tbuckley/cabot-search huggingface dataset:
Age of Islet Autoantibody Appearance and Mean Levels of Insulin, but Not GAD or IA-2 Autoantibodies, Predict Age of Diagnosis of Type 1 Diabetes
Authors: Andrea K. Steck, Kelly Johnson, Katherine J. Barriga, Dongmei Miao, Liping Yu, John C. Hutton, George S. Eisenbarth, Marian J. Rewers
Journal: Diabetes Care (2011)

OBJECTIVE We evaluated predictors of progression to diabetes in children with high-risk HLA genotypes and persistent islet autoantibodies. RESEARCH DESIGN AND METHODS The Diabetes Autoimmunity Study in the Young (DAISY) followed 2,542 children with autoantibodies measured to GAD, IA-2, and insulin. RESULTS Persistent islet autoantibodies developed in 169 subjects, and 55 of those progressed to diabetes. Children expressing three autoantibodies showed a linear progression to diabetes with 74% cumulative incidence by the 10-year follow-up compared with 70% with two antibodies and 15% with one antibody (P &amp;lt; 0.0001). Both age of appearance of first autoantibody and insulin autoantibody (IAA) levels, but not GAD or IA-2 autoantibodies, were major determinants of the age of diabetes diagnosis (r = 0.79, P &amp;lt; 0.0001). CONCLUSIONS In the DAISY cohort, 89% of children who progressed to diabetes expressed two or more autoantibodies. Age of diagnosis of diabetes is strongly correlated with age of appearance of first autoantibody and IAA levels.
Fine Specificity of High Molecular Weight-Melanoma-Associated Antigen-Specific Cytotoxic T Lymphocytes Elicited by Anti-Idiotypic Monoclonal Antibodies in Patients with Melanoma
Authors: James L. Murray, Michael Gillogly, Kouichiro Kawano, Clay L. Efferson, Jeffrey E. Lee, Merrick Ross, Xinhui Wang, Soldano Ferrone, Constantin G. Ioannides
Journal: Cancer Research (2004)

Abstract HLA-A2-restricted CTLs, which lysed high molecular weight (HMW)-melanoma-associated antigen (MAA)+ melanoma cells, were induced in patients with melanoma immunized with MELIMMUNE, a combination of the murine anti-idiotypic (anti-id) monoclonal antibodies (mAb) MEL-2 and MF11–30 (MW Pride et al., Clin Cancer Res 1998;4:2363.). In the present study we investigated whether CTL epitopes are present in anti-id mAb MF-11–30 and activate T cells to recognize HMW-MAA on melanoma cells. One candidate epitope in the mAb MF11–30 VH chain, VH (3–11), was selected based on the presence of HLA-A2 anchor residues and partial homology with the HMW-MAA epitope, HMW-MAA (76–84). Lymphocytes from HLA-A2+-immunized patients proliferated to VH (3–11) peptide and to a variant HMW-MAA peptide to a significantly greater extent than autologous lymphocytes stimulated with an irrelevant peptide and lymphocytes from nonimmunized patients. No proliferative response was detected to the wild-type HMW-MAA peptide (76–84). Significant increase in IFN-γ production but not in interleukin 10 production in response to VH (3–11) and to variant HMW-MAA peptide (76–84) was observed in lymphocytes from the immunized patients. Stimulation of lymphocytes from HLA-A2+ patients with the two peptides induced CTL, which lysed HMW-MAA+/HLA-A2+ A375SM melanoma cells. This is the first report documenting the presence of immunogenic peptides in a murine anti-id mAb for a defined epitope expressed by a human melanoma-associated antigen. These results may be relevant for development of novel vaccines based on homology between anti-id mAb and tumor-associated antigen amino acid sequences.
Hospital Outbreak of Middle East Respiratory Syndrome Coronavirus
Authors: Abdullah Assiri, Allison McGeer, Trish M Perl, Connie S Price, Abdullah A Al Rabeeah, Derek A T Cummings, Zaki N Alabdullatif, Maher Assad, Abdulmohsen Almulhim, Hatem Makhdoom, Hossam Madani, Rafat Alhakeem, Jaffar A Al-Tawfiq, Matthew Cotten, Simon J Watson, Paul Kellam, Alimuddin I Zumla, Ziad A Memish
Journal: New England Journal of Medicine (2013)

In September 2012, the World Health Organization reported the first cases of pneumonia caused by the novel Middle East respiratory syndrome coronavirus (MERS-CoV). We describe a cluster of health care-acquired MERS-CoV infections.Medical records were reviewed for clinical and demographic information and determination of potential contacts and exposures. Case patients and contacts were interviewed. The incubation period and serial interval (the time between the successive onset of symptoms in a chain of transmission) were estimated. Viral RNA was sequenced.Between April 1 and May 23, 2013, a total of 23 cases of MERS-CoV infection were reported in the eastern province of Saudi Arabia. Symptoms included fever in 20 patients (87%), cough in 20 (87%), shortness of breath in 11 (48%), and gastrointestinal symptoms in 8 (35%); 20 patients (87%) presented with abnormal chest radiographs. As of June 12, a total of 15 patients (65%) had died, 6 (26%) had recovered, and 2 (9%) remained hospitalized. The median incubation period was 5.2 days (95% confidence interval [CI], 1.9 to 14.7), and the serial interval was 7.6 days (95% CI, 2.5 to 23.1). A total of 21 of the 23 cases were acquired by person-to-person transmission in hemodialysis units, intensive care units, or in-patient units in three different health care facilities. Sequencing data from four isolates revealed a single monophyletic clade. Among 217 household contacts and more than 200 health care worker contacts whom we identified, MERS-CoV infection developed in 5 family members (3 with laboratory-confirmed cases) and in 2 health care workers (both with laboratory-confirmed cases).Person-to-person transmission of MERS-CoV can occur in health care settings and may be associated with considerable morbidity. Surveillance and infection-control measures are critical to a global public health response.
Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by Liver X receptor α through a sterol regulatory element-binding protein 1c-dependent mechanism in mice
Authors: Jing Wu, Chunjiong Wang, Shuo Li, Sha Li, Wanyi Wang, Jing Li, Yujing Chi, Hang Yang, Xiaomu Kong, Yunfeng Zhou, Chengyan Dong, Fan Wang, Guoheng Xu, Jichun Yang, Jan-Åke Gustafsson, Youfei Guan
Journal: Hepatology (2013)

The protein, thyroid hormone-responsive SPOT 14 homolog (Thrsp), has been reported to be a lipogenic gene in cultured hepatocytes, implicating an important role of Thrsp in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Thrsp expression is known to be regulated by a variety of transcription factors, including thyroid hormone receptor, pregnane X receptor, and constitutive androstane receptor. Emerging in vitro evidence also points to a critical role of liver X receptor (LXR) in regulating Thrsp transcription in hepatocytes. In the present study, we showed that Thrsp was up-regulated in livers of db/db mice and high-fat-diet–fed mice, two models of murine NAFLD. Hepatic overexpression of Thrsp increased triglyceride accumulation with enhanced lipogenesis in livers of C57Bl/6 mice, whereas hepatic Thrsp gene silencing attenuated the fatty liver phenotype in db/db mice. LXR activator TO901317 induced Thrsp expression in livers of wild-type (WT) and LXR-β gene-deficient mice, but not in LXR-α or LXR-α/β double-knockout mice. TO901317 treatment significantly enhanced hepatic sterol regulatory element-binding protein 1c (SREBP-1c) expression and activity in WT mice, but failed to induce Thrsp expression in SREBP-1c gene-deficient mice. Sequence analysis revealed four LXR response-element–like elements and one sterol regulatory element (SRE)-binding site within a −2,468 ˜+1-base-pair region of the Thrsp promoter. TO901317 treatment and LXR-α overexpression failed to induce, whereas overexpression of SREBP-1c significantly increased Thrsp promoter activity. Moreover, deletion of the SRE site completely abolished SREBP-1c–induced Thrsp transcription. Conclusion : Thrsp is a lipogenic gene in the liver that is induced by the LXR agonist through an LXR-α–mediated, SREBP-1c–dependent mechanism. Therefore, Thrsp may represent a potential therapeutic target for the treatment of NAFLD. (Hepatology 2013;58:617–628)
Neurolymphomatosis: an International Primary CNS Lymphoma Collaborative Group report
Authors: Sigal Grisariu, Batia Avni, Tracy T. Batchelor, Martin J. van den Bent, Felix Bokstein, David Schiff, Outi Kuittinen, Marc C. Chamberlain, Patrick Roth, Anatoly Nemets, Edna Shalom, Dina Ben-Yehuda, Tali Siegal
Journal: Blood (2010)
Synthetic Lethality Screens Reveal RPS6 and MST1R as Modifiers of Insulin-like Growth Factor-1 Receptor Inhibitor Activity in Childhood Sarcomas
Authors: Jenny C. Potratz, Darren N. Saunders, Daniel H. Wai, Tony L. Ng, Steven E. McKinney, Joan M. Carboni, Marco M. Gottardis, Timothy J. Triche, Heribert Jürgens, Michael N. Pollak, Samuel A. Aparicio, Poul H.B. Sorensen
Journal: Cancer Research (2010)

The insulin-like growth factor-1 receptor (IGF1R) is emerging as a promising therapeutic target in human cancers. In the high-risk childhood sarcomas Ewing family tumor and rhabdomyosarcoma, IGF1R-blocking antibodies show impressive antitumor activity in some but not all patients, and acquired resistance is observed. Because tumor IGF1R mutations are not described, the basis of IGF1R inhibitor resistance remains unknown. We hypothesized that compensatory signaling cascades bypassing targeted IGF1R inhibition might be involved. To test this systematically, we performed small interfering RNA (siRNA) screens in sarcoma cell lines to identify IGF1R pathway components or related protein tyrosine kinase (PTK) networks that modulate the antitumor efficacy of the BMS-536924 IGF1R kinase inhibitor. This strategy revealed (a) that sarcoma cells are exquisitely sensitive to loss of distal rather than proximal IGF1R signaling components, such as ribosomal protein S6 (RPS6); (b) that BMS-536924 fails to block RPS6 activation in resistant sarcoma cell lines; and (c) that siRNA knockdown of the macrophage-stimulating 1 receptor tyrosine kinase (MST1R; also known as RON) restores BMS-536924 efficacy, even in highly drug-resistant cell lines. We confirmed MST1R expression across a broad panel of childhood sarcomas, and found that loss of MST1R by RNA interference blocks downstream RPS6 activation when combined with BMS-536924 in vitro. These findings underscore the importance of fully understanding PTK networks for successful clinical implementation of kinase inhibitor strategies.
Hyperphosphaturia and Hypermagnesuria in Children With IDDM
Authors: Stephen W Ponder, Ben H Brouhard, Luther B Travis
Journal: Diabetes Care (1990)

Urinary excretion of calcium, inorganic phosphorus, magnesium, glucose, and creatinine was measured in first-void spot urine samples collected 4 days apart in 220 insulin-dependent diabetic (IDDM) children (mean age 11.9 yr) attending a summer camp. A single control urine sample was obtained from 33 healthy nondiabetic siblings (mean age 11.2 yr). Mean ± SD urinary calciumcreatinine ratios (UCa/cr) did not significantly differ between IDDM and control subjects (0.14 ± 0.09 vs. 0.12 ± 0.09, respectively, P = 0.156). Mean urinary magnesium-creatinine ratios (UMg/Cr) were elevated in IDDM compared with control subjects (0.15 ± 0.06 vs. 0.08 ± 0.03, respectively, P = 0.0001). Similarly, mean urinary phosphorus-creatinine ratios (UP/cr) were significantly increased over those in control subjects (1.12 ± 0.33 vs. 0.40 ± 0.22, respectively, P = 0.0001). Uca/cr′ UMg/Cr′, and Up/Cr were correlated with increasing mean urine glucose content (P = 0.0001). No correlations were found when Uca/cr′ UMg/Cr′, or Up/Cr were compared with patient age, duration of diabetes, glycosylated hemoglobin, or insulin dosage. Urine losses of phosphorus and magnesium were present even when glycemic control was considered good by several methods (glycosylated hemoglobin, short-term glycemic index, or urinary glucose content). Glomerular hyperfiltration was unable to account for increased urinary mineral content. In conclusion, the data indicate that urinary excretion of phosphorus and magnesium is elevated in children with IDDM, regardless of glycemic control. In the presence of glucosuria, this loss is further enhanced. Urinary calcium excretion is significantly higher only during periods of glucosuria. The data suggest that children with IDDM could be at risk for mineral deficiencies in the absence of intensive insulin management.
Phase I Dose-Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid Tumors
Authors: Kazuhiko Yamada, Noboru Yamamoto, Yasuhide Yamada, Hiroshi Nokihara, Yutaka Fujiwara, Taizo Hirata, Fumiaki Koizumi, Kazuto Nishio, Noriyuki Koyama, Tomohide Tamura
Journal: Clinical Cancer Research (2011)

Abstract Purpose: E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors. Experimental Design: In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis. Results: Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, Cmax and area under the plasma concentration–time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(−) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect. Conclusion: E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors. Clin Cancer Res; 17(8); 2528–37. ©2011 AACR.
Patterns of Insulin Concentration During the OGTT Predict the Risk of Type 2 Diabetes in Japanese Americans
Authors: Tomoshige Hayashi, Edward J. Boyko, Kyoko Kogawa Sato, Marguerite J. McNeely, Donna L. Leonetti, Steven E. Kahn, Wilfred Y. Fujimoto
Journal: Diabetes Care (2012)

OBJECTIVE To examine whether the patterns of insulin concentration during the oral glucose tolerance test (OGTT) predict type 2 diabetes. RESEARCH DESIGN AND METHODS We followed 400 nondiabetic Japanese Americans for 10–11 years. Insulin concentrations at 30, 60, and 120 min during a 2-h 75-g OGTT at baseline were used to derive the following possible patterns of insulin: pattern 1 (30-min peak, higher insulin level at 60 than at 120 min), pattern 2 (30-min peak, lower or equal level at 60 vs. 120 min), pattern 3 (60-min peak); pattern 4 (120-min peak, lower level at 30 than at 60 min), and pattern 5 (120-min peak, equal or higher level at 30 vs. 60 min). Insulin sensitivity was estimated by homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda index. Insulin secretion was estimated by the insulinogenic index (IGI) [Δinsulin/Δglucose (30–0 min)] and disposition index (IGI/HOMA-IR). RESULTS There were 86 incident cases of type 2 diabetes. The cumulative incidence was 3.2, 9.8, 15.4, 47.8, and 37.5% for patterns 1, 2, 3, 4, and 5, respectively. Compared with pattern 1, patterns 4 and 5, characterized by a lasting late insulin response, were associated with significantly less insulin sensitivity as measured by the Matsuda index and lower early insulin response by the disposition index. The multiple-adjusted odds ratios of type 2 diabetes were 12.55 (95% CI 4.79–32.89) for pattern 4 and 8.34 (2.38–29.27) for pattern 5 compared with patterns 1 and 2. This association was independent of insulin secretion and sensitivity. CONCLUSIONS The patterns of insulin concentration during an OGTT strongly predict the development of type 2 diabetes.
Measures to Define Chronic Kidney Disease
Authors: Ann M. O’Hare
Journal: JAMA (2013)

Based on the finding that estimated glomerular filtration rate (eGFR) and albuminuria were associated with mortality and treated end-stage renal disease in younger and older adults, Dr Hallan and colleagues1 concluded that there should be �a common definition and staging of CKD [chronic kidney disease] based on eGFR and albuminuria for all age groups.�
Perception of sound and gravity by TMC1 and TMC2
Authors: Xi Lin
Journal: Journal of Clinical Investigation (2011)

Central to our ability to hear and sense gravity is a cellular process known as mechanotransduction, which is initiated by the opening of mechanosensitive cation channels located near the tips of the stereocilia of auditory and vestibular inner ear hair cells. The molecular identity of the mechanotransduction channels has eluded researchers despite intensive investigations over the years. In this issue of the JCI, Kawashima et al. report their results obtained using mice with targeted deletion of both transmembrane channel–like 1 (Tmc1) and Tmc2. The use of inner ear hair cells isolated from these mice provided a nearly perfect system for testing the mechanotransduction channels without disrupting functions of other accessory proteins needed in the complicated molecular apparatus, and it allowed the authors to show that the proteins encoded by these genes are integral components of the mechanotransduction complex.
High-Dose Therapy and Autologous Blood Stem-Cell Transplantation Compared With Conventional Treatment in Myeloma Patients Aged 55 to 65 Years: Long-Term Results of a Randomized Control Trial From the Group Myelome-Autogreffe
Authors: Jean-Paul Fermand, Sandrine Katsahian, Marine Divine, Veronique Leblond, Francois Dreyfus, Margaret Macro, Bertrand Arnulf, Bruno Royer, Xavier Mariette, Edouard Pertuiset, Coralie Belanger, Maud Janvier, Sylvie Chevret, Jean Claude Brouet, Philippe Ravaud
Journal: Journal of Clinical Oncology (2005)

To study the impact of high-dose therapy (HDT) with autologous stem-cell support in patients with symptomatic multiple myeloma (MM) between the ages of 55 and 65 years.One hundred ninety patients between 55 and 65 years old who had newly diagnosed stage II or III MM were randomly assigned to receive either conventional chemotherapy (CCT; ie, monthly courses of a regimen of vincristine, melphalan, cyclophosphamide, and prednisone) or HDT and autologous blood stem-cell transplantation (using either melphalan alone 200 mg/m(2) intravenous [IV] or melphalan 140 mg/m(2) IV plus busulfan 16 mg/kg orally as pretransplantation cytoreduction).Within a median follow-up of 120 months, median event-free survival (EFS) times were 25 and 19 months in the HDT and CCT groups, respectively. Median overall survival (OS) time was 47.8 months in the HDT group compared with 47.6 months in the CCT group. A trend to better EFS (P = .07) was observed in favor of HDT, whereas OS curves were not statistically different (P = .91). The period of time without symptoms, treatment, and treatment toxicity (TwiSTT) was significantly longer for the HDT patients than for the CCT patients (P = .03).With a median follow-up time of approximately 10 years, this randomized trial confirmed a benefit of HDT in terms of EFS and TwiSTT but did not provide evidence for superiority of HDT over CCT in OS of patients aged 55 to 65 years with symptomatic newly diagnosed MM.
Critical role of TRPC6 channels in G2 phase transition and the development of human oesophageal cancer
Authors: Y Shi, X Ding, Z-H He, K-C Zhou, Q Wang, Y-Z Wang
Journal: Gut (2009)

<h3>Background:</h3> Oesophageal squamous cell carcinoma (OSCC) is one of the leading causes of cancer-related death worldwide. However, the mechanism by which the OSCC develops remains largely unknown. Ion channels are important for cancer development. Whether the transient receptor potential canonical (TRPC), known as the non-selective cation channels, plays a role in OSCC development is unknown. <h3>Methods:</h3> The expression of TRPC6, a member of TRPC subfamily, was examined in samples from patients with OSCC by immunostaining and in situ hybridisation. The effects of TRPC6 channels on OSCC cell cycle progression, cell growth and in vivo tumour formation were investigated. The functional TRPC6 channels were found in OSCC cells by electrophysiology and Ca<sup>2+</sup> imaging analysis. <h3>Results:</h3> The expression of TRPC6 at protein and mRNA levels was markedly increased in human OSCC specimens than that in normal human oesophageal tissues. Blockade of TRPC6 channels in human OSCC cells inhibited elevation of intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) and activation of Cdc2 kinase. Meanwhile, the OSCC cell cycle was arrested at G2 phase and the cell growth was suppressed. Furthermore, inhibition of TRPC6 channels suppressed in nude mice the tumour formation generated by injection of the OSCC cells. <h3>Conclusion:</h3> TRPC6 channels play a critical role in the development of OSCC. The [Ca<sup>2+</sup>]<sub>i</sub> elevation regulated by TRPC6 channels is essential for G2 phase progression and OSCC development. These channels might be a novel target for therapeutic intervention of OSCC.
Attenuating the mortality risk of high serum uric acid: the role of physical activity underused
Authors: Jiunn-Horng Chen, Chi Pang Wen, Shiuan Bei Wu, Joung-Liang Lan, Min Kuang Tsai, Ya-Ping Tai, June Han Lee, Chih Cheng Hsu, Chwen Keng Tsao, Jackson Pui Man Wai, Po Huang Chiang, Wen Han Pan, Chao Agnes Hsiung
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> High serum uric acid (sUA) has been associated with increased mortality risks, but its clinical treatment varied with potential side effects. The role of physical activity has received limited attention. <h3>Methods</h3> A cohort, consisting of 467 976 adults, who went through a standard health screening programme, with questionnaire and fasting blood samples, was successively recruited between 1996 and 2008. High sUA is defined as uric acid above 7.0 mg/dL. Leisure time physical activity level was self-reported, with fully active defined as those with 30 min per day for at least 5 days a week. National death file identified 12 228 deaths with a median follow-up of 8.5 years. Cox proportional model was used to analyse HRs, and 12 variables were controlled, including medical history, life style and risk factors. <h3>Findings</h3> High sUA constituted one quarter of the cohort (25.6%). Their all-cause mortality was significantly increased [HR: 1.22 (1.15–1.29)], with much of the increase contributed to by the inactive (HR: 1.27 (1.17–1.37)), relative to the reference group with sUA level of 5–6 mg/dL. When they were fully active, mortality risks did not increase, but decreased by 11% (HR: 0.89 (0.82–0.97)), reflecting the benefits of being active was able to overcome the adverse effects of high sUA. Given the same high sUA, a 4–6 years difference in life expectancy was found between the active and the inactive. <h3>Conclusions</h3> Physical activity is a valuable alternative to pharmacotherapy in its ability to reduce the increases in mortality risks from high sUA. By being fully active, exercise can extend life span by 4–6 years, a level greater than the 1–4 years of life-shortening effect from high sUA.