tbuckley/cabot-search huggingface dataset:
RABL6A Is an Essential Driver of MPNSTs that Negatively Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors
Authors: Jordan L. Kohlmeyer, Courtney A. Kaemmer, Casey Pulliam, Chandra K. Maharjan, Allison Moreno Samayoa, Heather J. Major, Kendall E. Cornick, Vickie Knepper-Adrian, Rajesh Khanna, Jessica C. Sieren, Mariah R. Leidinger, David K. Meyerholz, K.D. Zamba, Jill M. Weimer, Rebecca D. Dodd, Benjamin W. Darbro, Munir R. Tanas, Dawn E. Quelle
Journal: Clinical Cancer Research (2020)

Malignant peripheral nerve sheath tumors (MPNST) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin-dependent kinases (CDK), commonly through loss of CDK-inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor-based therapy in MPNSTs.We examined patient-matched MPNSTs and precursor lesions by RNA sequencing (RNA-Seq) and IHC. Molecular and biological effects of silencing RABL6A and/or p27 in MPNST lines and normal human Schwann cells were determined. Tumor-suppressive effects of CDK inhibitors were measured in MPNST cells and orthotopic tumors.RABL6A was dramatically upregulated in human MPNSTs compared with precursor lesions, which correlated inversely with p27 levels. Silencing RABL6A caused MPNST cell death and G1 arrest that coincided with p27 upregulation, CDK downregulation, and RB1 activation. The growth-suppressive effects of RABL6A loss, and its regulation of RB1, were largely rescued by p27 depletion. Importantly, reactivation of RB1 using a CDK4/6 inhibitor (palbociclib) killed MPNST cells in vitro in an RABL6A-dependent manner and suppressed MPNST growth in vivo. Low-dose combination of drugs targeting multiple RB1 kinases (CDK4/6, CDK2) had enhanced antitumorigenic activity associated with potential MPNST cell redifferentiation.RABL6A is a new driver of MPNST pathogenesis that acts in part through p27-RB1 inactivation. Our results suggest RB1 targeted therapy with multiple pathway drugs may effectively treat MPNSTs.
A nationwide evaluation of deceased donor kidney transplantation indicates detrimental consequences of early graft loss
Authors: Michèle J. de Kok, Alexander F. Schaapherder, Jacobus W. Mensink, Aiko P. de Vries, Marlies E. Reinders, Cynthia Konijn, Frederike J. Bemelman, Jacqueline van de Wetering, Arjan D. van Zuilen, Maarten H. Christiaans, Marije C. Baas, Azam S. Nurmohamed, Stefan P. Berger, Rutger J. Ploeg, Ian P. Alwayn, Jan H. Lindeman
Journal: Kidney International (2020)
A Nurse-led Parental Eczema Education Programme On Chinese Parents Of Children With Eczema: A Randomised Controlled Trial
Authors: Nam Sze Cheng, Janita Pak Chun Chau, Ellis Kam Lun Hon, Chung Mo Chow, Kai Chow Choi, Suzanne Hoi Shan Lo, Ting Fan Leung
Journal: Journal of Allergy and Clinical Immunology (2020)
COVID-19 and artificial intelligence: protecting health-care workers and curbing the spread
Authors: Becky McCall
Journal: The Lancet Digital Health (2020)

Confirmed cases of coronavirus disease 2019 (COVID-19) exceed those of severe acute respiratory syndrome (SARS), and, at time of publication, now stand at over 73,435 confirmed cases and over 2000 deaths globally, nearly all in China. By comparison, SARS killed 774 people in 2003, again mostly in China, the epicentre of both outbreaks. Both COVID-19 and SARS spread across continents, infect animals and humans, and use similar mechanics to enter and infect the cell. On the frontline, tactical response to COVID-19 is similar to that of SARS but one major difference exists: in the 17 years since SARS, a powerful new tool has emerged that could potentially be instrumental in keeping this virus within reasonable limits—namely, artificial intelligence (AI).
Aberrant anti-viral response of natural killer cells in severe asthma
Authors: Justine Devulder, Cécile Chenivesse, Valérie Ledroit, Stéphanie Fry, Pierre-Emmanuel Lobert, Didier Hober, Anne Tsicopoulos, Catherine Duez
Journal: European Respiratory Journal (2020)

Rhinovirus infections are the main cause of asthma exacerbations. As natural killer (NK) cells are important actors of the antiviral innate response, we aimed at evaluating the functions of NK cells from severe asthma patients in response to rhinovirus-like molecules or rhinoviruses. Peripheral blood mononuclear cells from patients with severe asthma and healthy donors were stimulated with pathogen-like molecules or with the rhinoviruses (RV)-A9 and RV-2. NK cell activation, degranulation and interferon (IFN)-γ expression were analysed. NK cells from severe asthma patients were less cytotoxic than those from healthy donors in response to toll-like receptor (TLR)3, TLR7/8 or RV-A9 but not in response to RV-2 stimulation. Furthermore, when cultured with interleukin (IL)-12+IL-15, cytokines which are produced during viral infections, NK cells from patients with severe asthma were less cytotoxic and expressed less IFN-γ than NK cells from healthy donors. NK cells from severe asthmatics exhibited an exhausted phenotype, with an increased expression of the checkpoint molecule Tim-3. Together, our findings indicate that the activation of NK cells from patients with severe asthma may be insufficient during some but not all respiratory infections. The exhausted phenotype may participate in NK cell impairment and aggravation of viral-induced asthma exacerbation in these patients.
Outcomes of patients with pancreatic-only oligometastatic renal cell carcinoma (RCC).
Authors: Cassandra Duarte, Nieves Martinez Chanza, Katharine Collier, Nazli Dizman, Nityam Rathi, Rana R. McKay, Justine Panian, Vivek Narayan, Benedito A. Carneiro, Anthony E. Mega, Junxiao Hu, Cheryl Meguid, Neeraj Agarwal, Sumanta K. Pal, Amir Mortazavi, Lauren Christine Harshman, Elaine Tat Lam
Journal: Journal of Clinical Oncology (2020)

681 Background: Patients (pts) with RCC and oligometastatic pancreas metastases are treated with pancreatectomy, stereotactic body radiation therapy (SBRT), or systemic therapy. The optimal approach is not clear. We aimed to evaluate the comparative efficacy of the modalities in terms of progression-free survival (PFS) and overall survival (OS). Methods: This IRB-approved, multi-institutional, retrospective study evaluated pts with pancreatic-only RCC metastasis without concurrent metastases elsewhere. Data on pt demographics, tumor characteristics, treatment, and outcomes were collected. PFS and OS in pts treated with pancreatectomy vs. systemic therapy were compared by log rank tests. Results: Fifty-one pts from 9 institutions were included. All had clear cell RCC; 50 pts had nephrectomy; 30 pts (58.8%) and 18 pts (35.3%) had IMDC favorable and intermediate risk, respectively. Median time from RCC diagnosis to oligometastatic disease was 120 months (mo) (range: 0, 175). As initial treatment, 23 (45%) pts had pancreatectomy (mostly partial); 25 (49%) had systemic therapy (VEGFR TKI and/or immunotherapy); 1 had SBRT; 2 had other treatments. Too few pts had SBRT for comparison. With a median follow-up of 25 mo (2, 68), median PFS for the population was 25 mo (17, 42 95% CI). Median PFS was 36 mo (8, 43 95% CI) for surgery pts and 22 mo (17, NR 95% CI) for systemic therapy pts; this was not statistically significant (NS), p = 0.3. Median OS for the population was 121 mo (100, NR 95% CI). With a median follow-up of 51 mo (2, 217), OS was 121 mo (100, NR 95% CI) for surgery pts and not reached (64, NR 95% CI) for systemic therapy pts; NS, p = 0.52. Conclusions: In this retrospective series, RCC pts with oligometastatic pancreatic-only disease had similar PFS and OS outcomes from initial pancreatectomy or systemic therapy. RCC pts with pancreas-only metastases represent a unique patient population and studies informing the underlying biology are needed to optimize clinical management.
Retrospective evaluation of PD-L1 expression in tumor tissue of patients with lung carcinoma and correlation with clinical and demographical data from a tertiary care institute of northern India
Authors: K.R. Domadia, U. Batra, P. Jain, M. Sharma, S. Gupta, S.J. Bothra, S. Pasricha, K. Chaudhari, G. Vishwakarma
Journal: Annals of Oncology (2018)

Background: It has been widely recognized that response rates of immunotherapy drugs correlates with PD-L1 (Programmed Death-Ligand 1) expression with higher response rates with higher PD-L1 expression. As there is extreme paucity of PD-L1 expression data from the Indian perspective, we studied the clinical and demographical profile of PD-L1 in lung cancer patients. Methods: 134 cases of lung cancer patients from June 2017 to June 2018, in whom, membranous PD-L1 expression testing was done by using rabbit Anti-Human PD-L1 monoclonal antibody (clone SP263) on VENTANA BENCHMARK XT were retrospectively evaluated in terms of histological and demographical profile. PD-L1 expression of > =1% was regarded as positive. All statistical analysis were done using SPSS Version 23.0. p value < = 0.05 was considered to be significant. Results: The median age was 62 Years (Range 27-89). PD-L1 positivity was seen in 53.3% and 38.6% with age < =60 years and >60 years respectively (p = 0.09). 51% of male and 33.4% of female patients had PD-L1 > =1% (p = 0.08). Out of 134 cases, 63 (47%) had PD-L1 > =1%.On further stratification, 20.1%, 3% and 23.9% PD-L1 positivity was noted in subgroups of 1 – 24, 25-49 and > =50% PD-L1 expression respectively. PD-L1 positivity was commoner in non smokers (52.1%) than in active or former smokers (44.2%) but the difference was statistically insignificant (p = 0.37). PD-L1 positivity in Non squamous NSCLC and squamous histology was 50.5% and 47.7% respectively (p = 0.812). None of the SCLC cases had PD-L1 positivity. PD-L1 positivity in brain, skeletal only, extra thoracic visceral and intra thoracic metastasis was 47.9%, 53.6%, 51.3% and 41.4% respectively (p = 0.803).35% of EGFR mutant cases had PD-L1 positivity. There were 2 ALK positive cases and both had PD-L1 > =1%. Conclusions: In this first analysis of PD-L1 expression in lung cancer patients from India, we found a PD-L1 positivity rate of 47%. There was no statistically significant difference in PD-L1 expression in respect to age, gender, smoking, histology, sites of metastasis and molecular profile, although more studies with larger sample sizes will be necessary to fill in the knowledge gaps. Legal entity responsible for the study: Rajiv Gandhi Cancer Institute & Research Centre, Delhi. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Real-world survival improvements in patients with newly diagnosed metastatic prostate cancer treated in the United States.
Authors: Carlo Cattrini, Elisa Zanardi, Alessandra Rubagotti, Linda Zinoli, Matteo Capaia, Paola Barboro, Francesco Boccardo
Journal: Journal of Clinical Oncology (2020)

48 Background: New drugs have become available for the treatment of metastatic prostate cancer (mPCa) during the last two decades. Here, we explored the clinical outcomes of de novo mPCa in 3 large cohorts of patients diagnosed in 3 treatment eras: pre-docetaxel 2000-2003 (T1), docetaxel 2004-2010 (T2) and new androgen-receptor signalling inhibitors (ARSi) + cabazitaxel 2011-2016 (T3). Methods: The USA Surveillance Epidemiology and End Results (SEER) Incidence Data were investigated using the SEER*Stat software. We used the Kaplan – Meier method, log-rank test, Cox regression, hazard ratio (HR) and confidence intervals (CI) to analyse overall survival (OS) and cancer-specific survival (CSS). The maximum follow-up time point was 5 years. Results: A total 34.034 patients with de novo mPCa were analysed for OS, of these 6.621 T1, 12.711 T2 and 14.702 T3. Median OS was 29 months (mo) [95% CI: 28.5-29.5], 28 mo [27.0-28.9], 28 mo [27.3-28.7] and 31 mo [30.2-31.8] in whole, T1, T2 and T3 cohorts, respectively. In the multivariable model, adjusted for age and race, T3 patients showed better OS compared to T1 and T2 patients (HR: 0,92 [95% CI: 0,88-0,95] and 0,92 [0,89 to 0,95], respectively, p&lt;0.001). A total of 33.641 patients were analysed for CSS, of these 6.514 T1, 12.540 T2 and 14.587 T3. Median CSS was 36 mo [35.3-36.7], 34 mo [32.6-35.3], 34 mo [33.0-35.0] and 38 mo [36.9-39.1] in whole, T1, T2, T3 cohorts, respectively. T3 patients had better CSS compared to T1 and T2 patients (HR: 0,93 [0,89-0,97] and 0,92 [0,89 to 0,96], respectively, p&lt;0.001). No difference in OS or CSS was found between T1 and T2 cohorts. Conclusions: The prognosis of patients with de novo mPCa remains poor, with a median CSS of 3 years and a 5-year CSS of 35%. Approximately 8% decrease in the risk of death was found in the era of ARSi and cabazitaxel. The recent intensification of therapy in metastatic hormone-sensitive setting might lead to better outcomes in the next years.[Table: see text]
Effectiveness of benralizumab in patients with severe asthma
Authors: Hirofumi Watanabe, Taisuke Akamatsu, Keita Hirai, Hiromasa Nakayasu, Kanami Tamura, Toshihiro Masuda, Shingo Takahashi, Yuko Tanaka, Yutaro Kishimoto, Kyohei Oishi, Mika Saigusa, Akito Yamamoto, Satoru Morita, Kazuhiro Asada, Toshihiro Shirai
Journal: Journal of Allergy and Clinical Immunology (2020)
Forced oscillation technique for optimising PEEP in ventilated extremely preterm infants
Authors: Linda Wallström, Chiara Veneroni, Emanuela Zannin, Raffaele L. Dellacà, Richard Sindelar
Journal: European Respiratory Journal (2020)

<b>PEEP during ventilation of extremely preterm infants, evaluated by bedside forced oscillation technique in the first week of life, is lower than clinically set PEEP, suggesting that surfactant treated lungs can be easily overdistended even at low PEEP</b>http://bit.ly/2FW1ZAQ
Association of tumor burden with the eligibility of upfront therapy in patients with castration-naive prostate cancer: A multicenter retrospective study.
Authors: Hiromichi Iwamura, Shingo Hatakeyama, Shintaro Narita, Toshihiko Sakurai, Sadafumi Kawamura, Senji Hoshi, Fumitada Saito, Toshiaki Kawaguchi, Koji Mitsuzuka, Akihiro Ito, Norihiko Tsuchiya, Yoichi Arai, Tomonori Habuchi, Chikara Ohyama
Journal: Journal of Clinical Oncology (2020)

107 Background: Although several large-scale studies reported a robust benefit of upfront therapy for mHNPC, not all patients with mHNPC experienced mCRPC progression. As there is a concern for overtreatment in patients with low-risk/volume disease, we aimed to identify potential candidates for upfront therapy in patients with metastatic hormone-naïve prostate cancer (mHNPC). Methods: We retrospectively evaluated 679 patients with mHNPC who were initially treated with conventional androgen deprivation therapy. We defined the patients with progression to metastatic castration-resistant prostate cancer (mCRPC) as potential candidates for upfront therapy. To estimate the suitable candidate for upfront therapy, we retrospectively compared mCRPC progression rate, mCRPC-free survival, and overall survival (OS) after castration-resistance (OS-CR) between the low- and high-volume disease groups. Furthermore, we tried to develop a novel prediction model using deep learning algorithm. Results: The number of patients with mCRPC progression (potential candidates for upfront therapy) was 119 (52%) and 319 (71%) in the low- and high-volume disease groups. The mCRPC progression rate and CRPC-free survival were significantly worse in high-volume disease group ( P &lt; 0.01), but no difference was found for OS-CR. Multivariate Cox regression analysis showed no significant association between tumor volume and OS-CR (HR 1.14, P=0.52). The deep learning model showed not high accuracy of mCRPC prediction (AUC 0.66). Conclusions: Approximately a half of patients with low-volume disease had progression to mCRPC. As the OS-CR in the patients with low-volume disease showed poor prognosis as well as those with high-volume disease, upfront therapy may be needed for a half of patients with low-volume disease.
Prenatal Indoor Dog Exposure and Early Life Gut Microbiota in the Microbes, Asthma, Allergy and Pets Birth Cohort
Authors: Edward Zoratti, Ariane Panzer, Alexandra Sitarik, Kyra Jones, Ganesa Wegienka, Suzanne Havstad, Nicholas Lukacs, Homer Boushey, Christine Cole Johnson, Dennis Ownby, Susan Lynch
Journal: Journal of Allergy and Clinical Immunology (2020)
Effects of updated demography, disability weights, and cervical cancer burden on estimates of human papillomavirus vaccination impact at the global, regional, and national levels: a PRIME modelling study
Authors: Kaja M Abbas, Kevin van Zandvoort, Marc Brisson, Mark Jit
Journal: The Lancet Global Health (2020)

The Papillomavirus Rapid Interface for Modelling and Economics (PRIME) has been used around the world to assess the health impact and cost-effectiveness of human papillomavirus (HPV) vaccination in girls. We updated PRIME with new data and methods for demography, disability weights, and cervical cancer burden, and generated revised estimates of the health impact of HPV vaccination at the global, regional, and national levels for 177 countries.PRIME was updated with population demography of the UN World Population Prospects (UNWPP) 2019 revision, disability weights of the Global Burden of Disease (GBD) 2017 study, and cervical cancer burden from the Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2018 database. We estimated the lifetime health benefits for bivalent or quadrivalent and nonavalent vaccination of 9-year-old and 12-year-old girls at 90% coverage during 2020-29 in 177 countries. Health impact was presented in terms of cervical cancer cases, deaths, or disability-adjusted life-years (DALYs) averted per 1000 vaccinated girls in comparison with the counterfactual scenario of no vaccination, and the number of girls needed to be vaccinated to prevent a single case, death, or DALY.In estimating the health impact of HPV vaccination of 9-year-old girls, the combined updates to demography, disability weights, cervical cancer burden estimates resulted in a 26% increase in the estimated number of cases averted, a 51% increase in deaths averted, and a 72% increase in DALYs averted per 1000 vaccinated girls for both the bivalent or quadrivalent and nonavalent vaccines, compared with previous estimates. With the updated model, the bivalent or quadrivalent HPV vaccine was estimated to avert 15 cases, 12 deaths, and 243 DALYs per 1000 vaccinated girls, and the nonavalent HPV vaccine was estimated to avert 19 cases, 14 deaths, and 306 DALYs per 1000 vaccinated girls. The health benefits of vaccination of 12-year-old girls were estimated to be similar but slightly decreased in comparison with vaccination of 9-year-old girls.HPV vaccination provides greater health benefits and is more cost-effective than was previously estimated. The demography update, which incorporates population aging, has the largest effect on the health impact estimates. The WHO African region is expected to gain the greatest health benefits and should be prioritised for HPV vaccination.Gavi, the Vaccine Alliance; Bill & Melinda Gates Foundation.
Comparison of Caucasian and African-American DNA repair alterations in men with metastatic prostate cancer.
Authors: Ellen Jaeger, Earle Frederick Burgess, Jason Zhu, Beth Dellinger, Sara Elrefai, Whitley Hatton, Marcus W. Moses, Anjali Lankford, Alexa Zaheri, Elisa Marie Ledet, Pedro C. Barata, Jodi Lyn Layton, Brian E. Lewis, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2020)

199 Background: Data on germline DNA repair defects and VUS rates are sparse in African American (AA) men with metastatic prostate cancer (PCa). Methods: Germline testing data from two centers with a significant percentage of metastatic AA PCa patients were combined and compared to Caucasian American (CA) with metastatic PCa. Fourteen canonical DNA repair genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, RAD51D) were assessed in all tested patients (pts) using a pathogenic/likely pathogenic (P/LP) classification. Variants of unknown significance (VUS) were assessed in an Invitae-derived dataset with consistent VUS reporting. Results: A total of 105 AA men with metastatic disease were evaluated and 7/105 of these men (6.67%) had P/LP alteration. Among the AA pt alterations, there were 4 pts with BRCA2, 2 pts with BRCA1, and 1 pt with PALB2. A total of 39/417 (9.3%) of CA metastatic patients had P/LP alterations in the canonical 14 genes. No differences were detected in the AA vs CA metastatic comparison (p=0.39). A total of 1/105 (0.95%) AA pts and 23/418 (5.5%) CA had non-BRCA P/LP mutations. The number of non-BRCA P/LP mutations were lower in the AA as compared to the CA men (p=0.045). When evaluating VUS calls in the metastatic AAs using Invitae multi-gene panels, 28/92 (30.43%) pts had a VUS in the canonical 14 genes as compared to 67/366 (18.31%) of the CA men. AAs were more likely than CA to have a VUS (p=0.010). These data indicate that metastatic AA pts and CA are not significantly distinct in the P/LP alterations in 14 canonical DNA repair genes but that there were lower percentages of P/LP in the AA non-BRCA gene subset. Further, when assessing these genes, it is clear that a VUS is more likely to be called in the AA men. Conclusions: Among men with metastatic PCa, AAs have similar rates of inherited P/LP alterations in 14 well accepted DNA repair genes as compared to CA men, however the non-BRCA gene P/LP alterations were less frequent among the AAs. Variants classified as a VUS were clearly higher in these AA pts as compared to the CA pts.
Common fibrin deposition and tissue plasminogen activator downregulation in nasal polyps with distinct inflammatory endotypes
Authors: Cai-Ling Chen, Yin Yao, Li Pan, Si-Tao Hu, Jin Ma, Zhi-Chao Wang, Robert C. Kern, Robert P. Schleimer, Zheng Liu
Journal: Journal of Allergy and Clinical Immunology (2020)
Prognostic Factors and Validation of Prognostic Nomograms in Patients (PTS) Treated with 3 Targeted Therapies (TTS) for Metastatic Renal Cell Carcinoma (MRCC): Results from an Italian Survey
Authors: R. Iacovelli, M. Rizzo, V. Lorusso, F. Atzori, P.A. Zucali, C. Sacco, F. Boccardo, F. Valduga, F. Massari, G. Procopio
Journal: Annals of Oncology (2012)
Addressing disparities in the health of persons with HIV attributable to unstable housing in the United States: The role of the Ryan White HIV/AIDS Program
Authors: Amy Griffin, Antigone Dempsey, Wendy Cousino, Latham Avery, Harold Phillips, Emeka Egwim, Laura Cheever
Journal: PLoS Medicine (2020)

points• There are an estimated 1.1 million people aged 13 and older who have HIV in the United States, including an estimated 162,500 (14%) people whose infections had not been diagnosed.In 2017, 38,281 people received an HIV diagnosis in the US and dependent areas.• Unstably housed people with HIV are a key population for ending the HIV epidemic in the US, because of their difficulty accessing HIV care, high rates of mental health disorders, substance use, and economic and food insecurity, which can lead to poor health outcomes and low viral suppression.• The Health Resources and Services Administration's Ryan White HIV/AIDS Program (HRSA RWHAP) serves more than half of all people with diagnosed HIV in the United States, including over 25,000 unstably housed people.From 2010 through 2017, the percentage of RWHAP clients with stable housing increased from 82% to 87%.• However, only 71% of unstably housed RWHAP clients were virally suppressed, compared with 86% of all RWHAP clients.This is lower than rates of viral suppression in other key population groups like youth (74%) and transgender people (81%).• HRSA and the RWHAP promote increased access to housing services for people with HIV through (a) innovative federal partnerships with the Department of Housing and Urban Development, (b) policy guidance for HRSA grant recipients, and (c) developing and implementing innovative models and interventions.