applied over many years or even for the entire life. Currently, the only curative treatment is allogeneic stem cell transplantation which is increasingly considered as "standard of care" if an HLA-matched sibling donor is available.11,34,35 Stem cell transplantation from alternative donors, that is matched unrelated or mismatched family donors, is associated with a high morbidity and even a mortality in the range of 10% and is reserved for selected patients with a severe course of SCD.36–38
Principles of gene therapy for the hemoglobinopathies
SCD and TDT are monogenic disorders and particularly amenable to gene therapy because the genetic defect needs to be corrected in hematopoietic stem cells giving rise to erythroid precursors only. With a history of allogeneic stem cell transplantation over more than 50 years,39,40 methods for the collection and manipulation of hematopoietic stem cells are readily available. Gene therapy41 offers the potential of cure for patients with TDT and with SCD even if no suitable stem cell donor is available and is not associated with the risk of Graft-versus-Host-Disease (GvHD). A tailored conditioning without the need for immunosuppression promises a reduced risk for short- and long-term toxicity in comparison to allogeneic stem cell transplantation.
Gene therapies for the hemoglobinopathies in clinical use or clinical development all rely on ex vivo manipulation of hematopoietic stem cells and resemble autologous stem cell transplantation (Fig. 1).42–44 Several conditions must be met for the cure of a hemoglobinopathy. First, a sufficient number of hematopoietic stem cells must be obtained and manipulated without damaging or reducing their capacity of engraftment, self-renewal, proliferation and differentiation. Second, the gene defect must be corrected in a large majority of stem cells. Third, the manipulated stem cells have to be given into an environment that promotes survival and long term expansion, requiring myeloablative conditioning. A characteristic of thalassemias is the limited maturation potential of erythroid precursors, conferring a selective advantage to those precursors whose genetic defect has been repaired by gene therapy. Such an effect was first demonstrated after allogeneic stem cell transplantation for thalassemia, when a proportion of 20% of all nucleated bone marrow cells suffices to produce exclusively donor-derived erythrocytes.45 However, this selective advantage is by far less pronounced as compared to that of corrected T-cells in severe combined immunodeficiency- one of the reasons, why historically immunodeficiencies were the first targets of gene therapy.46–48
Ex vivo gene therapy for hemoglobinopathies. Stem cells are mobilized by G-CSF and/or plerixafor (1) and harvested by leukapheresis (2). Alternatively, bone marrow without preceding mobilization can be harvested. Stem cells are enriched from the apheresis product by positive selection for CD34 (3). The vector is manufactured under GMP-conditions (4) and incubated with the purified stem cells (5). After the product has been subjected to rigorous quality controls and is released (6), the patient is treated with myeloablative chemotherapy (7). The manipulated stem cell product is applied either intravenously or intraosseously (8).
History of gene therapy
With the advent of recombinant DNA-technologies and the cloning of ß-globin as first human gene in the mid-70ies49 very early and, from today's perspective, premature attempts for gene therapy of thalassemia were made.50 Because major obstacles—efficiency, longevity, and safety of gene transfer into hematopoietic stem cells—could not be overcome at that time, gene therapy for thalassemia and SCD remained a hypothetical option that had not become reality for decades (Fig. 2).
Selected milestones of ex vivo gene therapy for hematologic disorders.
γ-retroviral vectors
A breakthrough for the clinical application of gene therapy has been the development of retroviral vectors. These vectors use the intrinsic capacity of retroviruses such as the Moloney Murine Leukemia Virus for efficient integration into the host genome and subsequent stable expression of viral genes. After the elimination of pathogenic sections of the viral genome, vectors derived from γ-retroviruses allow the transduction of hematopoietic stem cells and the expression of recombinant therapeutic genes in maturing and mature blood cells (Fig. 3). This revolutionary technique was first used for the treatment of inborn immunodeficiencies46–48,51,52 where already a low level expression of the therapeutic gene can correct the phenotype and where transduced cells acquire a selective advantage over cells that did not receive the therapeutic gene. In consequence, the first ex vivo gene therapy receiving marketing authorization in Europe in 2016 was that for ADA-SCID, a very rare severe combined immunodeficiency (SCID) caused by a deficiency of adenosine desaminase (ADA).53
Vectors used for gene addition. A: The vector used for the first clinical application of gene transfer into human hematopoietic stem cells.51 This vector was based on the Moloney murine leukemia virus. LTR- long terminal repeat, ψ+ extended packaging signal; ADA, human ADA cDNA; SV, SV40 early region promoter; NEO, neomycin resistance gene. The viral LTR sequencing mediate high-level expression of the transgene and genomic integration in the vicinity of transcriptionally active genes, resulting in the risk of oncogene activation. B: The self-inactivating lentiviral vector used for manufacturing of Zynteglo, the first approved gene therapy for ß-thalassemia.43,96 Hybrid LTR - hybrid long terminal repeat: the CMV enhancer and promoter replace the HIV U3 enhancer and promoter (allowing for Tat-independent translation), HIV R/U5 regions are preserved; ψ+ - extended packaging signal (carrying 2 stop codons to prevent readthrough from the CMV promoter); cPPT - central polypurine track (facilitates nuclear import of the viral preintegration complex); RRE – Rev responsive element (facilitates nuclear export of viral RNA in the packaging cell lines); I, II, III – human ß globin exons (the reverse orientation enables maintenance of the intron structure of the transgene; the Thr87Gln mutation confers anti-sickling properties without affecting hemoglobin function and enables tracking of therapeutic gene expression; a deletion in intron 2 is indicated by a triangle); HS2, HS3, HS4 – hypersensitive sites (HS) of the human ß-globin locus control region (stimulating ß-globin expression via looping to the ß-globin promoter); ppt – polypurine tract; ΔU3 – HIV LTR U3 region carrying a 400 bp deletion that results in self-inactivation after transduction (because the 3' UTR serves as template for both LTRs); R – HIV LTR R region (including viral polyA signal); pA - rabbit ß-globin polyA signal (as additional safety measure).
In parallel, trials for the treatment of other rare immunodeficiencies were at least partially successful in terms of cure of the underlying disorder.54–58 Although gene therapy proved to be safe and effective in ADA-SCID, the therapeutic gene has been demonstrated to preferentially integrate in proximity of oncogenes in several other indications.59–62 The genotoxic potential of retroviruses was most drastically illustrated by the first series of patients treated for Wiskott-Aldrich syndrome: Seven of nine patients developed leukemia,63 a complication that scotched the enthusiasm for γ-retroviral vectors.
The insertional mutagenesis by γ-retroviral vectors is caused by the preferential integration of the vector into transcriptionally active regulatory regions of the host genome that results in a selection of modified cells with an activated oncogene that stimulates proliferation.62–66 The selectivity for transcriptionally active regions und thus the risk for an oncogenic insertion is mediated by the retroviral "long terminal repeats" (LTR).67 Because of the potential for the induction of leukemias, γ-retroviral vectors are no longer in clinical use.
New self-inactivating (SIN) lentiviral vectors
Viral vectors that are used in current gene therapy approaches are derived from the human immunodeficiency virus (HIV) by deleting accessory virulence factors and regulatory genes from the viral genome. The envelope protein is exchanged by that of another virus (typically vesicular stomatitis virus- VSV) and expressed from a separate plasmid in the packaging cell line, as are the genes required for virus packaging, gag, pol, and rev. Deletions in the viral LTR preclude virus replication once the viral DNA is integrated in the host genome. The promoter function of the LTR is replaced by a constitutively active promoter that is independent from viral factors such as tat. Expression of the therapeutic gene is driven from the endogenous promoter and regulatory sequences.68–73 These self-inactivating (SIN) lentiviral vectors randomly integrate into the host genome without preference for regulatory regions.74 In addition, the loss of the LTRs limits their potential to activate genes in proximity of the integration site. With a vector copy number that typically reaches two to three per host genome, the risk of oncogene activation is statistically low, but cannot be completely excluded. In a growing number (>300) of patients treated for different genetic disorders in trials using lentiviral vectors, no malignancy related to lentiviral insertional mutagenesis has so far been detected.43,48,74–82 However, the number of patients treated for hemoglobinopathies with lentiviral gene therapy is still too low (approximately 10043,44,83–85) to be certain about the oncogenic risk in this specific indication.
Challenges in gene therapy for ß-hemoglobinopathies
Although self-inactivating lentiviral vectors offer an efficient and hopefully safe way of manipulating hematopoietic stem cells, a clinically successful gene therapy still requires an optimization of all steps (Fig. 1).
Historically, the first source of stem cells for gene therapy of hemoglobinopathies was bone marrow. However, hematopoietic stem cells obtained from bone marrow are limited in quantity, typically requiring two or more harvesting procedures.76,86 In addition, chronic inflammation may impede the potential of proliferation and transduction of bone marrow stem cells in patients with SCD.87 For these reasons, hematopoietic stem cells collected from the peripheral blood have replaced bone marrow as a cell source for gene therapy.
For patients with thalassemia, the protocols for the mobilization of hematopoietic stem cells resemble that of other indications. However, the cell numbers required for the manufacturing process are much higher in comparison to that required for an autologous rescue after high dose chemotherapy and mobilization by chemotherapy is not indicated for a benign disorder. For this reason, the combination of G-CSF with (off-label) plerixafor is used most frequently.43,44,88 Stem cells mobilized by this combination are readily transduced by lentiviral vectors and produce more ß-globin per gene copy as compared to stem cells mobilized by other regimens. The higher expression level of the therapeutic gene after mobilization with the combination of G-CSF and plerixafor in comparison to other mobilization regimens may be related to a preferential integration into transcriptionally active chromatin regions.89
For patients with SCD, however, G-CSF is contraindicated, because it can precipitate fatal vaso-occlusive crises.90,91 Therefore, (off-label) plerixafor has been used as the only mobilization agent92–94 and results in stem cells that are well suited for transduction and expression of the therapeutic ß-globin.89
The apheresis procedure needs to account for the particular sedimentation properties of blood cells in patients with hemoglobinopathies. In comparison to other indications, the stem cell fraction typically needs to be collected with a much higher admixture of erythrocytes.92
In order to revert the transfusion requirement in TDT by gene addition, transduced stem cells must be able to differentiate into a sufficient number of erythroid precursors that produce as much ß-globin as a healthy ß-globin locus would do. The number of vector copies per genome in the peripheral blood after gene therapy is correlated with the number of vector copies in the manipulated stem cells.43,44 Although the level of hemoglobin expressed from the therapeutic gene increases with the proportion of transduced stem cells in the cell product and with the resulting vector copy number in the peripheral blood, the characteristics of the cell product do not fully predict the success of the gene therapy. One vector copy per periphal blood genome appears to be sufficient to render the patient independent from red blood cell transfusions.43,44
For this reason, the ideal cellular product with the lowest possible risk of insertional mutagenesis would be characterized by one vector copy in each cell. Although the success of gene therapy is determined by several factors and cannot easily be predicted, the quantity of therapeutic ß-globin that is required to correct TDT is reduced if the patient carries at least one ß+-globin allele that allows for a residual expression of ß-globin. In this context, it must be noted that the quantity of residual ß-globin chain synthesis depends on the type of the ß+-thalassemia mutation and varies from less than 5% to more than 20%.89 In order to reach the optimal vector copy number with a near to complete transduction of all cells in the graft, the transduction procedure itself needs to be optimized.71,72 Parameters that can improve transduction efficiency are the viral coat proteins,95 the use of growth factors and of polycations such as protamine,96 and the ratio of vector to target cells. Consequently, the enrichment of hematopoietic stem cells by the use of cell surface markers can greatly reduce the amount of lentiviral vector required.97 Before the graft can be re-transplanted, stringent quality controls have to ensure successful gene transfer into the host genome, viability and sterility.
In contrast to severe immunodeficiencies, the corrected cells in the hemoglobinopathies only slightly benefit from a proliferative advantage in comparison to cells with the uncorrected genetic defect.45,98–100 This is why the myeloablative conditioning of the recipient is of paramount importance. Unlike allogeneic stem cell transplantation, gene therapy does not require immunoablation with serotherapy or lymphotrophic chemotherapy such as fludarabine or cyclophosphamide. In clinical trials, either busulfan42,43,76,101 or the combination of treosulfan with thiotepa44 was used. An earlier trial with submyeloablative busulfan did not succeed but was hampered by a relatively low transduction efficiency resulting in copy numbers of approximately 0.5 per cell in the cellular product.89,102,103
The acute toxicity of gene therapy is determined by the myeloablative conditioning and comparable to that of high dose chemotherapy with mucositis, bacterial infections, bleeding and sinusoidal obstruction syndrome.43 In addition, chemoconditioning results in long term sequelae, most importantly infertility and treatment-induced malignancies. The latter has rarely been observed within the first ten years after conditioning with busulfan for allogeneic transplantation, but is a major concern in the long term follow-up.104,105 In order to avoid the toxicities of chemotherapy, alternative ways of myeloablation are being tested preclinically. These employ the depletion of CD45+ or CD117+ precursors with toxic immune conjugates106–108 and promise complete myeloablation with minimal systemic toxicity.
Most patients with SCD suffer from chronic vasculopathy with the risk of vasoocclusive crises at the time of gene therapy. As with allogeneic stem cell transplantation, prophylactic measures such as exchange transfusion and anticonvulsive prophylaxis are necessary to reduce the risk of acute complications.109
As for allogeneic stem cell transplantation, stem cells corrected by gene therapy are usually applied intravenously.42,43,101 A mouse model suggests that a direct intraosseous application may result in a more efficient homing of stem cells. Although some patients were successfully treated by the intraosseous application of genetically modified stem cells,44 neither of these application routes has been demonstrated to be superior over the other in a controlled trial.
After the infusion of genetically modified stem cells, several weeks of bone marrow aplasia carry the risk of infections and bleeding before hematopoiesis is finally restored. The full expression of the therapeutic gene can be expected after 3 to 6 months and can be correlated with a reduction or, ideally, complete resolution of the transfusion requirement.43,44 A possible reason for the delay between application of the graft and full expression of therapeutic hemoglobin may be a selection for clones that most efficiently express the transgene. This clonal evolution of hematopoiesis derived from manipulated stem cells can be monitored by integration site analysis that demonstrates dynamic changes in the clonal composition even after years.43 Vectors that code for a ß-globin with an amino acid substitution allow for the quantification of the expression of the therapeutic gene in relation to endogenous ß-globin by hemoglobin separation.71,96 In addition, the physicochemical properties of the therapeutic ß-globin can be modified by amino acid substitutions to interfere with the polymerization of HbS. Similarly to an increased expression of HbF, the expression of such therapeutic ß-globins tackles the pathophysiology of SCD at the very root.110,111
Clinical results of "gene addition" for transfusion-dependent thalassemia and for sickle cell disease
A first patient treated with lentiviral gene addition for TDT in 2007 reached independence from transfusions, but showed clonal hematopoiesis likely caused by insertional mutagenesis which persisted for years.43,112 Subsequently, with vectors that were modified to reduce the risk of insertional mutagenesis, several trials demonstrated a success of gene therapy for thalassemia without inducing clonal hematopoiesis. Both made use of a lentiviral gene addition therapy, either with the vector BB30542,43,113 or the GLOBE vector.44 Most important predictors for the success of gene therapy were genotype and patient age.
The HGB-204 and HGB-205 trials run by bluebird bio reported that 12 of 13 evaluable patients with a non-ß0/ß0 genotype became independent from transfusions (median duration 38 months for HGB-204).43,83 The subsequent trial HGB-207 used an improved transduction procedure and reached independence from transfusions for at least 6 months in 10 of 11 patients.114 Based on these results, the European Medicines Agency conditionally licensed gene therapy by lentiviral gene addition (Zynteglo™) for patients with TDT aged 12 years or older and a non-ß0/ß0 genotype for whom no HLA-matched sibling is available as a stem cell donor.115
Treatment of TDT in patients with a ß0/ß0 genotype proved to be more difficult: In the HGB204 trial, transfusion frequency was reduced in all patients, but only four of eight evaluable patients reached complete transfusion independence.43,83 This suboptimal albeit promising result was attributed to an insufficient transduction efficiency with low vector copy numbers in the hematopoietic stem cells and to an insufficient proportion of transduced stem cells. While the follow-up is still too short to draw final conclusions, first results of the succeeding trial HGB-212 show that with an improved transduction procedure three of four TDT patients with a ß0/ß0 genotype were off transfusions for at least six months after gene therapy.116,117 It must be noted, however, that even patients who become transfusion independent following gene therapy may not have been completely cured. In a study of 8 such patients there was remaining, albeit improved ineffective erythropoiesis and a marker profile indicating disturbed iron homeostasis likely resulting in inappropriate iron resorption.118 Therefore, these patients may have to be monitored for extramedullary erythropoiesis and may still require (costly) iron chelation.
With the GLOBE vector, four of 6 children but none of 3 adults with TDT became independent from transfusions. However, only one of these patients had a non-ß0/ß0 genotype with relevant residual synthesis of endogenous ß-globin and was successfully treated. The authors attributed the difference between children and adults to a defect of the stem cell niche induced by long-term transfusions.44,119
In SCD, successful gene therapy must reduce the frequency and severity of vaso-occlusive complications such as pain crises or acute chest syndrome and ultimately prevent or even reverse end organ damage. Patients with compound heterozygosity for the HbS mutation and a second allele resulting in the persistence of γ-globin until adulthood are free of symptoms if all erythrocytes contain at least 30% of HbF.16 In analogy, a pancellular expression of a therapeutic ß-globin chain interfering with the polymerization of HbS to the same level is expected to blunt the symptoms and freeze progression of SCD.
This goal was partially reached in the first patient treated by gene addition with the lentiviral vector BB305.42,113 In further patients, however, the vector copy number and subsequently the expression of anti-sickling ß-globin did not suffice to clearly improve the complications of SCD.76,113 As for the TDT trials, the gene therapy protocol for SCD needed optimization at several levels. With the use of plerixafor for mobilization and improved technology for transduction, the most recently treated group of patients expressed approximately 6 g/dl of therapeutic hemoglobin, distributed in a pancellular fashion. As expected, with this expression level of the anti-sickling ß-globin, laboratory parameters for hemolysis normalized and the frequency of vasoocclusive complications was reduced.76,85,101
Gene therapy beyond gene addition
Besides "gene addition," several other strategies either aim at a direct repair of the pathogenic mutation or at neutralizing the pathogenic mutation by the introduction of genomic changes in trans (Fig. 4). While preclinical studies are far advanced, only very limited clinical experience with these techniques is available (Table 1).
Alternatives to gene addition for correction of hemoglobinopathies. A: In cells with active HDR (homology directed repair) double strand breaks introduced by nucleases can be repaired with the help of a template, resulting in the correction of pathogenic mutations.41 Because a specific template is needed for each mutation and because HDR is not active in hematopoietic stem cells, this approach is not in clinical use for the hemoglobinopathies. An alternative technique of direct correction of pathogenic mutations is "base editing" by deaminases that result in C to T or G to A changes in a sequence context defined by a guide RNA.122 While this technique does not require any endogenous DNA repair activity, it suffers from limited specificity and thus from off target effects. B: Induction of γ-globin expression by introduction of mutations that activate the expression of γ-globin as can be naturally observed in HPFH (hereditary persistence of fetal hemoglobin), presumably by abrogating BCL11A binding.130,131 C: Induction of γ-globin expression by disruption of an erythroid-specific BCL11A enhancer.132,136–138 Approaches B and C can be used for all ß-hemoglobinopathies and rely on non-homologous end joining or microhomology-mediated end joining that are active in hematopoietic stem cells. D: Induction of γ-globin expression by depletion of BCL11A via shRNA expressed from a lentiviral vector.93,133 E: Induction of γ-globin expression by forced chromatin looping mediated by a Zink-Finger/Ldb1-fusion protein expressed from a lentiviral vector.146 Approaches D and E can be used in principle for all ß-hemoglobinopathies and do not rely on endogenous DNA repair activity.
Active Clinical Trials for Gene Therapy of ß-hemoglobinopathies (https://www.clinicaltrials.gov, Accessed 09.04.2020, Filtering Criteria Were "Thalassemia OR Sickle Cell Disease" AND "Gene Therapy" AND "Recruiting OR Active/Non-recruiting").
A direct correction of pathogenic mutations (Fig. 4A) could be achieved by inserting a therapeutic DNA fragment with the help of homology-directed repair (HDR). However, the poor efficiency of HDR in hematopoietic stem cells precluded its use for gene therapy of hemoglobinopathies so far.120 Specific base editing can alternatively be achieved by expressing cytidine deaminases that are guided by small RNAs to a specific target sequence and result in C>T or G>A mutations.121,122 Due to restrictions in the targeting of the "base editors" to a target sequence and because of off-target effects, this technique has not been employed clinically so far.
While for SCD the direct repair of the underlying mutations appears attractive once the technical issues are solved, in TDT the direct repair of the underlying ß-globin mutations is cumbersome because more than 300 different mutations in the ß-globin gene resulting in a thalassemia phenotype would need to be addressed.
This is why all genome editing approaches that are currently being developed do not target the ß-globin gene but aim at the re-activation of the γ-globin gene and at the expression of HbF. Despite the difference in oxygen affinity when compared to HbA, HbF is a fully functional globin chain even in adult life and can replace the lacking HbA in ß-thalassemia.15 HbF can prevent or limit the polymerization of deoxygenized HbS in SCD, offering a therapeutic target for both ß-hemoglobinopathies. Patients with hereditary persistence of fetal hemoglobin (HPFH) demonstrate that HbF can substitute for HbA without major functional limitations15 and protect from polymerization of HbS if co-expressed with the HbS mutation.16 Such an indirect strategy of modifying globin synthesis thus carries the potential of curing both TDT and SCD,123,124 although cure of ß-thalassemia by this strategy will require a more pronounced reactivation of γ-globin chain synthesis than will likely be required for SCD.
The techniques used for genome editing in hematopoietic stem cells do not aim at reverting or introducing a specific mutation, but rather at the inactivation of certain DNA sequences. Such an inactivation can be achieved in a sequence-specific manner without the need for endogenous homology-directed repair activity by the CRISPR/Cas9 system. The CRISPR/Cas9 system is making use of prokaryotic enzymes that recognize and degrade DNA sequences introduced into bacteria by bacteriophages.125,126 Specific guide RNAs recruit the endonuclease Cas9 to specific sites of the genome, where Cas9 introduces double strand breaks that will be repaired by nonhomologous end joining (NHEJ). Imprecisions in the repair process result in small insertions or deletions that inactivate the target gene.127,128 An alternative technique of introducing targeted double strand breaks into DNA involves nucleases that directly bind to the target sequence without the need of a specific guide RNA. Double strand breaks introduced by such Transcription Activator-Like Effector Nucleases (TALEN) or by Zink finger enzymes inactivate the respective gene as do double strand breaks introduced by Cas9.129
Several strategies employ genome editing to boost HbF expression, most directly by the introduction of activating mutations in the γ-globin promoter that abrogate binding of postnatal repressors (Fig. 4B).130,131 The most frequently modified target of genome editing for the ß-hemoglobinopathies is BCL11A. BCL11A encodes a transcription factor that is required to turn off γ-globin expression during the perinatal hemoglobin switch. Inactivation of BCL11A in erythroid precursors results in an increased synthesis of HbF.132–134 Similarly, disruption of the interaction of LRF, another transcription factor promoting the hemoglobin switch, with the γ-globin promoter induces HbF expression.135
BCL11A can be specifically inactivated (Fig. 4C) in erythroid cells by targeting a TALEN nuclease136,137 or a CRISPR/Cas9 nuclease132 against a lineage specific enhancer of BCL11A. This lineage specificity138 is important, because BCL11A is not only crucial for erythroid, but also for lymphoid139 and neuronal140 differentiation. If BCL11A is disabled in erythroid precursors derived from edited hematopoietic stem cells, there is a robust induction of HbF.132,136,137 Very first patients with TDT and with SCD were treated with a CRISP/Cas9-mediated inactivation of BCL11A (Table 1, NCT03745287 and NCT03655678). While follow up is short and numbers small, preliminary results are encouraging.141 Similarly, disruption of BCL11A in hematopoetic stem cells by Zink finger nucleases resulted in HbF induction both in erythroid cells and in first patients with TDT who received these stem cells.142,143
Another way of inducing HbF by repressing BCL11A makes use of the expression of short hairpin (sh)RNAs that are introduced into hematopoietic stem cells by a lentiviral vector (Fig. 4D). By specific hybridization to and degradation of the target mRNA, these shRNAs downmodulate the expression of their target gene. Inducing HbF by downmodulating BCL11A in hematopoietic stem cells by shRNA is currently explored as treatment of SCD.133 Preliminary results of this "transcriptome editing" approach in three patients with SCD who were followed at least 6 months after gene therapy showed a lineage-specific induction of HbF and an improvement of hemolysis.93
Yet another alternative to "genome editing" is the expression of an engineered fusion protein between Ldb1 and a Zink finger protein from a lentiviral vector (Fig. 4E) that forces the ß-globin locus control region into proximity of the γ-globin gene. As a result, HbF expression is reactivated and exceeds that of HbS in vitro144–146—a situation compatible with cure of SCD if achieved in vivo.
A combination of more than one of the mentioned strategies would have the potential to optimize the expression of a therapeutic gene product. Such a combination may for instance include the expression of ß-globin via lentiviral gene addition and at the same time repressing BCL11A via shRNAs encoded by the same vector and could result in a success rate that robustly outperforms that of allogeneic stem cell transplantation.147
The current standard of care for TDT and SCD is a disease modifying treatment with red blood cell transfusions, iron chelation and pharmacologic induction of HbF that needs to be combined with the treatment of symptoms and complications. Recently, additional treatments for TDT that aim at improving the survival of erythroid precursors have emerged.148 However, the only established curative option is allogeneic stem cell transplantation that, depending on patient age and the type of donor, is associated with relevant morbidity including graft versus host disease, infertility and other long term complications.104,105 While transplantation from an HLA-matched sibling is widely accepted as standard of care, for most patients such a donor is not available and transplantation from alternative donors still carries a risk of treatment-related mortality of 10% or higher that is considered not acceptable for non-malignant disorders.34,37,109,149
Gene therapy bypasses two of the most relevant shortcomings of allogeneic transplantation—limited donor availability and risk of GvHD—while possibly offering cure in 80% of patients with TDT with a non-ß0/ß0 genotype. So far, no treatment-related mortalities have been reported after gene therapy for hemoglobinopathies. These results have led to the licensing of the first gene therapy for transfusion dependent thalassemia in Europe and offer the chance to assess the potential of gene therapy under real world conditions and in a larger number of patients.
Two major obstacles currently preclude the widespread use of gene therapy. First, current protocols still require myeloablative conditioning. Even if in comparison to allogeneic stem cell transplantation the cumulative dose of chemotherapy is reduced, long term sequelae such as infertility and the risk of secondary neoplasms will likely remain a challenge. Second, the sophisticated logistics and the costs of gene therapy150 limit its use in patients and health care systems with sufficient resources while prohibiting its use in countries with a high prevalence of hemoglobinopathies which cannot provide the required infrastructure and resources. Obviously, the development of conditioning regimens with reduced toxicity and lowering the costs of gene therapy are the most important steps required to bring this treatment options to more than a small number of selected patients.
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Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.
HemaSphere4(5):e479, October 2020.
Articles in PubMed by Joachim B. Kunz
Articles in Google Scholar by Joachim B. Kunz
Other articles in this journal by Joachim B. Kunz
the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.


He was more famously the founder of the Army of Conde which fought against the French Republic after the Revolution.
3) Lt-General duc de Sourches. I have not been able to find out much about this chap.
although he was quite active in the WAS he was getting quite long in the tooth by the SYW.
The last pictures shows some brigade commanders (Marechal de camp) although one of them, Rougrave, wears the yellow/blue of his cavalry regiment.
Nothing like lots of officers, in addition to colorful units, to enliven the tabletop.
Good stuff Nigel- keep up the good work.


The Beacon Hill Fabric Eva Velvet White is 56 inches wide and contains 57% Viscose, 43% Cotton. It is sampled in Velvet Textures and the pattern repeat size is Horizontal: - and Vertical: - and is manufactured in INDIA.
This item is offered in the following store categories: Beacon Hill, Linen, Upholstery, Drapery, Velvet, Cotton, White, Texture.


text:
Book Series Catalogue of Early Netherlandish Painting: Royal Museums of Fine Arts of Belgium, vol. 2
The Flemish Primitives II
Bouts-Christus-Memling-Goes
C. Stroo, P. Syfer-d'Olne, A. Dubois, R. Slachmuylders
Language(s):English
€ 100,00 EXCL. VAT RETAIL PRICE
In this volume, a wealth of documentation is presented on fifteenth century southern Netherlandish paintings in the Royal Museums of Fine Arts of Belgium in Brussel, containing colour reproductions, analyses and other visual documentation.
Libraries & Archives : history & collections
Low Countries (c. 500-1500)
Medieval painting
"With its wealth of clearly presented technical information on the paintings, its very knowledgeable discussions of the subjects represented and of questions of attribution and date, this volume is, like the first, a valuable addition to the literature on early Netherlandish painting."
Jeltje Dijkstra, in: The Burlington Magazine, nov. 2000
The publication of the second in a five-volume scholarly catalogue of the 15th-century Southern Netherlandish paintings in the Royal Museums of Fine Arts of Belgium in Brussels is a long awaited event not only in Belgium but troughout the art world. The museums' rich collection of Flemish Primitives boasts paintings by Rogier van der Weyden, Gerard David, Petrus Christus, Dirk Bouts, Hans Memling and Hieronymus Bosch. It also includes several important works by artists with provisional names from the Schools of Tournai, Bruges and Brussels, such as th Master of Flémalle, the Master of the St Lucy Legend and the Master of the Life of Joseph. This multi-volume English-language catalogue will include approximately 100 paintings. Each work is the subject of a thorough analysis covering technical, iconographical and stylistic aspects. Information is drawn from documents in the Institut royal du Patrimoine artistique/Koninklijk Instituut voor het Kunstpatrimonium and the Centre international d'étude de la peinture médiévale des bassins de l'Escaut et de la Meuse/ Internationaal Studiecentrum voor de Middeleeuwse Schilderkunst in het Schelde-en Maasbekken. The project was made possible by the Federal Prime Minister's Office for Scientific, Technical and Cultural Affairs which created an interuniversity research network in collaboration with federal scientific and cultural agencies. Launched in 1993, the project benefits from the cooperation of three institutions: the Royal Museums of Fine Arts of Belgium (Eliane De Wilde), the Université catholique de Louvain (Roger Van Schoute) and the Katholieke Universiteit Leuven (Maurits Smeyers). The entries were written by four art historians, Cyriel Stroo, Pascale Syfer-d'Olne, Anne Dubois and Roel Slachmuylders, and the infrared reflectography was performed by Freya Maes. The catalogue contains colour reproductions of all the paintings as well as other visual documentation from laboratory investigations, photographs of related works and diagrams of original frames.
The Flemish Primitives I View publication
The Flemish Primitives V View publication
The Flemish Primitives VI View publication
The Flemish Primitives IV View publication


People may not want to have money on their mind all the time, yet no one can deny how important it is. Of course, most people simply turn to work or side hustles to supplement their income and ignore other ways to make money like old smartphones.
Yes, those devices collecting dust in some forgotten drawer can provide cash in some of the following ways.
One of the most interesting ways to make some extra cash using old phones is using apps that pay you. You have probably heard of this concept before and probably thought it was too good to be true. Sure, there are some apps that do not pay much while some offer something worthwhile. The best part is that some apps allow you to earn income passively, meaning that you do not really have to sit there playing with your phone all day just to make extra bucks.
Now, do not expect to make millions, but you will be making a little extra cash each month and any little bit helps. The only trouble is finding the apps that work for you. One of the more popular apps that you can use to earn some cash is SlideJoy. This app plays little ads on your lock screen.
You are given a few cents a day for looking at these ads before entering your phone's menu. This app can be installed on a couple of phones, meaning that you'll be earning more than a few cents per day, which should add up given enough time. There are other options for you like Perk and Swagbucks, so go ahead and start hunting.
Making money by using smartphone apps is definitely a great idea, but there are a number of reasons why that approach will not work out for some. Sometimes, your phone is so old that the apps are not compatible with it. Other phones run on an operating system that is not compatible with the apps you need. Some people may have phones that so beat up that they do not turn on like they used to.
Do not fret about this; you can still make money off of your old phone if you simply look at sites that are hungry for used cell phones for sale. The right site can match your smartphone with a willing buyer. Sure, you will not be making passive income like you might have using some of the tools mentioned earlier, but at least your smartphone gave you one last cash bump.
Like any business transaction, there are a few things you should do if you are going to sell your smartphone. For example, you should definitely do your research to find out how much people are willing to pay for your phone in the condition it is in. It may also be a great idea to find out if it is smarter for you to sell the phone piece by piece or as a whole. You may be able to make more if you sell piece by piece though there will be times when it will be better for you to sell as a whole.
These are just some of the steps you can take to make some extra cash using old phones. Those old devices weren't making any money before, so go ahead and give these suggestions a try even if they seem tedious. You will be happy to have that extra cash in your pocket, and you'll be getting rid of clutter if you do decide to sell.


For our Valentine's Day edition, we asked community members to share their love stories with our readers. And you rose to the occasion, with stories ranging from a random motorcycle ride that turned to love, a first-date marriage proposal and relationship that bloomed from a delicate situation on the ski slopes. To mark this special day, we've chosen a few of our favorite vignettes that illustrate what most Villagers already know: Love is ever-blooming in Laguna Woods Village.
A boyfriend had given me a blue motorcycle helmet, which was strange because I wore pink leathers. A blue helmet didn't match. Turned out to be the best present ever.
Fast forward two years, sans helmet-giving boyfriend. I'm living in Laguna Woods Village. I was out for a walk one sunny day when I saw a fellow washing his motorcycle. His blue motorcycle.
As I walked by him and his blue bike I said, "If you ever want a passenger, I have my own helmet." I didn't even stop, just said it as I walked by. A couple weeks later he was riding the bike, saw me out walking, and followed me home.
That was 10 years ago. Robert and I are still riding a (newer) blue Yamaha FJR 1300 motorcycle.
The David Hartman and Sunshine Lutey saga is a true Village love story. Both long-time residents, David and his first wife, Phyllis, came to the Village in 1994; Sunshine and Lloyd, her first husband, arrived one year later. David and Lloyd became golf buddies.
Early in 2005, after 53 years of marriage, David lost Phyllis to catastrophic illness; a few months later, Sunshine lost Lloyd, her husband of 43 years. In 2006, David and Sunshine discovered a life together filled with love, travel, golf and music. In 2008, they married. They planned and performed in musical events for various charities and with friends and many talented entertainers from the Village formed the Sunshine Performance Club. They produced 20 major shows in the 10 years from 2008 through 2017 in both Clubhouses Three and Five and donated well over $100,000 to charity. In 2018, they switched to smaller productions. They continue to perform in weekly adult day care shows, which began in February 2015. The couple is thrilled that serendipity brought them together and continues to play a large part in their lives, filled with love, happiness and music; they plan to share the joy of music as long as possible.
I met the boy next door at 17, in Pasadena. Ted just got out of the Navy, and every time passed by his house, he would whistle at me. We finally met and before you knew it, we dated and were married in 1960. He was a handsome Greek boy and we were married for 51 1/2 years. I use to have a shop In Laguna called Cupids Corner because my husband thought I looked like a Cupid when I was younger. Later we opened a bed and breakfast called Cupids Castle in north county San Diego, where I was a minister. I would marry 150 couples. I even found husbands for my sisters and daughter. My sweet husband died seven years ago in the Romeo And Juliet room at the castle and now I'm here in Laguna Woods. A real true love story. Cupid is still alive in Laguna Woods, and if you want to get married. I can do it for you. Everyone knows me as Cupid. I really miss my Ted, and my heart belongs to him, I will always love my teddy bear.
Was it our first unexpected meeting at the California Club dinner dance? He smiled at me and then asked if he could buy me a glass of wine. On the return to the dinner table, he asked me to dance. He said he like the black stockings I was wearing. Or was it our first date at Clubhouse Five to watch the Super Bowl game? I invited him to dinner that same day. We are celebrating the third anniversary of both; we have since married and having as much fun as when it all began. We both enjoy golf, dancing, cooking, watching sports and traveling. He is such a romanticist, and I know I won't be disappointed with his Valentine's gift.
A magnificent crow landed in the palm tree right in front of the hospital window. I was sitting beside my husband gazing out the window; he was in intensive care after lung cancer surgery.
Soon the crow's partner followed and landed gracefully beside him. They sweetly cawed to one another. Next, they groomed each other using their beaks like delicate fingers. Then they cuddled into each other's wings to soft cooing and shut their eyes as the sun set.
I've read crows mate for life and that they are among the most intelligent creatures on our planet. But that day, and into the night they transported their love right through that window, to us.
When they awakened they flew off, wing to wing, I knew then the love of my life would be alright and it made me wonder where love begins and does it ever end?
When my husband's birthday came I was still feeling the crow glow and so I drew him a pair of doves cuddling in each other's wings. I didn't need to tell him their story – he already knew it.
I met my Nancy in 1959 at the Merry-Go-Round Restaurant. One night I was there when this cute little redhead walked in. My buddy bet me I couldn't get a date. I offered her a ride. As she left the car, I grabbed her wrist and we talked until her curfew. We were inseparable for the entire year. After graduation, Nancy stayed in Florida and I moved to St. Louis to work in my family's meatpacking business, before the Army. When I came out in 1964, I called her, and it was as though we had never been apart. So I flew to Miami and we got married.
We met when my sister and her boyfriend asked me to go with them to a Young Singles Dance. About one hour into the start of the dance, a young man asked if I would dance with him. Our conversation revealed that we both lived in the same Brooklyn, New York, neighborhood. Later, Chuck offered to drive me home. My intuition was that he truly was a gentleman. Mid-week, Chuck called and asked me out for a date. That first date went well; we went to various venues, restaurants, movies. He even obtained tickets to The Ice Capades. I was impressed.
After a few dates, we realized that we were of different religions. I, a devout Catholic; he, Jewish. His parents did not approve. Soon we were talking about marriage. Chuck asked my parents, who did support us. We were blessed to find a rabbi who helped in my conversion to Judaism. It was explained to us that this would be the best way to put our marriage on a firm foundation. We had a beautiful wedding ceremony on Nov. 23, 1969. Once grandchildren came into the picture, Chuck and his parents reconciled and entered into the family dynamic.
We are happy to share our love story. Each day is Valentine's Day!
We went on our first skiing trip as freshmen at the University of Colorado, on Thanksgiving vacation in 1950. Upon reaching the top of the lift, I skied off of the chair where I stopped, bent over to adjust my boot and heard that dreaded split sound as the strain was too much for the threads in the seat of my pants. A nice guy came off behind me and offered me his ski sweater to wrap around my waist. We spent the entire day skiing together. Little did we know that we would be spending 69 more years together, joined at the hip.
He was funny, cute and a good skier. As he has reiterated through the years, "Her face wasn't the first thing I saw." With his canted sense of humor, I have seen grown men cry with laughter at Al. But along with those characteristics, his kindness and loving nature still exist in spite of a bit of a memory loss. What a great life we have had together. He was and will always be my Valentine.
When someone asks how we met I tell them I picked Gary up on the tennis court.
We both played tennis at the Pacific Palisades Park. I was a young mom going through a divorce. I thought he was very attractive and a really good tennis player, but the few times I called his home on tennis club business a woman answered. I assumed he was married or had a girlfriend. Then someone mentioned he was a bachelor father. His daughter was 17 and graduating from high school. I asked him to play in the club mixed doubles tournament and he said yes. We made plans to practice the next day. I was an hour late and he almost didn't wait. But we hit the ball for a while and I asked him back for dinner, and that is how it all began. And we won the tournament!
My co-worker, Betty, was asked out on a date by Dr. Bill. Betty agreed on the condition that it be a double date that included me.Several days later, Dr. Bill told me that he had "the perfect man" for me to meet on this blind date. Really? How many times had I heard that phrase?
The next week, the four of us met at Betty's apartment in Manhattan. We then set out in Jerry's VW Beetle (a car the size of a four-person bathtub). We went on to a French restaurant known for its excellent cuisine and low prices — just get there early to avoid long wait lines. Next, on to a play (Equity Actors, and pass the basket for donations at the end of the performance). Jerry and I had a wonderful evening, sharing many common interests. He told me that I was perspicacious. I looked up the definition immediately after I was home.
Three weeks later, after several enjoyable meetings, I received three Valentine cards: one from "Elvis," one from "unknown admirer," and one from Jerry. Ten months later we were married!
The beat goes on — we shared almost 60 years of love and friendship.