tbuckley/cabot-search huggingface dataset:
Hormonal and Metabolite Regulation of Hepatic Glucokinase
Authors: Loranne Agius
Journal: Annual Review of Nutrition (2016)

Liver glucose metabolism is dependent on glucokinase activity. Glucokinase expression is transcriptionally regulated by hormones and metabolites of glucose, and glucokinase activity is dependent on reversible binding of glucokinase to a specific inhibitor protein, glucokinase regulatory protein (GKRP), and to other binding proteins such as 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK2/FBP2), which functions as an activator. Glucokinase is inhibited in the postabsorptive state by sequestration in the nucleus bound to GKRP, and it is activated postprandially by portal hyperglycemia and fructose through dissociation from GKRP, translocation to the cytoplasm, and binding to PFK2/FBP2. Glucagon dissociates this interaction, promoting translocation back to the nucleus. In humans, changes in glucokinase expression and activity are associated with poorly controlled type 2 diabetes and with nonalcoholic fatty liver disease, and a common variant of GKRP with altered binding affinity for glucokinase is associated with increased blood and liver lipids and other metabolic traits that implicate a role for GKRP in maintaining intrahepatic metabolite homeostasis.
A pilot, single arm, prospective trial using neoadjuvant rapamycin prior to definitive therapy in head and neck squamous cell carcinoma.
Authors: Keisuke Shirai, Terry A Day, Eva Szabo, Carter Van Waes, Paul E. O'Brien, Maria Gisele Matheus, Kristina Godwin, Amit J Sood, Julie A Vick, Daniel Martin, Lynn Vitale-Cross, Alfredo Molinolo, Jorge Silvio Gutkind
Journal: Journal of Clinical Oncology (2015)

6071 Background: Deregulated PI3K-AKT-mTOR signaling is one of the most common abnormalities in head and neck squamous cell carcinoma (HNSCC). We previously showed that mTOR inhibition with rapamycin significantly inhibited the growth of human HNSCC xenografts and oral cancers in multiple genetically-defined and chemically-induced mouse models. A pilot trial of neoadjuvant rapamycin treatment was developed to assess its effect on clinical response and mTOR signaling. Methods: Patients with untreated stage II-IVA HNSCC received 21 days of rapamycin treatment (15 mg on day 1, 5 mg on days 2-21) prior to definitive treatment with surgery or chemoradiation. Treatment responses were assessed clinically and radiographically with CT and FDG-PET. Pre- and post-treatment biopsies and blood were obtained for toxicity, immune monitoring and immunohistochemical assessment of mTOR signaling. Results: Sixteen patients (8 oral cavity, 8 oropharyngeal) completed rapamycin and definitive treatment (15-surgery, 1-chemoradiation). Half of patients were p16 positive. Fifteen of 16 patients showed clinical improvement. One patient had pathological CR. two met RECIST criteria for response (1 CR, 1 PR, 14 SD). Treatment was well tolerated with no grade 4 or unexpected toxicities. Two grade 3 toxicities (1 post-operative wound complication, 1 hypokalemia) and 3 grade 2 toxicities (1 wound infection, 1 mucositis, 1 hyperglycemia) were seen. The most common toxicity was grade 1 thrombocytopenia (n = 5). Two asymptomatic patients required dose reduction due to elevated rapamycin levels. No significant immune suppression was observed. The level of phosphorylated S6 (pS6) showed statistically significant decrease in all evaluable (13/16) patients (34-87% decrease). Inhibition of phosphorylated AKTS473 (pAKTS473) was observed in 12/13 evaluable patients (27-97% decrease in 12 patients, 16% increase in one patient). Conclusions: Rapamycin treatment was well tolerated and resulted in significant clinical responses despite the brief treatment duration. Significant reduction in pS6 and pAKTS473 supported successful inhibition of mTOR signaling. Clinical trial information: NCT01195922.
Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma
Authors: Michinori Ogura, Kensei Tobinai, Kiyohiko Hatake, Andrew Davies, Michael Crump, Revathi Ananthakrishnan, Taro Ishibashi, M. Luisa Paccagnella, Joseph Boni, Erik Vandendries, David MacDonald
Journal: Clinical Cancer Research (2016)

To evaluate the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immunochemotherapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL).In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin. Part 2 (n = 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose-limiting toxicity rate of <33% in cycle 1 and <33% of patients discontinuing before cycle 3 due to treatment-related adverse events (AEs). Part 3 (n = 22) evaluated the preliminary efficacy of inotuzumab ozogamicin plus R-CVP.The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m2 The most common treatment-related grade ≥3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10). Overall, 13 patients died, including one death due to treatment-related pneumonia secondary to neutropenia. Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84% (n = 32), including 24% (n = 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n = 27) and 57% for those with aggressive histology lymphoma (n = 21).Inotuzumab ozogamicin at 0.8 mg/m2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22+ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 22(19); 4807-16. ©2016 AACR.
Disease vectors in the era of next generation sequencing
Authors: David C. Rinker, R. Jason Pitts, Laurence J. Zwiebel
Journal: Genome biology (2016)

Almost 20 % of all infectious human diseases are vector borne and, together, are responsible for over one million deaths per annum. Over the past decade, the decreasing costs of massively parallel sequencing technologies have facilitated the agnostic interrogation of insect vector genomes, giving medical entomologists access to an ever-expanding volume of high-quality genomic and transcriptomic data. In this review, we highlight how genomics resources have provided new insights into the physiology, behavior, and evolution of human disease vectors within the context of the global health landscape.
Pancreatic Cyst Disease
Authors: Alexander Stark, Timothy R. Donahue, Howard A. Reber, O. Joe Hines
Journal: JAMA (2016)

<h3>Importance</h3> Cystic lesions of the pancreas are common and increasingly detected in the primary care setting. Some patients have a low risk for developing a malignancy and others have a high risk and need further testing and interventions. <h3>Observations</h3> Pancreatic cysts may be intraductal mucinous neoplasms, mucinous cystic neoplasms, serous cystadenomas, solid pseudopapillary neoplasms, cystic variations of pancreatic neuroendocrine tumors, pancreatic ductal adenocarcinomas, or 1 of several types of nonneoplastic cysts. Mucinous (intraductal mucinous neoplasm or mucinous cystic neoplasm) lesions have malignant potential and should be distinguished from serous lesions (serous cystadenomas) that are nearly always benign. Symptomatic patients or those having high-risk features on initial imaging (eg, main pancreatic duct dilatation, a solid component, or mural nodule) require further evaluation with advanced imaging, possibly followed by surgical resection. Advanced imaging includes endoscopic ultrasound with cyst fluid analysis and cytology to confirm the type of cyst and determine the risk of malignancy. Small cysts (size &lt;3 cm) in asymptomatic patients without any suspicious features may be observed with serial imaging because the risk for malignancy is low. <h3>Conclusions and Relevance</h3> The management of pancreatic cysts requires risk stratification for malignant potential based on the presence or absence of symptoms and high-risk features on cross-sectional imaging. Because pancreatic cysts are becoming more frequently diagnosed, clinicians should have a systematic approach for establishing a diagnosis and determining which patients require treatment.
False positive results: a challenge for psychiatric screening in primary care
Authors: A C Leon, L Portera, M Olfson, M M Weissman, R G Kathol, L Farber, D V Sheehan, A M Pleil
Journal: American Journal of Psychiatry (1997)

The goal of this study was to characterize primary care patients with false positive results on screens for mental disorders.A sample of 1,001 primary care patients completed self-administered screens and structured interviews for DSM-IV diagnoses.A substantial proportion of the patients with false positive screen results for at least one diagnosis met the diagnostic criteria for other psychiatric disorders. They also had significantly greater functional impairment and higher rates of recent use of mental health services than the subjects with true negative results on the screens.Although the positive predictive values of screens for specific mental disorders are in line with those of other medical screens, false positive results are not uncommon. This may be due in part to the sensitivity of brief screening instruments to nonspecific symptoms. The results suggest that as with other screens used in primary care, patients with false positive results on screens for mental disorders should receive clinical attention.
Automatic Data Processing Techniques for Carcinogenesis Studies<xref ref-type="fn" rid="FN2">2</xref>
Authors: Melvin Greenblatt, M.D., Ruggero Montesano, M.D., Louise Wombolt, B.S., Philippe Shubik, B.Ch., B.M., D.Phil.
Journal: JNCI Journal of the National Cancer Institute (1970)

Automatic data processing techniques for chronic carcinogenesis studies are discussed, and a program which adequately fulfills the requirements of a system for use at the experimental laboratory level is outlined. Suggestions regarding the standardized reporting of the results of this type of data are made.
Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a <i>VAC14</i> Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy
Authors: Daniel L. Hertz, Kouros Owzar, Sherrie Lessans, Claudia Wing, Chen Jiang, William Kevin Kelly, Jai Patel, Susan Halabi, Yoichi Furukawa, Heather E. Wheeler, Alexander B. Sibley, Cameron Lassiter, Lois Weisman, Dorothy Watson, Stefanie D. Krens, Flora Mulkey, Cynthia L. Renn, Eric J. Small, Phillip G. Febbo, Ivo Shterev, Deanna L. Kroetz, Paula N. Friedman, John F. Mahoney, Michael A. Carducci, Michael J. Kelley, Yusuke Nakamura, Michiaki Kubo, Susan G. Dorsey, M. Eileen Dolan, Michael J. Morris, Mark J. Ratain, Howard L. McLeod
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P &amp;lt; 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.
Brief Communication: The Dependence of Successful Immunotherapy on Adequate Tumor Burden as Shown by the Treatment of AKR Leukemia With Poly A·poly U
Authors: W. Jefferson Pendergrast, Walter P. Drake, Michael R. Mardiney
Journal: JNCI Journal of the National Cancer Institute (1975)

The therapeutic efficacy of polyadenlyic-polyuridylic acid (poly A-poly U) on the transplantable AKR leukemia varied with the dose of tumor cells implanted. The greater the number of AKR tumor cells injected into 8-week-old AKR mice free of clinical evidence of cancer, the greater the effect of poly A-poly U in mediating host immunologic control of the tumor. Poly A-poly U was either ineffective or could enhance tumor growth when smaller doses of tumor cells were transferred. The efficacy of an immune adjuvant depended on a tumor burden affording optimum host responsiveness. This does not necessarily arise in the host bearing minimal tumor burden.
Healthcare services in police custody: a view from France
Authors: Aude Lepresle, Camille Vidal, Patrick Chariot
Journal: BMJ (2016)

Forrester and colleagues disagree with the UK government’s decision not to pursue the transfer of custody healthcare commissioning to NHS England.1 They consider this decision as a missed opportunity to improve the quality of healthcare provided to arrestees detained in police cells. The authors confine their statements to the UK but the situation …
Atenolol in seasonal affective disorder: a test of the melatonin hypothesis
Authors: N E Rosenthal, F M Jacobsen, D A Sack, J Arendt, S P James, B L Parry, T A Wehr
Journal: American Journal of Psychiatry (1988)

To test the hypothesis that the antidepressant effects of bright light in seasonal affective disorder are mediated by the suppression of melatonin, 19 patients with this disorder were given atenolol, which suppresses melatonin secretion, and placebo in a double-blind crossover study. No difference in antidepressant efficacy was found between drug and placebo in the sample as a whole, which argues against the melatonin hypothesis of phototherapy. However, in three of the patients atenolol provided repeated, marked, and sustained relief of symptoms, suggesting that it may be useful in treating the winter depressive symptoms of some patients with seasonal affective disorder.
Gradual Versus Abrupt Smoking Cessation
Authors: Nicola Lindson-Hawley, Miriam Banting, Robert West, Susan Michie, Bethany Shinkins, Paul Aveyard
Journal: Annals of Internal Medicine (2016)

Background: Most smoking cessation guidelines advise quitting abruptly. However, many quit attempts involve gradual cessation. If gradual cessation is as successful, smokers can be advised to quit either way. Objective: To examine the success of quitting smoking by gradual compared with abrupt quitting. Design: Randomized, controlled noninferiority trial. (International Standardized Randomized Controlled Trial Number Register: ISRCTN22526020) Setting: Primary care clinics in England. Participants: 697 adult smokers with tobacco addiction. Intervention: Participants quit smoking abruptly or reduced smoking gradually by 75% in the 2 weeks before quitting. Both groups received behavioral support from nurses and used nicotine replacement before and after quit day. Measurements: The primary outcome measure was prolonged validated abstinence from smoking 4 weeks after quit day. The secondary outcome was prolonged, validated, 6-month abstinence. Results: At 4 weeks, 39.2% (95% CI, 34.0% to 44.4%) of the participants in the gradual-cessation group were abstinent compared with 49.0% (CI, 43.8% to 54.2%) in the abrupt-cessation group (relative risk, 0.80 [CI, 0.66 to 0.93]). At 6 months, 15.5% (CI, 12.0% to 19.7%) of the participants in the gradual-cessation group were abstinent compared with 22.0% (CI, 18.0% to 26.6%) in the abrupt-cessation group (relative risk, 0.71 [CI, 0.46 to 0.91]). Participants who preferred gradual cessation were significantly less likely to be abstinent at 4 weeks than those who preferred abrupt cessation (38.3% vs 52.2%; P = 0.007). Limitations: Blinding was impossible. Most participants were white. Conclusion: Quitting smoking abruptly is more likely to lead to lasting abstinence than cutting down first, even for smokers who initially prefer to quit by gradual reduction. Primary Funding Source: British Heart Foundation.
The Undiagnosed Diseases Program—Reply
Authors: William A. Gahl, Anastasia L. Wise, Euan A. Ashley
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Phase II study of TS-1 (S) plus cisplatin (P) with concurrent thoracic radiotherapy for unresectable stage III non-small cell lung cancer (NSCLC)
Authors: F. Ohyanagi, N. Yamamoto, A. Horiike, T. Horai, K. Gomi, H. Murakami, H. Harada, T. Takahashi, Y. Nakamura, M. Nishio
Journal: Journal of Clinical Oncology (2007)

18070 Background: Although combined chemoradiotherapy is the standard of care in stage III NSCLC, the optimal chemotherapy regimen is not established. S-1, a fourth-generation oral fluoropyrimidine is an active new agent for NSCLC and the combination with cisplatin has a favorable toxicity profile. The objective of this study was to evaluate feasibility and efficacy of S plus P with concurrent radiation for unresectable stage III NSCLC. Methods: Patients with histologically or cytologically confirmed NSCLC, 20 to 75 years in age, performance status 0–1, with no prior chemotherapy were eligible for the study. Patients were treated with P (60 mg/m 2 on day 1) and S (orally at 40 mg/m 2 /dose bid (80 mg/m 2 /d), on days 1 to 14) repeated every 3–4 weeks for 4 cycles and TRT (60 Gy/30 fr over 6 weeks starting on day 2). The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 28 patients (Simon’s two-stage minimax design, P0=70%, P1=90%, a =0.1, β = 0.1). Results: Of 28 patients enrolled between August 2005 and October 2006, 28 were evaluable. There were 24 males and 4 females, median age of 63 (range 40–74) and 11 IIIA and 17 IIIB. Chemoradiotherapy was well tolerated; 2 cycles of SP and 60 Gy of TRT were administered in all patients and 24 (86%) patients received 4 cycles of SP. During concurrent chemoradiotherapy, grade 3 toxicities were neutropenia (8 pts), leukopenia (6 pts), fatigue (6 pts), anorexia (5 pts), febrile neutropenia (4 pts) and, esophagitis (4 pts). Only one grade 4 leukopenia were observed. During consolidation therapy, grade 3–4 neutropenia, anemia, esophagitis, and pneumonitis were developed in 4, 1, 1 and 2 patients, respectively. No toxic deaths have occurred. Overall RR was 85.7% (95% CI: 79.1- 98.7%) with 4 SDs and 24 PRs. The median progression-free survival and median survival is not mature enough to estimate as only 4 progression and no deaths have occurred. Conclusions: This chemoradiotherapy regimen produced promising response rate in patients with stage III NSCLC and it seems to be well-tolerated. No significant financial relationships to disclose.
Treatment-Emergent Hypertension and Efficacy in the Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (Select)
Authors: L.J. Wirth, M. Tahara, B. Robinson, S. Francis, M. Brose, M.A. Habra, K. Newbold, N. Kiyota, C. Dutcus, B.D.L. Heras, J. Zhu, S. Sherman, M. Schlumberger
Journal: Annals of Oncology (2014)
Inhibition of BATF/JUN transcriptional activity protects against osteoarthritic cartilage destruction
Authors: Jinseol Rhee, Seo-Hee Park, Seul-Ki Kim, Jin-Hong Kim, Chul-Won Ha, Churl-Hong Chun, Jang-Soo Chun
Journal: Annals of the Rheumatic Diseases (2016)

Objective The basic leucine zipper transcription factor, ATF-like (BATF), a member of the Activator protein-1 family, promotes transcriptional activation or repression, depending on the interacting partners (JUN-B or C-JUN). Here, we investigated whether the BATF/JUN complex exerts regulatory effects on catabolic and anabolic gene expression in chondrocytes and contributes to the pathogenesis of osteoarthritis (OA). Methods Primary cultured mouse chondrocytes were treated with proinflammatory cytokines (interleukin-1β, IL-6 or tumour necrosis factor-α) or infected with adenoviruses carrying the Batf gene (Ad- Batf ). Expression of BATF and JUN was examined in human and mouse experimental OA cartilage samples. Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of Ad- Batf . The chromatin immunoprecipitation assay was used to examine the binding of BATF and JUN to the promoter regions of candidate genes. Results Overexpression of BATF, which forms a heterodimeric complex with JUN-B and C-JUN, induced upregulation of matrix-degrading enzymes and downregulation of cartilage matrix molecules in chondrocytes. BATF expression in mouse joint tissues promoted OA cartilage destruction, and conversely, knockout of Batf in mice suppressed experimental OA. Pharmacological inhibition of BATF/JUN transcriptional activity reduced the expression of matrix-degrading enzymes and protected against experimental OA in mice. Conclusions BATF/JUN-B and BATF/C-JUN complexes play important roles in OA cartilage destruction through regulating anabolic and catabolic gene expression in chondrocytes. Our findings collectively support the utility of BATF as a therapeutic target for OA.