tbuckley/cabot-search huggingface dataset:
Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production
Authors: J. Setterfield, J. Theron, R.W. Vaughan, K.I. Welsh, E. Mallon, F. Wojnarowska, S.J. Challacombe, M.M. Black
Journal: British Journal of Dermatology (2008)

Background Class I human leucocyte antigens (HLA) ‐A, ‐B, ‐Cw and class II HLA‐DRB1, ‐DQB1 alleles were determined in 131 British Caucasian patients with mucous membrane pemphigoid (MMP) using serological and DNA‐based methods. Objectives To analyse the class I and II alleles expressed in well‐defined clinical and immunopathological subgroups of MMP, in order to establish whether specific alleles or haplotypes might in part explain disease susceptibility, clinical sites of involvement or disease severity. Methods Subgroups of patients were analysed according to the following clinical criteria: age of onset, sex, sites of clinical involvement (oral, ocular, skin, nasal, genital, pharyngeal, oesophageal, laryngeal, perianal), disease severity and history of autoimmune disease. Subgroups were also analysed according to the following immunopathological criteria: autoantibody profile, the presence of circulating antibasement membrane IgG or IgA antibodies and the detection of target basement membrane zone (BMZ) antigens (BP230 and BP180) by IgG autoantibodies. Results Class I HLA typing showed no significant disease or subgroup associations. Class II DRB1 typing showed a significantly increased allelic frequency in MMP vs. controls for DRB1*11 (RR = 2·08, Pc < 0·0000056). For DQB1, MMP vs. controls, there was a significantly increased allelic frequency for DQB1*0301 (Pc < 0·00000028) in both males and females; all clinical sites of involvement, with the exception of laryngeal, oesophageal and perianal sites and in patients with detectable circulating anti‐BMZ IgG compared with those negative for IgG (P < 0·0096, Pc < 0·019). A positive trend was noted in patients with ocular involvement compared with no ocular involvement and in patients with a clinical score 10 compared with < 10. We found no difference in DQB1*0301 allele frequency between subgroups with or without BP180 or BP230 target antigens. Haplotype frequencies showed an increase in DRB1*04, DQB1*0301 (Pc < 0·000066) and DRB1*11, DQB1*0301 (Pc < 0·000002) among patients compared with controls. Conclusions The DQB1*0301 allele confers a predisposition to all subgroups of MMP and may have a role in T‐cell recognition of basement membrane antigens, resulting in the production of anti‐BMZ IgG autoantibodies. The positive trend between increased allelic expression of DQB1*0301 in patients with ocular disease and in those with a higher clinical score, further suggests a role for this allele in disease severity.
The paradoxical effect of climate on time perspective considering resource accumulation
Authors: Gábor Orosz, Philip G. Zimbardo, Beáta Boőthe, István Tóth-Király
Journal: Behavioral and Brain Sciences (2017)

Abstract Considering purely climate, southern countries are less harsh and more predictable than northern countries. From a historical perspective, freezing winters resulting in fewer available resources contribute to the development of strong future orientation. The paradox is that future orientation contributes to accumulation of resources in the long run, making individuals' immediate living conditions less harsh, leading to slower life strategies.
Plasma Amino Acid Levels and Insulin Secretion in Obesity
Authors: Philip Felig, Errol Marliss, George F. Cahill
Journal: New England Journal of Medicine (1969)

Of 20 plasma amino acids measured, valine, leucine, isoleucine, tyrosine and phenylalanine were increased, and glycine decreased, in obese subjects compared with age- and sex-matched controls. The concentration of each of the amino acids elevated in obesity correlated directly with serum insulin. In addition, these were the amino acids most sensitive to the action of insulin in lowering plasma amino acid levels, as evidenced by a diminution in concentration after glucose infusion. Despite a significantly greater increment in serum insulin in the obese group, the magnitude of the decline in amino acids after glucose administration was identical in the two groups. Hyperaminoacidemia appears to be a manifestation of the insulin ineffectiveness characteristic of obesity. Furthermore, hyperaminoacidemia may provide the feedback signal to the beta cell through which insulin resistance is accompanied by an appropriately augmented secretory rate of insulin.
Efficacy and safety of the APE (actinomycin D, cisplatin, etoposide) regimen for the management of high-risk gestational trophoblastic neoplasia.
Authors: Catherine Lhomme, Caroline Even, Pierre Duvillard, Patricia Pautier, Anne Floquet, Pierre Kerbrat, Frederic Troalen, Annie Rey, Corinne Balleyguier, Philippe Morice, Karim Fizazi, Jean Pierre Droz
Journal: Journal of Clinical Oncology (2012)

5028 Background: Patients (pts) with high risk gestational trophoblastic neoplasia (GTN) or who fail low risk single agent chemotherapy (CT) require multi agent CT to be cured. The most common regimen is etoposide (E), methotrexate and actinomycin D (A) alternating weekly with cyclophophamide and vincristine (EMA/CO). Cisplatin (P) is a very active drug but its role is controversial and usually restricted to second line. We report results of a platinum based therapy: APE. Methods: We evaluated the efficacy and safety on 103 pts treated at Institut Gustave Roussy (IGR) (n=80) or other French centers (n=23) between 1983 and 2010 with APE for high risk GTN (defined by IGR criteria [Azab, Cancer, 1988] and/or FIGO score &gt;6). Pts with brain metastasis were excluded. Results: Efficacy was evaluated on 59 pts treated for high risk GTN in first line, and on 39 pts in &gt;2nd line including 13 pts after multi agent CT. We excluded pts with placental site trophoblastic tumors (n=2), or with FIGO score &lt;7 and without IGR criteria (n=3). Complete remission (CR) rate was 95%. Seven pts (7 %) relapsed and a second CR was obtained for all with surgery and/or CT. Only one patient died due to GTN, after successive CRs obtained with 3 regimens. Five year overall survival (median follow-up 6.6 years) was 98%. Toxicity was evaluated on 95 pts. No toxic death occurred. Given good efficacy and to avoid acute hematotoxicity and long-term G&gt;1 neuro and ototoxicity APE regimen was modified as detailed in the Table (below). Long-term neuro (5 pts, G1), oto (2 pts, G1 and 2 pts, G2) and renal toxicities (1 pt, G1 ) were recorded. No long-term G2 toxicities were observed with APE3. One pt developed an AML 4 after 4cy APE and 6 cy EMA/CO. 37 pts of 40 who wished to be pregnant succeeded and all of them had at least one live birth. Conclusions: With a 98% long-term overall survival rate, an excellent reproductive outcome, and no detectable long-term toxicity, APE-3 should be regarded as an alternative standard option to EMA/CO for high-risk GTN. [Table: see text]
Interleukin 4 promotes the development of ex-Foxp3 Th2 cells during immunity to intestinal helminths
Authors: Victoria S. Pelly, Stephanie M. Coomes, Yashaswini Kannan, Manolis Gialitakis, Lewis J. Entwistle, Jimena Perez-Lloret, Stephanie Czieso, Isobel S. Okoye, Dominik Rückerl, Judith E. Allen, Frank Brombacher, Mark S. Wilson
Journal: The Journal of Experimental Medicine (2017)

Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4+Foxp3+ regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex–T reg Th2 cells develop and contribute to type-2 immunity. Using multigene reporter and fate-reporter systems, we demonstrate that a significant proportion of Th2 cells derive from Foxp3+ cells after Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus. Through selective deletion of Il4ra on Foxp3+ cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting T reg cells into Th2 cells could concomitantly enhance Th2 cells and limit T reg cell–mediated suppression.
2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery: Executive Summary
Authors: Lee A. Fleisher, Kirsten E. Fleischmann, Andrew D. Auerbach, Susan A. Barnason, Joshua A. Beckman, Biykem Bozkurt, Victor G. Davila-Roman, Marie D. Gerhard-Herman, Thomas A. Holly, Garvan C. Kane, Joseph E. Marine, M. Timothy Nelson, Crystal C. Spencer, Annemarie Thompson, Henry H. Ting, Barry F. Uretsky, Duminda N. Wijeysundera
Journal: Circulation (2014)

evaluation; surgical procedures; ventricular premature beats; ventricular tachycardia; and volatile anesthetics.An independent ERC was commissioned to perform a systematic review of a critical question, the results of which were incorporated into this CPG.See the systematic review report published in conjunction with this CPG 9 and its respective data supplements. 1.2.
Notes from the Field: Ongoing Transmission of <i>Candida auris</i> in Health Care Facilities — United States, June 2016–May 2017
Authors: Sharon Tsay, Rory M. Welsh, Eleanor H. Adams, Nancy A. Chow, Lalitha Gade, Elizabeth L. Berkow, Eugenie Poirot, Emily Lutterloh, Monica Quinn, Sudha Chaturvedi, Janna Kerins, Stephanie R. Black, Sarah K. Kemble, Patricia M. Barrett, Kerri Barton, D.J. Shannon, Kristy Bradley, Shawn R. Lockhart, Anastasia P. Litvintseva, Heather Moulton-Meissner, Alicia Shugart, Alex Kallen, Snigdha Vallabhaneni, Tom M. Chiller, Brendan R. Jackson
Journal: MMWR Morbidity and Mortality Weekly Report (2017)
A phase I/II study of biweekly docetaxel (D) in combination with fixed-dose cisplatin plus fluorouracil (CF) in patients (pts) with advanced esophageal cancer (AEC) (JCOG0807).
Authors: Shuichi Hironaka, Yasuhiro Tsubosa, Junki Mizusawa, Takayuki Kii, Ken Kato, Takahiro Tsushima, Keisho Chin, Akihisa Tomori, Tatsuya Okuno, Toshikatsu Taniki, Takashi Ura, Hisayuki Matsushita, Takashi Kojima, Yuichiro Doki, Kazumasa Fujitani, Koichi Taira, Shiko Seki, Tsutomu Nakamura, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2013)

e15016 Background: Thougha triplet chemotherapy with D plus CF (DCF) has shown promising activity, high incidence of adverse events (AEs) especially in febrile neutropenia (FN) was observed in previous studies for head and neck cancer (TAX323, 324) and gastric cancer (TAX325). To reduce its AEs with keeping activity, we conducted a multicenter open-label phase I/II study of biweekly D plus CF for AEC. Methods: Eligibility criteria included histologically proven AEC with measurable disease, age 20 to 75, non-resectable or recurrent disease, performance status (PS) 0 to 1. Pts received escalating doses of D (dose level (DL) 1: 30 mg/m 2 , DL 2: 40 mg/m 2 , on days 1, 15) in combination with fixed dose of CF (cisplatin 80 mg/m 2 on day 1, fluorouracil 800 mg/m 2 on days 1-5) repeated every 4 weeks with 3+3 design in phase I part (P-I). The primary endpoint of P-I was dose limiting toxicity (DLT) and that of phase II part (P-II) was response rate (RR) defined by central peer review. Based on a SWOG two stage design (p0=35%, p1=50%; one-sided a=0.1, β =0.2) at least 22 responders among 50 eligible pts should be observed to satisfy the primary endpoint. Results: Between Feb 2009 and Mar 2010, 62 pts were enrolled for P-I and P-II. In P-I, 10 pts were enrolled with DLT of 0/3 in DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended dose for P-II was determined as DL1. Thus, 3 (P-I) and additional 52 pts (P-II) were analyzed: 53 for efficacy (excluded 2 ineligible pts) and 55 for safety. Pts characteristics were as follows: male/female 49/6, age median 61 (range 44 to 75), PS 0/1 39/16. The RR was 62% (95% confidence interval, 48-75%, p&lt;0.0001) by central peer review. Median OS and PFS were 11.1 and 5.8 months. Grade 3/4 toxicity was observed in neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%) and nausea (11%). No grade 3/4 FN was observed. Treatment related death occurred in one patient due to pneumonitis. Conclusions: Biweekly D (30mg/m 2 ) combined with CF showed promising activity and tolerability. A phase III study comparing CF with DCF is warranted. Clinical trial information: UMIN000001737.
Results of telomerase activity measurements from live circulating tumor cells captured on a slot microfilter in a phase III SWOG-coordinated prostate cancer trial (S0421).
Authors: Amir Goldkorn, Benjamin Ely, David I. Quinn, Catherine M. Tangen, Yu-Chong Tai, Przemyslaw Twardowski, Peter J. Van Veldhuizen, Neeraj Agarwal, Michael Anthony Carducci, J. P. Monk, Mark Garzotto, Philip C. Mack, Primo Lara, Celestia S. Higano, Maha Hussain, Nicholas J. Vogelzang, Richard J Cote, Ian Murchie Thompson
Journal: Journal of Clinical Oncology (2012)

4663 Background: Analysis of circulating tumor cells (CTC) is a promising biomarker strategy in advanced prostate cancer, and telomerase activity (TA) is a recognized cancer marker. To test whether CTC TA is prognostic for survival (OS), we developed a novel Parylene-C slot microfilter capable of capturing live CTC and used it to measure CTC TA as part of a Phase III SWOG-coordinated therapeutic trial in metastatic castration resistant prostate cancer (S0421). Methods: Blood samples were drawn into EDTA tubes and shipped overnight to a central processing site. After Ficoll centrifugation, low constant pressure was used to pass the mononuclear cell layer through two slot microfilters in series as published previously (filter1 captures CTC + background white blood cells; filter2 captures only background white blood cells). Filter-trapped cells were lysed in CHAPS buffer and assayed for TA using qPCR-based telomeric repeat amplification. In parallel, CTC were enumerated using CellSearch (J&amp;J). Cox regression was used to evaluate the association between baseline (pre-treatment) TA and OS overall, and within subgroups characterized by good prognosis (&lt;5) vs. poor prognosis (&gt;=5) baseline CTC counts. CART regression was used to explore potential prognostic subgroups based on baseline PSA, CTC, and TA cutpoints. Results: Samples were obtained from 263 patients. While no association was observed between TA and OS overall, in patients with baseline CTC &gt;=5 (108 of 263 or 41% of patients), TA filter2 – TA filter1 representing high CTC TA relative to background blood cells was associated with a hazard ratio (HR) of 1.14 (95% CI 1.05-1.23, p&lt;0.001) for OS after adjusting for risk factors and remained significant when also adjusting for CTC: HR 1.14 (95% CI 1.04-1.23; p=0.005). Exploratory CART regression assessing baseline PSA, CTC, and TA identified risk groups based only on CTC and TA values. Conclusions: Baseline TA from CTC live-captured on a new slot microfilter is the first CTC biomarker shown to be prognostic of OS in men with CTC counts &gt;=5 in a prospective clinical trial. CTC TA may be useful for further identifying prognostic groups in this population.
Novel Treatment Options for Neuroendocrine Tumors
Authors: Matthew H. Kulke
Journal: Journal of the National Comprehensive Cancer Network (2017)

Neuroendocrine tumors (NETs) are not as rare as once thought, with a current prevalence that is estimated to be higher than that of many other gastrointestinal tumors. Multiple treatment options are available for these tumors, which are categorized according to their histology and site of origin. For patients with metastatic disease, somatostatin analogues are often the initial treatment, with other options considered when these drugs fail.
National Outcomes of Cataract Extraction I
Authors: Jonathan C. Javitt, Susan Vitale, Joseph K. Canner, Henry Krakauer, A. Marshall McBean, Alfred Sommer
Journal: Ophthalmology (1991)

Rehospitalization for retinal detachment (RD) was studied in 338,141 Medicare beneficiaries older than 65 years of age who were undergoing inpatient cataract extraction in 1984. Extracapsular cataract extraction (ECCE) was performed in 60% of patients, intracapsular cataract extraction (ICCE) in 31%, and phacoemulsification in 9%. The risk of rehospitalization for RD within 4 years of ICCE was 1.55% over 1.5 times the risk associated with ECCE (0.9%). The risk of RD after phacoemulsification was 1.17%. Cataract surgery accompanied by anterior vitrectomy was associated with a 5.0%, likelihood of RD at 4 years, which is 4.5 times greater than that for cataract surgery alone (1.12%). White patients were 1.7 times more likely to be rehospitalized for RD than were black patients (1.15% versus 0.67%; P less than 0.001). In both races, younger patients were more likely to be rehospitalized for RD than were older patients (P less than 0.001). While the increased rate of RD after ICCE versus ECCE confirms previously held clinical beliefs, the increase in the risk following phacoemulsification (P less than 0.0001) has not been reported previously.
Metformin (M), diabetes (DM), and colorectal cancer (CRC) survival among U.S. veterans.
Authors: Jessica K Paulus, Furha Iram Cossor, Christina D. Williams, Robert E. Martell, Michael J. Kelley
Journal: Journal of Clinical Oncology (2014)

3535 Background: Although diabetes (DM) is associated with a worse colorectal cancer (CRC) prognosis, metformin (M) use has been associated with improved overall and CRC-specific survival in several prior studies. We examined the impact of M use on overall survival (OS) in patients with type 2 DM and CRC among US veterans while adjusting for treatment, stage and diabetic severity, offering the largest cohort study examining this issue to date. Methods: There were 21,352 patients with CRC were diagnosed between 2001 and 2008 in the US Veterans Health Administration. OS was compared across four groups: patients without DM (n=16,355); patients with DM on M (n= 2,038); patients with DM on anti-DM medications other than M (n=2,136); and patients with DM not on anti-DM medication (n=823). Multivariate Cox proportional hazards models were used to estimate the association between M use, DM and OS while adjusting for age, race, stage, body mass index, HbA1C, comorbidity index, and cancer treatment. Results: Median survival was 61 months in non-diabetics, 67 months in metformin users, 45 months in users of other diabetic medications, and 51 months in diabetics not on anti-DM medication. HbA1C levels were 6.9%, 6.8%, and 6.2% in patients with DM on metformin, other, or no anti-DM medication, respectively. In the subset of CRC patients with DM, those patients taking M had a 21% decrease in the risk of death compared to patients with diabetes taking anti-DM medications other than M (HRadj 0.79; 95% CI 0.73-0.86, p=<0.001), while diabetic patients not on any anti-DM medications had a 13% decrease in risk of death (HRadj 0.87; 95% CI 0.78-0.97, p=0.02). No interaction between M and BMI was observed (p=0.86). In the entire cohort, patients with DM on anti-DM medications other than M had a statistically significant increase in risk of death compared to non-diabetics (HRadj 1.26; 95% CI 1.19-1.33, p=<0.0001). However, patients with DM on M had similar OS as compared to non-diabetics (HRadj 1.05; 95% CI 0.99-1.12, p=0.11), as did patients with DM not on anti-diabetic medication (HRadj1.08; 95% CI 0.99-1.18, p=0.07). Conclusions: Among diabetics with CRC, M use is associated with improved survival as compared to the use of other medications. Metformin may reduce the survival disadvantage associated with DM among CRC patients.
Phase II trial of the histone deacetylase inhibitor, vorinostat, to restore hormone sensitivity to the antiestrogen tamoxifen in patients with advanced breast cancer who progressed on prior hormone therapy
Authors: P. N. Munster, M. Lacevic, S. Thomas, C. Christian, R. Ismail-Khan, M. Melisko, H. Rugo, S. E. Minton
Journal: Journal of Clinical Oncology (2009)

1075 Background: Modulation of estrogen receptor signaling is one of the most successful modalities in the treatment of estrogen receptor (ER) positive breast cancers. However, hormone therapy resistance remains a challenging problem. Histone deacetylases (HDAC) have emerged as a recent strategy to interfere with hormone receptor signaling by modulating the estrogen and progesterone receptor. Here we report the findings from a phase II trial evaluating the HDAC inhibitor, vorinostat and the anti-estrogen, tamoxifen, placed in context with correlative studies. Methods: Patients with ER-positive metastatic breast cancer who progressed on prior hormonal therapy and up to three chemotherapy regimens were treated with 400 mg vorinostat daily for three of four weeks and 20 mg tamoxifen daily, continuously. Histone acetylation was evaluated in peripheral blood mononuclear cells. Results: To date, 29 patients [median age 53 years (34–71)] have been treated with the combination. Pulmonary emboli were observed in 2/29 (7%) patients. Other grade 3/4 toxicities included fatigue (5/29, 17%), anorexia (2/29, 7%), diarrhea (1/29, 3%), nausea/vomiting (3/29, 10%), hypokalemia (1/29, 3%), liver enzyme elevation (1/29, 3%), lymphopenia (5/29, 17%) and leukopenia (4/29, 13%). Predominant grade 2 toxicities included fatigue, nausea/vomiting/diarrhea, hyperglycemia, anorexia, and myelosuppression. Six (21%) patients had an objective response, and 3/29 (10%) additional patients had disease stabilization for &gt;6 months; 13/29 (45%) patients had at least one prior chemotherapy regimen for metastatic disease, 28/29 (92%) patients had progressed after exposure to at least one and 16/29 (55%) patients after two aromatase inhibitors, and 18/29 (62%) patients had received prior adjuvant tamoxifen. H3 and H4 histone acetylation was seen at day 8 suggesting adequate vorinostat plasma levels. Histone acetylation and baseline HDAC expression will be presented. Conclusions: These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have progressed on prior hormonal therapy and/or adjuvant tamoxifen may restore hormone sensitivity. No significant financial relationships to disclose.
Education of medicinal chemists in departments of medicinal chemistry (U.S.A.)
Authors: C. Robin Ganellin, Lester A. Mitscher, John G. Topliss
Journal: Medicinal Research Reviews (1998)

The present state of faculties, student bodies, and curricula in departments of medicinal chemistry have been surveyed by questionnaire and analyzed in the context of perceptions of quality and content. The results reveal a healthy diversity of educational objectives and a broader range of educational objectives than those uncovered in previous surveys of the perceived needs of industrial departments of medicinal chemistry in their search for drug discovery personnel. © 1998 John Wiley & Sons, Inc. Med Res Rev, 18, No. 2, 121–137, 1998.