tbuckley/cabot-search huggingface dataset:
Abstract 2300: Deleterious germline mutations in the <i>BRCA1</i> gene are associated with increased risk for cancers of the female reproductive system other than breast and ovarian as well as other cancers
Authors: Candace Middlebrooks, Kenzhane Pantin, Mark Stacey, Carrie Snyder, Murray J. Casey, Trudy Shaw, Joan E. Bailey-Wilson, Henry T. Lynch
Journal: Cancer Research (2020)

Abstract Introduction: Mutations within the BRCA1 gene have been linked to up to an 80% lifetime risk of breast cancer as well as increased risk for ovarian, pancreatic and melanoma cancers. In this study we examined families with known germline mutations in BRCA1 after long-term follow-up to determine whether carriers experience higher rates of other cancers that have not yet been associated with germline mutations in the BRCA1 gene. Methods: We studied 127 Hereditary Breast and Ovarian Cancer (HBOC) syndrome families (N = 23,078 individuals who have been followed at Creighton University) in which a causal mutation in the BRCA1 gene was identified. We performed survival analysis and a mixed effects cox regression with age at follow-up or cancer event as our time variable and presence or absence of BRCA1-related or other cancers (separate analyses) as our indicator variable. Results: The survival curves showed a significant age effect with carriers having a younger age at cancer onset for BRCA1-related (as expected) as well as other cancers than that of non-carriers. The cox regression models were also highly significant (P = 1.77E-37 and P = 1.04E-07 for the BRCA1-related and other cancers, respectively). Of the cancers with enough samples to do stratified analyses, uterine, skin, lymphoma and colon cancers occurred at higher rates and at earlier ages in mutation carriers. Conclusions: These analyses support the hypothesis that the BRCA1 mutations carriers of HBOC syndrome have increased risk for early onset of several additional cancer types, especially cancers that arise in estrogen-influenced tissues. Citation Format: Candace Middlebrooks, Kenzhane Pantin, Mark Stacey, Carrie Snyder, Murray J. Casey, Trudy Shaw, Joan E. Bailey-Wilson, Henry T. Lynch. Deleterious germline mutations in the BRCA1 gene are associated with increased risk for cancers of the female reproductive system other than breast and ovarian as well as other cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2300.
Gut commensal microbiota and decreased risk for <i>Enterobacteriaceae</i> bacteriuria and urinary tract infection
Authors: Matthew Magruder, Emmanuel Edusei, Lisa Zhang, Shady Albakry, Michael J. Satlin, Lars F. Westblade, Line Malha, Christina Sze, Michelle Lubetzky, Darshana M. Dadhania, John R. Lee
Journal: Gut Microbes (2020)

Urinary tract infection (UTI) is a common complication in kidney transplant recipients and can lead to significant morbidity and mortality. Recent evidence supports a role for the gut as a source for UTIs but little is known about the relationship between gut commensal bacteria and UTI development. We hypothesized that the abundance of gut commensal bacteria is associated with a lower risk of developing bacteriuria and UTIs. We performed gut microbiome profiling using 16S rRNA gene sequencing of the V4-V5 hypervariable region on 510 fecal specimens in 168 kidney transplant recipients. Fifty-one kidney transplant recipients (30%) developed Enterobacteriaceae bacteriuria within the first 6 months after transplantation (Enterobacteriaceae Bacteriuria Group) and 117 did not (No Enterobacteriaceae Bacteriuria Group). The relative abundances of Faecalibacterium and Romboutsia were significantly higher in the fecal specimens from the No Enterobacteriaceae Bacteriuria Group than those from the Enterobacteriaceae Bacteriuria Group (Adjusted P value<.01). The combined relative abundance of Faecalibacterium and Romboutsia was inversely correlated with the relative abundance of Enterobacteriaceae (r = −0.13, P = .003). In a multivariable Cox Regression, a top tercile cutoff of the combined relative abundance of Faecalibacterium and Romboutsia of ≥13.7% was independently associated with a decreased risk for Enterobacteriaceae bacteriuria (hazard ratio 0.3, P = .02) and Enterobacteriaceae UTI (hazard ratio 0.4, P = .09). In conclusion, we identify bacterial taxa associated with decreased risk for Enterobacteriaceae bacteriuria and Enterobacteriaceae UTI in kidney transplant recipients, which supports future studies on modulating the gut microbiota as a novel treatment for preventing UTIs.
Nanotechnology Responses to COVID‐19
Authors: Eduardo Ruiz‐Hitzky, Margarita Darder, Bernd Wicklein, Cristina Ruiz‐Garcia, Raquel Martín‐Sampedro, Gustavo del Real, Pilar Aranda
Journal: Advanced Healthcare Materials (2020)

Abstract Researchers, engineers, and medical doctors are made aware of the severity of the COVID‐19 infection and act quickly against the coronavirus SARS‐CoV‐2 using a large variety of tools. In this review, a panoply of nanoscience and nanotechnology approaches show how these disciplines can help the medical, technical, and scientific communities to fight the pandemic, highlighting the development of nanomaterials for detection, sanitation, therapies, and vaccines. SARS‐CoV‐2, which can be regarded as a functional core–shell nanoparticle (NP), can interact with diverse materials in its vicinity and remains attached for variable times while preserving its bioactivity. These studies are critical for the appropriate use of controlled disinfection systems. Other nanotechnological approaches are also decisive for the development of improved novel testing and diagnosis kits of coronavirus that are urgently required. Therapeutics are based on nanotechnology strategies as well and focus on antiviral drug design and on new nanoarchitectured vaccines. A brief overview on patented work is presented that emphasizes nanotechnology applied to coronaviruses. Finally, some comments are made on patents of the initial technological responses to COVID‐19 that have already been put in practice.
Abstract 15601: Cost Effectiveness Analysis and Payment Policy Recommendation - Population Based Survey With Big Data Methodology of Readmission Prevention of Patients With Paroxysmal Supraventricular Tachycardia Treated by Radiofrequency Catheter Ablation
Authors: Ai Hsien A Li, Chien-Lung Chan, Hsiang-An Chung
Journal: Circulation (2018)

Introduction: The readmission risk of Paroxysmal supraventricular tachycardia (PSVT) patients treated with Radiofrequency Catheter ablation (RFCA) is lower in previous reports than patients without...
Association of Selective Serotonin Reuptake Inhibitor Use After Intracerebral Hemorrhage With Hemorrhage Recurrence and Depression Severity
Authors: Patryk Kubiszewski, Lansing Sugita, Christina Kourkoulis, Zora DiPucchio, Kristin Schwab, Christopher D. Anderson, M. Edip Gurol, Steven M. Greenberg, Anand Viswanathan, Jonathan Rosand, Alessandro Biffi
Journal: JAMA Neurology (2020)

<h3>Importance</h3> Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat poststroke depression but are associated with increased incidence of first-ever intracerebral hemorrhage (ICH) in the general population. The decision to treat ICH survivors with SSRIs must therefore balance potential risks of ICH recurrence with presumed benefits on depressive symptoms. <h3>Objective</h3> To determine whether SSRI use among survivors of primary ICH was associated with ICH recurrence and decreased severity of depressive symptoms. <h3>Design, Setting, and Participants</h3> Longitudinal ICH cohort study at a tertiary care center enrolling from January 2006 to December 2017, with follow-up for a median of 53.2 months (interquartile range, 42.3-61.2 months). The study included 1279 consenting individuals (1049 White, 89 Black, 77 Hispanic, and 64 other race/ethnicity) of 1335 eligible patients presenting with primary ICH and who were discharged alive from initial hospitalization for stroke. <h3>Main Outcomes and Measures</h3> We conducted univariable and multivariable analyses for ICH recurrence risk and depression severity, including subset analyses for patients with 1 or more of the following characteristics associated with high ICH recurrence risk: (1) lobar ICH; (2) presence of the apolipoprotein ε2/ε4 gene variants; (3) prior history of ICH/TIA/ischemic stroke; and (4) Black or Hispanic race/ethnicity. <h3>Results</h3> Mean age of study participants was 71.3 years, with 602 women (47%); of the 1279 participants, 1049 were White, 89 were Black, 77 were Hispanic, and 64 were other race/ethnicity. SSRI exposure was associated with both ICH recurrence (subhazard ratio [SHR], 1.31; 95% CI, 1.08-1.59) and resolution of post-ICH depression (SHR, 1.53; 95% CI, 1.12 2.09). Among those individuals at high risk for recurrent ICH, SSRIs were associated with further elevation in risk for ICH recurrence (SHR, 1.79; 95% CI, 1.22-2.64) compared with all other survivors of ICH (SHR, 1.20; 95% CI, 1.01-1.42;<i>P</i> = .008 for comparison of effect sizes). The association of SSRI with reduced depressive symptoms did not differ between high those at high risk for recurrent ICH and all other ICH survivors. <h3>Conclusions and Relevance</h3> Selective serotonin reuptake inhibitor exposure after ICH is associated with both improvement in depressive symptoms and increased risk of recurrent hemorrhagic stroke. Clinical history, neuroimaging data, and genetic biomarkers may help to identify survivors of ICH more likely to safely tolerate SSRI use.
Abstract 3260: The preclinical characterization of CS1001, an anti-PD-L1 IgG4 monoclonal antibody and its activity beyond T cell regulation
Authors: Juan Zhang, Zhenhu Li, Liang Tang, Linlin Liu, Zhaoxiang Ren, Jingshu Ma, Qingmei Shi, Yuanwu Bao, Liang Lu, Yong Zheng, Baotian Yang, Jing Li, Xinzhong Jon Wang
Journal: Cancer Research (2020)

Abstract CS1001 is a high-affinity, fully human programmed death ligand-1 (PD-L1) blocking IgG4 monoclonal antibody. So far three therapeutic anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab) have been approved by US FDA in different cancer indications. CS1001 selectively bound to PD-L1 and blocked PD-L1/PD-1 ligation. The crystal structure of CS1001 complexed with human PD-L1 solved at 2.3Å revealed that CS1001 bound perpendicularly to PD-L1 and the binding epitope region well overlapped with the hPD1-binding region. In the Mixed Lymphocyte Reaction (MLR) assay, CS1001 effectively induced the proliferation of CD4+ T lymphocytes and the production of interferon-γ (IFN-γ) and interleukin-2 (IL-2). CS1001 employs IgG4 isotype and lacks antibody-dependent cellular mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Furthermore, the in vivo efficacy of CS1001 in inhibiting tumor growth was demonstrated in the subcutaneous MC38-hPD-L1 murine colon carcinoma (murine MC38 cells expressing human PD-L1) in human PD-1 knock-in mouse (Biocytogen) model. In another dual-humanized animal model, i.e. PD-1/PD-L1 dual knock-in mice implanted with MC38-hPD-L1 tumor (Biocytogen) where human PD-L1 expressed in both tumor and host system, it is interestingly noticed that CS1001 not only enhanced the cytotoxic T cell/regulatory T cell ratio, but also significantly upregulated M1 macrophage &amp; down-regulated MDSC population, suggesting that anti-PD-L1 antibody may play the pro-anti-tumor immune response through modulating myeloid cells that also express PD-L1, thus a non-ADCC/CDC antibody design could be beneficial. CS1001 is currently explored clinically in 5 registration trials as monotherapy or in combination with standard of care therapies. CS1001 monotherapy or combo with chemotherapy or targeted therapy were safe and well tolerated. CS1001 demonstrated promising efficacy in multiple tumor types and support full development of CS1001 as mono/combo therapy for multiple indications in ongoing and planned clinical trials including cHL, ENKTL, GC, EC, and NSCLC. Citation Format: Juan Zhang, Zhenhu Li, Liang Tang, Linlin Liu, Zhaoxiang Ren, Jingshu Ma, Qingmei Shi, Yuanwu Bao, Liang Lu, Yong Zheng, Baotian Yang, Jing Li, Xinzhong Jon Wang. The preclinical characterization of CS1001, an anti-PD-L1 IgG4 monoclonal antibody and its activity beyond T cell regulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3260.
Abstract 5403: Targeting death-receptors in therapy resistant progressive neuroblastoma: A preliminary insight
Authors: Dinesh Babu Somasundaram, Andrew Maher, Sheeja Aravindan, Terence S. Herman, Natarajan Aravindan
Journal: Cancer Research (2020)

Abstract Neuroblastoma is the most common cancer in infants and accounts for 9.1% of childhood cancer-related deaths. Despite the current standard of care (SOC), drug-resistant neuroblastoma significantly compromises patient survival. Hence it is critical to identify new and less toxic therapeutic approaches for better patient outcomes. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which mediates its effect through the activation of the death receptor (DR) 4 and 5 are found on many cell types and are the main pathway for apoptosis. These can death receptors can kill most tumor cell types expressing TRAIL-receptor 1. Mining RNA-Seq data across multiple cohorts of neuroblastoma patients indicated that high levels of DR4 and DR5 significantly associated with poor clinical outcomes (OS, EFS, RFS). Further, examining the surface expression of DR4 and DR5 by immunohistochemistry using anti-human rabbit monoclonal antibodies on custom-archived TMAs for 100 NB patients revealed profound correlation with poor OS and RFS. Immunoblot analysis for DR4 and DR5 level in a panel of stage 4 patient-derived cell-lines during diagnosis and from progressive disease after therapy displayed high-levels of death receptor expression in progressive disease. Preliminary co-culture investigations with genetically engineered mesenchymal stem cells (MSCs) expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) mimicking targeted delivery showed heightened differentiation and death (limited dilution tumorosphere assay) of therapy resistant cells. Further these studies exhibited inhibition of tumor cell migration and invasion. The results demonstrate the benefit of targeted TRAIL delivery in in the treatment of therapy resistant neuroblastoma and further imply that the genetically engineered MSCs could serve as a clinically valuable tool for improved therapeutic strategy in this setting. Citation Format: Dinesh Babu Somasundaram, Andrew Maher, Sheeja Aravindan, Terence S. Herman, Natarajan Aravindan. Targeting death-receptors in therapy resistant progressive neuroblastoma: A preliminary insight [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5403.
SERUM FERRITIN - A GLIAL TUMOR MARKER
Authors: Heidemarie Jaksch, Nikolaus Bresgen, SM Golaszewski, W Kleindienst, Peter Strasser, K Bordihn, R Al-Schameri, S Spiegl-Kreinecker, B Richling, G Ladurner
Journal: Neuro-Oncology (2008)
The BMA's annual representative meeting
Authors: L Beecham, J Smith, J Mayor, L Bristow
Journal: BMJ (1994)

The BMA's annual representative meeting Fetal tissue may be used for research not infertility treatment * Deplored the situation where sex discrimina- tion legislation applied to partnerships of any size whereas race discrimination legislation applied only to partnerships with six or more partners * Noted with concern the intention of the NHS Management Executive in Scotland to axe 5000 acute beds and 8000 long stay beds * Criticised the attitude of those government departments which refuse to honour the fees agreed with the Treasury for doctors undertaking part time work for central government.
Delay or Avoidance of Medical Care Because of COVID-19–Related Concerns — United States, June 2020
Authors: Mark É. Czeisler, Kristy Marynak, Kristie E.N. Clarke, Zainab Salah, Iju Shakya, JoAnn M. Thierry, Nida Ali, Hannah McMillan, Joshua F. Wiley, Matthew D. Weaver, Charles A. Czeisler, Shantha M.W. Rajaratnam, Mark E. Howard
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Temporary disruptions in routine and nonemergency medical care access and delivery have been observed during periods of considerable community transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1). However, medical care delay or avoidance might increase morbidity and mortality risk associated with treatable and preventable health conditions and might contribute to reported excess deaths directly or indirectly related to COVID-19 (2). To assess delay or avoidance of urgent or emergency and routine medical care because of concerns about COVID-19, a web-based survey was administered by Qualtrics, LLC, during June 24-30, 2020, to a nationwide representative sample of U.S. adults aged ≥18 years. Overall, an estimated 40.9% of U.S. adults have avoided medical care during the pandemic because of concerns about COVID-19, including 12.0% who avoided urgent or emergency care and 31.5% who avoided routine care. The estimated prevalence of urgent or emergency care avoidance was significantly higher among the following groups: unpaid caregivers for adults* versus noncaregivers (adjusted prevalence ratio [aPR] = 2.9); persons with two or more selected underlying medical conditions† versus those without those conditions (aPR = 1.9); persons with health insurance versus those without health insurance (aPR = 1.8); non-Hispanic Black (Black) adults (aPR = 1.6) and Hispanic or Latino (Hispanic) adults (aPR = 1.5) versus non-Hispanic White (White) adults; young adults aged 18-24 years versus adults aged 25-44 years (aPR = 1.5); and persons with disabilities§ versus those without disabilities (aPR = 1.3). Given this widespread reporting of medical care avoidance because of COVID-19 concerns, especially among persons at increased risk for severe COVID-19, urgent efforts are warranted to ensure delivery of services that, if deferred, could result in patient harm. Even during the COVID-19 pandemic, persons experiencing a medical emergency should seek and be provided care without delay (3).
Abstract 5681: Design, synthesis and study of small molecules with both AR degradation and AKR1C3 inhibitory activities
Authors: Enming Xing, Xiaotian Kong, Wei Lou, Ruihua Shi, Xiaolin Cheng, Allen C. Gao, Pui Kai Li
Journal: Cancer Research (2020)

Abstract Prostate cancer is the most common cancer in men and it is estimated that 32,000 men in the US alone will die of this cancer in 2019. Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer therapy. However, most of the patients will progress to castration resistance prostate cancer (CRPC) after several years of treatment. The current treatment of CRPC includes chemotherapeutic agents (docetaxel) and agents that target androgen signaling (abiraterone, enzalutamide and apalutamide). Ultimately, however, most patients develop resistance to the treatments. Two of the mechanisms of resistance involve the expression of constitutively active androgen receptor variant (AR-V7) and the increase in intra-tumoral biosynthesis of androgens. Several treatment strategies targeting AR-V7 have been reported. For the intra-tumoral biosynthesis of androgens, one of the enzymes, AKR1C3, plays a critical role in the development of CRPC and has been reported to be consistently elevated in CRPC patients who are resistant to abiraterone and enzalutamide. We have been involved in the development of agents to treat CRPC and overcome drug resistance of CRPC patients. We reported that niclosamide, an FDA-approved anthelminthic agent, could degrade AR-V7. We also reported that niclosamide, as well as an AKR1C3 inhibitor, indomethacin, were able to overcome enzalutamide and abiraterone resistance in several prostate cancer cell lines, suggesting that niclosamide is also an AKR1C3 inhibitor. By examining the reported structures of AKR1C3 inhibitors, niclosamide was found to contain the core scaffold of 4-Hydroxy-1-(4-methoxybenzyl)-N-(3-(trifluoromethyl) phenyl)-1H-1,2,3-triazole-5-carboxamide. Using this knowledge, we designed a series compounds with dual AR degrading and AKR1C3 inhibitory activities. Preliminary studies showed the compounds caused AR-V7 degradation and to a lesser extent AR full length degradation. The compounds also inhibited AKR1C3 and caused a dose dependent growth inhibition of several prostate cancer cell lines. Citation Format: Enming Xing, Xiaotian Kong, Wei Lou, Ruihua Shi, Xiaolin Cheng, Allen C. Gao, Pui Kai Li. Design, synthesis and study of small molecules with both AR degradation and AKR1C3 inhibitory activities [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5681.
Vascular Changes in Cancer Treatment—Seeing Is Believing
Authors: Michal R. Tomaszewski
Journal: Cancer Research (2020)

Abstract Understanding the effects of novel cancer drugs on the tumor microenvironment will be crucial for their successful use in patients. In this issue of Cancer Research, Ghosh and colleagues discuss the effect of two promising heme-targeting agents on the vascular network in mouse models of lung cancer, utilizing emerging optoacoustic imaging approaches. The findings demonstrating significant, dynamic modulation of tumor hypoxia with the heme-targeting drug treatments create important opportunities for image-guided combination therapy. See related article by Ghosh et al., p. 3542
Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery
Authors: Shaojun Peng, Boshu Ouyang, Yongjie Xin, Wei Zhao, Shun Shen, Meixiao Zhan, Ligong Lu
Journal: Acta Pharmaceutica Sinica B (2020)

Tumor microenvironment has been widely utilized for advanced drug delivery in recent years, among which hypoxia-responsive drug delivery systems have become the research hotspot. Although hypoxia-responsive micelles or polymersomes have been successfully developed, a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear. Herein, we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based (HPMPC) nanogel for tumor drug delivery. The obtained HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility, which leads to high and long-lasting accumulation in tumor tissue. Furthermore, HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment, which leads to the effective release of the loaded drug. Impressively, HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel, owing to the more complete drug release. Overall, the drug-loaded HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects, which showed great potential as nanocarrier for advanced tumor drug delivery.