tbuckley/cabot-search huggingface dataset:
Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes
Authors: Helen K. Reddel, Leonard B. Bacharier, Eric D. Bateman, Christopher E. Brightling, Guy G. Brusselle, Roland Buhl, Alvaro A. Cruz, Liesbeth Duijts, Jeffrey M. Drazen, J. Mark FitzGerald, Louise J. Fleming, Hiromasa Inoue, Fanny W. Ko, Jerry A. Krishnan, Mark L. Levy, Jiangtao Lin, Kevin Mortimer, Paulo M. Pitrez, Aziz Sheikh, Arzu A. Yorgancioglu, Louis-Philippe Boulet
Journal: European Respiratory Journal (2021)

<b>The GINA Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention. This article summarizes key recommendations from GINA 2021, and the evidence underpinning the new changes.</b>https://bit.ly/3FZblIS
When Doctors and Families Disagree in the Neurologic Intensive Care Unit—Misunderstandings and Optimistic Beliefs
Authors: Susanne Muehlschlegel
Journal: JAMA Network Open (2021)

Whitney A. Kiker, MD; Rachel Rutz Voumard, MD; Leah I. B. Andrews, BA; Robert G. Holloway, MD, MPH; Lyndia C. Brumback, PhD; Ruth A. Engelberg, PhD; J. Randall Curtis, MD, MPH; Claire J. Creutzfeldt, MD
Differences in State Traumatic Brain Injury–Related Deaths, by Principal Mechanism of Injury, Intent, and Percentage of Population Living in Rural Areas — United States, 2016–2018
Authors: Jill Daugherty, Hong Zhou, Kelly Sarmiento, Dana Waltzman
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Traumatic brain injuries (TBIs) have contributed to approximately one million deaths in the United States over the last 2 decades (1). CDC analyzed National Vital Statistics System (NVSS) mortality data for a 3-year period (2016-2018) to examine numbers and rates of TBI-related deaths, the percentage difference between each state's rate and the overall U.S. TBI-related death rate, leading causes of TBI, and the association between TBI and a state's level of rurality. During 2016-2018, a total of 181,227 TBI-related deaths (17.3 per 100,000 population per year) occurred in the United States. The percentage difference between state TBI-related death rates and the overall U.S. rate during this period ranged from 46.2% below to 101.2% above the overall rate. By state, the lowest rate was in New Jersey (9.3 per 100,000 population per year); the states with the highest rates were Alaska (34.8), Wyoming (32.6), and Montana (29.5). States in the South and those with a higher proportion of residents living in rural areas had higher rates, whereas states in the Northeast and those with a lower proportion of residents living in rural areas had lower TBI-related death rates. In 43 states, suicide was the leading cause of TBI-related deaths; in other states, unintentional falls or unintentional motor vehicle crashes were responsible for the highest numbers and rates of TBI-related deaths. Consistent with previous studies (2), differences in TBI incidence and outcomes were observed across U.S. states; therefore, states can use these findings to develop and implement evidence-based prevention strategies, based on their leading causes of TBI-related deaths. Expanding evidence-based prevention strategies that address TBI-related deaths is warranted, especially among states with high rates due to suicide, unintentional falls, and motor vehicle crashes.
Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors
Authors: Ku-Geng Huo, Hirotsugu Notsuda, Zhenhao Fang, Ningdi Feng Liu, Teklab Gebregiworgis, Quan Li, Nhu-An Pham, Ming Li, Ni Liu, Frances A. Shepherd, Christopher B. Marshall, Mitsuhiko Ikura, Nadeem Moghal, Ming-Sound Tsao
Journal: Journal of Thoracic Oncology (2021)

Mutations in BRAF occur in 2% to 4% of patients with lung adenocarcinoma. Combination dabrafenib and trametinib, or single-agent vemurafenib is approved only for patients with cancers driven by the V600E BRAF mutation. Targeted therapy is not currently available for patients harboring non-V600 BRAF mutations.A lung adenocarcinoma patient-derived xenograft model (PHLC12) with wild-type and nonamplified EGFR was tested for response to EGFR tyrosine kinase inhibitors (TKIs). A cell line derived from this model (X12CL) was also used to evaluate drug sensitivity and to identify potential drivers by small interfering RNA knockdown. Kinase assays were used to test direct targeting of the candidate driver by the EGFR TKIs. Structural modeling including, molecular dynamics simulations, and binding assays were conducted to explore the mechanism of off-target inhibition by EGFR TKIs on the model 12 driver.Both patient-derived xenograft PHLC12 and the X12CL cell line were sensitive to multiple EGFR TKIs. The BRAFG469V mutation was found to be the only known oncogenic mutation in this model. Small interfering RNA knockdown of BRAF, but not the EGFR, killed X12CL, confirming BRAFG469V as the oncogenic driver. Kinase activity of the BRAF protein isolated from X12CL was inhibited by treatment with the EGFR TKIs gefitinib and osimertinib, and expression of BRAFG469V in non-EGFR-expressing NR6 cells promoted growth in low serum condition, which was also sensitive to EGFR TKIs. Structural modeling, molecular dynamic simulations, and in vitro binding assays support BRAFG469V being a direct target of the TKIs.Clinically approved EGFR TKIs can be repurposed to treat patients with non-small cell lung cancer harboring the BRAFG469V mutation.
Early Antibiotic Exposure Is Not Detrimental to Therapeutic Effect from Immunotherapy in Hepatocellular Carcinoma
Authors: Petros Fessas, Muntaha Naeem, Matthias Pinter, Thomas U. Marron, David Szafron, Lorenz Balcar, Anwaar Saeed, Tomi Jun, Sirish Dharmapuri, Anuhya Gampa, Yinghong Wang, Uqba Khan, Mahvish Muzaffar, Musharraf Navaid, Pei-Chang Lee, Anushi Bulumulle, Bo Yu, Sonal Paul, Neil Nimkar, Dominik Bettinger, Hannah Hildebrand, Yehia I. Abugabal, Tiziana Pressiani, Nicola Personeni, Naoshi Nishida, Masatoshi Kudo, Ahmed Kaseb, Yi-Hsiang Huang, Celina Ang, Anjana Pillai, Lorenza Rimassa, Abdul Rafeh Naqash, Elad Sharon, Alessio Cortellini, David J. Pinato
Journal: Liver Cancer (2021)

Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC.In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within -30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria.Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494).Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.
Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial
Authors: Man-Fung Yuen, Jeong Heo, Jeong-Won Jang, Jung-Hwan Yoon, Young-Oh Kweon, Sung-Jae Park, Yvonne Tami, Shihyun You, Phillip Yates, Yu Tao, Jennifer Cremer, Fiona Campbell, Robert Elston, Dickens Theodore, Melanie Paff, C. Frank Bennett, T. Jesse Kwoh
Journal: Nature Medicine (2021)

Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml-1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naïve participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n = 3) or day 36 (n = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population.
Bullous Dermatoses and Depression
Authors: Sarah P. Pourali, Yasmin Gutierrez, Alison H. Kucharik, Jeffrey R. Rajkumar, Madison E. Jones, Isabela Ortiz, Michelle David, April W. Armstrong
Journal: JAMA Dermatology (2021)

Importance There is a lack of evidence synthesis on the association between bullous skin disease and depression. Objective To synthesize and interpret the current evidence on the association between bullous skin disease and depression. Evidence Review This review was conducted according to PRISMA guidelines and reviewed literature related to bullous skin disease and depression in the PubMed, Embase, PsycInfo, and Cochrane databases published between 1945 and February 2021. The quality of each included article was assessed via the Newcastle-Ottawa Scale. This review was registered with PROSPERO ( CRD42021230750 ). Findings A total of 17 articles were identified that analyzed a total of 83 910 patients (55.2% female; specifically, 6951 patients with bullous pemphigoid, 1669 patients with pemphigus, and 79 patients with epidermolysis bullosa were analyzed). The prevalence of depressive symptoms among patients with bullous dermatoses ranged from 40% to 80%. The prevalence of depression diagnosis among patients with bullous dermatoses ranged from 11.4% to 28%. Conclusions and Relevance In this systematic review, high rates of depression and depressive symptoms existed among patients with bullous skin disease. Adequate treatment of bullous dermatoses may be associated with a decrease in mental health burden on patients.
Covid-19: Why Africa’s pandemic is different
Authors: Meera Senthilingam
Journal: BMJ (2021)

Covid-19: Why Africa's pandemic is different Africa's initially slow burn pandemic puzzled scientists.Meera Senthilingam examines the factors at play, and explores the impact of the new variants Meera Senthilingam freelance journalist "Inequity" is a word firmly attached to Africa, and not just in the pandemic.Inequity in resources, funding, and infrastructure means that diseases-malaria, tuberculosis, HIV, and intestinal worms, among others-persist in Africa long after other regions overcame them.
Array-comparative genomic hybridization analyses of chromosome 18q in prostate tumor samples
Authors: Devon C. Hall, Sapna Vijayakumar, Susan Naylor, Dean A. Troyer, Xavier T. Reveles, Teresa L. Johnson-Pais, Robin J. Leach
Journal: Cancer Research (2005)

3578  Chromosomal alterations, such as amplification and deletions, are frequently observed during the progression of cancer. Although prostate cancer has a major genetic component, many of the specific genes involved in prostate cancer incidence and progression have remained elusive. Several studies revealed that loss of chromosome 18q occurs in approximately 19% to 48% of prostate cancer cases and that this loss is associated with metastasis. Allelic imbalance (AI) analysis of metastatic prostate cancer samples revealed at least two distinct regions of loss, one located at 18q21.2-q21.32 (7 cM) and the other at 18q22.3 (6 cM). Somatic cell genetic experiments have demonstrated that the introduction of chromosome 18 into prostate cancer cell lines affect both the growth and metastatic potential of these cancer cells. These data support the presence of one or more tumor suppressor genes on chromosome 18q. To localize the tumor suppressor gene(s) on 18q, we are using comparative genomic hybridization on a high-resolution genomic array (Array-CGH). The array contains 160 bacterial artificial chromosomes (BACs) which covers the two regions of 18q identified by AI analysis. This high resolution array allowed us to identify individual BACs which were amplified and deleted in prostate cancer specimens. In particular, BAC RPCI11 25L3 was found to be deleted in 50% of the human prostate tumors analyzed (10/20). Fluorescence in situ hybridization (FISH) analysis on paraffin embedded tumor samples verified the homozygous deletion of the BAC clone in the 4 prostate samples analyzed. Using flanking markers, the region of loss in the tumors is being further characterized. The identification of this tumor suppressor gene will help us better understand the molecular basis of prostate cancer.
Human embryonic stem cell-derived neural crest model unveils CD55 as a cancer stem cell regulator for therapeutic targeting in<i>MYCN</i>-amplified neuroblastoma
Authors: Zhihui Weng, Jiacheng Lin, Jiaozi He, Lin Gao, Sien Lin, Lai Ling Tsang, Hang Zhang, Xiaoyan He, Guang Wang, Xuesong Yang, Hu Zhou, Hui Zhao, Gang Li, Lin Zou, Xiaohua Jiang
Journal: Neuro-Oncology (2021)

Abstract Background Neuroblastoma (NB) is a common childhood malignant tumor of neural crest (NC) origin with remarkable heterogeneity in outcomes. Amplification of the oncogene MYCN is strongly associated with highly malignant behaviour and poor prognosis. Methods This study aims to use a human embryonic stem cell (hESC)-derived NC model to identify novel downstream effectors of MYCN that can be potentially used as prognostic marker and/or therapeutic target. Results We show that MYCN-driven NB derived from human neural crest cells (hNCCs) recapitulate the pathological and molecular features of MYCN-amplified neuroblastoma (MNA-NB). By using this platform, we identify a group of 14 surface protein-encoding genes that are associated with MYCN expression level in MNA-NB. Among these genes, high CD55 expression is correlated with poor survival in MNA-NB but not in non-MNA-NB. Furthermore, CD55 promotes tumorigenesis, tumor growth, and cancer stemness in MNA-NB cell lines (MNA-NBL) through regulating the JNK pathway. Mechanistically, MYCN binds to both canonical and noncanonical E-boxes on the promoter of CD55 to regulate its transcriptional expression. Finally, neutralizing antibody targeting CD55 significantly attenuates cancer stemness, suppresses tumor growth, and improves survival exclusively in MNA-NBL-inoculated mice. Conclusion MYCN shapes CD55 into a cancer stem cell regulator which represents a prognostic marker and therapeutic target of MNA-NB. The hESC-derived NC model serves as a valuable platform for investigating NB initiation and progression and developing potential therapeutic targets.
P40.01 Maintenance Anlotinib After Induction Therapy With Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer: A Phase 2 Study
Authors: Y. Shu, Y. Liu, J. Cui, X. Chen, L. Miao, Y. Li, X. Zhu, J. He, P. Chen, S. Dai
Journal: Journal of Thoracic Oncology (2021)
The mechanism of bicarbonate reabsorption in the proximal and distal tubules of the kidney. 1965.
Authors: F C Rector, N W Carter, D W Seldin
Journal: Journal of the American Society of Nephrology (1998)

The mechanism of HCO3- reabsorption in proximal and distal tubules was examined in rats undergoing NaHCO3 diuresis. The steady-state intratubular pH was measured with pH-sensitive glass microelectrodes and compared with the equilibrium pH calculated from the HCO3- concentration of the tubular fluid (measured with quinhydrone electrodes) and plasma Pco2. In the proximal tubule the intratubular pH and the equilibrium pH were identical, indicating no accumulation of excess H2CO3. After inhibition of carbonic anhydrase, however, intratubular pH was significantly lower (0.85 pH U) than the equilibrium pH. It was concluded that HCO3- reabsorption in the proximal tubule was mediated by H+ secretion, but that carbonic anhydrase located in the luminal membrane of the cell prevented H2CO3 from accumulating in the tubular fluid. In the distal tubule the intratubular pH was 0.85 U lower than the equilibrium pH. This difference could be obliterated by an intravenous injection of carbonic anhydrase. It was concluded that HCO3- reabsorption in this segment was also accomplished by H+ secretion. The accumulation of excess H2CO3 in the tubular fluid indicated that, in contrast to the proximal tubule, carbonic anhydrase was not located in the luminal membrane of distal tubular cells.
P40.12 Cardiotoxicity in Lung Cancer Patients Treated With Immune-Checkpoints Inhibitors
Authors: M. Blanco Clemente, Y. Garitaonaindia, M. Torrente, F. Franco, V. Calvo, A. Collazo-Lorduy, M. Martínez-Cutillas, C. Traseira, A. Morito, R. Aguado, B. De La Puente, G. Visedo, M. Provencio
Journal: Journal of Thoracic Oncology (2021)
Aging at Evolutionary Crossroads: Longitudinal Gene Co-expression Network Analyses of Proximal and Ultimate Causes of Aging in Bats
Authors: Guillaume Bernard, Jérôme Teulière, Philippe Lopez, Eduardo Corel, François-Joseph Lapointe, Eric Bapteste
Journal: Molecular Biology and Evolution (2021)

Abstract How, when, and why do organisms, their tissues, and their cells age remain challenging issues, although researchers have identified multiple mechanistic causes of aging, and three major evolutionary theories have been developed to unravel the ultimate causes of organismal aging. A central hypothesis of these theories is that the strength of natural selection decreases with age. However, empirical evidence on when, why, and how organisms age is phylogenetically limited, especially in natural populations. Here, we developed generic comparisons of gene co-expression networks that quantify and dissect the heterogeneity of gene co-expression in conspecific individuals from different age-classes to provide topological evidence about some mechanical and fundamental causes of organismal aging. We applied this approach to investigate the complexity of some proximal and ultimate causes of aging phenotypes in a natural population of the greater mouse-eared bat Myotis myotis, a remarkably long-lived species given its body size and metabolic rate, with available longitudinal blood transcriptomes. M. myotis gene co-expression networks become increasingly fragmented with age, suggesting an erosion of the strength of natural selection and a general dysregulation of gene co-expression in aging bats. However, selective pressures remain sufficiently strong to allow successive emergence of homogeneous age-specific gene co-expression patterns, for at least 7 years. Thus, older individuals from long-lived species appear to sit at an evolutionary crossroad: as they age, they experience both a decrease in the strength of natural selection and a targeted selection for very specific biological processes, further inviting to refine a central hypothesis in evolutionary aging theories.
A Magnetically Powered Stem Cell‐Based Microrobot for Minimally Invasive Stem Cell Delivery via the Intranasal Pathway in a Mouse Brain (Adv. Healthcare Mater. 19/2021)
Authors: Sungwoong Jeon, Sun Hwa Park, Eunhee Kim, Jin‐young Kim, Sung Won Kim, Hongsoo Choi
Journal: Advanced Healthcare Materials (2021)

Microrobots In article number 2100801 by Sung Won Kim, Hongsoo Choi, and co-workers, a magnetically powered stem cell-based microrobot (named Cellbot) is proposed for the minimally invasive targeted delivery of stem cells to the brain via the intranasal passage. The Cellbot is developed by internalizing superparamagnetic iron oxide nanoparticles into human turbinate stem cells. This approach has the potential to effectively treat central nervous system disorders in a minimally invasive manner.
Covid-19: US cases drop overall but increase among children
Authors: Janice Hopkins Tanne
Journal: BMJ (2021)

Covid-19: US cases drop overall but increase among children Janice Hopkins TanneHospital admissions for covid-19 among children aged 5-11, who are not yet eligible for vaccination, have reached an all time high in the US, with 1.1 hospital admissions per 100 000 for the week ending 25 September, according to the Centers for Disease Control and Prevention. 17 Baker M, Ivory D. Public health crisis grows with distrust and threats.
Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence
Authors: Amy S. Huang, Victor Ramos, Thiago Y. Oliveira, Christian Gaebler, Mila Jankovic, Michel C. Nussenzweig, Lillian B. Cohn
Journal: The Journal of Experimental Medicine (2021)

Latent intact HIV-1 proviruses persist in a small subset of long-lived CD4+ T cells that can undergo clonal expansion in vivo. Expanded clones of CD4+ T cells dominate latent reservoirs in individuals on long-term antiretroviral therapy (ART) and represent a major barrier to HIV-1 cure. To determine how integration landscape might contribute to latency, we analyzed integration sites of near full length HIV-1 genomes from individuals on long-term ART, focusing on individuals whose reservoirs are highly clonal. We find that intact proviruses in expanded CD4+ T cell clones are preferentially integrated within Krüppel-associated box (KRAB) domain–containing zinc finger (ZNF) genes. ZNF genes are associated with heterochromatin in memory CD4+ T cells; nevertheless, they are expressed in these cells under steady-state conditions. In contrast to genes carrying unique integrations, ZNF genes carrying clonal intact integrations are down-regulated upon cellular activation. Together, the data suggest selected genomic sites, including ZNF genes, can be especially permissive for maintaining HIV-1 latency during memory CD4+ T cell expansion.