tbuckley/cabot-search huggingface dataset:
Distribution of faulty and out of date PPE is “national scandal,” says BMA
Authors: Abi Rimmer
Journal: BMJ (2020)

The head of the BMA has called reports that faulty and out of date personal protective equipment (PPE) was distributed to healthcare workers "a national scandal."In March, NHS England reassured NHS trusts that their PPE had passed stringent tests that demonstrate they are safe.In the same month, however, it was reported that GP practices had been sent out of date face masks. 1 In June, Pulse magazine reported that the government had told GPs to throw away batches of out of date face masks distributed to practices after finding they posed a risk to staff. 2 Commenting on the news, BMA Council chair Chaand Nagpaul said, "These reports, if true, are nothing short of a national scandal."If doctors and health and care workers have been supplied with, and worn, faulty, re-dated masks, this is clearly a dereliction of the duty to ensure the safety of NHS staff and patients.Suggestions that these faults were known in May, and yet action is only now being taken, are alarming."The government now needs to answer questions about how these masks were distributed and allowed to be used, Nagpaul said."Crucially, we need a cast iron guarantee that no faulty or out of date PPE is currently on the front line or in community care."Every single item of faulty PPE should now be withdrawn and replaced with sufficient equipment that is in date-not re-dated-and with rigorous quality control measures to ensure these properly protect health and care staff."A Department of Health and Social Care spokesperson said, "The safety of frontline staff has been a priority throughout this unprecedented pandemic.After being made aware of a defect with some Cardinal Health Type IIR surgical masks, we urgently gave advice last week to health and care providers to check if their stock included these masks and to dispose of them.The matter is now resolved." 1 Leclere M. Coronavirus Kent: GPs sent "out of date" protective masks after new labels stuck over batches sent to surgeries.www.kentonline.co.
Neoadjuvant Immunotherapy–Based Systemic Treatment in MMR-Deficient or MSI-High Rectal Cancer: Case Series
Authors: Rahel Demisse, Neha Damle, Edward Kim, Jun Gong, Marwan Fakih, Cathy Eng, Leslie Oesterich, Madison McKenny, Jingran Ji, James Liu, Ryan Louie, Kit Tam, Sepideh Gholami, Wissam Halabi, Arta Monjazeb, Farshid Dayyani, May Cho
Journal: Journal of the National Comprehensive Cancer Network (2020)

Treatment options for locally advanced rectal cancer have continued to consist largely of chemotherapy, chemoradiation, and/or surgical resection. For patients who are unable to undergo these therapeutic modalities or who do not to experience a response to them, treatment options are limited. We report 3 cases of mismatch repair–deficient (dMMR) locally advanced adenocarcinoma of the rectum that showed significant response with neoadjuvant immunotherapy–based systemic treatment. The first patient was not eligible for standard therapy because of a history of radiotherapy to the prostate with concurrent comorbidities and therefore received single-agent pembrolizumab. The second patient did not respond to total neoadjuvant chemoradiation and subsequently received combined nivolumab and ipilimumab. The third patient had a known family history of Lynch syndrome and presented with locally advanced rectal cancer and a baseline carcinoembryonic antigen level of 1,566 ng/mL. She was treated using neoadjuvant pembrolizumab and FOLFOX (folinic acid, fluorouracil, oxaliplatin). In this small series, we suggest that single-agent and combined-modality neoadjuvant immunotherapy/chemotherapy appear to be safe and effective treatment options for patients with (dMMR) locally advanced rectal cancer. Our findings encourage further studies to investigate the role of neoadjuvant immunotherapy as a viable treatment strategy in this population.
THU-021-Loss of bile salt export pump (Bsep/Abcb11) aggravates lipopolysaccharide induced hepatic inflammation in mice
Authors: Jelena Remetic, Veronika Mlitz, Victoria Kunczer, Hubert schargl, Tatjana Stojakovic, Claudia Fuchs, Michael Trauner
Journal: Journal of Hepatology (2019)
Targeting nuclear import and export in hematological malignancies
Authors: Boaz Nachmias, Aaron D. Schimmer
Journal: Leukemia (2020)

Abstract The transport of proteins across the nuclear membrane is a highly regulated process, essential for the cell function. This transport is actively mediated by members of the karyopherin family, termed importins, or exportins, depending on the direction of transport. These proteins play an active part in tumorigenesis, through aberrant localization of their cargoes, which include oncogenes, tumor-suppressor genes and mediators of key signal transduction pathways. Overexpression of importins and exportins is reported in many malignancies, with implications in cell growth and viability, differentiation, drug resistance, and tumor microenvironment. Given their broad significance across tumors and pathways, much effort is being put to develop specific inhibitors as a novel anticancer therapeutics. Already, selinexor, a specific inhibitor of exportin-1 (XPO1), is approved for clinical use. This review will focus on the role of importins and exportins in hematological malignancies. We will discuss current preclinical and clinical data on importins and exportins, and demonstrate how our growing understanding of their functions has identified new therapeutic targets.
Does Pain at an Earlier Stage of Chondropathy Protect Female Mice Against Structural Progression After Surgically Induced Osteoarthritis?
Authors: Isabell S. von Loga, Vicky Batchelor, Clare Driscoll, Annika Burleigh, Shi‐Lu L. Chia, Bryony Stott, Jadwiga Miotla‐Zarebska, David Riley, Francesco Dell’Accio, Tonia L. Vincent
Journal: Arthritis & Rheumatology (2020)

Female C57BL/6 mice exhibit less severe chondropathy than male mice. This study was undertaken to test the robustness of this observation and explore underlying mechanisms.Osteoarthritis was induced in male and female C57BL/6 or DBA/1 mice (n = 6-15 per group) by destabilization of the medial meniscus (DMM) or partial meniscectomy (PMX). Some mice were ovariectomized (OVX) (n = 30). In vivo repair after focal cartilage defect or joint immobilization (sciatic neurectomy) following DMM was assessed. Histologic analysis, evaluation of gene expression in whole knees, and behavioral analysis using Laboratory Animal Behavior Observation Registration and Analysis System (LABORAS) and Linton incapacitance testing (n = 7-10 mice per group) were performed.Female mice displayed less severe chondropathy (20-75% reduction) across both strains and after both surgeries. Activity levels after PMX were similar for male and female mice. Some repair-associated genes were increased in female mouse joints after surgery, but no repair differences were evident in vivo. Despite reduced chondropathy, female mice developed pain-like behavior at the same time as male mice. At the time of established pain-like behavior (10 weeks after PMX), pain-associated genes were significantly up-regulated in female mice, including Gdnf (mean ± SEM fold change 2.54 ± 0.30), Nrtn (6.71 ± 1.24), Ntf3 (1.92 ± 0.27), and Ntf5 (2.89 ± 0.48) (P < 0.01, P < 0.01, P < 0.05, and P < 0.001, respectively, versus male mice). Inflammatory genes were not regulated in painful joints in mice of either sex.We confirm strong structural joint protection in female mice that is not due to activity or intrinsic repair differences. Female mice develop pain at the same time as males, but induce a distinct set of neurotrophins. We speculate that heightened pain sensitivity in female mice protects the joint by preventing overuse.
Covid-19: Four in 10 cases in Italian town that locked down early were asymptomatic
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Covid-19: Four in 10 cases in Italian town that locked down early were asymptomatic Elisabeth MahaseMass testing and quarantining in the small Italian town of Vo'-which experienced the first known covid-19 death in the country-enabled the community to suppress the virus in just a few weeks, according to researchers. 1
The D2 and D3 Sublineages of Human Papilloma Virus 16–Positive Cervical Cancer in Guatemala Differ in Integration Rate and Age of Diagnosis
Authors: Hong Lou, Joseph F. Boland, Edmundo Torres-Gonzalez, Anaseidy Albanez, Weiyin Zhou, Mia K. Steinberg, Lena Diaw, Jason Mitchell, David Roberson, Michael Cullen, Lisa Garland, Sara Bass, Robert D. Burk, Meredith Yeager, Nicolas Wentzensen, Mark Schiffman, Enrique Alvirez Freites, Eduardo Gharzouzi, Lisa Mirabello, Michael Dean
Journal: Cancer Research (2020)

Abstract Human papillomavirus (HPV) 16 displays substantial sequence variation; four HPV16 lineages (A, B, C, and D) have been described as well as multiple sublineages. To identify molecular events associated with HPV16 carcinogenesis, we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A total of 65% (62/96) of the samples had integrated HPV16 sequences and integration was associated with an earlier age of diagnosis and premenopausal disease. HPV16 integration sites were broadly distributed in the genome, but in one tumor, HPV16 integrated into the promoter of the IFN regulatory factor 4 (IRF4) gene, which plays an important role in the regulation of the IFN response to viral infection. The HPV16 D2 and D3 sublineages were found in 23% and 30% of the tumors, respectively, and were significantly associated with adenocarcinoma. D2-positive tumors had a higher rate of integration, earlier age of diagnosis, and a lower rate of somatic mutation, whereas D3-positive tumors were less likely to integrate, had later age of diagnosis, and exhibited a higher rate of somatic mutation. In conclusion, Guatemalan cervical tumors have a high frequency of very high-risk HPV16 D2 and D3 sublineages harboring distinct histology, which may help guide future therapeutic strategies to target the tumor and reduce recurrence. Significance: This study details the biological and molecular properties of the most pathogenic forms of HPV16, the cause of the majority of cervical cancers.
Is stratified shielding from covid-19 feasible and ethical?
Authors: Irene Petersen
Journal: BMJ (2020)

The concept of stratified shielding from covid-19 is interesting but complex and potentially unethical to implement in practice. As described by Davey Smith and Spiegelhalter,1 the risk of covid-19 mortality can be described as a two step process: the risk of getting infected and the risk of dying after infection.

In theory, it would be relatively straightforward to derive a risk prediction …
Chemotherapeutic nucleoside analogues and DNA polymerase β
Authors: Subarna Hamid, Kristin A. Eckert
Journal: Cancer Research (2005)

1369  DNA polymerase β (pol β) was used as a model system to study the mechanism of nucleoside analogues Cytosine Arabinoside (AraC), Cytosine 2’-Fluorodeoxyriboside (2F-dC), and Cytosine 2’, 2’-difluorodeoxyriboside (Gemcitabine). AraC and Gemcitabine are widely used for the treatment of human cancers, and must be incorporated into the nascent DNA strand by DNA polymerases for optimal anti-tumor activity. Nucleoside analogues are often administered in combination with alkylating agents that can result in up-regulation of DNA repair enzymes such as pol β. This project used a structure-function approach to investigate the mechanism of nucleotide analogue discrimination by DNA pol β. The pol βvariants studied were located both in the active site (Tyr-271), and the loop region of the palm domain (Arg-253 and Pro-242). Discrimination of incoming nucleosides by these variants was examined using an in vitro HSV-thymidine kinase forward mutation assay, mutational spectra, and steady-state kinetic analyses. Active site variants Y271L and Y271G have a similar enzymatic activity relative to wild type (WT) pol β. The HSV-tk assay showed a three-fold higher mutation frequency for the Tyr to Gly change, implying a steric role of the Tyr-271 in pol β nucleoside incorporation. This is especially interesting because other family X polymerases, pol λ and μ, have a highly conserved glycine in the corresponding position. The loop variant P242R is the only identified human polymorphism in the pol βgene coding region, and its effect on nucleoside discrimination is yet to be determined. We constructed the variant by PCR site-directed mutagenesis and determined that its inherent enzymatic activity is similar to WT. P242R has a four-fold decreased mutation frequency and an altered mutation spectra, relative to WT. R253M, also in the loop, is known to confer an AZT-resistant in vivo phenotype (Kosa, et. al, 1999) and we confirmed this anti-mutator tendency. By in vitro incorporation assays, R253K and R253C showed similar enzymatic activity compared to WT, while R253G was relatively inactive. The catalytic activity (Vmax/Km) for AraCTP incorporation by pol β WT and variants P242R and R253M were two- to three- fold lower compared to dCTP incorporation, while the catalytic activity for 2F-dCTP incorporation was seven- to twelve- fold lower compared to dCTP. This study established that pol β recognizes AraCTP and 2F-CTP to different extents, although both nucleotide analogues have 2’-ribose modifications. Our results support the hypothesis that the loop of the palm domain region of pol β is involved in pre-selection of incoming nucleotides prior to basepairing, and a polymorphism involving this region can potentially result in an altered response to chemotherapeutic nucleoside analogues.
Identification of druggable inhibitory immune checkpoints on Natural Killer cells in COVID-19
Authors: Olivier Demaria, Julien Carvelli, Luciana Batista, Marie-Laure Thibult, Ariane Morel, Pascale André, Yannis Morel, Frederic Vély, Eric Vivier
Journal: Cellular and Molecular Immunology (2020)

Infection with SARS-COV-2 is the cause of COVID-19 and has generated an unprecedented health crisis worldwide. While most of the patients experience mild symptoms, around 20% develop severe disease, characterized by pneumonia and in the worst cases by acute respiratory distress syndrome (ARDS).1 The analysis and understanding of the immune responses arising in the course of SARS-COV-2 infection may help to propose therapeutic solutions. Due to the crucial role of Natural Killer (NK) cells in antiviral immune responses,2 we analyzed NK cells in blood from a cohort of 82 individuals: 10 healthy controls (HC), 10 paucisymptomatic COVID-19 patients (pauci), 34 patients with pneumonia (pneumo) and 28 patients with ARDS due to SARS-CoV-2 infection. The absolute numbers of peripheral blood NK cells, B, CD4+, and CD8+ T lymphocytes were lower in the pneumonia and ARDS groups than in healthy controls, consistent with previously published results3 (Fig. 1a). We investigated the NK cell subsets further and found that among CD45+CD3−CD56+ total NK cells the proportion of mature NK cells, a subset defined on the basis of its expression of the CD16 and CD57 cell surface receptors, was markedly lower in patients with ARDS (Fig. 1b). Given their role in viral infection, the loss of mature NK cells may contribute to the pulmonary complications occurring in the most severe cases of COVID-19. We then focused our analysis on molecular pathways likely to improve NK cell antiviral activity to promote SARS-CoV-2 clearance, and analyzed the expression of several immune checkpoints. Given the availability of therapeutic monoclonal antibodies blocking the immunosuppressive functions of PD-1,4 NKG2A,5 and CD396 initially developed for cancer therapies, we analyzed the expression of these molecules on NK cells in our cohort. PD-1 and NKG2A are cell surface receptors, and their engagement with their ligands, PD-L1 and HLA-E, respectively, inhibits the function of T and NK cells. CD39 is an ectoenzyme that cleaves extracellular ATP and ADP, which can be released from dead cells upon viral infection, leading to the generation of adenosine, which has strong immunosuppressive effects on T and NK cells.
Abstract B43: A serum protein biomarker signature for the detection of early stages of ovarian cancer
Authors: Amy P. Skubitz, Kristin L. Boylan, Timothy K. Starr, Xuan Pu, Qing Cao, Kate Geschwind, Robert C. Bast, Karen H. Lu, Joseph Celestino, Ashley J. Petersen
Journal: Clinical Cancer Research (2020)

Abstract The two bes- known ovarian cancer biomarkers, CA125 and HE4, are neither adequately sensitive nor specific to be used to screen the general population for early stages of ovarian cancer. The purpose of this study was to develop a multiprotein classifier that would combine additional protein biomarkers with CA125 and HE4 in order to increase their sensitivity and specificity. We used the Olink Proseek Multiplex Oncology II panel to simultaneously quantify the expression levels of 92 cancer-related proteins using proximity extension assay technology. We analyzed serum from two institutions: 143 women with early-stage (I/II) ovarian cancer (serous, endometrioid, clear-cell, mucinous, and others) and compared the values obtained to 341 age-matched healthy women. We identified 24 proteins whose relative expression between cancers and controls was significantly different between the samples from the two institutions; therefore, we removed these proteins from downstream analysis. Principle Component Analysis and T-distributed Stochastic Neighbor Embedding separated the ovarian cancer samples from the healthy controls, with minimal misclassification. Data from the Proseek plates for CA125 levels exhibited a strong correlation with previously measured clinical values for CA125 (correlation coefficient of 0.81). CA125 and HE4 were detected at low levels in samples from healthy women, while higher levels were observed in the early-stage ovarian cancer cases. We identified 31 proteins that differed significantly (p &amp;lt; 0.001) between ovarian cancer and healthy samples, several of which are novel serum biomarkers for ovarian cancer. In total, 11 proteins had an estimated area under the ROC curve of 0.70 or greater. CA125 alone achieved a sensitivity of 81.0% at a specificity of 98%. However, by adding three proteins to CA125, we increased the assay sensitivity to 86.2%, while holding the specificity fixed at 98%. In conclusion, our data demonstrate that the inclusion of several protein biomarkers can improve the sensitivity and specificity of CA125 alone for the detection of early stages of ovarian cancer. Validation of this multiprotein classifier is currently under way using serum samples from other institutions. Citation Format: Amy P. Skubitz, Kristin L. Boylan, Timothy K. Starr, Xuan Pu, Qing Cao, Kate Geschwind, Robert C. Bast, Jr., Karen H. Lu, Joseph Celestino, Ashley J. Petersen. A serum protein biomarker signature for the detection of early stages of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B43.
Sensitive and broadly applicable residual disease detection in acute myeloid leukemia using flow cytometry‐based leukemic cell enrichment followed by mutational profiling
Authors: Shruti Daga, Angelika Rosenberger, Karl Kashofer, Ellen Heitzer, Franz Quehenberger, Iris Halbwedl, Ricarda Graf, Nina Krisper, Barbara Prietl, Gerald Höfler, Andreas Reinisch, Armin Zebisch, Heinz Sill, Albert Wölfler
Journal: American Journal of Hematology (2020)

Persistent measurable residual disease (MRD) is an increasingly important prognostic marker in acute myeloid leukemia (AML). Currently, MRD is determined by multi-parameter flow cytometry (MFC) or PCR-based methods detecting leukemia-specific fusion transcripts and mutations. However, while MFC is highly operator-dependent and difficult to standardize, PCR-based methods are only available for a minority of AML patients. Here we describe a novel, highly sensitive and broadly applicable method for MRD detection by combining MFC-based leukemic cell enrichment using an optimized combinatorial antibody panel targeting CLL-1, TIM-3, CD123 and CD117, followed by mutational analysis of recurrently mutated genes in AML. In dilution experiments this method showed a sensitivity of 10-4 to 10-5 for residual disease detection. In prospectively collected remission samples this marker combination allowed for a median 67-fold cell enrichment with sufficient DNA quality for mutational analysis using next generation sequencing (NGS) or digital PCR in 39 out of 41 patients. Twenty-one samples (53.8%) tested MRD positive, whereas 18 (46.2%) were negative. With a median follow-up of 559 days, 71.4% of MRD positive (15/21) and 27.8% (5/18) of MRD negative patients relapsed (P = .007). The cumulative incidence of relapse (CIR) was higher for MRD positive patients (5-year CIR: 90.5% vs 28%, P < .001). In multivariate analysis, MRD positivity was a prominent factor for CIR. Thus, MFC-based leukemic cell enrichment using antibodies against CLL-1, TIM-3, CD123 and CD117 followed by mutational analysis allows high sensitive MRD detection and is informative on relapse risk in the majority of AML patients.
COVID-19 testing in Africa: lessons learnt
Authors: Pascale Ondoa, Yenew Kebede, Marguerite Massinga Loembe, Jinal N Bhiman, Sofonias Kifle Tessema, Abdourahmane Sow, Amadou Alpha Sall, John Nkengasong
Journal: The Lancet Microbe (2020)

COVID-19 testing in Africa: lessons learntLaboratory testing is a pillar of the COVID-19 outbreak response.Unlike the 2014 Ebola epidemic, Africa has reacted early and collectively to the COVID-19 pandemic, ramping up severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic capacity from two to 43 countries between February and April, 2020.The Africa Centres for Disease Control and Prevention (Africa CDC)-led African Task Force for Coronavirus Preparedness and Response (AFTCOR)-a coalition between the African Union (AU), AU member states, the WHO Regional Office for Africa, and other stakeholdershas been instrumental in this impressive achievement, promoting coordination and alignment for evidencebased public health action.AFTCOR has led COVID-19 testing capacity scale-up as one of the key objectives under the Africa joint continental strategy for COVID-19 outbreak. 1FTCOR collaborated with the South African National Institute for Infectious Diseases, the Senegalese Institute Pasteur of Dakar, and the West African Health Organization to train expert staff from reference laboratories for molecular detection of SARS-CoV-2.To date, 1•6 million tests donated by the Jack Ma Foundation (Hangzou, China), and more than 1 million tests procured by Africa CDC have been distributed across the 55 AU member states.By May 21, 2020, Africa had reported more than 95 000 confirmed cases of COVID-19. 2 The Africa CDC Pathogen Genomics Intelligence Institute, which is also part of the joint continental COVID-19 strategy, provides training and resources to 16 AU member states to generate up to 2500 SARS-CoV-2 whole-genome sequences and will enable the submission of these sequences to the Global Initiative on Sharing all Influenza Data platform. 3,4With Africa currently contributing only 1% of all sequences submitted globally, this boost will support the design of locally relevant assays, therapeutics, and vaccines.To limit further spread of COVID-19, AU member states must expand diagnostic capacity at the subnational level.Africa CDC aims to increase the number of tests from 1300 to 16 000 per million population, while supporting countries to use every positive result for case isolation, contact tracing and quarantine, and supportive care.PCR testing platforms' footprint within national disease control programmes, and the private and We declare no competing interests.