tbuckley/cabot-search huggingface dataset:
A phase II trial of lenvatinib plus toripalimab and hepatic arterial infusion chemotherapy as a first-line treatment for advanced hepatocellular carcinoma (LTHAIC study).
Authors: MinKe He, Shi Ming, Zhicheng Lai, QiJiong Li
Journal: Journal of Clinical Oncology (2021)

4083 Background: Combining systemic and locoregional therapies represents a promising treatment strategy for patients with advanced hepatocellular carcinoma (HCC). We investigated the efficacy and safety of combined lenvatinib and toripalimab (recombinant, humanized programmed cell death receptor-1 monoclonal antibody) plus hepatic arterial infusion chemotherapy (HAIC) as a first-line treatment in this patient population. Methods: This single-arm, phase II study included treatment-naive adult (≥18 years) patients with advanced HCC, Eastern Cooperative Oncology Group performance status 0–2, and Child-Pugh Class A liver function (NCT04044313). Patients initiated lenvatinib (8 mg for bodyweight &lt; 60 kg or 12 mg for bodyweight ≥60 kg, orally once daily) 3-7 days prior to initial HAIC to confirm tolerability, and then received 21-day treatment cycles of lenvatinib (day 1 to day 21), toripalimab (240 mg by IV infusion, on day 1), and HAIC (day 1 to day 2) with the FOLFOX regimen (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , 5-fluorouracil bolus 400 mg/m 2 on day 1, and 5-fluorouracil infusion 2400 mg/m 2 for 24 hours) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at six months, evaluated using RECIST 1.1. Secondary endpoints were median PFS and overall survival (OS), objective response rate (ORR) per RECIST 1.1 and mRECIST, and safety. Results: Between August 2019 and May 2020, 36 patients (33 men and 3 women; median age, 49 years) were enrolled. The median tumor size was 11.2 cm, 86.1% of patients had portal vein invasion, and 27.8% had extrahepatic metastasis. The primary endpoint showed a 6-month PFS rate of 80.6%. After a median follow up of 11.2 months, the median PFS was 10.5 months (95% CI, 6.21−14.79), and the median OS was not reached. The ORR per RECIST was 63.9% (95% CI, 40.9−73.0), and per mRECIST was 66.7% (95% CI, 43.3−75.1) including five (13.9%) patients who achieved a complete radiological response. The median duration of response was 12.1 months (95% CI, 4.52−19.69). Furthermore, eight patients achieved sufficient downstaging to be converted to resectable disease. Among them, one patient received liver transplantation, and four received curative surgical resection. One of them achieved pathological complete response. Grade 3-4 treatment-related adverse events (AEs) occurred in 72.2% of patients, and the most common were thrombocytopenia (13.9%), elevated aspartate aminotransferase (13.9%), and hypertension (11.1%). All AEs were expected and manageable, and no treatment-related deaths were reported. Conclusions: Combination treatment with lenvatinib and toripalimab plus HAIC showed promising antitumor activity and manageable toxicity in patients with advanced HCC. Further randomized, controlled trials are warranted to validate our findings. Clinical trial information: NCT04044313.
Application of Text Mining in Risk Assessment of Chemical Mixtures: A Case Study of Polycyclic Aromatic Hydrocarbons (PAHs)
Authors: Imran Ali, Kristian Dreij, Simon Baker, Johan Högberg, Anna Korhonen, Ulla Stenius
Journal: Environmental Health Perspectives (2021)

Background: Cancer risk assessment of complex exposures, such as exposure to mixtures of polycyclic aromatic hydrocarbons (PAHs), is challenging due to the diverse biological activities of these compounds. With the help of text mining (TM), we have developed TM tools—the latest iteration of the Cancer Risk Assessment using Biomedical literature tool (CRAB3) and a Cancer Hallmarks Analytics Tool (CHAT)—that could be useful for automatic literature analyses in cancer risk assessment and research. Although CRAB3 analyses are based on carcinogenic modes of action (MOAs) and cover almost all the key characteristics of carcinogens, CHAT evaluates literature according to the hallmarks of cancer referring to the alterations in cellular behavior that characterize the cancer cell. Objectives: The objective was to evaluate the usefulness of these tools to support cancer risk assessment by performing a case study of 22 European Union and U.S. Environmental Protection Agency priority PAHs and diesel exhaust and a case study of PAH interactions with silica. Methods: We analyzed PubMed literature, comprising 57,498 references concerning priority PAHs and complex PAH mixtures, using CRAB3 and CHAT. Results: CRAB3 analyses correctly identified similarities and differences in genotoxic and nongenotoxic MOAs of the 22 priority PAHs and grouped them according to their known carcinogenic potential. CHAT had the same capacity and complemented the CRAB output when comparing, for example, benzo[a]pyrene and dibenzo[a,l]pyrene. Both CRAB3 and CHAT analyses highlighted potentially interacting mechanisms within and across complex PAH mixtures and mechanisms of possible importance for interactions with silica. Conclusion: These data suggest that our TM approach can be useful in the hazard identification of PAHs and mixtures including PAHs. The tools can assist in grouping chemicals and identifying similarities and differences in carcinogenic MOAs and their interactions. https://doi.org/10.1289/EHP6702
Identification of germline cancer predisposition variants during clinical ctDNA testing.
Authors: Leigh Anne Anne Stout, Nawal Kassem, Cynthia Hunter, Santosh Philips, Milan Radovich, Bryan P. Schneider
Journal: Journal of Clinical Oncology (2020)

e15555 Background: Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. Identification of inherited germline cancer predisposition mutations that have significant implications for at-risk relatives may be missed during routine ctDNA testing. Allele frequency has the potential to enhance the likelihood that a mutation is germline; and is often reported in many NGS tests from ctDNA. Here, we report on the fidelity of allele frequency in ctDNA as a predictor for pathogenic germline variant carriage. Methods: ctDNA sequencing of patients with metastatic cancer from the Indiana University Health Precision Genomics Program was performed using the FoundationOne Liquid assay. All variants detected by the ctDNA assay report were considered. All patients also had germline testing information and pathogenicity of germline variants were determined using ClinVar. Germline variants with conflicting interpretations were manually reviewed to determine pathogenicity. Comparisons between ctDNA results with known germline status were performed. Results: Of 91 previously identified germline cancer predisposition variants, 36 (40%) were also identified by ctDNA analysis. All germline variants that were tested for in the ctDNA assay (n = 36, 100%) were identified. When detected, the allele frequencies of detected germline variants in the ctDNA ranged from 39-87.6% with an average of 52.1%. Conversely, 111 of 160 (69%) variants identified by ctDNA analysis with allele frequency between 40-60% in a cancer predisposition gene were found to be germline in origin (regardless of pathogenicity). Variants in the BRCA2, BRCA1, and CDH1 genes were most likely to be germline in origin (26/27 [96%], 20/22 [91%], 13/15 [87%], respectively). Variants in the TP53 and APC genes were least likely to be germline in origin (9/36 [25%] and 1/6 [17%], respectively). There was an 85% (95/111) concordance in actionability between the somatic testing lab and ClinVar germline classifications. Of the 16 discordant variants, 100% were determined to be actionable by the somatic testing lab but not actionable in ClinVar. Conclusions: ctDNA allele frequency can alter the likelihood that a variant is germline. Importantly, however, this testing is far from comprehensive and should not be used as a replacement for germline testing. Variants with allele frequency between 40-60% in cancer predisposition genes should induce a high level of suspicion for germline status.
A small molecule UPR modulator for diabetes identified by high throughput screening
Authors: Valeria Marrocco, Tuan Tran, Siying Zhu, Seung Hyuk Choi, Ana M. Gamo, Sijia Li, Qiangwei Fu, Marta Diez Cunado, Jason Roland, Mitch Hull, Van Nguyen-Tran, Sean Joseph, Arnab K. Chatterjee, Nikki Rogers, Matthew S. Tremblay, Weijun Shen
Journal: Acta Pharmaceutica Sinica B (2021)

Unfolded protein response (UPR) is a stress response that is specific to the endoplasmic reticulum (ER). UPR is activated upon accumulation of unfolded (or misfolded) proteins in the ER's lumen to restore protein folding capacity by increasing the synthesis of chaperones. In addition, UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER. Herein, we describe a cell-based ultra-high throughput screening (uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and in vivo disease models. Using asialoglycoprotein receptor 1 (ASGR) fused with Cypridina luciferase (CLuc) as reporter assay for folding capacity, we have screened a million small molecule library and identified APC655 as a potent activator of protein folding, that appears to act by promoting chaperone expression. Furthermore, APC655 improved pancreatic β cell viability and insulin secretion under ER stress conditions induced by thapsigargin or cytokines. APC655 was also effective in preserving β cell function and decreasing lipid accumulation in the liver of the leptin-deficient (ob/ob) mouse model. These results demonstrate a successful uHTS campaign that identified a modulator of UPR, which can provide a novel candidate for potential therapeutic development for a host of metabolic diseases.
Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma
Authors: Oliver Van Oekelen, Charles R. Gleason, Sarita Agte, Komal Srivastava, Katherine F. Beach, Adolfo Aleman, Katerina Kappes, Tarek H. Mouhieddine, Bo Wang, Ajai Chari, Carlos Cordon-Cardo, Florian Krammer, Sundar Jagannath, Viviana Simon, Ania Wajnberg, Samir Parekh, Radhika Banu, Maria C. Bermúdez-González, Rachel L. Chernet, Emily D. Ferreri, Daniel L. Floda, Adolfo Firpo-Betancourt, Giulio Kleiner, Kayla T. Russo, Ashley-Beathrese T. Salimbangon, Miti S. Saksena, Amber A. Shin, Julia Matthews, Wanni Mendez, Levy Sominsky, Lubbertus C.F. Mulder, Rao Mendu
Journal: Cancer Cell (2021)
MYC protein interactors in gene transcription and cancer
Authors: Corey Lourenco, Diana Resetca, Cornelia Redel, Peter Lin, Alannah S. MacDonald, Roberto Ciaccio, Tristan M. G. Kenney, Yong Wei, David W. Andrews, Maria Sunnerhagen, Cheryl H. Arrowsmith, Brian Raught, Linda Z. Penn
Journal: Nature reviews. Cancer (2021)
Voucher-Based Kidney Donation and Redemption for Future Transplant
Authors: Jeffrey L. Veale, Nima Nassiri, Alexander M. Capron, Gabriel M. Danovitch, H. Albin Gritsch, Matthew Cooper, Robert R. Redfield, Peter T. Kennealey, Sandip Kapur
Journal: JAMA Surgery (2021)

Policy makers, transplant professionals, and patient organizations agree that there is a need to increase the number of kidney transplants by facilitating living donation. Vouchers for future transplant provide a means of overcoming the chronological incompatibility that occurs when the ideal time for living donation differs from the time at which the intended recipient actually needs a transplant. However, uncertainty remains regarding the actual change in the number of living kidney donors associated with voucher programs and the capability of voucher redemptions to produce timely transplants.To examine the consequences of voucher-based kidney donation and the capability of voucher redemptions to provide timely kidney allografts.This multicenter cohort study of 79 transplant centers across the US used data from the National Kidney Registry from January 1, 2014, to January 31, 2021, to identify all family vouchers and patterns in downstream kidney-paired donations. The analysis included living kidney donors and recipients participating in the National Kidney Registry family voucher program.A voucher was provided to the intended recipient at the time of donation. Vouchers had no cash value and could not be sold, bartered, or transferred to another person. When a voucher was redeemed, a living donation chain was used to return a kidney to the voucher holder.Deidentified demographic and clinical data from each kidney donation were evaluated, including the downstream patterns in kidney-paired donation. Voucher redemptions were separately evaluated and analyzed.Between 2014 and 2021, 250 family voucher-based donations were facilitated. Each donation precipitated a transplant chain with a mean (SD) length of 2.3 (1.6) downstream kidney transplants, facilitating 573 total transplants. Of those, 111 transplants (19.4%) were performed in highly sensitized recipients. Among 250 voucher donors, the median age was 46 years (range, 19-78 years), and 157 donors (62.8%) were female, 241 (96.4%) were White, and 104 (41.6%) had blood type O. Over a 7-year period, the waiting time for those in the National Kidney Registry exchange pool decreased by more than 3 months. Six vouchers were redeemed, and 3 of those redemptions were among individuals with blood type O. The time from voucher redemption to kidney transplant ranged from 36 to 155 days.In this study, the family voucher program appeared to mitigate a major disincentive to living kidney donation, namely the reluctance to donate a kidney in the present that could be redeemed in the future if needed. The program facilitated kidney donations that may not otherwise have occurred. All 6 of the redeemed vouchers produced timely kidney transplants, indicating the capability of the voucher program.
Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis
Authors: Junjie Yu, Changyu Zhu, Xiaobo Wang, KyeongJin Kim, Alberto Bartolome, Paola Dongiovanni, Katherine P. Yates, Luca Valenti, Michele Carrer, Thorsten Sadowski, Li Qiang, Ira Tabas, Joel E. Lavine, Utpal B. Pajvani
Journal: Science Translational Medicine (2021)

Increased Jagged1 in pericentral hepatocytes causes liver fibrosis in response to hepatocyte TLR4–NF-κB pathway activation in NASH.
Impact of Admission Hyperglycemia on Heart Failure Events and Mortality in Patients With Takotsubo Syndrome at Long-term Follow-up: Data From HIGH-GLUCOTAKO Investigators
Authors: Pasquale Paolisso, Luca Bergamaschi, Pietro Rambaldi, Gianluca Gatta, Alberto Foà, Francesco Angeli, Michele Fabrizio, Gianni Casella, Michelangela Barbieri, Nazzareno Galiè, Raffaele Marfella, Carmine Pizzi, Celestino Sardu
Journal: Diabetes Care (2021)

To investigate admission hyperglycemia effects on the sympathetic system and long-term prognosis in Takotsubo syndrome (TTS).In patients with TTS and hyperglycemia (n = 28) versus normoglycemia (n = 48), serum norepinephrine and 123I-labeled metaiodobenzylguanidine (MIBG) cardiac scintigraphy were assessed. Heart failure (HF) occurrence and death events over 2 years were evaluated.At hospitalization, those with hyperglycemia versus normoglycemia had higher levels of inflammatory markers and B-type natriuretic peptide and lower left ventricular ejection fraction. Glucose values correlated with norepinephrine levels (R2 = 0.39; P = 0.001). In 30 patients with TTS, 123I-MIBG cardiac scintigraphy showed lower late heart-to-mediastinum ratio values in the acute phase (P < 0.001) and at follow-up (P < 0.001) in those with hyperglycemia. Patients with hyperglycemia had higher rates of HF (P < 0.001) and death events (P < 0.05) after 24 months. In multivariate Cox regression analysis, hyperglycemia (P = 0.008), tumor necrosis factor-α (P = 0.001), and norepinephrine (P = 0.035) were independent predictors of HF events.Patients with TTS and hyperglycemia exhibit sympathetic overactivity with a hyperglycemia-mediated proinflammatory pathway, which could cause worse prognosis during follow-up.
Reducing the Need for HLA-Matched Platelet Transfusion
Authors: Anthony Cardillo, Joanna M. Heal, Kelly Henrichs, Debra Masel, Thomas Fountaine, Jane Liesveld, Suzie Noronha, Christine Cahill, Andy Ngo, Gaurav K. Gupta, Majed A. Refaai, Neil Blumberg
Journal: New England Journal of Medicine (2021)

Reducing the Need for HLA-Matched Platelet Transfusion Some patients with acute leukemia or myelodysplastic syndromes with thrombocytopenia may become resistant to random donor transfusions of plat...
Abstract 447: Longitudinal Improvement in CPR Quality Following RQI Implementation in a Pediatric Emergency Department
Authors: Aaron Donoghue, Mary Kate Abbadessa, Shannon Gaines, Debra Heard, Sage Myers, Dana E Niles, Vinay M Nadkarni, Russell E Griffin
Journal: Circulation (2019)

Introduction and Objective: The optimal retraining interval in CPR for healthcare providers is unknown. The Resuscitation Quality Improvement Program (RQI ® ) is a competency based, low-dose high-frequency quality improvement solution CPR psychomotor skills. We sought to describe the longitudinal change in skill performance during simulated CPR over a one year period following the implementation of RQI in a tertiary pediatric ED. Methods: Observational study in a single pediatric ED. All healthcare providers involved in resuscitative care in the ED were enrolled in RQI in October 2017. Once per 3-month period, each provider completed a feedback-guided skills session for 4 basic BLS skills (Infant compressions, infant ventilation, adult compressions, adult ventilation). A weighted scoring algorithm (range 0-100%) was used to score each subject’s performance. In the event of a score of less than 75%, repeated attempt(s) were required until a passing score was achieved. Q4 2017 median overall scores and first daily scores were compared to Q3 2018 median overall scores and first daily scores using a Wilcoxon Signed-Rank Test. Results: 159 providers completed all four quarterly training sessions in the 12-month study period. Median scores stratified by quarter and difference scores between the first and last quarter for each task are shown in Table 1. Overall scores and first daily scores for all four psychomotor CPR skills improved significantly for all tasks between Q4 2017 and Q3 2018. Conclusions: Pediatric ED providers enrolled in RQI showed improved CPR skill performance over a one year period. Future research should link RQI training and skill performance with CPR performance during actual patient care.
Diagnosing active tuberculosis in primary care
Authors: Ruvandhi R Nathavitharana, Dolores Freire Jijon, Pankaj Pal, Saurabh Rane
Journal: BMJ (2021)

### What you need to know

A 58 year old transportation worker in India with uncontrolled diabetes (HbA1c 97 mmol/mol) presents with a three month history of productive cough and decreased energy level. He has been treated empirically for community acquired pneumonia twice without improvement in symptoms. 

A 24 year old student who arrived in Canada from the Philippines three years ago presents with a two month history of bilateral multiple enlarged cervical lymph nodes. 

Of the 10 million people who develop active tuberculosis (TB) disease each year, approximately three million are not identified by national TB care programmes and many are undiagnosed.1 Diagnostic delays are common in both low and high resource settings2 and lead to worse individual outcomes and ongoing transmission.34 Patients often see several healthcare providers before the disease is diagnosed.56 TB most commonly presents with pulmonary involvement, but can present in a number of ways, most commonly lymphadenitis, pleural effusions, and …
Dear Sajid Javid: open letter to a new minister of health
Authors: Fiona Godlee
Journal: BMJ (2021)

Dear secretary of state, 

You arrive at a crucial time in the pandemic and have the chance to shake off past mistakes and do things differently (doi:10.1136/bmj.n1649).1 We suggest 10 urgent actions.

1.  Abandon mass asymptomatic testing. The UK’s testing strategy adopted a poorly performing test and has used it badly, squandering precious funds, failing to contain the virus, and damaging public trust (doi:10.1136/bmj.n1636).2 Instead we should move to targeted testing of people most at risk (doi:10.1136/bmj.n1638).3

2.  Establish proper financial support for those who need to isolate. Testing works only if people are willing to be tested …
Abstract 95: The Role of TGFβ Signaling in a Fibrotic cMyBP-C HCM/HF Model
Authors: Qinghang Meng, Bidur Bhandary, Md. Shenuarin Bhuiyan, Hanna Osinska, Jeffrey Robbins
Journal: Circulation Research (2016)

Purpose: Hypertrophic cardiomyopathy (HCM) is considered one of the most common genetic heart disorders with a prevalence of about 1 in 500 people, with 35% of those affected being attributed to mutations within the gene encoding cardiac myosin-binding protein C (cMyBP-C). Cardiac stress, as well as cMyBP-C mutations, can trigger production of a 40kDa truncated fragment derived from the amino terminus of cMyBP-C. Genetic expression of this 40kDa fragment in mouse cardiomyocytes ( Mybp3 40kDa ) leads to HCM, fibrosis and heart failure, mimicking human disease progression. The transforming growth factor-β (TGFβ) signaling pathway has been implicated in a variety of fibrotic processes. The goal of this study is to define the role of TGFβ signaling in distinct cell populations, the cardiomyocyte and fibroblast, in the cMyBP-C HCM/HF model. Methods and results: Masson’s Trichrome staining, PCR arrays, immunohistochemistry and western blots were performed to characterize the fibrotic progression in Mybp3 40kDa transgenic mice. Cardiac fibrosis was initially detected 4 weeks after transgene expression. Extensive interstitial fibrosis and severe atrial fibrosis were detected at 16 weeks. Both canonical and non-canonical TGFβ pathways were active during fibrotic progression. To specifically block TGFβ signaling in Mybp3 40kDa transgenic mice, compound mutant mice were generated, in which the tgfbr1 or tgfbr2 alleles were ablated, either in cardiomyocytes or in activated fibroblasts (myofibroblasts) by αMHC-Cre or Periostin-MerCreMer-Cre respectively. Blockage of TGFβ signaling in either cardiomyocytes or myofibroblasts alleviated cardiac fibrosis. Furthermore, treatment with the non-canonical TGFβ signaling inhibitor MMI-0100 also alleviated cardiac fibrosis and increased the life span of the Mybp3 40kDa transgenic mice. Conclusions: TGFβ signaling is activated in the Mybp3 40kD HCM/HF model. Genetic or pharmaceutical inhibition of TGFβ signaling inhibited fibrosis and increased the life span in this model.