tbuckley/cabot-search huggingface dataset:
The Evolution of Human Cancer Gene Duplications across Mammals
Authors: Marc Tollis, Aika K Schneider-Utaka, Carlo C Maley
Journal: Molecular Biology and Evolution (2020)

Cancer is caused by genetic alterations that affect cellular fitness, and multicellular organisms have evolved mechanisms to suppress cancer such as cell cycle checkpoints and apoptosis. These pathways may be enhanced by the addition of tumor suppressor gene paralogs or deletion of oncogenes. To provide insights to the evolution of cancer suppression across the mammalian radiation, we estimated copy numbers for 548 human tumor suppressor gene and oncogene homologs in 63 mammalian genome assemblies. The naked mole rat contained the most cancer gene copies, consistent with the extremely low rates of cancer found in this species. We found a positive correlation between a species' cancer gene copy number and its longevity, but not body size, contrary to predictions from Peto's Paradox. Extremely long-lived mammals also contained more copies of caretaker genes in their genomes, suggesting that the maintenance of genome integrity is an essential form of cancer prevention in long-lived species. We found the strongest association between longevity and copy numbers of genes that are both germline and somatic tumor suppressor genes, suggesting that selection has acted to suppress both hereditary and sporadic cancers. We also found a strong relationship between the number of tumor suppressor genes and the number of oncogenes in mammalian genomes, suggesting that complex regulatory networks mediate the balance between cell proliferation and checks on tumor progression. This study is the first to investigate cancer gene expansions across the mammalian radiation and provides a springboard for potential human therapies based on evolutionary medicine.
Doctors welcome plan to scrap NHS fee for overseas staff
Authors: Abi Rimmer
Journal: BMJ (2020)

Doctors have welcomed the government’s decision to scrap the immigration health surcharge for overseas healthcare workers.

Speaking at the 21 May daily briefing, England’s health and social care secretary, Matt Hancock, said, “We can remove NHS and care workers from the NHS surcharge as soon as possible, and I am very pleased to be able to do that.”

He added, “The purpose of the immigration health surcharge within the NHS is a fair one. The purpose is to …
Age-dependent response of the human nasal epithelium to rhinovirus infection
Authors: Jakob Usemann, Marco P. Alves, Nicole Ritz, Philipp Latzin, Loretta Müller
Journal: European Respiratory Journal (2020)

<b>After rhinovirus (RV) infection, RV viral loads are higher and immune factor expressions lower in nasal epithelial cells from children <i>versus</i> adults <i>in vitro</i>. This may explain age-dependent severity of RV infections and association with asthma development</b>https://bit.ly/2zNfJhD
Is It Time to Introduce PET/CT in Colon Cancer Guidelines?
Authors: Anna Margherita Maffione, Domenico Rubello, Paola Caroli, Patrick M. Colletti, Federica Matteucci
Journal: Clinical Nuclear Medicine (2020)

Abstract International colon cancer guidelines suggest 18 F-FDG PET/CT in a few circumstances: (1) at disease presentation in case of suspected or proven metastatic synchronous adenocarcinoma; (2) in the workup of recurrent colon cancer with metachronous metastases documented by CT, MRI, or biopsy and in case of serial CEA elevation with negative colonoscopy and negative CT; and (3) in case of contraindication to iodine- and gadolinium-based contrast agents. However, review of the literature has shown that PET/CT can also be used in other scenarios with significant levels of diagnostic advantage. This review aims to emphasize differences between guidelines and scientific literature for the use of PET/CT in colon cancer.
MOFA+: a statistical framework for comprehensive integration of multi-modal single-cell data
Authors: Ricard Argelaguet, Damien Arnol, Danila Bredikhin, Yonatan Deloro, Britta Velten, John C. Marioni, Oliver Stegle
Journal: Genome biology (2020)

Abstract Technological advances have enabled the profiling of multiple molecular layers at single-cell resolution, assaying cells from multiple samples or conditions. Consequently, there is a growing need for computational strategies to analyze data from complex experimental designs that include multiple data modalities and multiple groups of samples. We present Multi-Omics Factor Analysis v2 (MOFA+), a statistical framework for the comprehensive and scalable integration of single-cell multi-modal data. MOFA+ reconstructs a low-dimensional representation of the data using computationally efficient variational inference and supports flexible sparsity constraints, allowing to jointly model variation across multiple sample groups and data modalities.
One-armed 5D5 (OA5D5) is a potent humanized HGF-blocking anti-c-Met monovalent antibody that inhibits HGF-dependent activity in vitro and demonstrates anti-tumor efficacy in vivo
Authors: Mark Merchant, Zhong Zheng, Maria Romero, Arthur Huang, Camellia Adams, Barbara Moffat, Min Zhang, Yvonne Chen, Liping Wang, Monique La Fleur, Janet Tien, Sarajane Ross, Minhong Yan, William Mallet, Hani Bou Reslan, Jed Ross, Richard Carano, Renhui Yang, Hongkui Jin, Gail Colbern, Mark Dennis, Daniel Yansura, Ralph Schwall
Journal: Cancer Research (2007)

LB-372  The receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor/scatter factor (HGF/SF) are correlated with poor prognosis in numerous human cancers. We demonstrate here a novel monovalent antibody-based approach to block HGF/c-Met signaling. One-armed 5D5 (OA5D5) is an E. coli produced, humanized, monovalent, antagonistic anti-c-Met antibody, derived from the agonistic monoclonal antibody (mAb) 5D5. While the 5D5 mAb blocks HGF from binding to c-Met, it dimerizes and activates c-Met, stimulating receptor phosphorylation, downstream pathway activity and cellular responses, such as migration, morphogenesis and mitogenesis. 5D5 Fab fragments also block HGF from binding to c-Met, however do so without agonizing c-Met and instead act as antagonists. As it is difficult to achieve and maintain therapeutic levels of Fab fragments in vivo, a monovalent Fab/Fc form of 5D5 (OA5D5) was engineered. The novel design of OA5D5 utilizes knobs-into-holes mutations in the buried CH3-CH3 interface that enable proper assembly into a functional monovalent antibody when expressed in E. coli. OA5D5 binds to c-Met with high affinity and remains on the cell surface with c-Met, preventing HGF binding and subsequent c-Met phosphorylation as well as downstream signaling activity and cellular responses. In mice, OA5D5 is stable much longer than the 5D5 Fab, with a half-life of approximately 3-6 days. OA5D5 has significant anti-tumor efficacy in human glioblastoma (U87 MG) and pancreatic ductal carcinoma (KP4) subcutaneous and orthotopic xenograft models where HGF is produced as an autocrine growth factor. Anti-tumor efficacy is observed with single OA5D5 doses of 7.5 mg/kg and above. Together, these results show that OA5D5 is a potent, anti-c-Met monovalent antibody with promise as a therapeutic antibody in human cancer.
Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs
Authors: Kai Yuan, Xiao Wang, Haojie Dong, Wenjian Min, Haiping Hao, Peng Yang
Journal: Acta Pharmaceutica Sinica B (2020)

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. To date, three selective CDK4/6 inhibitors have received approval from the U.S. Food and Drug Administration (FDA), and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers. In this perspective, we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells, analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment, review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds, explain the mechanisms associated with CDK4/6 inhibitor resistance and describe solutions to overcome this issue, and briefly introduce proteolysis targeting chimera (PROTAC), a new and revolutionary technique used to degrade CDK4/6.
IgM and IgA in addition to IgG autoantibodies against FcɛRIα are frequent and associated with disease markers of chronic spontaneous urticaria
Authors: Sabine Altrichter, Vasiliki Zampeli, André Ellrich, Ke Zhang, Martin K Church, Marcus Maurer
Journal: Allergy (2020)

ABSTRACT Background IgG autoantibodies against the high‐affinity IgE receptor, FcɛRIα, contribute the pathogenesis of autoimmune chronic spontaneous urticaria (CSU). However, it is not known whether such patients also exhibit IgM or IgA autoantibodies against FcɛRIα. To address this question we developed an ELISA to assess serum levels of IgG, IgM, and IgA autoantibodies against FcɛRIα and investigated whether their presence is linked to clinical features of CSU including the response to autologous serum skin testing (ASST). Methods Serum samples of 35 CSU patients (25 ASST‐positive) and 52 healthy control individuals were analyzed using a newly developed competitive ELISA for IgG, IgM, and IgA autoantibodies to FcɛRIα. Results One in four CSU patients (8/35, 24%) had elevated serum levels of IgG‐anti‐FcɛRIα compared with (3/52, 6%) healthy controls. More than half of patients had IgM (21/35, 60%) and IgA (20/35, 57%) vs (3/52, 5%) each in healthy controls. Elevated IgM, but not IgG or IgA, autoantibodies were significantly more frequent in ASST‐positive CSU patients (18/25, 72%) compared with ASSTnegative patients (3/10, 33%, P = .022). Also, elevated levels of IgM‐anti‐FcɛRIα, but not of IgG or IgA against FcɛRIα, were linked to low blood basophil ( r = .414, P = .021) and eosinophil ( r = .623, P &lt; .001) counts. Conclusions Increased serum levels of IgM‐anti‐FcɛRIα are common in patients with CSU and linked to features of autoimmune CSU. The role and relevance of autoantibodies to FcɛRIα in CSU can and should be further characterized in future studies, and our novel assay can help with this.
Treatment of AF in American Indians and Alaska Natives
Authors: Umair Khalid, Lucas N. Marzec, Nicholas Mantini, Spero M. Manson, Gheorghe Doros, Christopher P. Cannon, Yang Song, Liyan Dong, Jonathan C. Hsu, Mark Y. Jeong, Salim S. Virani, Thomas M. Maddox
Journal: Journal of the American College of Cardiology (2020)
Revitalized AHCPR Pursues Research on Quality
Authors: Joan Stephenson
Journal: JAMA (1997)

AFTER a "near-death experience" that nearly wiped it out of existence 2 years ago, the Agency for Health Care Policy and Research (AHCPR) appears to be remarkably robust these days. In 1995, the agency, known for developing evidence-based clinical practice guidelines, came under fire when it published a guideline on back pain that said that most spinal surgery was unnecessary and that more conservative treatment was usually as effective and far less expensive. Angry surgeons lobbied Congress to cut the agency off at the knees. Congress responded, slashing the Rockville, Md-based agency's budget from $159 million for 1995 to $125 million for 1996. But AHCPR, which is part of the Public Health Service in the US Department of Health and Human Services, has survived, keeping its mission of quality improvement and cost containment intact while changing how it pursues this mission. While it no longer develops its own clinical practice
Effect of Pharmacologic Prophylaxis on Venous Thromboembolism After Radical Prostatectomy: The PREVENTER Randomized Clinical Trial
Authors: Hiten D. Patel, Farzana A. Faisal, Bruce J. Trock, Gregory A. Joice, Zeyad R. Schwen, Phillip M. Pierorazio, Michael H. Johnson, Trinity J. Bivalacqua, Misop Han, Michael A. Gorin, H. Ballentine Carter, Alan W. Partin, Christian P. Pavlovich, Mohamad E. Allaf
Journal: European Urology (2020)
80O Patient (pt) preference and satisfaction with the subcutaneous fixed-dose combination of pertuzumab (P) and trastuzumab (H) in pts with HER2-positive early breast cancer (HER2+ eBC): Interim analysis of the open-label, randomised cross-over PHranceSCa study
Authors: J. O'Shaughnessy, S.P. Sousa, J. Cruz, L.J. Fallowfield, P. Auvinen, C. Pulido, A. Cvetanovic, S. Wilks, L. Ribeiro, M. Burotto, D. Klingbiel, D. Messeri, A. Alexandrou, P. Trask, J. Fredriksson, L. Stamatovic
Journal: Annals of Oncology (2020)
Homotrimer cavin1 interacts with caveolin1 to facilitate tumor growth and activate microglia through extracellular vesicles in glioma
Authors: Lin Wang, Chao Yang, Qixue Wang, Qi Liu, Yunfei Wang, Junhu Zhou, Yansheng Li, Yanli Tan, Chunsheng Kang
Journal: Theranostics (2020)

Background: Intercellular communication via extracellular vesicles (EVs) plays a critical role in glioma progression. However, little is known about the precise mechanism regulating EV secretion and function. Our previous study revealed that Cavin1 was positively correlated with malignancy grades of glioma patients, and that overexpressing Cavin1 in glioma cells enhanced the malignancy of nearby glioma cells via EVs. Methods: The current study used bioinformatics to design a variant Cavin1 (vCavin1) incapable of interacting with Caveolin1, and compared the effects of overexpressing Cavin1 and vCavin1 in glioma cells on EV production and function. Results: Remarkably, our results indicated that Cavin1 expression enhanced the secretion, uptake, and homing ability of glioma-derived EVs. EVs expressing Cavin1 promoted glioma growth in vitro and in vivo. In addition, Cavin1 expressing murine glioma cells recruited and activated microglia via EVs. However, vCavin1 neither was loaded onto EVs nor altered EV secretion and function. Conclusion: Our findings suggested that Cavin1-Caveolin1 interaction played a significant role in regulating production and function of glioma-EVs, and may act as a promising therapeutic target in gliomas that express high levels of Cavin1.
Trachyonychia (rough nails)
Authors: P.D. Samman
Journal: British Journal of Dermatology (1978)

Journal Article Trachyonychia (rough nails) Get access P.D. Samman P.D. Samman The Westminster Hospital, London Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 99, Issue s16, 1 December 1978, Page 13, https://doi.org/10.1111/j.1365-2133.1978.tb15206.x Published: 01 December 1978
44P Obesity is associated with a late-stage diagnosis in triple-negative breast cancer
Authors: A. Aranda-Gutierrez, A.S. Ferrigno, M. Moncada-Madrazo, A. Gomez-Picos, C. De la Garza-Ramos, F. Mesa-Chavez, H. Diaz-Perez, S. Cardona, R. Ortiz-Lopez, C. Villarreal-Garza
Journal: Annals of Oncology (2020)
Abstract 131: PDE1 Inhibition Improves Cardiac Protein Quality Control
Authors: Hanming Zhang, Xuejun "XJ" Wang
Journal: Circulation Research (2016)

Protein quality control (PQC) functions to minimize the level and toxicity of misfolded proteins in the cell. PQC relies on molecular chaperones and the targeted degradation of misfolded proteins. The latter is currently known to require the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP). Virtually all cardiovascular diseases end up heart failure (HF), the leading cause of death of our society. UPS function insufficiency is implicated in the genesis of a large subset of HF, making cardiac PQC enhancement via promoting UPS and ALP function a promising therapeutic strategy to treat HF. Previously, we have demonstrated that stimulating protein kinase G (PKG) genetically or via inhibition of the type 5 phosphodiesterase (PDE5) improves UPS performance, facilitates the removal of misfolded proteins in cardiomyocytes and slows down the progression of cardiac proteinopathy in a transgenic mouse model (CryAB R120G ). PKA has also been shown to enhance proteasomal function. Our preliminary studies reveal that myocardial protein levels of PDE1A, which suppresses both PKG and PKA, are remarkably elevated in the CryAB R120G mice. Hence we hypothesize that PDE1 inhibition (PDE1I) stimulates cardiac proteasomes via PKG and PKA activation and thereby protects against cardiac proteotoxicity. To test our hypothesis, we took advantage of a proven surrogate UPS substrate (GFPu or GFPdgn) as well as a bona fide misfolded protein (CryAB R120G ) that is known to induce cardiac proteinopathy in human and mice. In cultured cardiomyocytes, PDE1 inhibitor LSN2790158 dose- and time-dependently decreased GFPu. Cycloheximide (CHX) chase assays further confirmed that PDE1I shortened the half-life of GFPu, indicative of improved UPS performance. Furthermore, PDE1I promoted the degradation of CryAB R120G . Our in vivo findings revealed that GFPdgn mice treated with LSN2790158 (3mg/kg, i.p.) displayed a significant reduction of myocardial GFPdgn protein but not mRNA levels. Taken together, our data strongly indicate that PDE1I improves cardiac UPS performance and PDE1 represents a potential target to treat cardiac diseases with elevated proteotoxicity.
Re: Andrea Necchi, Marco Bandini, Giuseppina Calareso, et al. Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study. Eur Urol 2020;77:636–43
Authors: Yunjin Bai, Yubo Yang, Yin Tang
Journal: European Urology (2020)
Extracellular Vesicle–Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models
Authors: Li Yang, Bing Han, Zhiting Zhang, Shuguo Wang, Ying Bai, Yuan Zhang, Ying Tang, Lingli Du, Ling Xu, Fangfang Wu, Lei Zuo, Xufeng Chen, Yu Lin, Kezhong Liu, Qingqing Ye, Biling Chen, Bin Li, Tianci Tang, Yu Wang, Ling Shen, Guangtian Wang, Minzi Ju, Mengqin Yuan, Wei Jiang, John H. Zhang, Gang Hu, Jianhong Wang, Honghong Yao
Journal: Circulation (2020)

Background: Stroke is a leading cause of adult disability that can severely compromise the quality of life of patients, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNA) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of the potential therapeutic roles for circRNAs. Methods: Circular RNA SCMH1 (circSCMH1) was screened from the plasma of patients with acute ischemic stroke by using circRNA microarrays. Engineered rabies virus glycoprotein-circSCMH1-extracellular vesicles were generated to selectively deliver circSCMH1 to the brain. Nissl staining was used to examine infarct size. Behavioral tasks were performed to evaluate motor functions in both rodent and nonhuman primate ischemic stroke models. Golgi staining and immunostaining were used to examine neuroplasticity and glial activation. Proteomic assays and RNA-sequencing data combined with transcriptional profiling were used to identify downstream targets of circSCMH1. Results: CircSCMH1 levels were significantly decreased in the plasma of patients with acute ischemic stroke, offering significant power in predicting stroke outcomes. The decreased levels of circSCMH1 were further confirmed in the plasma and peri-infarct cortex of photothrombotic stroke mice. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that circSCMH1 treatment improved functional recovery after stroke in both mice and monkeys, and we discovered that circSCMH1 enhanced the neuronal plasticity and inhibited glial activation and peripheral immune cell infiltration. CircSCMH1 binds mechanistically to the transcription factor MeCP2 (methyl-CpG binding protein 2), thereby releasing repression of MeCP2 target gene transcription. Conclusions: Rabies virus glycoprotein-circSCMH1-extracellular vesicles afford protection by promoting functional recovery in the rodent and the nonhuman primate ischemic stroke models. Our study presents a potentially widely applicable nucleotide drug delivery technology and demonstrates the basic mechanism of how circRNAs can be therapeutically exploited to improve poststroke outcomes.
Corrections to “Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance?”
Authors: D. Santini, B. Vincenzi, R. Addeo, C. Garufi, G. Masi, M. Scartozzi, A. Mancuso, A.M. Frezza, O. Venditti, M. Imperatori, G. Schiavon, G. Bronte, G. Cicero, F. Recine, E. Maiello, S. Cascinu, A. Russo, A. Falcone, G. Tonini
Journal: Annals of Oncology (2017)
Exercise protects proliferative muscle satellite cells against exhaustion via the Igfbp7-Akt-mTOR axis
Authors: Zhe Chen, Lei Li, Weiru Wu, Zhilong Liu, Yongxiu Huang, Li Yang, Qing Luo, Jieping Chen, Yu Hou, Guanbin Song
Journal: Theranostics (2020)

: The exhaustion of muscle satellite cells (SCs) is correlated with muscle diseases, including sarcopenia and Duchenne muscular dystrophy. Exercise benefits skeletal muscle homeostasis and promotes proliferation of SCs. Elucidating the molecular mechanism underlying the muscle function-improving effect of exercise has important implications in regenerative medicine.
The Landscape of Human Cancer Proteins Targeted by SARS-CoV-2
Authors: Beril Tutuncuoglu, Merve Cakir, Jyoti Batra, Mehdi Bouhaddou, Manon Eckhardt, David E. Gordon, Nevan J. Krogan
Journal: Cancer Discovery (2020)

Abstract Summary: The mapping of SARS-CoV-2 human protein–protein interactions by Gordon and colleagues revealed druggable targets that are hijacked by the virus. Here, we highlight several oncogenic pathways identified at the host–virus interface of SARS-CoV-2 to enable cancer biologists to apply their knowledge for rapid drug repurposing to treat COVID-19, and help inform the response to potential long-term complications of the disease.
The risk of multidrug- or rifampicin-resistance in males <i>versus</i> females with tuberculosis
Authors: C. Finn McQuaid, Katherine C. Horton, Anna S. Dean, Gwenan M. Knight, Richard G. White
Journal: European Respiratory Journal (2020)

Males are at an increased risk of tuberculosis (TB) disease compared to females. Additionally, several risk factors for multidrug-resistant (MDR) or rifampicin-resistant (RR) TB disease are more common in males, hence male TB patients may have a higher relative risk of MDR/RR-TB than female TB patients.We used sex-disaggregated data of TB patients reported to the World Health Organization for 106 countries to calculate male-to-female (M:F) risk ratios of having MDR/RR-TB.There was no evidence of either sex being more at risk of MDR/RR-TB in 81% (86 out of 106) of countries, with an overall random-effects weighted M:F risk ratio of 1.04 (95% CI 0.97-1.11). In 12% (13 out of 106) of countries there was evidence that males were more at risk, while in 7% (seven out of 106), females were more at risk. The risk of having TB that was MDR/RR increased for males compared to females as MDR/RR-TB incidence increased, and was higher for males than females in the former Soviet Union, where the risk ratio was 1.16 (1.06-1.28). Conversely, the risk increased for females compared to males as gross domestic product purchase power parity increased, and was higher for females than males in countries where the majority of TB burden was found in the foreign-born population, where the risk ratio was 0.84 (0.75-0.94).In general, the risk of MDR/RR-TB, among those with TB, is the same for males as for females. However, males in higher MDR/RR-TB burden countries, particularly the former Soviet Union, face an increased risk that their infection is MDR/RR-TB, highlighting the need for a sex-differentiated approach to TB case-finding and care.