tbuckley/cabot-search huggingface dataset:
Conjugation of an anti-TfR IgG3-Avidin fusion protein with biotinylated saporin results in significant enhancement of its cytotoxicity against malignant hematopoietic cells.
Authors: Tracy R. Daniels, Patrick P. Ng, Tracie Delgado, Gustavo Helguera, Gary J. Schiller, Benjamin Bonavida, Manuel L. Penichet
Journal: Cancer Research (2006)

5461  We have developed an antibody fusion protein composed of avidin genetically fused to a human IgG3 specific for the human transferrin receptor. This fusion protein (anti-TfR IgG3-Av) is a universal vector that effectively delivers biotinylated compounds into cancer cells through receptor-mediated endocytosis. Furthermore, anti-TfR IgG3-Av possesses an intrinsic anti-proliferative/pro-apoptotic activity against hematopoietic malignant cell lines such as neoplastic plasma cells, which respond to the fusion protein with different sensitivities. Importantly, this cytotoxic activity may potentially be enhanced by the conjugation of the fusion protein to biotinylated compounds. In the present work we studied the efficacy of anti-TfR IgG3-Av as a dual function therapeutic conjugated to biotinylated saporin (b-sap), a toxin derived from the plant Saponaria officinalis that blocks protein synthesis. Using WST-1 viability and [3H]-thymidine incorporation assays we found that the anti-TfR IgG3-Av/b-sap complex synergistically enhanced the cytotoxicity of anti-TfR IgG3-Av or b-sap alone against less sensitive (U266) and highly sensitive (IM-9 or ARH77) cell lines. We observed that cells treated with the anti-TfR IgG3-Av/b-sap conjugate demonstrated morphological features consistent with the induction of apoptosis. This initial proof of principle of the anti-TfR IgG3-Av dual activity can be expanded to include conjugation of anti-TfR IgG3-Av to other biotinylated drugs and in other tumor models in vitro and in vivo. We anticipate that the utility of this therapeutic will not be restricted to the elimination of malignant plasma cells such as multiple myeloma cells in vivo, but can also be used for the in vitro approaches including the efficient purging of myeloma cells ex vivo in autologous transplantation in patients.
GPs need awareness about post-covid ME/CFS
Authors: Caroline Kamau-Mitchell
Journal: BMJ (2021)

Wise reports that general practitioners might be under-reporting long covid in patient records.1 Approximately 25% of people infected with SARS-CoV-1 developed debilitating fatigue and other symptoms that met diagnostic criteria for myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) that continued for more than four years.2 So patients with long covid who have had chronic fatigue for …
Altered Expression of Pdgfrα and Its Downstream Signalling Components May be Causal in the Development of Imatinib Induced Thrombocytopenia in CML Patients Receiving Imatinib Treatment
Authors: Sameer Ahmad Guru, Musadiq Ahmad Bhat, Imtiyaz Ahmad Najar, Ab. Rashid Rashid, Mariyam Zuberi, Mamta Sumi Sumi, Naresh Gupta, Alpana Saxena, Ajay Sharma
Journal: Blood (2017)
28552 Risk of COVID-19 and subsequent mortality among patients receiving immunosuppressive biologic therapy: A retrospective matched cohort study
Authors: Vartan Pahalyants, William S. Murphy, Nikolai Klebanov, Nicholas Theodosakis, R. Monina Klevens, Evelyn Lilly, Maryam Asgari, Yevgeniy R. Semenov
Journal: Journal of the American Academy of Dermatology (2021)

Introduction: It is unclear whether patients treated with immunosuppressive biologics are at an increased risk of COVID-19 infection or associated mortality. Methods: Retrospective study of 7361 patients prescribed biologics between July 1, 2019 and February 29, 2020 and 74,910 matched controls, cross-referenced with the Massachusetts Department of Public Health COVID-19 infection and all-cause mortality data from March 1 through June 19, 2020. A multivariable logistic regression was used on matched data to calculate the odds ratio (OR) for COVID-19 diagnosis between patients on biologics and controls, adjusting for age, sex, race, CCI severity grade, median income, and local infection rate. A multivariable Poisson regression was performed on patients diagnosed with COVID-19 to compare the risk for all-cause mortality, adjusting for sex, CCI severity grade, median income, and local COVID-19 rate. Results: 7361 patients treated with biologics and 74,910 matched controls were included in the analysis (mean age, 50.6 years; 56.0% women, 84.5% white; mean age adjusted CCI 2.8). There were 87 (1.2%) infections and 7 deaths (8.0%) in patients treated with biologics and 1063 (1.4%) infections and 71 deaths (6.7%) in the control group. Patients treated with immunosuppressive biologics were not at increased risk of COVID-19 diagnosis (OR 0.88, 95% CI 0.71-1.09, P = .25) or subsequent mortality (OR −3.07, P = .43). Conclusions: Our study builds on the evidence that biologic immunosuppressants do not increase the risk of COVID-19, which should be considered by dermatologists and patients when making decisions about therapy continuation during this pandemic.
Clinical Settings and Demographic Characteristics of Patients With Sunburn
Authors: Malgorzata K. Nowakowska, Yao Li, Desmond C. Garner, Carly F. Stender, Candice L. Hinkston, Sharon H. Giordano, Mackenzie R. Wehner
Journal: JAMA Dermatology (2021)

Discussion | This is the first large-scale controlled study demonstrating associations between GAHR and improved mental health outcomes, including decreased psychological distress, past-year smoking, and past-year suicidal ideation.These findings reinforce the only existing empirical investigation, to our knowledge, on this subject-a small-scale study demonstrating that GAHR is associated with improved mental health and quality of life. 6 Reverse causality is possible, as TGD people with better baseline mental health may be more likely to access GAHR.However, baseline mental health was not associated with exposure to GAHR in our models.Further studies are needed to clarify this relationship.This study's strengths include its large, national sample size and comprehensive adjustment for confounders.Limitations include its cross-sectional design, convenience sample, potential response bias, and lack of validity and reliability data for USTS questions.Nonetheless, this study contributes novel evidence of the potential mental health benefits of GAHR for TGD people.
Hepatic Mitochondrial SAB Deletion or Knockdown Alleviates Diet‐Induced Metabolic Syndrome, Steatohepatitis, and Hepatic Fibrosis
Authors: Sanda Win, Robert W.M. Min, Jun Zhang, Gary Kanel, Brad Wanken, Yibu Chen, Meng Li, Ying Wang, Ayako Suzuki, Filbert W.M. Aung, Susan F. Murray, Mariam Aghajan, Tin A. Than, Neil Kaplowitz
Journal: Hepatology (2021)

The hepatic mitogen-activated protein kinase (MAPK) cascade leading to c-Jun N-terminal kinase (JNK) activation has been implicated in the pathogenesis of nonalcoholic fatty liver (NAFL)/NASH. In acute hepatotoxicity, we previously identified a pivotal role for mitochondrial SH3BP5 (SAB; SH3 homology associated BTK binding protein) as a target of JNK, which sustains its activation through promotion of reactive oxygen species production. Therefore, we assessed the role of hepatic SAB in experimental NASH and metabolic syndrome. In mice fed high-fat, high-calorie, high-fructose (HFHC) diet, SAB expression progressively increased through a sustained JNK/activating transcription factor 2 (ATF2) activation loop. Inducible deletion of hepatic SAB markedly decreased sustained JNK activation and improved systemic energy expenditure at 8 weeks followed by decreased body fat at 16 weeks of HFHC diet. After 30 weeks, mice treated with control-antisense oligonucleotide (control-ASO) developed steatohepatitis and fibrosis, which was prevented by Sab-ASO treatment. Phosphorylated JNK (p-JNK) and phosphorylated ATF2 (p-ATF2) were markedly attenuated by Sab-ASO treatment. After 52 weeks of HFHC feeding, control N-acetylgalactosamine antisense oligonucleotide (GalNAc-Ctl-ASO) treated mice fed the HFHC diet exhibited progression of steatohepatitis and fibrosis, but GalNAc-Sab-ASO treatment from weeks 40 to 52 reversed these findings while decreasing hepatic SAB, p-ATF2, and p-JNK to chow-fed levels. Hepatic SAB expression increases in HFHC diet-fed mice. Deletion or knockdown of SAB inhibited sustained JNK activation and steatohepatitis, fibrosis, and systemic metabolic effects, suggesting that induction of hepatocyte Sab is an important driver of the interplay between the liver and the systemic metabolic consequences of overfeeding. In established NASH, hepatocyte-targeted GalNAc-Sab-ASO treatment reversed steatohepatitis and fibrosis.
The Cochrane review of electronic cigarettes for smoking cessation: remaining focused on the evidence
Authors: Caitlin Notley, Ailsa R. Butler, Nicola Lindson, Chris Bullen, Annika Theodoulou, Rachna Begh, Hayden McRobbie, Peter Hajek, Nancy Rigotti, Jamie Hartman-Boyce
Journal: European Respiratory Journal (2021)

<b>Evaluating new and emerging technologies for helping more people who smoke to quit is vital. The authors respond to a previous commentary on the Cochrane review, presenting the evidence using gold standard Cochrane methods.</b>https://bit.ly/3xDcv8B
Cetuximab Rechallenge Plus Avelumab in Pretreated Patients With <i>RAS</i> Wild-type Metastatic Colorectal Cancer
Authors: Erika Martinelli, Giulia Martini, Vincenzo Famiglietti, Teresa Troiani, Stefania Napolitano, Filippo Pietrantonio, Davide Ciardiello, Marinella Terminiello, Carola Borrelli, Pietro Paolo Vitiello, Filippo De Braud, Federica Morano, Antonio Avallone, Nicola Normanno, Anna Nappi, Evaristo Maiello, Tiziana Latiano, Alfredo Falcone, Chiara Cremolini, Daniele Rossini, Giuseppe Santabarbara, Carmine Pinto, Daniele Santini, Claudia Cardone, Nicoletta Zanaletti, Alessandra Di Liello, Daniela Renato, Lucia Esposito, Francesca Marrone, Fortunato Ciardiello
Journal: JAMA Oncology (2021)

Rechallenge therapy with anti-epidermal growth factor receptor (EGFR) drugs has been suggested in patients with chemo-refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC) after initial response to anti-EGFR-based first-line treatment. The association of treatment with cetuximab plus avelumab with overall survival (OS) may be worthy of investigation in this setting.To assess the efficacy and safety of cetuximab rechallenge therapy plus avelumab.This single-arm, multicenter phase 2 trial enrolled patients from August 2018 to February 2020. Eligible patients with RAS WT mCRC had a complete or partial response to first-line chemotherapy plus anti-EGFR drugs, developed acquired resistance, and failed second-line therapy. Baseline circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R mutation analysis was done.Patients received avelumab (10 mg/kg every 2 weeks) and cetuximab (400 mg/m2 and, subsequently, 250 mg/m2 weekly) until disease progression or unacceptable toxic effects.The primary end point was OS. Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety.Seventy-seven patients were enrolled (42 men, 35 women; median age, 63 years); 71 had microsatellite stable tumors (MSS), 3 microsatellite instability-high tumors (MSI-H), 3 unknown. The study met the primary end point, with median OS (mOS) of 11.6 months (95% CI, 8.4-14.8 months). Median PFS (mPFS) was 3.6 months (95% CI, 3.2-4.1 months). Common grade-3 adverse events were cutaneous eruption, 11 (14%), and diarrhea, 3 (4%). For 67 of 77 (87%) patients, baseline analysis of plasma circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R variations was feasible. Forty-eight patients had WT disease, whereas 19 had mutations. Patients with RAS/BRAF WT ctDNA had mOS of 17.3 months (95% CI, 12.5-22.0 months) compared with 10.4 months (95% CI, 7.2-13.6 months) in patients with mutated ctDNA (hazard ratio [HR], 0.49; 95% CI, 0.27-0.90; P = .02). The mPFS was 4.1 months (95% CI, 2.9-5.2 months) in RAS/BRAF WT patients compared with 3.0 months (95% CI, 2.6-3.5 months) in patients with mutated ctDNA (HR, 0.42; 95% CI, 0.23-0.75; P = .004).The findings of this single-arm phase 2 trial suggest that cetuximab plus avelumab is an active, well tolerated rechallenge therapy in RAS WT mCRC. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit.ClinicalTrials.gov Identifier: NCT04561336.
Moving pictures: Highlights 2016 open for submissions
Authors: Joanna Palmer, Zoë Mullan
Journal: The Lancet (2016)

Last autumn the image of a young Syrian boy lying dead on a Turkish beach highlighted the humanitarian plight of refugees and influenced public opinion. The photograph of Alan Kurdi spoke to people more powerfully than any words could have done. Photographs can move us, enrage us, challenge our ideas, and provoke us to action. Other pictures can bring joy and hope. In last year's Lancet Highlights photography competition, one of the winning images showed a 5-year-old boy in Zimbabwe looking in a mirror with rapt attention at his newly repaired cleft lip. These two pictures remind us how photographs capture a moment in a powerful and moving way. Images can highlight an important health issue and we invite readers to send us photographs for our annual photography competition, Highlights 2016. Whether your focus is local or global, we want you to send us photographs that surprise and move us by telling a story about health today. We are interested in photographs that capture any health issue in a thought-provoking way. As in previous years, The Lancet and The Lancet Global Health will run the competition together. Winning photographs will be published in The Lancet's final issue of 2016 and could be selected for the front cover of The Lancet Global Health. Each entry should be submitted with 300 accompanying words that put the image in context. Submissions should not have been previously published in print or online. If a person or patient is featured then you must obtain and keep written consent from the individual or, where this is not an option, their next of kin. Please complete the patient consent section of the author statements form while retaining copies of the signed forms. We also encourage you to submit any additional media to support your submission online, such as video or audio features. All photographs—colour or black and white—should be submitted through our online editorial submission system, along with the required text and any supporting material for online publication. Please select Lancet Photograph as the article type. If a digital camera is used please set it to the highest possible quality setting and submit images as JPEG files. If you are using a film camera please submit an 8 × 11 inch glossy print to The Lancet in the post. The entries will be judged by Lancet editors and there will be a £300 prize for winning entries. The deadline for entries is Nov 7, 2016. So share your photos with The Lancet and The Lancet Global Health: we look forward to looking at the stories you capture.
Covid-19: One in nine patients in hospital with covid during first wave became infected after admission
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Covid-19: One in nine patients in hospital with covid during first wave became infected after admission Elisabeth MahaseAround one in nine hospital patients who had covid-19 during the first wave of the pandemic in the UK were infected after being admitted, researchers have reported. 1 The team of researchers from the universities of Lancaster, Liverpool, Edinburgh, Birmingham, and Imperial College London looked at the records of 82 000 patients with covid-19 in UK hospitals who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) Clinical Characterisation Protocol UK study 2 and who became ill before 1 August 2020.
Efficacy & Efficiency of Genome Editing With CRISPR/Cas9 in a Humanized Knock-In Mouse Model of PLNR14del
Authors: Francesca Stillitano, Nour Raad, Zhang Lu, Anthony Fargnoli, Dongtak Jeong, Delaine Ceholski, Erik Kohlbrenner, Jaydev Dave, Cai Chenleng, Fadi Akar, Roger J. Hajjar
Journal: Circulation (2018)
Role of thoracic ultrasound in pleurodesis pathways for malignant pleural effusions: the SIMPLE randomised trial
Authors: I Psadillas, M Hassan, A Yousuf, T Duncan, S Leyakathali Khan, K G Blyth, M Evison, J P Corcoran, S Barnes, R Reddy, P I Bonta, R Bhatnagar, G Kagithala, M Dobson, R Knight, S J Dutton, R Luengo-Fernandez, E Hedley, H Piotrowska, L Brown, K A Musa Asa’ari, R Mercer, R Asciak, E O Bedawi, R J Halifax, M Slade, R Benamore, A Edey, R F Miller, N A Mackell, N M Rahman
Journal: The Lancet Respiratory Medicine (2021)
Radiation Dose During Lung Cancer Screening with Low-Dose Computed Tomography: How Low Is Low Dose?
Authors: H. Marshall, I. Smith, B. J. Keir, R. V. Bowman, J. Crossin, M. Fuentes, R. Slaughter, L. Passmore, E. McCaul, D. Courtenay, M. Webb, M. Windsor, I. A. Yang, P. V. Zimmerman, R. Hayes, S. Redmond, K. M. Fong
Journal: Journal of Thoracic Oncology (2011)
Fighting type 2 diabetes: Formulation strategies for peptide-based therapeutics
Authors: Carlos Bendicho-Lavilla, Iria Seoane-Viaño, Francisco J. Otero-Espinar, Asteria Luzardo-Álvarez
Journal: Acta Pharmaceutica Sinica B (2021)

Diabetes mellitus is a major health problem with increasing prevalence at a global level. The discovery of insulin in the early 1900s represented a major breakthrough in diabetes management, with further milestones being subsequently achieved with the identification of glucagon-like peptide-1 (GLP-1) and the introduction of GLP-1 receptor agonists (GLP-1 RAs) in clinical practice. Moreover, the subcutaneous delivery of biotherapeutics is a well-established route of administration generally preferred over the intravenous route due to better patient compliance and prolonged drug absorption. However, current subcutaneous formulations of GLP-1 RAs present pharmacokinetic problems that lead to adverse reactions and treatment discontinuation. In this review, we discuss the current challenges of subcutaneous administration of peptide-based therapeutics and provide an overview of the formulations available for the different routes of administration with improved bioavailability and reduced frequency of administration.
How Would You Manage This Male Patient With Hypogonadism?
Authors: Howard Libman, Marc L. Cohen, Michael S. Irwig, Gerald W. Smetana
Journal: Annals of Internal Medicine (2021)

Male hypogonadism is defined as an abnormally low serum testosterone concentration or sperm count. As men age, often in the context of obesity and other comorbid conditions, serum testosterone levels may decrease. Normalizing serum testosterone levels in male adults with hypogonadism may improve symptoms related to androgen deficiency, but controversies exist regarding the long-term benefits and risks of hormone supplementation in this setting. In 2020, the American College of Physicians published a clinical guideline for the use of testosterone supplementation in adult men based on a systematic review of available evidence. Among their recommendations were that clinicians discuss whether to initiate testosterone treatment in men with age-related low testosterone with sexual dysfunction who want to improve sexual function and not initiate testosterone treatment in men with age-related low testosterone to improve energy, vitality, physical function, or cognition. Here, two clinicians with expertise in this area, one a generalist and the other an endocrinologist, debate the management of a patient with sexual symptoms and a low serum testosterone level. They discuss the diagnosis of male hypogonadism, the indications for testosterone therapy, its potential benefits and risks, how it should be monitored, and how long it should be continued.
A database and deep learning toolbox for noise-optimized, generalized spike inference from calcium imaging
Authors: Peter Rupprecht, Stefano Carta, Adrian Hoffmann, Mayumi Echizen, Antonin Blot, Alex C. Kwan, Yang Dan, Sonja B. Hofer, Kazuo Kitamura, Fritjof Helmchen, Rainer W. Friedrich
Journal: Nature Neuroscience (2021)
Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study
Authors: Jie Ming, Xinwen Yu, Xiaoqiang Xu, Li Wang, Chao Ding, Zhifeng Wang, Xuan Xie, Sheli Li, Wenjuan Yang, Shu Luo, Qingzhen He, Yafang Du, Zhufang Tian, Xiling Gao, Kaiyan Ma, Yujie Fang, Chen Li, Jiajun Zhao, Xiaokai Wang, Qiuhe Ji
Journal: Genome Medicine (2021)

Berberine and Bifidobacterium have been reported to improve glucose tolerance in people with hyperglycemia or other metabolic disorders. This study aimed to assess the hypoglycemic effect and the regulation of the gut microbiota caused by berberine and Bifidobacterium and the possible additive benefits of their combination.
P-24 A prospective phase 1b dose de-escalation open-label clinical study to evaluate the safety and efficacy of sorafenib with metformin and atorvastatin in advanced hepatocellular carcinoma (SMASH)
Authors: P. Bhargava, V. Ostwal, A. Ramaswamy, S. Srinivas, S. Mandavkar, D. Naughane, V. Gota, S. Patkar, M. Goel, S. Banavali, N. Shetty
Journal: Annals of Oncology (2021)
Two doses of the SARS-CoV-2 BNT162b2 vaccine enhance antibody responses to variants in individuals with prior SARS-CoV-2 infection
Authors: Richard A. Urbanowicz, Theocharis Tsoleridis, Hannah J. Jackson, Lola Cusin, Joshua D. Duncan, Joseph G. Chappell, Alexander W. Tarr, Jessica Nightingale, Alan R. Norrish, Adeel Ikram, Ben Marson, Simon J. Craxford, Anthony Kelly, Guruprasad P. Aithal, Amrita Vijay, Patrick J. Tighe, Jonathan K. Ball, Ana M. Valdes, Benjamin J. Ollivere
Journal: Science Translational Medicine (2021)

Antibody responses to SARS-CoV-2 variants increase after two doses of BNT162b2 vaccine in both previously infected and naïve individuals.
An Insulin Resistance Score Improved Diabetes Risk Assessment in the Malmö Prevention Project—A Longitudinal Population-Based Study of Older Europeans
Authors: Dov Shiffman, Judy Z. Louie, James B. Meigs, James J. Devlin, Michael J. McPhaul, Olle Melander
Journal: Diabetes Care (2021)

The worldwide prevalence of type 2 diabetes (T2D) continues to increase, despite the established efficacy of T2D prevention interventions. Identifying individuals at high risk and making them the focus of preventive interventions may reduce the incidence of diabetes and global disease burden. We recently showed that T2D risk assessment in white middle-aged men and women can be improved with addition of an insulin resistance measure (assessed by HOMA of insulin resistance) to glycemia and other established risk factors (1). We have also developed an insulin resistance score (IRScore), comprising fasting insulin and C-peptide measured by mass spectrometry, to assess the probability of existing insulin resistance where insulin resistance was defined as being in the top tertile of steady-state plasma glucose level (≥198 mg/dL) (2).

In the current study, we asked whether this IRScore improved T2D risk assessment beyond glycemia and established risk factors in a population of older Europeans. Older populations are of particular interest given the steady increase in the average age worldwide, especially in Europe, Japan, China, and the U.S. We conducted a case-cohort study based on the …
Abstract 10784: Oxidative Stress Post-Translational Modification Landscape in Cardiac Hypertrophy Revealed by Machine Learning Approaches
Authors: Jie Wang, Jessica Lee, Bilal Mirza, Neo C Chuang, Howard Choi, Dominic Ng, Ding Wang, John Caufield, John Yates, Peipei Ping
Journal: Circulation (2018)

Introduction: Oxidative stress has been implicated as a major pathological event driving cardiac hypertrophy. However, both its molecular foundation and targets remain poorly characterized. Recentl...