tbuckley/cabot-search huggingface dataset:
Abstract 2096: Gefitinib analogue V1801 induces apoptosis of T790M EGFR-harboring lung cancer cells by up-regulation of the BH-3 only protein Noxa .
Authors: Bo Zhang, Zhujun Yao, Guangbiao Zhou
Journal: Cancer Research (2013)

Abstract Treatment of non-small cell lung cancer (NSCLC) with drugs targeting the epidermal growth factor receptor (EGFR), e.g., gefitinib and erlotinib, will eventually fail because of the development of secondary mutations such as T790M in EGFR. Strategies to overcome this resistance are therefore an urgent need. In this study, we synthesized a dozen of novel gefitinib analogues and evaluated their effects on L858R/T790M-EGFR harboring NSCLC cells, and reported that one of these gefitinib mimetics, N-(2-romo-5-(trifluoromethyl)phenyl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)uinazolin-4-amine (hereafter, V1801), triggered apoptosis of the NSCLC cells and overcame gefitinib-resistance in mice inoculated with NCI-H1975 cells. Though V1801 only moderately inhibited EGFR kinase activity, it markedly induced the expression of the BH3-only protein Noxa, and Noxa silencing significantly reduced V1801-induced apoptosis of NCI-H1975 cells. It is showed that V1801 interfered with the expression of the transcription factor c-Myc and the extracellular signal regulated kinase (Erk) pathway. V1801 in combination with proteasome inhibitor bortezomib exerted enhanced cytotoxicity in NCI-H1975 cells possibly due to potentiated induction of Noxa expression. These data indicate that gefinitib analogues with weak EGFR inhibitory activity may overcome drug-resistance via activation of BH-3 only pro-apoptotic proteins, and V1801 may have therapeutic potentials for NSCLC. Citation Format: Bo Zhang, Zhujun Yao, Guangbiao Zhou. Gefitinib analogue V1801 induces apoptosis of T790M EGFR-harboring lung cancer cells by up-regulation of the BH-3 only protein Noxa . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2096. doi:10.1158/1538-7445.AM2013-2096
Polycystic Kidney Disease
Journal: New England Journal of Medicine (1989)

The Polycystic Kidney Disease (PKD) is a genetic disease which is characterized by the gradual emergence of cystic lesions in the kidneys, which replace the renal parenchyma causing deterioration of its function to stage 5. The PKD is one of the causes of Chronic Kidney Disease on renal replacement therapy (RRT). The Polycystic Kidney Disease has two patterns of inheritance: autosomal dominant pattern and the autosomal recessive pattern. The dominant form is more common but less severe than autosomal recessive form. PKD is known that is caused by mutations in several loci of the human genome. The autosomal dominant form can be caused by mutations in two different genes (PKD1 and PKD2), unlike the autosomal recessive form only has a causal gene (PKHD1). At present the international scientific community efforts toward deeper understanding of the pathophysiology of this entity for the purpose of developing therapeutic alternatives that avoid the appearance of cysts or progression of those already in place. The aim is to systematize the available scientific knowledge about Polycystic Kidney Disease and provide a source of consultation update on clinical characteristics and therapeutic options for patients with PKD.
The transcription factor ETS1 is an important regulator of human NK cell development and terminal differentiation
Authors: Sylvie Taveirne, Sigrid Wahlen, Wouter Van Loocke, Laura Kiekens, Eva Persyn, Els Van Ammel, Katrien De Mulder, Juliette Roels, Laurentijn Tilleman, Marc Aumercier, Patrick Matthys, Filip Van Nieuwerburgh, Tessa C.C. Kerre, Tom Taghon, Pieter Van Vlierberghe, Bart Vandekerckhove, Georges Leclercq
Journal: Blood (2020)
Collectively Answering the Venetoclax BTK Inhibitor Sequencing Question in CLL
Authors: Kerry A. Rogers
Journal: Clinical Cancer Research (2020)

Whether BTK inhibitors are effective when used after venetoclax in patients with chronic lymphocytic leukemia is an important unanswered question. In a large retrospective cohort study examining outcomes for next line treatment after venetoclax, BTK inhibitors were found to result in durable responses in patients who were not previously BTK inhibitor resistant.See related article by Mato et al., p. 3589.
PTH-025 Are endoscopists planning on adhering to BSG quality standards in upper GI endoscopy guidance
Authors: Freddie Betteridge, Luke Materacki, Karl Yong, Dushen Murugich, Ben Colleypriest
Journal: Endoscopy (2018)

<h3>Introduction</h3> The BSG and AUGIS recently published a position statement, '<i>Quality Standards in upper gastrointestinal endoscopy',</i> outlining minimal standards in diagnostic gastroscopy. These new standards may represent a significant change of practice for some endoscopists and would need to be adopted by a majority to enforce change. The purpose of this survey was to determine how much of a change in practice these standards represent and to gauge the initial likely acceptance. <h3>Methods</h3> Six simple questions were selected from the new recommendations to determine current and future practice in a multiple choice design. A questionnaire was sent to 467 UK based endoscopists using Survey Monkey. <h3>Results</h3> The response rate was 31.7%(148) and the majority(78%) of the respondents were Gastroenterologists. <h3>Conclusions</h3> Our results demonstrate that a number of the recommendations are contentious and are currently not being planned to be adopted by a significant proportion of endoscopist. Some of the recommendation such as biopsies for eosinophilic oesophagitis in the context of dysphagia are current practice for the majority of endoscopists and are planned to be adopted by the remainder. Whilst other standards such as recording inspection time for surveillance procedures and gastric antral biopsies for iron deficiency anaemia are only currently practiced in the minority and the majority are not planning to adopt. Interestingly the current adherence, planned uptake and no planned change in practice mirrored the strength of evidence behind the standard and the strength of recommendation. Such that the most contentious standards with largest percentage of endoscopists not planning to adopt had weak evidence and were weak recommendations. Whilst it is important to improve training and practice in gastrocopy and develop minimal acceptable standards this survey would suggest that standards with weak recommendation and with weak evidence may need revision.
Précis of<i>Doing without Concepts</i>
Authors: Edouard Machery
Journal: Behavioral and Brain Sciences (2010)

Although cognitive scientists have learned a lot about concepts, their findings have yet to be organized in a coherent theoretical framework. In addition, after twenty years of controversy, there is little sign that philosophers and psychologists are converging toward an agreement about the very nature of concepts. Doing without Concepts (Machery 2009) attempts to remedy this state of affairs. In this article, I review the main points and arguments developed at greater length in Doing without Concepts.
Treatment of Angina Pectoris
Authors: P. E. Jackson
Journal: BMJ (1969)

SIR,-It is regrettable that your leading article cii angina pectoris (19 April, p. 134) again fails to stress the importance of a search for and correction of anaemia in the management of this condition.I have recently seen two patients, (one with iron deficiency and one with vitamin B12 de- ficiency) presenting with classical effort angina.In both cases the angina was totally relieved by appropriate treatment of the anaemia.-Iam, etc.,
Implementation of Advanced Methods for Reproductive Pharmacovigilance in Autism: A Meta-Analysis of the Effects of Prenatal Antidepressant Exposure
Authors: Monica L. Vega, Graham C. Newport, Durim Bozhdaraj, Samantha B. Saltz, Charles B. Nemeroff, D. Jeffrey Newport
Journal: American Journal of Psychiatry (2020)

Observational studies of prenatal antidepressant safety are hindered by methodological concerns, including susceptibility to surveillance bias. Some studies address potential bias by using alternative strategies to operationalize study comparison groups. In a meta-analysis of the association between prenatal antidepressant exposure and autism risk, the authors examined the utility of comparison group operationalization in reducing surveillance bias.A systematic search of multiple databases through August 2017 was conducted, selecting controlled observational studies of the association of prenatal antidepressant exposure with autism. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analysis produced summary effect measures with 95% confidence intervals stratified by comparator group composition, antidepressant class, and trimester of exposure.Fourteen studies were included, with 13 reporting results using a population-based comparison group, five using a psychiatric control group, and four using a discordant-sibling control group. Eight of the 14 studies were rated poor because of inadequate control for prenatal depression and maternal ethnicity. Autism risk estimates after prenatal exposure to any antidepressant were decidedly different for population-based designs (hazard ratio=1.42, 95% CI=1.18, 1.70; odds ratio=1.58, 95% CI=1.25, 1.99) compared with psychiatric control (hazard ratio=1.14, 95% CI=0.84, 1.53; odds ratio=1.24, 95% CI=0.93, 1.66) and discordant-sibling (hazard ratio=0.97, 95% CI=0.68, 1.37; odds ratio=0.85, 95% CI=0.54, 1.35) designs. Findings for prenatal exposure to selective serotonin reuptake inhibitors were similar. Meta-regression of population-based studies demonstrated that despite statistical adjustment, ethnicity differences remained a significant source of study heterogeneity.In this meta-analysis, neither psychiatric control nor discordant-sibling designs supported an association between prenatal antidepressant exposure and autism. Discordant-sibling designs effectively addressed surveillance bias in pharmacovigilance reports derived from national registries and other large databases.
ProCAID: A phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone (DP) chemotherapy for metastatic castration resistant prostate cancer (mCRPC).
Authors: Simon J. Crabb, Alison J. Birtle, Karen Martin, Nichola Downs, Megan Bowers, Ian Ratcliffe, Mary Ellis, Gareth Griffiths, Stuart Thompson, Vincent Khoo, Robert J. Jones
Journal: Journal of Clinical Oncology (2016)

228 Background: DP extends survival in mCRPC. However emergent clinical resistance is effectively inevitable. Serine/threonine protein kinase AKT (protein kinase B) pathway activation is highly prevalent in mCRPC contributing to disease progression and DP therapeutic resistance. AZD5363 is a potent oral pan-AKT inhibitor. Pre-clinical data suggest activity in mCRPC and synergy with docetaxel. This phase I trial was to develop a DP/AZD5363 combination in mCRPC. Methods: Eligibility included chemotherapy naive histologically/cytologically proven measurable/evaluable mCRPC, PSA or radiographic disease progression, ECOG performance status 0 or 1, serum testosterone &lt;1.7 nmol/L. Treatment comprised DP up to 10 cycles (75 mg/m 2 , IV, day 1; prednisolone 5 mg BID, PO, day 1–21) and AZD5363 to disease progression. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from cycle 1, day 2. We utilised a conventional 3+3 dose escalation to determine a recommended phase II dose (RP2D) for AZD5363 combined with DP according to defined dose limiting toxicity (DLT) using CTCAEv4. Results: 10 patients were recruited (4 DL1, 6 DL2), median age 67.5 (Range: 56-72). A median of 6.5 cycles (Range: 3-10) of DP and 4 cycles (Range: 1-13) of AZD5363 were administered. No DLTs were seen in DL1. 2 patients in DL2 experienced DLTs (G3 rash, G3 diarrhoea). 7 pts (70%) had at least one G3/4 IMP-related AE with neutropenia (n=3) and maculo-papular rash (n=3) the most common. G3/4 AEs considered related to AZD5363 occurred in 3 patients (0 DL1, 3 DL2) including maculo-papular rash, diarrhoea and neutropenia. Transient hyperglycaemia occurred in all patients (Random glucose C1D2 pre dose mean 6.0 mmol/L, 2 hour mean 8.7 mmol/L, 4 hour mean 9.5 mmol/L, 8 hour mean 6.5 mmol/L). Conclusions:The RP2D for AZD5363 is 320 mg bd 4 days on/3 days off in combination with full dose DP for mCRPC. A placebo controlled randomised phase II trial for this approach has commenced recruitment. This work was supported by CRUK [C9317/A16029]. CRUK Reference: CRUK/12/042. This research was conducted with support from the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Cancer Research Network. Clinical trial information: NCT02121639.
Estimating the generation interval for coronavirus disease (COVID-19) based on symptom onset data, March 2020
Authors: Tapiwa Ganyani, Cécile Kremer, Dongxuan Chen, Andrea Torneri, Christel Faes, Jacco Wallinga, Niel Hens
Journal: Eurosurveillance (2020)

BackgroundEstimating key infectious disease parameters from the coronavirus disease (COVID-19) outbreak is essential for modelling studies and guiding intervention strategies.AimWe estimate the generation interval, serial interval, proportion of pre-symptomatic transmission and effective reproduction number of COVID-19. We illustrate that reproduction numbers calculated based on serial interval estimates can be biased.MethodsWe used outbreak data from clusters in Singapore and Tianjin, China to estimate the generation interval from symptom onset data while acknowledging uncertainty about the incubation period distribution and the underlying transmission network. From those estimates, we obtained the serial interval, proportions of pre-symptomatic transmission and reproduction numbers.ResultsThe mean generation interval was 5.20 days (95% credible interval (CrI): 3.78-6.78) for Singapore and 3.95 days (95% CrI: 3.01-4.91) for Tianjin. The proportion of pre-symptomatic transmission was 48% (95% CrI: 32-67) for Singapore and 62% (95% CrI: 50-76) for Tianjin. Reproduction number estimates based on the generation interval distribution were slightly higher than those based on the serial interval distribution. Sensitivity analyses showed that estimating these quantities from outbreak data requires detailed contact tracing information.ConclusionHigh estimates of the proportion of pre-symptomatic transmission imply that case finding and contact tracing need to be supplemented by physical distancing measures in order to control the COVID-19 outbreak. Notably, quarantine and other containment measures were already in place at the time of data collection, which may inflate the proportion of infections from pre-symptomatic individuals.
The use of venetoclax‐based salvage therapy for post‐hematopoietic cell transplantation relapse of acute myeloid leukemia
Authors: Michael Byrne, Nathalie Danielson, Salyka Sengsayadeth, Adrianne Rasche, Katie Culos, Katie Gatwood, Houston Wyatt, Wichai Chinratanalab, Bhagirathbhai Dholaria, P. Brent Ferrell, Kristin Fogo, Stacey Goodman, Madan Jagasia, Reena Jayani, Adetola Kassim, Sanjay R. Mohan, Bipin N. Savani, Stephen A. Strickland, Brian G. Engelhardt, Michael Savona
Journal: American Journal of Hematology (2020)

For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting.
Pulmonary arterial enlargement and acute exacerbations of COPD
Authors: James Wells, George Washko, MeiLan Han, Naseer Abbas, Hrudaya Nath, Albert Mamary, Elizabeth Regan, William Bailey, Fernando Martinez, Elizabeth Westfall, Russell Bowler, Mark Dransfield
Journal: European Respiratory Journal (2012)

Background:  Exacerbations of  COPD (AECOPD) are associated with accelerated loss of lung function and mortality. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts AECOPD though pulmonary vascular abnormalities also occur early in the disease. We hypothesized that a computed tomography (CT) metric of pulmonary vascular disease (pulmonary artery (PA) enlargement as determined by a PA/Aorta (A) ratio > 1) would predict severe AECOPD.   Methods:  The COPDGene study is a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between PA/A>1 and severe AECOPD requiring hospitalization as reported at enrolment and then examined its utility as a predictor of these events in longitudinal follow-up as well as in an external validation cohort [Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE)] using logistic and zero-inflated negative binomial regression and adjusting for known risk factors for AECOPD.   Results:  Multivariate logistic regression demonstrated a significant association between PA/A>1 and severe AECOPD [OR 3.60 (95% CI, 2.49-5.22, p 1 also independently predicted the occurrence [OR 2.03 (95% CI, 1.17-3.49, p=0.01) in COPDGene and OR 2.80 (95% CI, 2.11-3.71, p 1 was the strongest predictor of severe AECOPD over both 1 and 3 years of follow-up.   Conclusions:  CT detected pulmonary artery enlargement (PA/A>1) predicts severe COPD exacerbations.
Adil El-Tayar: renowned NHS transplant surgeon who died from covid-19
Authors: Rebecca Wallersteiner
Journal: BMJ (2020)

Photo credit: Abbas Ghazanfar

On 25 March Adil El-Tayar, a renowned organ transplantation specialist, became the first working NHS surgeon to die from covid-19 in hospital in the UK. A healthy and active 64 year old, he is thought to have contracted the virus at a hospital in the Midlands, where he worked during the week. He cared deeply about the NHS, an institution he had spent his life serving.

Born in Atbara, Sudan, a railway city on the Nile, El-Tayar was the eldest son of a government clerk and a housewife. He had 11 siblings. A close knit community, Atbara had been built by the British to serve the railway line between Port Sudan on the Red Sea coast and the Wadi Halfa in the north. It was here that the first Sudanese labour movement started in 1948. El-Tayar attended the local school and was a diligent student. During his childhood, one of his brothers, Osman, became ill and died without suitable medical treatment. Although El-Tayar rarely spoke about his brother’s death, he named his …
Covid-19: EU states report 60% rise in emergency calls about domestic violence
Authors: Elisabeth Mahase
Journal: BMJ (2020)

A 60% increase in emergency calls from women subjected to violence by their intimate partner has been reported in the World Health Organization Europe member states.

Comparing April 2020 with the same period last year, WHO said that online inquiries to violence prevention support hotlines had also increased as much as fivefold. This comes as many countries are in lockdown or are restricting people’s ability to leave their homes because of the covid-19 pandemic.

The United Nations Population Fund has warned that continuing lockdowns for six months could result in an extra 31 million cases of gender based violence globally. It added that the pandemic was expected to “cause significant delays in programmes to end female …
Dynamic profile for the detection of anti-SARS-CoV-2 antibodies using four immunochromatographic assays
Authors: Baptiste Demey, Nagib Daher, Catherine François, Jean-Philippe Lanoix, Gilles Duverlie, Sandrine Castelain, Etienne Brochot
Journal: Journal of Infection (2020)

In order to fight the SARS-CoV-2 pandemic infection, there is a growing need and demand for diagnostic tools that are complementary and different from the RT-PCR currently in use. Multiple serological tests are or will be very soon available but need to be evaluated and validated. We have thus tested 4 immunochromatographic tests for the detection of antibodies to SARS-CoV-2. In addition, we assessed the kinetics of antibody appearance using these assays in 22 patients after they were tested positive by RT-PCR. We observed great heterogeneity in antibody detection post-symptom onset. The median antibody detection time was between 8 and 10 days according to the manufacturers. All the tests showed a sensitivity of 60 to 80% on day 10 and 100% on day 15. In addition, a single cross-reaction was observed with other human coronavirus infections. Thus, immunochromatographic tests for the detection of anti-SARS-CoV-2 antibodies may have their place for the diagnostic panel of COVID-19.
Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020
Authors: Silvia Garazzino, Carlotta Montagnani, Daniele Donà, Antonella Meini, Enrico Felici, Gianluca Vergine, Stefania Bernardi, Roberta Giacchero, Andrea Lo Vecchio, Paola Marchisio, Giangiacomo Nicolini, Luca Pierantoni, Ivana Rabbone, Giuseppe Banderali, Marco Denina, Elisabetta Venturini, Andrzej Krzysztofiak, Raffaele Badolato, Sonia Bianchini, Luisa Galli, Alberto Villani, Guido Castelli-Gattinara
Journal: Eurosurveillance (2020)

Data on features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adolescents are scarce. We report preliminary results of an Italian multicentre study comprising 168 laboratory-confirmed paediatric cases (median: 2.3 years, range: 1 day-17.7 years, 55.9% males), of which 67.9% were hospitalised and 19.6% had comorbidities. Fever was the most common symptom, gastrointestinal manifestations were frequent; two children required intensive care, five had seizures, 49 received experimental treatments and all recovered.