tbuckley/cabot-search huggingface dataset:
COVID-19 lung injury as a primer for immune checkpoint inhibitors (ICIs)-related pneumonia in a patient affected by squamous head and neck carcinoma treated with PD-L1 blockade: a case report
Authors: Angelo Dipasquale, Pasquale Persico, Elena Lorenzi, Daoud Rahal, Armando Santoro, Matteo Simonelli
Journal: Journal for ImmunoTherapy of Cancer (2021)

By the beginning of the global pandemic, SARS-CoV-2 infection has dramatically impacted on oncology daily practice. In the current oncological landscape, where immunotherapy has revolutionized the treatment of several malignancies, distinguishing between COVID-19 and immune-mediated pneumonitis can be hard because of shared clinical, radiological and pathological features. Indeed, their common mechanism of aberrant inflammation could lead to a mutual and amplifying interaction. We describe the case of a 65–year-old patient affected by metastatic squamous head and neck cancer and candidate to an experimental therapy including an anti-PD-L1 agent. COVID-19 ground-glass opacities under resolution were an incidental finding during screening procedures and worsened after starting immunotherapy. The diagnostic work-up was consistent with ICIs-related pneumonia and it is conceivable that lung injury by SARS-CoV-2 has acted as an inflammatory primer for the development of the immune-related adverse event. Patients recovered from COVID-19 starting ICIs could be at greater risk of recall immune-mediated pneumonitis. Nasopharyngeal swab and chest CT scan are recommended before starting immunotherapy. The awareness of the phenomenon could allow an easier interpretation of radiological changes under treatment and a faster diagnostic work-up to resume ICIs. In the presence of clinical benefit, for asymptomatic ICIs-related pneumonia a watchful-waiting approach and immunotherapy prosecution are suggested.
TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors
Authors: Cecilia Ansalone, John Cole, Sabarinadh Chilaka, Flavia Sunzini, Shatakshi Sood, Jamie Robertson, Stefan Siebert, Iain B McInnes, Carl S Goodyear
Journal: Annals of the Rheumatic Diseases (2021)

Objectives Circulating myeloid precursors are responsible for post-natal osteoclast (OC) differentiation and skeletal health, although the exact human precursors have not been defined. Enhanced osteoclastogenesis contributes to joint destruction in rheumatoid arthritis (RA) and tumour necrosis factor (TNF) is a well-known pro-osteoclastogenic factor. Herein, we investigated the interplay between receptor activator of nuclear factor kappa-Β ligand (RANK-L), indispensable for fusion of myeloid precursors and the normal development of OCs, and TNF in directing the differentiation of diverse pre-OC populations derived from human peripheral blood. Methods Flow cytometric cell sorting and analysis was used to assess the potential of myeloid populations to differentiate into OCs. Transcriptomic, epigenetic analysis, receptor expression and inhibitor experiments were used to unravel RANK-L and TNF signalling hierarchy. Results TNF can act as a critical homoeostatic regulator of CD14 + monocyte (MO) differentiation into OCs by inhibiting osteoclastogenesis to favour macrophage development. In contrast, a distinct previously unidentified CD14 − CD16 − CD11c + myeloid pre-OC population was exempt from this negative regulation. In healthy CD14 + MOs, TNF drove epigenetic modification of the RANK promoter via a TNFR1-IKKβ-dependent pathway and halted osteoclastogenesis. In a subset of patients with RA, CD14 + MOs exhibited an altered epigenetic state that resulted in dysregulated TNF-mediated OC homoeostasis. Conclusions These findings fundamentally re-define the relationship between RANK-L and TNF. Moreover, they have identified a novel pool of human circulating non-MO OC precursors that unlike MOs are epigenetically preconditioned to ignore TNF-mediated signalling. In RA, this epigenetic preconditioning occurs in the MO compartment providing a pathological consequence of failure of this pathway.
Endoscopic Phenotype of the J Pouch in Patients With Inflammatory Bowel Disease: A New Classification for Pouch Outcomes
Authors: Shintaro Akiyama, Jacob E. Ollech, Victoria Rai, Laura R. Glick, Yangtian Yi, Cindy Traboulsi, Joseph Runde, Russell D. Cohen, Kinga B. Skowron, Roger D. Hurst, Konstantin Umanskiy, Benjamin D. Shogan, Neil H. Hyman, Michele A. Rubin, Sushila R. Dalal, Atsushi Sakuraba, Joel Pekow, Eugene B. Chang, David T. Rubin
Journal: Clinical Gastroenterology and Hepatology (2021)
Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study
Authors: Steven Fishbane, Mohamed A. El-Shahawy, Roberto Pecoits-Filho, Bui Pham Van, Mark T. Houser, Lars Frison, Dustin J. Little, Nicolas J. Guzman, Pablo E. Pergola
Journal: Journal of the American Society of Nephrology (2021)

Current anemia therapies for patients with non-dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis.In this double-blind phase 3 study, we randomized patients with non-dialysis-dependent CKD stages 3-5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events.The study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%).Roxadustat effectively increased hemoglobin in patients with non-dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo.Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627.
A Single-Dose of REGN1908-1909 Reduced Bronchoconstriction in Cat-Allergic Subjects with Mild Asthma for up to 3 months following a controlled cat allergen challenge: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study
Authors: Frederic De Blay De Gaix, Alina Gherasim, Nathalie Domis, Pretty Meier, Furat Shawki, Michelle DeVeaux, Divya Ramesh, Lorah Perlee, Gary Herman, David Weinreich, George Yancopoulos, Meagan OBrien
Journal: Journal of Allergy and Clinical Immunology (2021)
Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis
Authors: Elijah L. Carlson, Vengadeshprabhu Karuppagounder, William J. Pinamont, Natalie K. Yoshioka, Adeel Ahmad, Eric M. Schott, Heather K. Le Bleu, Michael J. Zuscik, Reyad A. Elbarbary, Fadia Kamal
Journal: Science Translational Medicine (2021)

Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein-coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein-coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is unknown. Thus, in a surgical OA mouse model, we performed genetic GRK2 deletion in chondrocytes or pharmacological inhibition with the repurposed U.S. Food and Drug Administration (FDA)-approved antidepressant paroxetine. Both GRK2 deletion and inhibition prevented CH, abated OA progression, and promoted cartilage regeneration. Supporting experiments with cultured human OA cartilage confirmed the ability of paroxetine to mitigate CH and cartilage degradation. Our findings present elevated GRK2 signaling in chondrocytes as a driver of CH in OA and identify paroxetine as a disease-modifying drug for OA treatment.
Abstract PO012: Characterization of molecular, phenotypic, and drug sensitivity changes due to estrogen receptor alpha mutations in endometrial cancer
Authors: Zannel Blanchard, Jeffery M. Vahrenkamp, Spencer Arnesen, Kristofer C. Berrett, Jason Gertz
Journal: Clinical Cancer Research (2021)

Abstract Estrogen signaling is essential for normal uterine function and has been shown to play critical roles in the development of endometrial cancer. Mutations in the ligand binding domain (LBD) of estrogen receptor alpha (ER) have been identified in primary endometrial cancer and hormone therapy resistant breast cancer. In endometrial cancer, ER mutations are associated with worse outcomes and obesity independent disease. However, additional molecular and phenotypic characterizations of these mutations are needed in the context of endometrial cancer. Utilizing a CRISPR/Cas9 tagging strategy to model the more common Y537S and D538G LBD mutations while epitope tagging ER’s endogenous locus in Ishikawa cells, we studied the regulatory and phenotypic consequences of mutant ER in endometrial cancer and have identified potential targeted therapies for the treatment of this disease. RNA sequencing (RNA-seq) experiments uncovered expression changes caused by ER mutations, including both estradiol-regulated genes and mutation-specific, estradiol-independent genes. We found mutation-specific changes in gene expression were not recapitulated with prolonged estrogen exposure in wildtype cells, suggesting the mutant ER transcriptome is distinct from constitutive ER activity. The unique mutant ER expression program was related to phenotypic changes in ER mutant endometrial cancer cells, including increased proliferation specifically in vivo and increased migration in vitro relative to wildtype cells, consistent with more aggressive endometrial tumors. Based on the transcriptional and phenotypic alterations caused by mutant ER, we explored gene regulation based drugs for the potential treatment of mutant ER endometrial tumors. We found that two small molecules, cyclin dependent kinase 9 (CDK9) inhibitor Alvocidib and steroid receptor coactivator 3 (SRC-3) inhibitor SI-2, decreased mutant ER’s ability to promote proliferation and migration. In conclusion, mutant ER confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells. This activity has led us to identify two drugs that show efficacy in treating mutant ER endometrial cancer cells, however further study is needed to ascertain whether they can be utilized as novel therapeutic targets in this disease. Citation Format: Zannel Blanchard, Jeffery M. Vahrenkamp, Spencer Arnesen, Kristofer C. Berrett, Jason Gertz. Characterization of molecular, phenotypic, and drug sensitivity changes due to estrogen receptor alpha mutations in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO012.
APOBEC and Cancer Viroimmunotherapy: Thinking the Unthinkable
Authors: Richard G. Vile, Alan Melcher, Hardev Pandha, Kevin J. Harrington, Jose S. Pulido
Journal: Clinical Cancer Research (2021)

Abstract The apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) family protects against infection by degrading incoming viral genomes through cytosine deamination. Here, we review how the potential to unleash these potent DNA mutagens comes at a price as APOBEC DNA mutagenesis can contribute to development of multiple types of cancer. In addition, because viral infection induces its expression, APOBEC is seen as the enemy of oncolytic virotherapy through mutation of the viral genome and by generating virotherapy-resistant tumors. Therefore, overall APOBEC in cancer has received very poor press. However, we also speculate how there may be silver linings to the storm clouds (kataegis) associated with APOBEC activity. Thus, although mutagenic genomic chaos promotes emergence of ever more aggressive subclones, it also provides significant opportunity for cytotoxic and immune therapies. In particular, the superpower of cancer immunotherapy derives in part from mutation, wherein generation of tumor neoantigens—neoantigenesis—exposes tumor cells to functional T-cell repertoires, and susceptibility to immune checkpoint blockade. Moreover, APOBECs may be able to induce suprathreshold levels of cellular mutation leading to mitotic catastrophe and direct tumor cell killing. Finally, we discuss the possibility that linking predictable APOBEC-induced mutation with escape from specific frontline therapies could identify mutated molecules/pathways that can be targeted with small molecules and/or immunotherapies in a Trap and Ambush strategy. Together, these considerations lead to the counterintuitive hypothesis that, instead of attempting to expunge and excoriate APOBEC activity in cancer therapy, it might be exploited—and even, counterintuitively, encouraged.
Home-based exercise programmes improve physical fitness of healthy older adults: A PRISMA-compliant systematic review and meta-analysis with relevance for COVID-19
Authors: H. Chaabene, O. Prieske, M. Herz, J. Moran, J. Höhne, R. Kliegl, R. Ramirez-Campillo, D.G. Behm, T. Hortobágyi, U. Granacher
Journal: Ageing Research Reviews (2021)
A global analysis of replacement of genetic variants of SARS-CoV-2 in association with containment capacity and changes in disease severity
Authors: Zigui Chen, Ka Chun Chong, Martin C.S. Wong, Siaw S. Boon, Junjie Huang, Maggie H. Wang, Rita W.Y. Ng, Christopher K.C. Lai, Paul K.S. Chan
Journal: Clinical Microbiology and Infection (2021)

ObjectivesTo examine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant replacement in association with containment capacity and changes in case fatality at country level.MethodsAltogether, 69 571 full SARS-CoV-2 genomes collected globally within the first 6 months of the pandemic were examined. The correlation between variant replacement and containment capacity was examined by logistic regression models using the WHO International Health Regulation (IHR) score, the Oxford COVID-19 Government Response Tracker (OxCGRT) and the vulnerability index INFORM as proxies, while correlation with changes in monthly crude case fatality ratios was examined by a mixed effect model.ResultsAt the global level, variant lineage G∗, characterized by the S-D614G mutation, replaced the older lineages L and S in March 2020. European countries—including Finland, France and Italy—were the first to reach a 50% increment of G∗, whereas only Singapore and South Korea had non-G∗ persisting throughout the first 6 months. Countries with higher IHR scores (β-coefficient –0.001, 95%CI –0.016, –0.001; p 0.034) and higher stringency indexes (OxCGRT) (β-coefficient –0.011, 95%CI –0.020, –0.001; p 0.035) were associated with lower levels of G∗ replacement, whereas higher vulnerability indexes (INFORM) (β-coefficient 0.049, 95%CI 0.001, 0.097; p 0.044) were associated with higher replacement levels. Crude case fatality ratio showed a positive correlation with G∗ replacement (β-coefficient: 0.034, 95%CI 0.011, 0.058; p 0.004), even after adjusting for testing capacity and other country-specific characteristics.ConclusionsSARS-CoV-2 variant lineage G∗ (S-D614G) replaced older lineages more efficiently in countries with lower containment capacity, and its possible association with increased disease severity deserves further investigation.
EXTRAVASCULAR LUNG WATER (EVLW): WHICH INDEXATION TO USE? A PROSPECTIVE STUDY WITH 696 TRANSPULMONARY THERMODILUTION (TPTD) MEASUREMENTS IN 50 MECHANICALLY VENTILATED PATIENTS AND COMPARISON TO AN EVALUATION COLLECTOlE INCLUDING 181 PATIENTS AND 1426 TPTDS
Authors: W. Huber, I. Hoellthaler, T. Schuster, A. Umgelter, M. Franzen, B. Saugel, R. M. Schmid, M. Malbrain
Journal: Intensive Care Medicine (2011)
Comparison of cardiovascular and renal outcomes between sodium glucose co– transporter–2 and dipeptidyl peptidase–4 inhibitors among type 2 diabetes patients: a real–world, retrospective cohort study
Authors: Iskandar Idris, Ruiqi Zhang, Jil Billy Mamza, Mike Ford, Tamsin Morris, Amitava Banerjee, Kamlesh Khunti
Journal: Metabolism (2021)
Interhemispheric transfer of working memories
Authors: Scott L. Brincat, Jacob A. Donoghue, Meredith K. Mahnke, Simon Kornblith, Mikael Lundqvist, Earl K. Miller
Journal: Neuron (2021)

Visual working memory (WM) storage is largely independent between the left and right visual hemifields/cerebral hemispheres, yet somehow WM feels seamless. We studied how WM is integrated across hemifields by recording neural activity bilaterally from lateral prefrontal cortex. An instructed saccade during the WM delay shifted the remembered location from one hemifield to the other. Before the shift, spike rates and oscillatory power showed clear signatures of memory laterality. After the shift, the lateralization inverted, consistent with transfer of the memory trace from one hemisphere to the other. Transferred traces initially used different neural ensembles from feedforward-induced ones, but they converged at the end of the delay. Around the time of transfer, synchrony between the two prefrontal hemispheres peaked in theta and beta frequencies, with a directionality consistent with memory trace transfer. This illustrates how dynamics between the two cortical hemispheres can stitch together WM traces across visual hemifields.
Diagnostic Dilemma on Novel Pathogenic Variant of Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) in a Family with Chronic ITP and Immune Dysregulation
Authors: Priyanka Timothy, Mary Ann Miranda, Jocelyn Farmer, Jolan Walter, Emma Westermann-Clark
Journal: Journal of Allergy and Clinical Immunology (2021)
Increased Prevalence of Autoimmune Diseases in Children with Chronic Spontaneous Urticaria
Authors: Michelle Le, Lydia Zhang, Sofianne Gabrielli, Elena Netchiporouk, Sharon Baum, Shoshana Greenberger, Luis Felipe Ensina, Fatemeh Jafarian, Xun Zhang, Moshe Ben-Shoshan
Journal: Journal of Allergy and Clinical Immunology (2021)
Cutting down the hematopoietic tree: E-cadherin reveals a landscape of differentiating basophils and mast cells
Authors: Joakim S. Dahlin
Journal: Science Immunology (2021)

GATA-2–mediated E-cadherin expression marks early progenitors primed to the basophil and mast cell lineages in mouse hematopoiesis (see the related Research Article by Wanet et al . ).
Response to: ‘Correspondence on ‘Non-surgical and surgical treatments for rotator cuff disease: a pragmatic randomised clinical trial with 2-year follow-up after initial rehabilitation’’ by Randelli<i>et al</i>
Authors: Sanna Cederqvist, Tapio Flinkkilä, Jari Ylinen, Hannu Kautiainen, Antti Tuominen, Ilkka Kiviranta, Juha Paloneva
Journal: Annals of the Rheumatic Diseases (2021)

We warmly thank Randelli and coworkers for their interest in our work.1 Our randomised, pragmatic, controlled trial compared surgical and non-surgical treatments for rotator cuff disease (RCD) with or without full-thickness tendon tears after unsuccessful initial rehabilitation.2

Randelli and coworkers commented that the power of our study lies in the fact that potential eligible patients underwent a systematic, adequately performed 3-month rehabilitation, after which only patients who remained symptomatic were randomised; we agree. Symptoms alleviated in 102 of the 417 shoulders with chronic RCD (mean duration of symptoms 9 months before recruitment) during the 3 month, pragmatic nonoperative treatment. This indicates that conservative management should be carried out in all patients with chronic RCD before considering surgical treatment for full-thickness rotator cuff tear.

Randelli and coworkers criticised us for not reporting baseline characteristics of the prespecified subgroups (RCD with and without full-thickness tendon rupture). They also noted that while 25% …
Covid-19: The E484K mutation and the risks it poses
Authors: Jacqui Wise
Journal: BMJ (2021)

The mutation E484K, first identified in the South African SARS-CoV-2 variant, has now been identified in the UK fast-spreading variant, prompting fears the virus is evolving further and could become resistant to vaccines. <b>Jacqui Wise</b> looks at what we know so far
Synergistic effects of magnesium ions and simvastatin on attenuation of high-fat diet-induced bone loss
Authors: Bingyang Dai, Xu Li, Jiankun Xu, Yuwei Zhu, Le Huang, Wenxue Tong, Hao Yao, Dick Ho-kiu Chow, Ling Qin
Journal: Bioactive Materials (2021)

Magnesium (Mg) has a prophylactic potential against the onset of hyperlipidemia. Similar to statin, Mg is recommended as lipid-lowering medication for hypercholesterolemia and concomitantly exhibits an association with increased bone mass. The combination of statin with Mg ions (Mg2+) may be able to alleviate the high-fat diet (HFD)-induced bone loss and reduce the side-effects of statin. This study aimed to explore the feasibility of combined Mg2+ with simvastatin (SIM) for treating HFD-induced bone loss in mice and the involving mechanisms.C57BL/6 male mice were fed with a HFD or a normal-fat diet (NFD). Mice were intraperitoneally injected SIM and/or orally received water with additional Mg2+ until sacrificed. Enzyme-linked immunosorbent assay was performed to measure cytokines and cholesterol in serum and liver lysates. Bone mineral density (BMD) and microarchitecture were assessed by micro-computed tomography (μCT) in different groups. The adipogenesis in palmitate pre-treated HepG2 cells was performed under various treatments.μCT analysis showed that the trabecular bone mass was significantly lower in the HFD-fed group than that in NFD-fed group since week 8. The cortical thickness in HFD-fed group had a significant decrease at week 24, as compared with NFD-fed group. The combination of Mg2+ and SIM significantly attenuated the trabecular bone loss in HFD-fed mice via arresting the osteoclast formation and bone resorption. Besides, such combination also reduced the hepatocytic synthesis of cholesterol and inhibited matrix metallopeptidase 13 (Mmp13) mRNA expression in pre-osteoclasts.The combination of Mg2+ and SIM shows a synergistic effect on attenuating the HFD-induced bone loss. Our current formulation may be a cost-effective alternative treatment to be indicated for obesity-related bone loss.
Evaluation of Efficacy and Safety of Nab-Paclitaxel vs Paclitaxel in Platinum-Refractory Metastatic Urothelial Cancer
Authors: Satoshi Funada, Takashi Yoshioka, Yan Luo
Journal: JAMA Oncology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue
Intensity of Renal Support for Acute Kidney Injury in the Critically Ill
Authors: Palevsky Pp, Zhang Jh, O'Connor Tz, Glenn M. Chertow, Crowley S, Choudhury D, Finkel K, Kellum Ja, Paganini E, Schein Rmh, Mark W. Smith, Swanson K, Thompson Bt, Vijayan A, Watnick S, Star Ra, Peduzzi P
Journal: New England Journal of Medicine (2008)