tbuckley/cabot-search huggingface dataset:
Abstract P166: Distribution of Cardiovascular Risk Factors in ESMaestras: A Cohort Study of 97,174 Mexican Women
Authors: Martin Lajous, Isabelle Romieu, Andres Catzin-Kuhlmann, Walter C Willett, Ruy Lopez-Ridaura
Journal: Circulation (2012)

Introduction: The ESMaestras study ( Estudio de Seguimiento la Salud de las Maestras ) is an effort to prospectively study the health effects of dietary and lifestyle factors in Mexico, a country undergoing a fast-paced nutritional and epidemiologic transition. Understanding risk factors for disease in this minimally studied population may provide insights on lifestyle-disease relations in other populations. Methods: We evaluated the cross-sectional distribution of cardiovascular risk factors in the baseline evaluation of the ESMaestras cohort study, an ongoing prospective study among 97,174 female teachers living in 12 different states in Mexico. In 2008, participants responded to a detailed questionnaire on lifestyle factors, diet and medical conditions that was sent and received by school district administration. Diet was assessed using a semi-quantitative food frequency questionnaire validated in a similar Mexican population. Results: Median age of participants was 44 years [(10 th , 90 th percentile) 33, 52] and 17.3% were postmenopausal. Median BMI was 26.7 [(10 th , 90 th percentile) 22.2, 33.6] and 66.4% were overweight or obese. Median moderate/vigorous recreational physical activity was 1 hr/week [(10 th , 90 th percentile) 0, 6.0]. Only 9.7% participants were current smokers and among them 21.5% reported smoking more than 5 cigarettes per day. Most participants reported alcohol consumption (62%) but daily consumption was very low (1.2% consumed ≥0.5 drink/day). Median (10 th , 90 th percentile) intake of fish was 0.98 servings/week (0.28, 3.3), of red meat 4.1 servings/week (1.3, 9.9), of fruits and vegetables 5.3 servings/day (1.8, 12.2) and of sugar-sweetened beverages 1.2 (0.3, 3.6). The prevalence of self-reported, treated conditions was 12.1% for hypertension, 4.3% for diabetes and 11.6% for elevated cholesterol. Conclusion: In this relatively young population of Mexican women we observed a high prevalence of some risk factors for cardiovascular disease. Adequate systematic follow-up with repeated evaluation of risk factors in this population may prove to be informative about lifestyle factor and cardiovascular disease relations in Latin-American women.
Social Factors in the Personality Disorders: A Biopsychosocial Approach to Etiology and Treatment, by Joel Paris
Authors: K. McKenzie
Journal: BMJ (1997)

Joel Paris Cambridge University Press, £35, pp 232. ISBN 0 521 47224 5

Personality disorders have been accepted by psychiatrists as a category of mental illness for only a few decades, and several problems remain. No universally accepted way exists for defining different types; relatively little research has been done on outcome and treatment; and many doctors do not understand them, do not see them as mental disorders, and think they are untreatable. The better understanding of their aetiology which Professor Paris hopes to foster would go a long way to producing agreed classifications and debunking the myths that surround the subject.

Society is important in the promotion of personality disorders, and what constitutes a disorder is different in different cultures. For instance, in some …
NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies
Authors: Alan P. Venook, Maria E. Arcila, Al B. Benson, Donald A. Berry, David Ross Camidge, Robert W. Carlson, Toni K. Choueiri, Valerie Guild, Gregory P. Kalemkerian, Razelle Kurzrock, Christine M. Lovly, Amy E. McKee, Robert J. Morgan, Anthony J. Olszanski, Mary W. Redman, Vered Stearns, Joan McClure, Marian L. Birkeland
Journal: Journal of the National Comprehensive Cancer Network (2014)

Defining treatment-susceptible or -resistant populations of patients with cancer through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies, because potential patient populations are divided into ever smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists, and information developers.
Defining the Need for Transitional Care From Pediatric to Adult Surgery for Young Adult Patients With Surgically Corrected Congenital Anomalies
Authors: Jane Y. Zhao, Priscilla P. L. Chiu, Roshni Dasgupta, Howard C. Jen, David H. Rothstein
Journal: JAMA Surgery (2015)

States to examine surgeons' knowledge about CPM.A study of 81 surgeons in Australia asked about CPM but did not question surgeons about CBC risk or survival after CPM. 6 What is not clear is how surgeons' knowledge translates into treatment patterns.Are patients undergoing CPM more frequently because surgeons are not adequately informing them?Could this be because the surgeons themselves are not well informed?Decision aids or teaching materials that address CPM and its utility for a patient with newly diagnosed breast cancer are needed.Part of this intervention will have to involve not only educating patients on CPM's risks and benefits, but also teaching surgeons how to effectively counsel patients on CPM to ensure informed decision making.
Development of an Interleukin-1β Vaccine in Patients with Type 2 Diabetes
Authors: Claudia Cavelti-Weder, Katharina Timper, Eleonora Seelig, Cornelia Keller, Martin Osranek, Ute Lässing, Gunther Spohn, Patrik Maurer, Philipp Müller, Gary T Jennings, Joerg Willers, Philippe Saudan, Marc Y Donath, Martin F Bachmann
Journal: Molecular Therapy (2015)

Interleukin-1β (IL-1β) is a key cytokine involved in inflammatory illnesses including rare hereditary diseases and common chronic inflammatory conditions as gout, rheumatoid arthritis, and type 2 diabetes mellitus, suggesting reduction of IL-1β activity as new treatment strategy. The objective of our study was to assess safety, antibody response, and preliminary efficacy of a novel vaccine against IL-1β. The vaccine hIL1bQb consisting of full-length, recombinant IL-1β coupled to virus-like particles was tested in a preclinical and clinical, randomized, placebo-controlled, double-blind study in patients with type 2 diabetes. The preclinical simian study showed prompt induction of IL-1β-specific antibodies upon vaccination, while neutralizing antibodies appeared with delay. In the clinical study with 48 type 2 diabetic patients, neutralizing IL-1β-specific antibody responses were detectable after six injections with doses of 900 µg. The development of neutralizing antibodies was associated with higher number of study drug injections, lower baseline body mass index, improvement of glycemia, and C-reactive protein (CRP). The vaccine hIL1bQb was safe and well-tolerated with no differences regarding adverse events between patients receiving hIL1bQb compared to placebo. This is the first description of a vaccine against IL-1β and represents a new treatment option for IL-1β-dependent diseases such as type 2 diabetes mellitus (ClinicalTrials.gov NCT00924105).
Abstract 18296: A Novel Flow Cytometry Approach Shows That Cardiac Myocyte Size and Myosin Heavy Chain Protein Content Are Disassociated in Normal Post-natal Development
Authors: Javier E Lopez, Janhavi Sharma, Taylor Wood, Jorge Avila, Andrew Wong, Jonathan VanDyke, Bat-erdene Myagmar, Philip Swigart, Paul Simpson, Nipavan Chiamvimonvat
Journal: Circulation (2014)

Introduction: We have reported previously that α-myosin heavy chain (α–MyHC) expressing myocytes (MCs), the predominant MC in adult mouse hearts, hypertrophy under pressure-overload without a proportionate increase in total MyHC protein (T-MyHC) content (Lopez et al, Circ. Res., 2011). It is not yet known if during normal physiological growth, these MCs increase their T-MyHC content in proportion to cell size.

Hypothesis: During normal post-natal growth, an increase in T-MyHC content is proportionate to changes in cardiac mass and MC size.

Methods: Individual cardiac cells were isolated by enzymatic digestion from male C57Bl/6 mice age in days 22+/-1 (young, n=4) and 88+/-6 (adult, n=4). Body and heart weights (wt), mean MC volumes by Coulter Multisizer (vol), and cell protein content-per-MC by BCA assay (TotProtMC) were used to measure cardiac growth. A new approach using large-particle fluorescent activated cell sorting (FACS, see Figure) was validated to isolate 15K Troponin-T expressing MCs (~97% α–MyHC+) per heart with 94+/-2% purity (n=5). Relative T-MyHC content was measured by immunoblotting equal numbers of sorted MCs (50 MCs/lane) that was validated to be in linear range for the assay.

Results: Body wt (gm), heart wt (mg), MC vol (μm3, in ~7,000 MCs per heart) and TotProtMC (ng/MC) were 3, 2.3, 2.7 and 2.5 fold greater in adult than young mice, respectively. The relative T-MyHC content per adult MC was 7.5 fold greater than in young MCs (441+/-107 vs. 59+/- 4 A.U./MC, n=3 each, p≤0.01).

Conclusions: Unexpectedly, the increase in T-MyHC protein per cell during post-natal growth is ~2.5 fold greater than predicted by changes in cardiac mass, MC size or cell protein content-per-MC. These data demonstrate that in normal physiological growth, MCs accumulate more T-MyHC protein per unit volume than predicted by changes in size alone. This form of growth, “normotrophy”, is in contrast to hypertrophy where T-MyHC protein accumulation is less or equal to changes in cell size.

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A phase I trial of TAS-102 administered on a three times a day schedule in patients with solid tumors
Authors: R. A. Wolff, P. M. Hoff, A. Mita, M. Fukushima, J. C. Blais, J. L. Abbruzzese, H. Q. Xiong
Journal: Journal of Clinical Oncology (2006)

2053 Background: TAS-102 consists of trifluorothymidine (FTD) and an inhibitor of thymidine phosphorylase (TP). FTD, like 5-fluorouracil, is an inhibitor of thymidylate synthase. However, when orally administered, FTD is rapidly degraded to an inactive form, primarily by TP. Co-administration of FTD with an inhibitor of TP elevates FTD concentrations. Since tumor xenograft models demonstrated greater anti-tumor activity with divided daily dosing of TAS-102, and a phase I trial of once-daily TAS-102 showed a short FTD half-life, this trial was designed to explore a three times a day dosing schedule. Methods: Patients with advanced solid tumors having received prior therapy, with adequate organ function, and performance status Zubrod 0–2, were eligible. TAS-102 was administered orally three times a day for 5 days a week for two weeks, followed by two weeks off. Courses were repeated every 4 weeks. Results: A total of 15 patients (8 female, age 37–72 years) were enrolled into the study; three at 60 mg/m 2 /day, 6 each at 70 mg/m 2 /day and 80 mg/m 2 /day. Nine patients had colorectal cancer, 2 carcinoma of unknown primary, 2 pancreatic cancer, one each medullary thyroid cancer and cholangiocarcinoma. Toxicity was assessed throughout all courses of therapy. Grade 3 and 4 hematological toxicities were the most common, including 3 episodes of grade 3 neutropenia at 60 mg/m 2 /day, 5 at 70 mg/m 2 /day, 5 at 80 mg/m 2 /day with only 1 instance of grade 3 thrombocytopenia at 80 mg/m 2 /day. Non-hematological grade 3 toxicities included nausea/vomiting (1 at 70 mg/m 2 /day), colitis, gout, and hematuria (1 each at 70 mg/m 2 /day), and fatigue (1 at 70 mg/m 2 /day and 2 at 80 mg/m 2 /day) Two episodes of dose-limiting toxicity were observed at 80 mg/m 2 /day: grade 3 fatigue and grade 4 neutropenia. Although there were no objective responses, nine patients (60%) maintained stable disease with a median duration of disease stabilization of 4.3 months (range, 1.9 to 8.6 months). Conclusions: TAS-102 is well tolerated with manageable hematologic toxicity and few non-hematological toxicities. The most common grade 3 or 4 toxicity was neutropenia. The suggested phase II dose of TAS-102 is 70 mg/m 2 /day when administered orally three times a day for 5 days a week for two weeks followed by two weeks off every 4 weeks. [Table: see text]
Structural genomic changes underlie alternative reproductive strategies in the ruff (Philomachus pugnax)
Authors: Sangeet Lamichhaney, Guangyi Fan, Fredrik Widemo, Ulrika Gunnarsson, Doreen Schwochow Thalmann, Marc P Hoeppner, Susanne Kerje, Ulla Gustafson, Chengcheng Shi, He Zhang, Wenbin Chen, Xinming Liang, Leihuan Huang, Jiahao Wang, Enjing Liang, Qiong Wu, Simon Ming-Yuen Lee, Xun Xu, Jacob Höglund, Xin Liu, Leif Andersson
Journal: Nature Genetics (2015)

Leif Andersson and colleagues report the genome sequence of the ruff, a bird species with three male morphs with different reproductive strategies. Satellite and faeder morphs differ from the common independent morph by a 4.5-Mb inversion that occurred approximately 3.8 million years ago, and multiple genetic changes within this inverted region are associated with the satellite and faeder morphs. The ruff is a Palearctic wader with a spectacular lekking behavior where highly ornamented males compete for females1,2,3,4. This bird has one of the most remarkable mating systems in the animal kingdom, comprising three different male morphs (independents, satellites and faeders) that differ in behavior, plumage color and body size. Remarkably, the satellite and faeder morphs are controlled by dominant alleles5,6. Here we have used whole-genome sequencing and resolved the enigma of how such complex phenotypic differences can have a simple genetic basis. The Satellite and Faeder alleles are both associated with a 4.5-Mb inversion that occurred about 3.8 million years ago. We propose an evolutionary scenario where the Satellite chromosome arose by a rare recombination event about 500,000 years ago. The ruff mating system is the result of an evolutionary process in which multiple genetic changes contributing to phenotypic differences between morphs have accumulated within the inverted region.
Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments
Authors: Arpita Baisantry, Sagar Bhayana, Song Rong, Esther Ermeling, Christoph Wrede, Jan Hegermann, Petra Pennekamp, Inga Sörensen-Zender, Hermann Haller, Anette Melk, Roland Schmitt
Journal: Journal of the American Society of Nephrology (2015)

Evidence suggests that autophagy promotes the development of cellular senescence. Because cellular senescence contributes to renal aging and promotes the progression from AKI to CKD, we investigated the potential effect of tubular autophagy on senescence induction. Compared with kidneys from control mice, kidneys from mice with conditional deletion of autophagy-related 5 (Atg5) for selective ablation of autophagy in proximal tubular S3 segments (Atg5 Δ flox/ Δ flox ) presented with significantly less tubular senescence, reduced interstitial fibrosis, and superior renal function 30 days after ischemia/reperfusion injury. To correlate this long-term outcome with differences in the early injury process, kidneys were analyzed 2 hours and 3 days after reperfusion. Notably, compared with kidneys of control mice, Atg5 Δ flox/ Δ flox kidneys showed more cell death in outer medullary S3 segments at 2 hours but less tubular damage and inflammation at day 3. These data suggest that the lack of autophagy prevents early survival mechanisms in severely damaged tubular cells. However, if such compromised cells persist, then they may lead to maladaptive repair and proinflammatory changes, thereby facilitating the development of a senescent phenotype and CKD.
Immune Correlates and Long Term Follow Up of a Phase Ia Study of Mpdl3280A, an Engineered Pd-L1 Antibody, in Patients with Metastatic Renal Cell Carcinoma (Mrcc)
Authors: D.F. McDermott, M. Sznol, J.A. Sosman, J-C. Soria, M.S. Gordon, O. Hamid, J. Delord, M. Fasso, Y. Wang, J. Bruey, G. Fine, T. Powles
Journal: Annals of Oncology (2014)
Open-label safety and efficacy pilot trial of intraperitoneal bevacizumab as palliative treatment in refractory malignant ascites
Authors: K. El-Shami, A. Elsaid, Y. El-Kerm
Journal: Journal of Clinical Oncology (2007)

9043 Background: One of the most burdensome complications of advanced cancer is the development of malignant ascites, impacting quality of life (QoL), gastrointestinal function, survival, and overall management costs. Recent studies have shown that malignant effusions arise in part from increased production and activity of vascular endothelial growth factors (VEGFs). VEGFs increase vascular permeability and establish an ideal environment for accumulation of malignant effusions. Methods: A pilot trial evaluating safety and efficacy of intraperitoneal administration of bevacizumab at 5 mg/kg monthly for as long as no disease progression or unacceptable toxicities are encountered. Patients with cytologically documented malignant ascites from any primary tumor refractory to standard therapy of diuretics, repeated paracentesis, and/or intraperitoneal chemotherapy were eligible. Patients were either off systemic therapy or had not had any changes in their systemic therapy for at least 4 weeks at the time of enrollment. Results: Between July 2006 and November 2006, 9 patients with refractory malignant ascites from colon cancer (3 pts), breast cancer (3 pts), uterine cancer (2 pts) and ovarian cancer (1 pt). Prior therapy included systemic chemotherapy and large volume paracentesis. Patients with ovarian and uterine cancer also received intraperitoneal cisplatin. All patients had rapid re-accumulation within 2 weeks of paracentesis before treatment. Patients were given intraperitoneal bevacizumab at 5 mg/kg monthly. Complications included grade I nausea in one patient, grade I abdominal pain in one patient, and partial small bowel obstruction in one patient that was managed conservatively. Malignant ascites resolved without reaccumulation or repeat paracentresis in 9/9 after a single intraperitoneal dose of bevacizumab over a median observation period of over two months. No objective tumor responses were observed. QoL assessment, pharmacokinetic studies of intraperitoneal Bevacizumab and pharmacodynamic studies on serum and ascites fluid VEGF are ongoing and will be reported. Conclusions: Intraperitoneal bevacizumab is a relatively safe and highly efficacious way to palliate the symptoms of refractory malignant ascites. No significant financial relationships to disclose.
Bispecific antibodies and their applications
Authors: Gaowei Fan, Zujian Wang, Mingju Hao, Jinming Li
Journal: Journal of Hematology & Oncology (2015)

Bispecific antibodies (BsAbs) recognize two different epitopes. This dual specificity opens up a wide range of applications, including redirecting T cells to tumor cells, blocking two different signaling pathways simultaneously, dual targeting of different disease mediators, and delivering payloads to targeted sites. The approval of catumaxomab (anti-EpCAM and anti-CD3) and blinatumomab (anti-CD19 and anti-CD3) has become a major milestone in the development of bsAbs. Currently, more than 60 different bsAb formats exist, some of them making their way into the clinical pipeline. This review summarizes diverse formats of bsAbs and their clinical applications and sheds light on strategies to optimize the design of bsAbs.
Preferential Radiosensitization of Mouse Sarcoma Relative to Normal Skin by Chronic Intra-Arterial Infusion of Halogenated Pyrimidine Analogs&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J. M. Brown, D. R. Goffinet, J. E. Cleaver, R. F. Kallman
Journal: JNCI Journal of the National Cancer Institute (1971)

Chronic intra-arterial infusion of the halogenated pyrimidine analog 5-bromo-2′-deoxycytidine (BCdR) into tumor-bearing mice was used to study the potential of this radiosensitizing drug for clinical radiotherapy. Dose-response curves were obtained for a multifraction regimen of 10 daily doses of 250 kv X rays delivered locally to KHT sarcoma implanted in thighs of syngeneic C3H mice. Comparisons were made of the radiation response of noninfused tumors and tumors chronically infused intra-arterially with either saline, BCdR, 2′-deoxy-5-fluorouridine (FUdR), or BCdR + FUdR. The tumor response used was delay in regrowth produced by irradiation. Parallel with the comparisons of tumor response, the skin reactions of the hind feet, which were included in the irradiation field, were observed. Infusion of BCdR continuously during the fractionated regimen sensitized the tumors to × irradiation by a dose modification factor (DMF) of 1.30 ± 0.01, whereas sensitization of normal tissue (skin) was insignificant (DMF = 1.03 ± 0.02). Addition of FUdR to the infused BCdR did not significantly alter the sensitization of the tumors (DMF = 1.32 ± 0.01), though it increased the degree of replacement of thymidine by 5-bromo-2′-deoxyuridine (as judged by cesium chloride gradient studies) from 5–17%. Therapeutic gain factors (= DMF for tumor/DMF for skin) of 1.26 ± 0.03 and 1.28 ± 0.03 were calculated for the BCdR and the BCdR + FUdR infusions, respectively. The action of intra-arterial infused BCdR in preferentially radiosensitizing the tumor cells relative to the normal cells is postulated to be a result of the difference in the generation times of the two predominant cell types. The potential applicability of these studies to the treatment of cancer by radiotherapy is discussed.
Assessing the Mitochondrial Membrane Potential in Cells and In Vivo using Targeted Click Chemistry and Mass Spectrometry
Authors: Angela Logan, Victoria R. Pell, Karl J. Shaffer, Cameron Evans, Nathan J. Stanley, Ellen L. Robb, Tracy A. Prime, Edward T. Chouchani, Helena M. Cochemé, Ian M. Fearnley, Sara Vidoni, Andrew M. James, Carolyn M. Porteous, Linda Partridge, Thomas Krieg, Robin A.J. Smith, Michael P. Murphy
Journal: Cell Metabolism (2015)

The mitochondrial membrane potential (Δψm) is a major determinant and indicator of cell fate, but it is not possible to assess small changes in Δψm within cells or in vivo. To overcome this, we developed an approach that utilizes two mitochondria-targeted probes each containing a triphenylphosphonium (TPP) lipophilic cation that drives their accumulation in response to Δψm and the plasma membrane potential (Δψp). One probe contains an azido moiety and the other a cyclooctyne, which react together in a concentration-dependent manner by "click" chemistry to form MitoClick. As the mitochondrial accumulation of both probes depends exponentially on Δψm and Δψp, the rate of MitoClick formation is exquisitely sensitive to small changes in these potentials. MitoClick accumulation can then be quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This approach enables assessment of subtle changes in membrane potentials within cells and in the mouse heart in vivo.
Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression
Authors: Tikvah K. Hayes, Nicole F. Neel, Chaoxin Hu, Prson Gautam, Melissa Chenard, Brian Long, Meraj Aziz, Michelle Kassner, Kirsten L. Bryant, Mariaelena Pierobon, Raoud Marayati, Swapnil Kher, Samuel D. George, Mai Xu, Andrea Wang-Gillam, Ahmed A. Samatar, Anirban Maitra, Krister Wennerberg, Emanuel F. Petricoin, Hongwei H. Yin, Barry Nelkin, Adrienne D. Cox, Jen Jen Yeh, Channing J. Der
Journal: Cancer Cell (2015)