All Activity

Solenn Heussaff, actress, model, singer and YouTube influencer (1m followers) has announced the birth of her second daughter. Solenn has compared her two pregnancies, and revealed that she had issues with her Protein S both times. https://entertainment.inquirer.net/478411/watch-solenn-heussaff-looks-back-on-pregnancy-journey-with-second-child

https://ash.confex.com/ash/2022/webprogram/Paper171707.html LBA-5 Low-Molecular-Weight Heparin Versus Standard Pregnancy Care for Women with Recurrent Miscarriage and Inherited Thrombophilia (ALIFE2): An Open-Label, Phase III Randomized Controlled Trial Tuesday, December 13, 2022, 9:00 AM-10:30 AM Siobhan Quenby, MD PhD1*, Katie Booth2*, Louise Hiller, PhD2*, Arri Coomarasamy3*, Eva Hamulyák, MD4*, Luuk Scheres5*, Paulien G. de Jong4*, Thijs van Haaps4*, Lauren J. Ewington2*, Shreeya Tewary2*, Mariëtte Goddijn, MD PhD4* and Saskia Middeldorp, MD, PhD6,7 Background Studies have shown an association between recurrent miscarriage and inherited thrombophilia. It has been hypothesized that anticoagulant therapy might reduce both number of miscarriages and adverse pregnancy outcomes in these women and this is widely practiced despite lack of solid evidence. In the absence of randomized controlled trials that assess the efficacy of low-molecular-weight heparin (LMWH) therapy in women with recurrent miscarriage and inherited thrombophilia, a randomized clinical trial that addresses this topic was highly needed. Results Between August 2012 and January 2021, 10,626 women with recurrent miscarriage were assessed for eligibility, most of whom were not eligible due to absence of inherited thrombophilia. A total of 428 women were registered, of whom 326 women conceived and were randomized. 164 were assigned to the LMWH group and 162 were assigned to the standard surveillance group. The mean age was 33 years, approximately one third being 36 years or older, and the majority was of caucasian ethnicity (83%). The median number of miscarriages prior to randomization was 3, and 70% had a history of 3 or more miscarriages. The most common thrombophilia types were heterozygosity for factor V Leiden (56%), prothrombin 20210A mutation (25%), and protein S deficiency (14%). Aspirin was used as co medication in 11%. Observed live birth rates were 116/162 (71.6%) in the LMWH group and 112/158 (70.9%) in the standard surveillance group (adjusted OR 1.08 (95% CI 0.65 to 1.78)(absolute difference 0.7% (95% CI -9.2% to 10.6%). Adverse events were reported for 39 women (23.8%) in the LMWH group and 37 (22.8%) women in the standard surveillance group. Interpretation Compared with standard surveillance, the use of LMWH did not result in higher live birth rates in women who had two or more pregnancy losses and confirmed inherited thrombophilia. On the basis of our findings, we do not advise routine use of LMWH in women with recurrent pregnancy loss and confirmed inherited thrombophilia, and we advise against routine testing for inherited thrombophilia in women with recurrent pregnancy loss.

https://endpts.com/a-new-vega-enters-the-galaxy-with-bleeding-disorder-antibody-set-for-2023-trial/ “We view these thousands of rare diseases almost like stars in the night sky. Individually, the vast number of stars seems overwhelming, but if you group them together, like constellations in the sky,” Rosenthal said, “we find that diseases that share a common path of biology can be treated potentially in the same way using a single therapy.”

https://www.businesswire.com/news/home/20221206005337/en/Vega-Therapeutics-launches-and-unveils-its-first-in-class-antibody-therapy-for-von-Willebrand-disease-at-ASH-Annual-Meeting Vega Therapeutics is a clinical stage biotechnology company developing novel, first-in-class therapies for rare blood disorders with overlooked patient needs, starting with von Willebrand disease (VWD). Von Willebrand disease (VWD) is a bleeding disorder in which the blood does not clot properly. On December 12th at the ASH Annual Meeting in New Orleans, Vega will describe VGA039’s novel mechanism of action as a monoclonal antibody that modulates Protein S - a key cofactor involved in thrombin generation during both initiation and propagation of coagulation. The presentation will also cover in vitro data demonstrating efficacy of VGA039 in numerous congenital bleeding disorders, including VWD, and the pharmacokinetics of VGA039 following intravenous (IV) and subcutaneous (SC) administration. By promoting thrombin generation through targeting Protein S, VGA039 is mechanistically well suited to overcome VWD pathophysiology, and as a subcutaneously self-administered antibody therapy, has potential to transform VWD treatment.

FMRP – the protein behind immunotherapy resistance By Jim Cornall https://www.labiotech.eu/trends-news/fmrp-protein-behind-immunotherapy-resistance/ Immunotherapy is a cutting-edge approach to treating cancer by turning the patient’s own immune system against their tumor. Despite success rates, immunotherapy has time and again met with a stubborn obstacle: tumor cells often evade the “radar” of immune cells seeking to destroy them. This in turn leads to treatment resistance, which in many cases would benefit from a deeper understanding of mechanisms that can help circumvent it. A new study led by scientists at Swiss university EPFL has now uncovered a protein that plays a key role in helping tumors evade immune destruction. The protein, fragile X mental retardation protein (FMRP), regulates a network of genes and cells in the tumor microenvironment that contribute to its ability to “hide” from immune cells. Normally, FMRP is involved in regulating protein translation and the stability of mRNA in neurons. But the researchers found it is up-regulated in multiple forms of cancer. The study, published in Science, was led by researchers in the group of Douglas Hanahan at the Swiss Institute for Experimental Cancer Research (ISREC) and the Lausanne Branch of the Ludwig Institute for Cancer Research, along with colleagues from the University Hospital of Lausanne (CHUV) and other Swiss institutions. The discovery has also led to an EPFL spin-off, Opna Bio, whose staff were also involved in the research. FMRP But why FMRP? The idea came from previous studies showing that cancer cells that naturally overexpress FMRP are invasive and metastatic. Other studies show that if, in contrast, FMRP fails to be expressed in developing neurons it can lead to cognitive defects (hence the “mental retardation” part of the protein’s name). With this evidence in mind, the researchers investigated the expression of FMRP in human tumors. They then assessed its tumor-promoting functions in mouse models of cancer, and finally studied its association with prognosis for human cancer patients. The study involved several data-gathering steps. First, the scientists performed immunostaining for FMRP on tissue from human tumors. The majority of the tumors tested positive, while corresponding normal tissue did not. This showed FMRP is specifically and highly expressed in cancer cells. The team then moved onto the main part of their research, which was to determine the functional significance of FMRP in those tumors –they express the protein, but what does it do? FMRP and the immune system To explore this, the scientists developed lines of “knockout” cancer cells. Knockout cells or organisms are genetically engineered to lose – “knock out” – a specific gene in order to find clues about its function. Essentially, whatever change occurs in knockout cells compared to cells that still have the gene – called “wild-type”– can generally be traced back to the missing gene. In this case, the scientists used CRISPR-Cas9 gene-editing to knock out the gene FMR1, which produces FMRP in mouse cancer cells arising from pancreas, colon, breast, and skin melanocytes. They then compared the FMRP-knockout cancer cells to cancer cells that still had the FMR1 gene and thus expressed the FMRP protein. The researchers evaluated survival rates between mice with tumors containing FMRP-knockout cancer cells and those with FMRP-wild-type cells, first in mice whose immune systems had been compromised. The comparison revealed similar survival rates. In contrast, when they compared the knockout tumors to wild-type tumors growing in mice with properly functioning immune systems, they found that tumors without FMRP were growing more slowly, and the animals survived longer. This showed FMRP is not involved in stimulating tumor growth per se, and rather implicated the adaptive immune system (the part of the immune system that is “trained” with vaccines). This was further confirmed by the observation that wild-type tumors had very few infiltrating T lymphocytes, whereas knockout tumors were highly inflamed. Depleting T cells from the FMRP-knockout tumors caused them to start growing more rapidly and reduced the survival rates of the mice, meaning that FMRP is somehow involved in tumors evading the immune system. How tumors with FMRP defend against immune cells The team continued with molecular genetic profiling of both knockout and wild-type tumors. This revealed significant differences in gene transcription across the entire genome, suggesting that FMRP interacts with multiple genes. In addition, the tumors showed marked differences in the abundance of cancer cells, macrophages, and T cells, further implicating the role of FMRP in modulating components of the immune system. The next phase of the study looked at the production of specific factors associated with the distinctive immune responses – evasion versus attack. The tumors expressing FMRP were found to produce interleukin-33, a protein that induces the production of regulatory T cells, a specialized subpopulation of T cells that inhibit immune responses. They also produce protein S, a glycoprotein known to promote tumor growth. Finally, the tumors produce exosomes – cell organelles that triggered the production of a type of macrophage cell that normally helps with wound healing and tissue repair. All three factors are immunosuppressive and contribute to the tumor’s barrier against attacks from T lymphocytes. In contrast, the FMRP knockout tumors cells actually downregulated all three factors (interleukin-33, protein S, and exosomes) while they up-regulated a different chemokine, C-C motif chemokine ligand 7 (CCL7), which helps recruit and activate T cells. This process is further aided by inducing immunostimulatory (and not immunosuppressive) macrophages. These cells produce three other proinflammatory proteins that work with CCL7 in recruiting T cells. Predicting immunotherapy outcomes in human patients In a clinical context, the question is whether levels of FMRP can help form a prognosis for patients undergoing immunotherapy. Counterintuitively, both mRNA of the FMR1 gene and FMRP protein levels were insufficient for predicting outcomes in cohorts of cancer patients. To address this, the researchers built on the fact that, in the cell, FMRP up- and down-modulates the stability of mRNA by binding it directly. This means FMRP might change RNA levels that could be picked up in transcriptome datasets, which could be collected to define a “gene signature” to help track its functional activity. The approach worked, allowing the scientists to track a gene signature of FMRP’s cancer regulatory activity with a network of 156 genes. The FMRP cancer network activity signature proved to be prognostic for poor survival across multiple human cancers, consistent with the immunosuppressive effects of FMRP, and, in some patients, it was linked to poor responses to immunotherapy treatments. The work shows that FMRP regulates a network of genes and cells in the tumor microenvironment, all of which help tumors to evade immune destruction. Hanahan said: “Having studied the complex cellular composition of solid tumors for decades, I am personally astonished by our discovery that a co-opted neuronal regulatory protein – FMRP – can orchestrate the formation of a multi-faceted protective barrier against attack by the immune system that consequently limits the benefit of immunotherapies, thereby presenting FMRP as a new therapeutic target for cancer.”

Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion https://www.science.org/doi/10.1126/science.abl7207 Many human cancers manifest the capability to circumvent attack by the adaptive immune system. In this work, we identified a component of immune evasion that involves frequent up-regulation of fragile X mental retardation protein (FMRP) in solid tumors. FMRP represses immune attack, as revealed by cancer cells engineered to lack its expression. FMRP-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, FMRP’s immunosuppression was multifactorial, involving repression of the chemoattractant C-C motif chemokine ligand 7 (CCL7) concomitant with up-regulation of three immunomodulators—interleukin-33 (IL-33), tumor-secreted protein S (PROS1), and extracellular vesicles. Gene signatures associate FMRP’s cancer network with poor prognosis and response to therapy in cancer patients. Collectively, FMRP is implicated as a regulator that orchestrates a multifaceted barrier to antitumor immune responses. INTRODUCTION Cancer biology and therapy have been transformed by knowledge about immunoregulatory mechanisms that govern adaptive immunity. Although some forms of treatment resistance are related to the intentionally transitory operations of the adaptive immune system, others reflect more subtle requirements to modulate the immune system in different contexts. In this work, we identified an immunoregulatory mechanism involving the neuronal RNA binding protein fragile X mental retardation protein (FMRP), which broadly regulates protein translation and mRNA stability and is aberrantly up-regulated in multiple forms of cancer. RATIONALE This study was motivated by reports that cancer cells naturally overexpressing FMRP, whose loss of expression in developing neurons causes cognitive defects, were invasive and metastatic. We investigated the expression of FMRP in human tumors, further assessed its tumor-promoting functions in mouse models of cancer, and evaluated its association with prognosis for human cancer patients. RESULTS When human tumor tissue microarrays were immunostained for expression of FMRP, a majority of tumors expressed FMRP, whereas cognate normal tissues did not. To investigate the functional significance of this broad up-regulation, the FMR1 gene was ablated through CRISPR-Cas9 gene editing (FMRP-KO, where KO indicates knockout) in mouse cancer cell lines that were inoculated into both immunodeficient and syngeneic immunocompetent mice to establish tumors in parallel with wild-type (WT) FMRP-expressing cell lines. Mice bearing FMRP-KO tumors had similar survival compared with isogenic WT tumors in immunodeficient hosts, indicating that FMRP was not involved in stimulating tumor growth per se. By contrast, tumor growth was impaired and survival extended in immunocompetent hosts, implicating the adaptive immune system. Indeed, FMRP-expressing WT tumors were largely devoid of T cells, whereas FMRP-KO tumors were highly inflamed. Depletion of CD8 and CD4 T cells restored tumor growth and reduced survival, implicating FMRP in immune evasion in WT tumors. WT and FMRP-KO tumors were profiled by single-cell RNA sequencing, revealing marked differences in genome-wide transcription and abundance of cancer cells, macrophages, and T cells. To elucidate the effects of this multifaceted regulatory protein, we performed several functional perturbations, revealing that: FMRP-expressing cancer cells produce the chemokine interleukin-33 (IL-33), which induces regulatory T cells, as well as tumor-secreted protein S (PROS1) ligand and exosomes that elicit tumor-promoting (M2) macrophages. Both cell types are immunosuppressive, collectively contributing to the barrier against T cell attack. By contrast, FMRP-KO cancer cells down-regulate all three factors and up-regulate C-C motif chemokine ligand 7 (CCL7), which helps recruit and activate T cells. Additionally, immunostimulatory macrophages develop in this context that express three proinflammatory chemokines—CCL5, CXCL9, and CXCL10—which cooperate with CCL7 in recruiting T cells. Finally, neither FMR1 mRNA nor FMRP protein levels were sufficient to predict outcomes in cohorts of cancer patients. Recognizing FMRP’s function as an RNA binding protein that modulates mRNA stability and hence levels in transcriptome datasets, a gene signature reflecting FMRP’s cancer regulatory activity (involving 156 genes) was developed by comparing FMRP-expressing versus FMRP-deficient cancer cells, both in culture and within tumors. Our FMRP cancer activity signature was prognostic for survival across multiple human cancers; anticorrelated with the intensity of T cell infiltration in different tumor types, consistent with FMRP’s immunosuppressive effects; and was associated with comparatively poor responses to immune checkpoint inhibitors and immune-dependent chemotherapy in selected cohorts. CONCLUSION FMRP is revealed as a regulator of a network of genes and cells in the tumor microenvironment that contribute to the capability of tumors to evade immune destruction.

MedicAlert have announced a change in their membership fees. From 1st October 2022 the annual fee is £36, or £33 if you pay by direct debit. https://www.proteinsdeficiency.com/services/medic-alert.php

Hello, I hope you are doing well! My name is Maulik and I am a part of a synthetic biology research team called iGEM representing Stony Brook University in an international competition. I am writing to let you know about a crowdfunding effort my team and I are undertaking to help fund our research project which involves finding a new, effective and safe solution for patients with a blood clotting disorder related to Protein S deficiency. I am attaching our project description and contribution link. Please check out our project and donate to our cause! We need your help and will deeply appreciate it if you could contribute and/or share our campaign link with anyone who would like to contribute! https://www.wesci.org/stonybrookigem22

Good Afternoon, I hope you are doing well! My name is Maulik and I am a part of a synthetic biology research team called iGEM representing Stony Brook University in an international competition. I am writing to let you know about a crowdfunding effort my team and I are undertaking to help fund our research project which involves finding a new, effective and safe solution for patients with a blood clotting disorder related to Protein S deficiency. iGEM, which stands for “International Genetically Engineered Machine,” is a competition where teams apply synthetic biology to solve specific problems all around the world. Our team is focused on Protein S deficiency, a disorder of blood clotting which affects people with a genetic disposition and those affected by severe cases of COVID-19. For a while now, our team has been facing the troubles of funding a research project. Especially for undergraduate projects like ours, funding is a huge issue. In our search for support, we realized that since we are primarily doing this project to help the community, crowdfunding may be a choice for us. This is why we have teamed up with WeSci.org - a crowdfunding platform where researchers can submit their unfunded ideas to receive funding directly from interested backers. By contributing to our project on WeSci you can have a direct impact on our research, which in the long run can bring help not only to patients with Protein S deficiency, but also those suffering from severe forms of COVID-19 who develop this deficiency as a side-effect. We would deeply appreciate it if you can back our campaign and help our us reach out to people who would be willing to contribute to our cause! Below is our campaign link, with our project description and contribution link! https://www.wesci.org/stonybrookigem22 Thank you for your time and kind consideration! Best, Maulik and the 2022 iGEM team.

Hereditary Thrombophilia Testing Among Hospitalized Patients: Is It Warranted? Omar K. Abughanimeh , Rosalyn I. Marar, Mohammad Tahboub, Anahat Kaur, Ayman Qasrawi, Mouhanna Abu Ghanimeh, Timothy Pluard Published: May 09, 2022 (see history) DOI: 10.7759/cureus.24855 Cite this article as: Abughanimeh O K, Marar R I, Tahboub M, et al. (May 09, 2022) Hereditary Thrombophilia Testing Among Hospitalized Patients: Is It Warranted?. Cureus 14(5): e24855. doi:10.7759/cureus.24855 Hereditary thrombophilias (HTs) are a group of inherited disorders that predispose the carrier to venous thromboembolism (VTE). It is estimated that 7% of the population has some form of HT. Although testing for HT has become routine for many hospitalized patients, knowing when to order the tests and how to interpret the results remains challenging. In the United States, there are no clear guidelines regarding testing for HT. We conducted a study to evaluate the utilization of HT testing among hospitalized patients to examine its impact on immediate management decisions and overall cost burden. In addition, we discuss the common reasons for healthcare providers to order these tests and review the data behind these reasons in the literature. Our study demonstrated that HT testing during hospitalization had a limited role in changing management and was associated with a significant cost. The decision to order HT tests should be considered following an individualized clinical risk assessment. https://www.cureus.com/articles/92682-hereditary-thrombophilia-testing-among-hospitalized-patients-is-it-warranted