tbuckley/cabot-search huggingface dataset:
Optimizing Diabetes Self-management Using the Novel Skills, Confidence, and Preparedness Index (SCPI)
Authors: Ronnie Aronson, Aihua Li, Ruth E. Brown, Ashleigh Walker, Ashley Lyons, Naomi Orzech
Journal: Diabetes Care (2019)

OBJECTIVE The Skills, Confidence, and Preparedness Index (SCPI) is an electronic tool designed to assess three dimensions (knowledge, confidence, and preparedness) in a clinically relevant measure with immediate feedback to guide the individualization of patient education. This study sought to assess the validity and reliability of the final SCPI generation, its relevance to glycemia, and its responsiveness to patient education. RESEARCH DESIGN AND METHODS In Part 1, patients with type 1 and type 2 diabetes were recruited from specialist clinics over a 6-month period and completed the 23-item SCPI using a tablet. In Part 2, participants also underwent a diabetes self-management education (DSME) program. Baseline SCPI score was used to guide the DSME, and SCPI and glycemia were assessed at completion. RESULTS In total, 423 patients met inclusion criteria and 405 had evaluable data. SCPI scores were found to have a high degree of validity, internal consistency, and test-retest reliability, with no floor or ceiling effects. Scoring was negatively correlated with HbA1c (type 1 diabetes: r = −0.26, P = 0.001; type 2 diabetes: r = −0.20, P = 0.004). In 51 participants who underwent a DSME intervention (6.4 ± 0.6 visits over a mean ± SD 3.4 ± 0.8 months), mean HbA1c improvement was 1.2 ± 0.2% (13.1 ± 2.2 mmol/mol, P &amp;lt; 0.0001). Total SCPI score and each subscore improved in parallel. CONCLUSIONS The SCPI tool is a quick and easy-to-use measurement of three domains: skills, confidence, and preparedness. The instant scoring and feedback and its relationship to glycemic control should improve the efficiency and quality of individualizing care in the diabetes clinic.
T-Cell Receptor Gene Therapy for Human Papillomavirus–Associated Epithelial Cancers: A First-in-Human, Phase I/II Study
Authors: Stacey L. Doran, Sanja Stevanović, Sabina Adhikary, Jared J. Gartner, Li Jia, Mei Li M. Kwong, William C. Faquin, Stephen M. Hewitt, Richard M. Sherry, James C. Yang, Steven A. Rosenberg, Christian S. Hinrichs
Journal: Journal of Clinical Oncology (2019)

Genetically engineered T-cell therapy is an emerging treatment of hematologic cancers with potential utility in epithelial cancers. We investigated T-cell therapy for the treatment of metastatic human papillomavirus (HPV)-associated epithelial cancers.This phase I/II, single-center trial enrolled patients with metastatic HPV16-positive cancer from any primary tumor site who had received prior platinum-based therapy. Treatment consisted of autologous genetically engineered T cells expressing a T-cell receptor directed against HPV16 E6 (E6 T-cell receptor T cells), a conditioning regimen, and systemic aldesleukin.Twelve patients were treated in the study. No dose-limiting toxicities were observed in the phase I portion. Two patients, both in the highest-dose cohort, experienced objective tumor responses. A patient with three lung metastases experienced complete regression of one tumor and partial regression of two tumors, which were subsequently resected; she has no evidence of disease 3 years after treatment. All patients demonstrated high levels of peripheral blood engraftment with E6 T-cell receptor T cells 1 month after treatment (median, 30%; range, 4% to 53%). One patient's resistant tumor demonstrated a frameshift deletion in interferon gamma receptor 1, which mediates response to interferon gamma, an essential molecule for T-cell-mediated antitumor activity. Another patient's resistant tumor demonstrated loss of HLA-A*02:01, the antigen presentation molecule required for this therapy. A tumor from a patient who responded to treatment did not demonstrate genetic defects in interferon gamma response or antigen presentation.Engineered T cells can induce regression of epithelial cancer. Tumor resistance was observed in the context of T-cell programmed death-1 expression and defects in interferon gamma and antigen presentation pathway components. These findings have important implications for development of cellular therapy in epithelial cancers.
Phase II study of nedaplatin and irinotecan as adjuvant chemotherapy in patients with completely resected non-small cell lung cancer.
Authors: Haruhiro Saito, Shuji Murakami, Tetsuro Kondo, Fumihiro Oshita, Hiroyuki Ito, Haruhiko Nakayama, Kouzo Yamada
Journal: Journal of Clinical Oncology (2013)

7531 Background: The aim of this phase II study was to evaluate the feasibility and safety of a nedaplatin and irinotecan combination regimen in the treatment of completely resected non-small cell lung cancer (NSCLC). Methods: Patients with completely resected pathologically documented stage IB, II or III NSCLC were treated with nedaplatin and irinotecan. Chemotherapy consisted of 4 cycles of nedaplatin at 50mg/m2 and irinotecan 50mg/m2 on days 1 and 8 every 4 -5 weeks. The primary endpoint of this study was the completion rate of 4 cycles. Results: Thirty nine patients were treated, and the patient's demographics were: median age 68 years (range 40-74), gender male (n = 16, 41%)/female (n = 23, 59%), stage IIA (n = 9, 23%), IIB (n = 13, 33%), IIIA (n = 16, 41%), IIIB(n=1,2% ). Thirty six patients (92.3%) received the 4 cycles of the chemotherapy regimen. Among the 3 patients who failed to complete 4 cycles, the reasons for stopping were anaphylaxy (n = 1), G3 infection and diarrhea (n = 2). The main adverse effects were hematological toxicity as well as grade 3/4 neutropenia (which occurred in 36% of the patients). Conclusions: Adjuvant chemotherapy with nedaplatin and irinotecan combination regimen has an acceptable toxicity profile, and the majority of patients completed 4 cycles of therapy.
ALG9 Mutation Carriers Develop Kidney and Liver Cysts
Authors: Whitney Besse, Alex R. Chang, Jonathan Z. Luo, William J. Triffo, Bryn S. Moore, Ashima Gulati, Dustin N. Hartzel, Shrikant Mane, Vicente E. Torres, Stefan Somlo, Tooraj Mirshahi
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Dominantly inherited polycystic kidney and liver phenotypes occur when epithelial cells in these organs have reduction of polycystin-1 functional dosage. In a cohort of genetically unresolved polycystic liver and kidney disease, the authors identified heterozygous loss of function mutations in ALG9 . ALG9 encodes an endoplasmic reticulum enzyme that builds N -glycans, and the authors show that Alg9 inactivation results in impaired polycystin-1 maturation. Using a novel ‘genotype-first’ approach to ascertain individuals based strictly on their ALG9 genotype from a large cohort of exome-sequenced individuals, the authors find that 7/8 (88%) of ALG9 mutation carriers over age 50 have multiple kidney cysts. Together, these findings identify ALG9 as a novel human polycystic kidney and liver disease gene and support the utility of a genotype-driven approach to candidate disease gene validation and genotype-phenotype correlation. Background Mutations in PKD1 or PKD2 cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the PKD1 gene product, the membrane protein polycystin-1 (PC1). Methods We used whole-exome sequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, ALG9 , and in vitro cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of ALG9 loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups. Results Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9 , which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations. Conclusions ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.
Chromatin occupancy and epigenetic analysis reveal new insights into the function of the GATA1 N terminus in erythropoiesis
Authors: Te Ling, Yehudit Birger, Monika J. Stankiewicz, Nissim Ben-Haim, Tomer Kalisky, Avigail Rein, Eitan Kugler, Wei Chen, Chunling Fu, Kevin Zhang, Hiral Patel, Jacek W. Sikora, Young Ah Goo, Neil Kelleher, Lihua Zou, Shai Izraeli, John D. Crispino
Journal: Blood (2019)
Cystic fibrosis drugs are rejected for NHS use in Scotland
Authors: Bryan Christie
Journal: BMJ (2019)

Expensive drugs to treat cystic fibrosis have been rejected for use on the NHS in Scotland, but discussions continue with the manufacturer to try to make them available.

The Scottish Medicines Consortium, which advises NHS Scotland on the use of new drugs, said that there remained “significant uncertainty” over the overall health benefits of Orkambi (combination of lumacaftor and ivacaftor) and Symkevi (tezacaftor and ivacaftor) in relation to their …
Second primary malignancies in acute myeloid leukemia.
Authors: Barsha Nepal, Krishna Bilas Ghimire, Binay Kumar Shah
Journal: Journal of Clinical Oncology (2013)

e20529 Background: Long-term survival rate in acute myeloid leukemia (AML) patients younger than 60 yrs is higher than 40% (Mayer RJ, et al N Engl J Med 2004). Development of second primary malignancy (SPM) in these patients is unknown. We analyzed the incidence of SPM in these AML patients using SEER database. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER*Stat) database: Incidence - SEER 13 Regs Research Data, Nov 2011 Sub, Vintage 2009 Pops (1992-2009) using multiple primary standardized incidence ratio (MP-SIR) session. We evaluated SPM incidence rate among adult AML patients (age 20-59 yrs) during the period 1992 - 2009. We used SEER*Stat software for statistical analysis. Results: Total number of AML patients (age 20-59 yrs) reported during 1992-2009 period was 5,544. Median age at the time of diagnosis of SPM was 54.33 yrs ( 22.33-72.42 yrs). Median follow up was 8.13 yrs (2months – 17.8 yrs) and median latency period was 51 months ( 2-193months). The total number of all site SPM among AML patients reported during same time period was 100 with observed/expected (O/E) ratio of 1.03, (95% CI: 0.84-1.26), excess risk of 1.62 per 10,000 population. Ninety patients with AML developed SPM; 86 AML patients developed only 1 SPM and 7 patients developed 2 SPMs. The risk of oral cavity and pharyngeal cancer was significantly increased in AML patients with O/E: 3.99, p&lt;0.05 (95% CI: 1.99-7.15), excess risk of 3.98 per 10,000 population. Similarly, cancer of urinary system was significantly increased in AML patients with O/E: 2.26, p&lt;0.05 (95% CI: 1.23-3.79), excess risk of 3.77 per 10,000 population. Conclusions: This study showed significantly higher risk of second primary malignancies of oral cavity/pharyngeal cancer, and of urinary system in AML patients. [Table: see text]
Pre-clinical toxicology for a potent anti-cancer agent, a human ribonuclease variant
Authors: Laura Strong, Mark Shahan, John Kink, Baigen Mei, Kerry Ervin, Ronald Raines
Journal: Cancer Research (2007)

677  The objective of this study was to determine the pre-clinical toxicology profile of QBI-139, a member of the Evade™ Ribonuclease family, which are a novel class of therapeutic agents being developed for the treatment of cancer. These proteins are variants of the naturally occurring human pancreatic ribonuclease, engineered to evade the native ribonuclease inhibitor. QBI-139 was selected for pre-clinical studies based on tumor growth inhibition in the range of 80-90% in several mouse xenograft models. The efficacy of QBI-139 has been compared to standard chemotherapy agents, including 5-fluorouracil (pancreatic) and cisplatin (lung), as well as newer therapies such as erlotinib (lung), and representative data will be provided.   The lead candidate QBI-139 was expressed in inclusion bodies in E. coli and purified by traditional column chromatography. The enzymatic activity was determined using a UV-based assay with cytidine 2’, 3’-cyclic monophosphate as the substrate. QBI-139 was tested for its ability to inhibit the growth of human tumors implanted in the flanks of nude mice (xenograft model). To evaluate the safety of QBI-139, toxicology studies were conducted. Acute dose studies were performed in both mice and rats to determine the maximum tolerated dose (MTD). Clinical observation, body weight, and clinical chemistry were used to identify organ-specific toxicities and determine the reversibility of the toxicities. The animals were dosed by bolus i.v. injection. The MTD for single dose administration in mice and rats was determined. A repeat dose (30 day) study in mice demonstrated the efficacious dose (75-100 mg/kg) is within the safe dose (>200 mg/kg).  The pre-clinical toxicology data for QBI-139 supports the development as therapeutic agents. QBI-139 was well tolerated in the dose ranges anticipated to be efficacious.
West Nile Virus and Other Domestic Nationally Notifiable Arboviral Diseases — United States, 2018
Authors: Emily McDonald, Stacey W. Martin, Kimberly Landry, Carolyn V. Gould, Jennifer Lehman, Marc Fischer, Nicole P. Lindsey
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Arthropodborne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. West Nile virus (WNV) is the leading cause of domestically acquired arboviral disease in the continental United States (1). Other arboviruses, including eastern equine encephalitis, Jamestown Canyon, La Crosse, Powassan, and St. Louis encephalitis viruses, cause sporadic cases of disease and occasional outbreaks. This report summarizes surveillance data reported to CDC for 2018 on nationally notifiable arboviruses. It excludes dengue, chikungunya, and Zika viruses because they are primarily nondomestic viruses typically acquired through travel. In 2018, 48 states and the District of Columbia (DC) reported 2,813 cases of domestic arboviral disease, including 2,647 (94%) WNV disease cases. Of the WNV disease cases, 1,658 (63%) were classified as neuroinvasive disease (e.g., meningitis, encephalitis, and acute flaccid paralysis), for a national incidence of 0.51 cases of WNV neuroinvasive disease per 100,000 population. Because arboviral diseases continue to cause serious illness and have no definitive treatment, maintaining surveillance is important to direct and promote prevention activities. Health care providers should consider arboviral infections in patients with aseptic meningitis or encephalitis, perform appropriate diagnostic testing, and report cases to public health authorities.
Cytoplasmic Transduction Peptide-Fused Recombinant Tumor-Associated Antigens Elicit Potent Myeloma-Specific Cytotoxic T Lymphocytes By Loading Onto Dendritic Cells: Implications of Feasible Tumor Antigens for Clinical Application Against Multiple Myeloma
Authors: Hyun-Ju Lee, Sung-Hoon Jung, Manh-Cuong Vo, Thangaraj Jaya Lakshmi, Hye-Sung Park, Tan-Huy Chu, Hyeoung-Joon Kim, Je-Jung Lee
Journal: Blood (2017)
How to fix doctors’ rotas: vacation policies and mutual respect
Authors: Eugene Yeung
Journal: BMJ (2019)

The main question is not “How to fix doctors’ rotas,” but what needs to be fixed?1

I understand the difficulty for both the rota coordinators and doctors dealing with insufficient resources and work scheduling. I learnt about mutual respect from the Canadian healthcare system. In the medical residency programmes in Ontario, Canada, policies state that vacation requests must …
Incidence of and mortality from epidermal necrolysis (Stevens–Johnson syndrome/toxic epidermal necrolysis) in France during 2003–16: a four‐source capture–recapture estimate
Authors: G. Chaby, C. Maldini, C. Haddad, B. Lebrun‐Vignes, F. Hemery, S. Ingen‐Housz‐Oro, S. Gonzalez‐Chiappe, P. Wolkenstein, O. Chosidow, A. Mahr, L. Fardet
Journal: British Journal of Dermatology (2019)

Because of its rarity, the exact incidence of and mortality from epidermal necrolysis (Stevens–Johnson syndrome/toxic epidermal necrolysis) is difficult to establish and closely depends on the size and type of the data source. To estimate the incidence of and mortality due to epidermal necrolysis in France over a 14‐year period. Data from four national databases were analysed. A capture–recapture analysis was performed. A total of 2635 incident cases of epidermal necrolysis were recorded in at least one of the four databases during the study period [males: 47·9%; median age: 52 (interquartile range 25–72) years]. On capture–recapture analysis, the estimated total number of cases was 5686, for an overall estimated annual incidence of 6·5 (95% confidence interval 4·1–8·9) cases per million inhabitants. The estimated annual incidence rates were 4·1 (0·3–7·9) cases per million inhabitants < 20 years of age, 3·9 (1·5–6·3) cases per million inhabitants aged 20–64 years and 13·7 (5·4–22·0) cases per million inhabitants ≥ 65 years of age. The estimated overall annual mortality rate from epidermal necrolysis was 0·9 (0·1–1·8) case per million inhabitants. It was 0·6 (0·1–1·5) case per million inhabitants aged 20–64 years and 2·8 (0·9–6·6) cases per million inhabitants ≥ 65 years of age (deaths in people < 20 years old were too rare to provide an accurate estimate). The annual incidence of epidermal necrolysis is higher than the one to five cases per million inhabitants usually reported. Such estimations could be helpful in establishing appropriate healthcare plans for people with epidermal necrolysis, in particular the need for specialized care units. What's already known about this topic? Few data are available regarding incidence of and mortality from epidermal necrolysis in the general population. Experts in epidermal necrolysis have recently proposed an annual incidence of one to five cases per million individuals. The overall mortality rate is usually reported to be between 10% and 20%. What does this study add? Using a four‐source capture–recapture method and data from a 14‐year period (2003–16), the annual incidence of and mortality from epidermal necrolysis were estimated to be 6·5 (95% confidence interval 4·1–8·9) and 0·9 (0·1–1·8) cases per million French inhabitants, respectively. Such estimations could be helpful in establishing appropriate healthcare plans, in particular the need for specialized care units.
Oxidative stress regulates expression of VEGFR1+ in myeloid cells: Link to angiogenesis and tumor-induced immune suppression in renal cell carcinoma
Authors: Evgeniy Eruslanov, Yoshihisa Sakai, Charles Rosser, Dietmar Siemann, Johannes Vieweg, Sergei Kusmartsev
Journal: Cancer Research (2008)

283  Metastatic renal cell carcinoma (RCC) is associates with overproduction of vascular endothelial growth factor (VEGF) due mutation/inactivation of VHL tumor suppressor gene. Here we demonstrate that implantation of human RCC tumor cells into nude mice promotes up-regulation of vascular endothelial growth factor receptor 1 (VEGFR1) in peripheral blood specifically in CD11b myeloid cells. Avastin-mediated VEGF neutralization was capable of significant reducing the numbers of circulating VEGFR1-positive cells in tumor-bearing mice. Conversely, up-regulation of VEGFR1 in myeloid cells also could be achieved in vitro by co-culturing of bone marrow cells with RCC-conditioned medium, or by short-term exposure of naive myeloid cells to the oxidative stress. Treatment myeloid cells with H2O2, or lipid peroxidation product 4-HNE or inhibitor of thioredoxin reductase all resulted in increased expression of VEGFR1. Furthermore, after exposure to oxidative stress, myeloid cells have acquired the immunosuppressive features and become capable of inhibiting T cell proliferation. Obtained data suggest that tumor-induced oxidative stress may promote both VEGFR1 up-regulation and immunosuppressive function in bone marrow-derived myeloid cells. Analysis of tumor tissue and peripheral blood from patients with metastatic RCC revealed that VEGFR1-positive cells can be also found in cancer patients. Restoration of immunocompetence in metastatic RCC patients by pharmacological elimination of VEGFR1-positive cells may have a significant impact on the therapeutic efficacy of cancer vaccines or other immune-based therapies.
Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury
Authors: Purvi Mehrotra, Michael Sturek, Javier A. Neyra, David P. Basile
Journal: Journal of Clinical Investigation (2019)

We hypothesized that the store-operated calcium entry (SOCE) channel, Orai1, participates in the activation of Th17 cells and influences renal injury. In rats, following renal ischemia/reperfusion (I/R), there was a rapid and sustained influx of Orai1+ CD4 T cells and IL-17 expression was restricted to Orai1+ cells. When kidney CD4+ cells of post-acute kidney injury (post-AKI) rats were stimulated with angiotensin II and elevated Na+ (10-7 M/170 mM) in vitro, there was an enhanced response in intracellular Ca2+ and IL-17 expression, which was blocked by SOCE inhibitors 2APB, YM58483/BTP2, or AnCoA4. In vivo, YM58483/BTP2 (1 mg/kg) attenuated IL-17+ cell activation, inflammation, and severity of AKI following either I/R or intramuscular glycerol injection. Rats treated with high-salt diet (5-9 weeks after I/R) manifested progressive disease indicated by enhanced inflammation, fibrosis, and impaired renal function. These responses were significantly attenuated by YM58483/BTP2. In peripheral blood of critically ill patients, Orai1+ cells were significantly elevated by approximately 10-fold and Th17 cells were elevated by approximately 4-fold in AKI versus non-AKI patients. Further, in vitro stimulation of CD4+ cells from AKI patients increased IL-17, which was blocked by SOCE inhibitors. These data suggest that Orai1 SOCE is a potential therapeutic target in AKI and CKD progression.