tbuckley/cabot-search huggingface dataset:
Abstract 6707: Inhibition of proteolytic cleavage of NKG2D ligands increases immune cell-mediated cell killing of tumor cells in vitro
Authors: Safak Yalcin, Vanessa Cicchini, Xin Du, Xin Wu, Tom Kaever, Neil Gibson
Journal: Cancer Research (2020)

Abstract Natural Killer Group 2, member D (NKG2D) is an activating receptor that is expressed on the key immune cells involved in the cytotoxic arm of the immune system. Ligands of NKG2D, such as MICA and MICB, are not normally expressed but are upregulated in response to stress, such as oxygen or nutrient deprivation, viral infection or oncogenic transformation. One mechanism that tumor cells, that express MICA and MICB, have adopted to evade the cytotoxic potential of NK and T cells, that express the NKG2D receptor, is to cleave MICA/B from the cell surface. Proteolytic cleavage of MICA/B occurs within the α-3 domain of MICA/B. In order to evaluate the therapeutic potential of blocking cleavage of MICA/B we have generated multiple antibodies that bind to the α-3 domain of MICA/B. The lead antibody, PDI-01, was found to bind to multiple recombinant human MICA alleles and human MICB and to recombinant MIC proteins derived from non-human primate sequences with low nM affinity. PDI-01 bound to target antigen on the surface of multiple cancer cell lines including HCT-116 colon carcinoma, HCC1534 lung carcinoma and PLC/PRF/5 liver cancer cell lines. Each of those tumor cell lines were positive for MICA and MICB expression. Low expression of other NKG2D ligands, known as UL-16 binding proteins 1-6 (ULBP 1-6), has been shown in those cell lines. PDI-01 was found to prevent cleavage of MICA from the surface of HCT-116, HCC1534 and PLC/PRF/5 cells via ELISA quantification of soluble MICA levels. Exposure of HCT-116, HCC1534 and PLC/PRF/5 tumor cell lines to PDI-01 increased surface MICA levels as measured by flow cytometry analysis. An increase in immune cell mediated killing of HCT-116, HCC1534 and PLC/PRF/5 cells was observed when tumor cells were incubated with NK-92 cells (NKG2D positive) in the presence of PDI-01. PDI-01 also enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) against these three tumor cell lines. Co-culture of PBMCs, or purified NK cells, with PLC/PRF/5 cells in the presence of PDI-01 led to an increase in TNF-α, IFN-γ, CCL4, CCL5 and IL-6. PDI-01 is being advanced into clinical development and the Phase 1 program is scheduled to be initiated in the 2Q, 2020. Citation Format: Safak Yalcin, Vanessa Cicchini, Xin Du, Xin Wu, Tom Kaever, Neil Gibson. Inhibition of proteolytic cleavage of NKG2D ligands increases immune cell-mediated cell killing of tumor cells in vitro [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 6707.
Poor care has become normalised at Shropshire hospitals, says chief inspector
Authors: Clare Dyer
Journal: BMJ (2020)

A hospital trust at the centre of a police investigation into its maternity services has seen both its hospitals rated inadequate overall for medical care and end of life care after the Care Quality Commission (CQC) warned that poor care had become “normalised.”1

Ted Baker, chief inspector of hospitals, said “failing leadership is perpetuating poor care” at Shrewsbury and Telford Hospitals NHS Trust.

Baker’s concerns about the trust were first revealed in a leaked letter to NHS England requesting an urgent meeting after the inspection in June.2

Commenting on the inspection reports, published on 14 August, he said, “We have repeatedly called …
Genetic or pharmacologic Nrf2 activation increases proteinuria in chronic kidney disease in mice
Authors: Brittney M. Rush, Corry D. Bondi, Sean D. Stocker, Kacie M. Barry, Sarah A. Small, Jason Ong, Soma Jobbagy, Donna B. Stolz, Sheldon I. Bastacky, Dionysios V. Chartoumpekis, Thomas W. Kensler, Roderick J. Tan
Journal: Kidney International (2020)
Racial and Ethnic Disparities in Seasonal Influenza Vaccination among Dialysis Facilities in the United States
Authors: John Danziger, Eric Weinhandl, David Friedman, Kenneth J. Mukamal
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement The current COVID-19 pandemic heightens the urgency of understanding current barriers to universal vaccination among patients with ESKD. Although studies have reported racial and ethnic disparities in vaccination, these disparities have not been investigated among patients with ESKD. In a study of how the proportion of Black and Hispanic patients in dialysis facilities affects those facilities’ rates of seasonal influenza vaccination, the authors found important racial and ethnic disparities, which seem to be worsening over time. Understanding and addressing these disparities will be important in preparing for any future widespread vaccination programs, as might be expected in response to COVID-19. Background Racial and ethnic disparities in vaccination rates for seasonal influenza exist. Whether such disparities extend to patients with ESKD, who simultaneously are at risk for complications of infection and have extensive contact with health care providers, has not been investigated. Methods To determine whether the proportion of patients vaccinated at a dialysis facility differs according to the facility’s racial and ethnic composition, we examined dialysis facility data reported to the Centers for Medicare and Medicaid Services. The main outcome was the proportion of facility patients vaccinated for influenza among 6735 Medicare-certified facilities operating between 2014 and 2017. Results Among dialysis facilities, the mean percentage of patients vaccinated during the influenza season was 72.1%. Facilities with higher proportions of Black and Hispanic patients had significantly lower vaccination percentages than less diverse facilities. The average proportion of patients vaccinated at each facility decreased significantly from 2014 to 2017 (a decrease of 1.05% vaccinated per year) and decreased significantly more so among facilities with higher minority proportions. The share of vaccinated patients in facilities in the quartile with the highest proportion of Black patients decreased 1.21% per year compared with a decrease of 0.88% per year in facilities in the quartile with the lowest proportion of Black patients. We found similar trends for Hispanic patients. Conclusions Rates of seasonal influenza vaccination are modestly but significantly lower among dialysis facilities with larger proportions of minority patients, and the gap seems to be widening over time. As wide-scale vaccination efforts grow more urgent amid the current COVID-19 pandemic, these disparities must be addressed to protect patients and communities equitably.
Abstract 6474: FAT1 and CASP8 co-mutations are associated with poor prognosis in HPV negative head and neck squamous cell carcinoma
Authors: Emrullah Yilmaz, David Lee, Andrew Cowan, Gregory Gan, Michelle Ozbun, Yan Guo
Journal: Cancer Research (2020)

Abstract INTRODUCTION: FAT1 alterations with somatic mutations or deletions are observed in head and neck squamous cell carcinomas (HNSCC). These alterations lead to loss of function of FAT1. FAT1 loss of function was known to be associated with aberrant Wnt activation, cell migration and invasion. In this study, we present analysis and outcomes of co-mutations seen in FAT1-mutation positive HNSCC. METHODS: TCGA data were analyzed for mutation, gene expression data and overall survival. We examined mutation data in 415 HPV negative samples and 72 HPV positive samples. The Fisher's Exact test was used to determine if differences in mutation frequency existed between the different cohorts. Mantel-Cox method was used for overall survival (OS) comparison between the cohorts. RESULTS: FAT1 somatic mutation was the third most commonly mutated gene in HPV-negative HNSCC while it was not common in HPV-positive HNSCC. FAT1 mutation was seen in 25.8% of HPV negative HNSCC (107/415), while 4.2% (3/72) HPV positive HNSCC had FAT1 mutation. We then analyzed the frequency of co-mutations in FAT1-mutated HPV-negative HNSCC. CDKN2A, NOTCH1, CASP8, FBXW7, ZFHX4, HRAS, DCC, ATR mutations were more common in FAT1-mutated cancers. CASP8 mutation was seen in 24.30% (26 out of 107 samples) of FAT1-mutations positive HPV negative HNSCC, while it was less common in FAT1-mutation negative HNSCC (9.08% 28/308) (P=0.002). The patients with FAT1 and CASP8 co-mutation were associated with shorter overall survival when compared with patients with FAT1-mutation (19.8 months vs 52.3 months P=0.02). FAT1 only or CASP8 only mutation without co-mutation did not affect survival. To determine the mutation impact of the FAT1 and CASP8 mutations in HNSCC, differentially expressed genes between mutated and non-mutated genes were analyzed in HNSCC. CASP8 mutation was the top gene among the genes with somatic mutation in HNSCC and associated with gene expression changes in more than 6000 genes. FAT1 was ranked 11th resulting in differential gene expression in more than 1000 genes. DISCUSSION: FAT1 somatic mutations are commonly seen in HPV negative HNSCC. We have demonstrated for the first time that CASP8 and FAT1 co-mutations are associated with poor prognosis with decreased overall survival in HPV negative HNSCC. Both CASP8 and FAT1 mutations are among the top genes with mutation impact on differential gene expression in HNSCC suggesting significance of these mutations in HNSCC. Citation Format: Emrullah Yilmaz, David Lee, Andrew Cowan, Gregory Gan, Michelle Ozbun, Yan Guo. FAT1 and CASP8 co-mutations are associated with poor prognosis in HPV negative head and neck squamous cell carcinoma [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 6474.
High circulating CCL5 is associated with poor prognosis in locally advanced pancreatic cancer (LAPC): Biomarker analysis from the randomized phase II SCALOP trial
Authors: F Willenbrock, C Cox, C Wilhelm-Benartzi, A Abraham, R Owens, A Sabbagh, C Hurt, T Maughan, E O'Neill, S Mukherjee
Journal: Cancer Research (2019)
Controlled loading of albumin-drug conjugates ex vivo for enhanced drug delivery and antitumor efficacy
Authors: Xinquan Liu, Rashmi P. Mohanty, Esther Y. Maier, Xiujuan Peng, Steven Wulfe, Agnieszka P. Looney, Kyaw L. Aung, Debadyuti Ghosh
Journal: Journal of Controlled Release (2020)
Intralesional rituximab in the treatment of indolent primary cutaneous B‐cell lymphoma
Authors: A. Chirico, M.H. Henderson Berg, D. Roberge, K. Pehr
Journal: British Journal of Dermatology (2020)

Primary cutaneous B-cell lymphomas (PCBCLs) are a heterogeneous group of extranodal lymphomas1 . Primary cutaneous marginal zone lymphoma (MZL) and follicle center lymphoma (FCL), the most prevalent PCBCLs, are typically indolent.
Diagnostic Accuracy of Symptoms, Physical Signs, and Laboratory Tests for Giant Cell Arteritis
Authors: Kornelis S. M. van der Geest, Maria Sandovici, Elisabeth Brouwer, Sarah L. Mackie
Journal: JAMA Internal Medicine (2020)

Current clinical guidelines recommend selecting diagnostic tests for giant cell arteritis (GCA) based on pretest probability that the disease is present, but how pretest probability should be estimated remains unclear.
Abstract #1237: Preclinical pharmacokinetic and pharmacodynamic data for TRC105 (anti-endoglin antibody) are consistent with clinical activity observed at low doses in patients with advanced cancer
Authors: Charles Theuer, David Myszka, Steven Sherwood, Francesca Incardona, David Haughey, Suzanne Benedict, Sharon Real, Bonne Adams, Bryan Leigh, Ben Seon
Journal: Cancer Research (2009)

Background: TRC105 is a human/murine chimeric IgG1 monoclonal antibody that inhibits angiogenesis and tumor growth. TRC105 binds human endoglin (CD105), an intravascular target required for angiogenesis that is highly over-expressed on the surface of proliferating vascular endothelial cells. During a Phase 1 study of TRC105 monotherapy for patients with advanced solid cancer, clinical activity was observed at doses as low as 0.01 mg/kg i.v. every 2 weeks. We present nonclinical PK and PD data that provide a rationale for the expectation of clinical anticancer activity at low doses of TRC105. Methods: TRC105 avidity to purified human CD105 was quantified by Biacore® and binding to CD105 on human umbilical endothelial cells (HUVECs) was determined by FACS. ADCC was assayed using natural killer effector cells and HUVEC target cells at a 10:1 ratio. Human PK was estimated using TRC105 PK parameters from Cynomolgus monkeys. Results: TRC105 binds to human CD105 with a KD of 31 pM (4.6 ng/mL), reflecting a ka of 8.25 x105 M-1 s-1 and kd of 2.51 x 10-5 s-1. Once bound, Biacore® studies predict that more than half of TRC105 remains bound to its target after 19 days. FACS binding studies on proliferating HUVECs indicate a KD of 2.3 ng/mL with saturation at 200 ng/mL. TRC105 produced dose-dependent increases in ADCC at concentrations between 16 and 2000 ng/mL. The volume of distribution in Cynomolgus monkeys was similar to serum volume and the terminal half-life was 6.2 days. PK modeling predicted that a TRC105 dose of 0.01 mg/kg would generate human serum concentrations above the antibody KD and within a concentration range expected to bind to CD105 and induce ADCC of proliferating vascular endothelial cells. Conclusion: TRC105 is a high avidity monoclonal antibody (KD = 2.3-4.6 ng/mL) to CD105, an intravascular target. The clinical anticancer activity observed at 0.01 mg/kg is consistent with preclinical pharmacodynamic properties and predicted intravascular exposures.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1237.
SARS-CoV-2 Infection Among Community Health Workers in India Before and After Use of Face Shields
Authors: M. Emmanuel Bhaskar, Santhanam Arun
Journal: JAMA (2020)

This study assesses SARs-CoV-2 transmission among community health workers in India before and after instituting use of face shields during family counseling sessions in households with a SARs-CoV-2–infected member.
Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia
Authors: Mercedes Prudencio, Jack Humphrey, Sarah Pickles, Anna-Leigh Brown, Sarah E. Hill, Jennifer M. Kachergus, J. Shi, Michael G. Heckman, Matthew R. Spiegel, Casey Cook, Yuping Song, Mei Yue, Lillian M. Daughrity, Yari Carlomagno, Karen Jansen-West, Cristhoper Fernandez de Castro, Michael DeTure, Shunsuke Koga, Ying-Chih Wang, Prasanth Sivakumar, Cristian Bodo, Ana Candalija, Kevin Talbot, Bhuvaneish T. Selvaraj, Karen Burr, Siddharthan Chandran, Jia Newcombe, Tammaryn Lashley, Isabel Hubbard, Demetra Catalano, Duyang Kim, Nadia Propp, Samantha Fennessey, Delphine Fagegaltier, Hemali Phatnani, Maria Secrier, Elizabeth M.C. Fisher, Björn Oskarsson, Marka van Blitterswijk, Rosa Rademakers, Neil R. Graff-Radford, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Keith A. Josephs, E. Aubrey Thompson, Towfique Raj, Michael Ward, Dennis W. Dickson, Tania F. Gendron, Pietro Fratta, Leonard Petrucelli
Journal: Journal of Clinical Investigation (2020)

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.
Abnormal physical performance and frailty in older men with biochemical recurrence of prostate cancer (PCa) on androgen deprivation therapy (ADT)
Authors: K. A. Bylow, J. Hemmerich, S. Mohile, W. Stadler, W. Dale
Journal: Journal of Clinical Oncology (2009)

e20578 Background: ADT has recognized toxicities including osteoporosis, muscle weakness and wasting, anemia, and fatigue. ADT is increasingly being used in men with biochemical recurrence (BCR) despite the fact that earlier initiation has not been shown to improve overall survival in this setting. Little is known about the impact of ADT on physical performance or the development of frailty in older patients. Methods: A case-control study (n=119) of men age 65+ with BCR on ADT ≥ 6 months with stable PSA (n=56) compared to controls with history of PCa status post radiation or surgery with no evidence of recurrence (n=63) was conducted. Frailty prevalence per Fried's criteria (validated measures of weight loss, exhaustion, grip strength, walking speed, and physical activity), Short Physical Performance Battery scores (SPPB: validated measure of balance, walking speed and timed chair stands) and falls were compared between groups. Exploratory analyses of proposed biomarkers of frailty (CRP, ESR, hemoglobin, albumin, and total cholesterol) were conducted. Results: Age, ethnicity and socioeconomic status were not different between groups. Total score on the SPPB was significantly lower in the ADT group (9.1 vs. 10.2, p = .01), indicating higher risk of incident morbidity and mortality. 7.2% of men in ADT group met Fried's criteria for frailty compared to 3.2% in control group and 58.9% met criteria for “prefrail” in ADT group compared to 41.9% controls (p=0.03 for trend). Quadriceps strength, as measured by chair stands in SPPB, was significantly worse for ADT group (p&lt;.01). Incident falls were higher in ADT group (14.3% vs. 3.2%, p=.05). With the exception of hemoglobin (12.7 vs 14.4 g/dl, p&lt; .01), putative frailty biomarkers were not significantly different between groups. Conclusions: Men with BCR of PCa on ADT have worse physical performance, are more frail, and have a higher incidence of falls than controls, but biomarkers suggest that mechanism of frailty is different than in the geriatric syndrome. A prospective trial is needed to establish a temporal link between initiation of ADT and frailty. No significant financial relationships to disclose.
Aging and Immunometabolic Adaptations to Thermogenesis
Authors: Daniele Lettieri-Barbato, Katia Aquilano
Journal: Ageing Research Reviews (2020)

Brown and subcutaneous adipose tissues play a key role in non-shivering thermogenesis both in mice and human, and their activation by adrenergic stimuli promotes energy expenditure, reduces adiposity, and protects against age-related metabolic diseases such as type 2 diabetes (T2D). Low-grade inflammation and insulin resistance characterize T2D. Even though the decline of thermogenic adipose tissues is well-established during ageing, the mechanisms by which this event affects immune system and contributes to the development of T2D is still poorly defined. It is emerging that activation of thermogenic adipose tissues promotes type 2 immunity skewing, limiting type 1 inflammation. Of note, metabolic substrates sustaining type 1 inflammation (e.g. glucose and succinate) are also used by activated adipocytes to promote thermogenesis. Keeping in mind this aspect, a nutrient competition between adipocytes and adipose tissue immune cell infiltrates could be envisaged. Herein, we reviewed the metabolic rewiring of adipocytes during thermogenesis in order to give important insight into the anti-inflammatory role of thermogenic adipose tissues and delineate how their decline during ageing may favor the setting of low-grade inflammatory states that predispose to type 2 diabetes in elderly. A brief description about the contribution of adipokines secreted by thermogenic adipocytes in modulation of immune cell activation is also provided. Finally, we have outlined experimental flow chart procedures and provided technical advices to investigate the physiological processes leading to thermogenic adipose tissue impairment that are behind the immunometabolic decline during aging.
SAT0660 PROPOSAL OF CORE OUTCOME DOMAINS IN MIXED CRYOGLOBULINEMIC VASCULITIS
Authors: Giulio Guerrini, Carlo Alberto Scirè, Licia Vultaggio, Simone Giambalvo, Marco Sebastiani, Caterina Vacchi, Luca Quartuccio, Maurizio Pietrogrande
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Cryoglobulinaemic vasculitis is immune complex mediated vasculitis of medium and small-size vessels. This vasculitis involves mainly kidneys, peripheral nervous system, skin and joints. Currently, no standardized outcome measures are available for the evaluation of treatments in patients with cryoglobulinemic vasculitis. <h3>Objectives:</h3> To identify a core set of outcome measure (what to measure) for clinical studies for mixed cryoglobulinemic syndrome, following the OMERACT filter 2.0. [Ref] <h3>Methods:</h3> A search was made in Medline (via PubMed) and Embase using a standardized search [filter https://omeracthandbook.org/]. This review considered studies that included patients with Mixed (type 2 and 3) cryoglobulinemic syndrome, any type of outcome measures, articles in the English language and considered only SLR, RCT, cohort, case control and case series (&gt;5 patients). Data were screened independently by three reviewers, recorded on a prespecified extraction form and summarized qualitatively. Considering core areas and core domain set was drafted. The results were presented and voted by a Consensus Committee including physicians with expertise in rheumatic, kidney and infectious diseases. Specific domains were separately voted and scored from 1 (strongly disagree) to 5 (strongly agree). Agreement was calculated as the percentage of agree/strongly agree. Consensus was reached in case of &gt;70% of agreement. <h3>Results:</h3> In the review were included 88 studies of which 4 randomised clinical trial (3%, 144 patients), 3 systematic literature reviews (9%, 401 patients), 25 cohort studies (27%, 1284 patients), and 56 other observational studies (61%, 2871 patients). The most frequent domains were : bio-humoral activity markers (e.g. cryocrit, rheumatoid factor, complementemia), viral infection and liver function, reversible and non reversible manifestation of skin, peripheral nerve, kidney, joint. Only a few studies included as life impact area, survival and safety. No studies analyzed included economical impact. Drafted core domains within core areas and percent agreement from the Delphi survey are reported in Table I. Additional core domains included adverse events and viral infection, considered as contextual factor. <h3>Conclusion:</h3> This is the first study aimed at identifying the core outcome measures in cryoglobulinemic vasculitis. Further studies will be needed to evaluate appropriate instruments to measure these outcome domains to be applied in clinical trials and practice. <h3>References</h3> [1] Boers M, Kirwan JR, Wells G, et al. Developing core outcome measurement sets for clinical trials: OMERACT filter 2.0. J Clin Epidemiol 2014;67:745–53. doi:10.1016/j.jclinepi.2013.11.013 <h3>Disclosure of Interests:</h3> None declared