tbuckley/cabot-search huggingface dataset:
Diseases of the Skin. A Text-Book for Students and Practitioners.
Journal: JAMA (1921)

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Addressing Reverse Causation Bias in the Obesity Paradox Is Not “One Size Fits All”
Authors: Deirdre K. Tobias
Journal: Diabetes Care (2017)

The obesity epidemic is a global crisis, extending well beyond the U.S. and Western countries. Korea is no exception, with the prevalence of overweight/obesity (BMI ≥23 kg/m2) escalating in recent decades to 61.3% for men and 45.3% for women in 2014 (1).

Despite the overwhelming evidence implicating excess adiposity in the development of several chronic diseases, there has been a prolonged debate surrounding the association between BMI and all-cause mortality. The public health implications of this relationship are not trivial and contribute to the ongoing attention given to this topic.

In this issue of Diabetes Care , Lee et al. (2) report their analysis of 12.8 million adults aged 18–99 years in the National Health Insurance Service of Korea at baseline examinations in 2001, with follow-up through 2013. BMI was evaluated in relation to all-cause mortality, demonstrating a U-shaped association between BMI and all-cause mortality. The authors concluded that the optimal BMI for survival after 10.5 years was 25.0–30.9 kg/m2 for men and 23.5–29.4 kg/m2 for women; thus, maintaining a body weight in the range of overweight and obesity appears ideal for longevity. This controversial finding has been observed by many, …
The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance—challenges and future research opportunities
Authors: Christopher L R Barratt, Lars Björndahl, Christopher J De Jonge, Dolores J Lamb, Francisco Osorio Martini, Robert McLachlan, Robert D Oates, Sheryl van der Poel, Bianca St John, Mark Sigman, Rebecca Sokol, Herman Tournaye
Journal: Human Reproduction Update (2017)

Herein, we describe the consensus guideline methodology, summarize the evidence-based recommendations we provided to the World Health Organization (WHO) for their consideration in the development of global guidance and present a narrative review of the diagnosis of male infertility as related to the eight prioritized (problem or population (P), intervention (I), comparison (C) and outcome(s) (O) (PICO)) questions. Additionally, we discuss the challenges and research gaps identified during the synthesis of this evidence. The aim of this paper is to present an evidence-based approach for the diagnosis of male infertility as related to the eight prioritized PICO questions. Collating the evidence to support providing recommendations involved a collaborative process as developed by WHO, namely: identification of priority questions and critical outcomes; retrieval of up-to-date evidence and existing guidelines; assessment and synthesis of the evidence; and the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation the quality of the supporting evidence was then graded and assessed for consideration during a WHO consensus. Evidence was synthesized and recommendations were drafted to address the diagnosis of male infertility specifically encompassing the following: What is the prevalence of male infertility and what proportion of infertility is attributable to the male? Is it necessary for all infertile men to undergo a thorough evaluation? What is the clinical (ART/non ART) value of traditional semen parameters? What key male lifestyle factors impact on fertility (focusing on obesity, heat and tobacco smoking)? Do supplementary oral antioxidants or herbal therapies significantly influence fertility outcomes for infertile men? What are the evidence-based criteria for genetic screening of infertile men? How does a history of neoplasia and related treatments in the male impact on (his and his partner's) reproductive health and fertility options? And lastly, what is the impact of varicocele on male fertility and does correction of varicocele improve semen parameters and/or fertility? This evidence synthesis analysis has been conducted in a manner to be considered for global applicability for the diagnosis of male infertility.
Proapoptotic effects of alpha-santalol as possible mechanism of skin cancer prevention
Authors: Kathryn Bremmon, Bhanu Arasada, Chandradhar Dwivedi
Journal: Cancer Research (2006)

4788  Skin cancer is the most prevalent of all cancers and its incidence is expected to increase substantially because of increased recreational exposure to sunlight and depletion of the ozone layer. It is estimated that more than one million Americans develop skin cancer every year. Chemoprevention involves the administration of chemical agents to prevent initiation and\or promotion, and\or progression that occurs during neoplastic development. Previous studies from our laboratory have indicated skin cancer chemopreventive effects of α-santalol in chemically induced SENCAR & CD-1 mice and UV-B induced SKH-1 mice. Further studies have shown the possible role of caspase-3 and 8. Objective: To study possible role of apoptotic proteins involved in the prevention of skin tumor development. SKH-1 mice were divided into three groups. Group 1 received acetone (0.1 ml, topical) one hour before UV-B treatments; Group 2 received α-santalol (0.1 ml, 5 % in acetone, topical) one hour before UV-B treatments; and Group 3 received α-santalol (0.1 ml, 5 % in acetone, topical) immediately after UV-B treatments. In long-term experiment the promotion phase was carried out for 30 weeks. The duration of short-term experiment 1 week. After the end the experiments, mice were sacrificed and dorsal skin samples were collected. The proteins from the skin samples were extracted and further used for SDS-PAGE and Western blot using specific antibodies against caspase-3 and 8. The cleaved caspase-3 levels were increased by 472 and 220% in Group 2 and 3 respectively when compared to Group 1. The cleaved caspase-8 levels were increased by 265 and 220% in Group 2 and 3 respectively when compared to Group 1. In short term experiment caspase 3 levels were increased by 164 and 144% in Group 2 and 3 respectively when compared to Group 1. Caspase 8 levels were increased by 138 and 127% in Group 2 and 3 respectively when compared to Group 1. Cox 2 levels were decreased by 49 and 55% in Group 2 and 3 respectively when compared to Group 1. Pretreatment with α-santalol reduces UV-B-induced skin cancer development possibly by activating proapoptotic proteins caspase-3 and 8.
Maytansine derivatives and metabolites of antibody-maytansinoid conjugates inhibit microtubule polymerization and strongly suppress microtubule dynamics
Authors: Manu Lopus, Emin Oroudjev, Leslie Wilson, Sharon Wilhelm, Wayne Widdison, Ravi Chari, Mary Ann Jordan
Journal: Cancer Research (2008)

1406  Maytansine is a potent microtubule-targeted compound that induces mitotic arrest and kills tumor cells at sub-nanomolar concentrations. Maytansine analogs, DM1 and DM4 (collectively DMx), were conjugated to monoclonal antibodies that selectively bind to antigens expressed on the surface of cancer cells. These antibody-maytansinoid conjugates displayed antigen-specific cytotoxicity in vitro and potent anti-tumor activity in vivo. Several antibody-DM1 and antibody-DM4 conjugates are currently undergoing clinical evaluation. We have investigated the ability of maytansinoid derivatives and metabolites derived from antibody-maytansinoid conjugates to inhibit microtubule polymerization and to suppress dynamic instability of microtubules assembled from bovine brain tubulin. In addition, we examined the stoichiometry of binding to microtubules and dissociation constant (Kd) of one thioether derivative, S-methyl DM1 (DM1-Me). DM1-Me inhibited the assembly of tubulin in a concentration-dependent manner with an IC50 of 4 ± 0.1 µM. Using 3[H]DM1-Me, we found that this compound binds to microtubules in a concentration-dependent fashion with a stoichiometry of 33 molecules of DM1-Me bound per microtubule at 0.1 µM. The dissociation constant (Kd) for the binding of DM1-Me to microtubules is found to be 0.4 µM, indicating strong binding of the maytansinoid to microtubules. The effects of DM1-Me, DM4-Me (S-methyl DM4) and several major target cell-derived metabolites of antibody-DM1 and antibody-DM4 conjugates on microtubule dynamic instability were studied by real-time imaging of axoneme-seeded microtubules assembled from bovine brain tubulin using differential interference contrast microscopy. The maytansinoids (0.1 µM) strongly suppressed microtubule dynamics. For instance, DM1-Me decreased the growing and shortening rates of microtubules by 24% and 67%, respectively. In addition, DM1-Me suppressed catastrophe and rescue frequencies by 90 % and 44 %, respectively. The overall dynamicity of microtubules was decreased by 87% by DM1-Me, and by 74% by DM4-Me. DM1-Me, DM4-Me and several of the target cell-derived metabolites were more potent than the parent compound maytansine, which suppressed the dynamicity of microtubules by 52%. These data, along with the previous finding of the low systemic toxicity and favorable pharmacokinetic behavior of antibody-maytansinoid conjugates bolsters the potential of DMx conjugates in cancer chemotherapy. Supported by grants NIH CA 57291 and NS13560.
CIB2 Negatively Regulates Oncogenic Signaling in Ovarian Cancer via Sphingosine Kinase 1
Authors: Wenying Zhu, Kate E. Jarman, Noor A. Lokman, Heidi A. Neubauer, Lorena T. Davies, Briony L. Gliddon, Houng Taing, Paul A.B. Moretti, Martin K. Oehler, Melissa R. Pitman, Stuart M. Pitson
Journal: Cancer Research (2017)

Abstract Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between proapoptotic and prosurvival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signaling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subsequent signaling, which included sensitization to TNFα-induced apoptosis and inhibition of Ras-induced neoplastic transformation. CIB2 was significantly downregulated in ovarian cancer and low CIB2 expression was associated with poor prognosis in ovarian cancer patients. Notably, reintroduction of CIB2 in ovarian cancer cells blocked plasma membrane localization of endogenous SK1, reduced in vitro neoplastic growth and tumor growth in mice, and suppressed cell motility and invasiveness both in vitro and in vivo. Consistent with the in vitro synergistic effects between the SK1-specific inhibitor SK1-I and standard chemotherapeutics, expression of CIB2 also sensitized ovarian cancer cells to carboplatin. Together, these findings identify CIB2 as a novel endogenous suppressor of SK1 signaling and potential prognostic marker and demonstrate the therapeutic potential of SK1 in this gynecologic malignancy. Cancer Res; 77(18); 4823–34. ©2017 AACR.
Increase in life expectancy in England has halted, new figures show
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The increase in life expectancy in England has almost “ground to a halt” since 2010 and austerity measures are likely to be a significant contributor, a leading expert on public health has said.

The warning came from Michael Marmot, director at University College London’s Institute of Health Equity, after new indicators showed that the rate of increase in life expectancy in England has almost halved since 2010 and is close to stalling.1

The institute’s analysis of the latest figures showed that life expectancy at birth in England was 79.38 years in males and 83.06 in females in 2013-15. This is only a slight increase from 78.31 in males and 82.33 in females in 2010. Until now, life expectancy has risen steadily …
Novel de novo BRCA1 mutation in a woman with early onset breast cancer
Authors: E. Tang, A. Kwong, C. Wong, F. Law, C. Wong, E. Ng, E. Ma, J. M. Ford
Journal: Journal of Clinical Oncology (2009)

e22143 Background: Germline mutations in BRCA1/2 account for a significant portion of hereditary breast/ovarian cancer. Mutation carriers usually have a family history of breast/ovarian cancer or early onset disease. Rarely, germline mutations are found only in the probands but not in any family members. Such de novo mutations have been reported in diseases such as hemophilia A, thalassaemia and familial adenomatous polyposis. De novo mutations in the BRCA1 or BRCA2 genes are rare and the few reported have been in BRCA2. Here, we describe de novo as well as novel mutation of the BRCA1 gene in a breast cancer patient. Methods: Blood DNA samples from a 30 year old Chinese woman with breast cancer and no family history of cancer was tested for a BRCA1/2 mutation by full gene sequencing and Multiple Ligation-dependent Probe Amplification (MLPA). Family members were analyzed for the same mutation. Paternity was determined by a set of highly polymorphic short tandem repeat (STR) markers. Results: Full gene sequencing found no deleterious mutation. MLPA revealed a large deletion of exons 1 to 12 of BRCA1 in the proband. MLPA performed on 5 family members: proband's mother and father (who were 1 st degree relative- cousins), stepmother (mother's biological sister), 2 sisters (1, same parents; 1, same father and stepmother) found no similar deletion. By using a set of highly polymorphic STR markers, the proband's father and mother were confirmed to be her biological parents. Conclusions: We report a novel de novo BRCA1 deletion mutation encompassing exons 1 - 12 in a Chinese breast cancer patient of early onset with no family history. Identification of this large deletion confirms the importance of pursuing rearrangement testing if full gene sequencing fails to detect a point mutation or short insertion deletion. The mutation found in this study is de novo. This may simply be a random mutation event which occurred in the parents' germ cells during their lifetime which passed onto one of their offspring or maybe a result of gene inversion or splicing deficiency. The relations of such mutations with consanguineous marriage cannot be ruled out. Mutation screening is important in early onset breast cancer patients even if there is no family history. No significant financial relationships to disclose.
Hypoxic pulmonary vasoconstriction in COPD-associated pulmonary hypertension: been there, done that?
Authors: Harm Jan Bogaard
Journal: European Respiratory Journal (2017)

To many of us involved in teaching pulmonary physiology and gas exchange to medical students, hypoxic pulmonary vasoconstriction (HPV) is a favourite topic. The unique property of small pulmonary arteries to constrict in response to a reduced alveolar oxygen tension allows us to cover not only the complexities of ventilation perfusion matching, but also to dive into the more exciting "physiological classics", such as the fetal circulation and high altitude adaptation. Ever since von Euler and Liljestrand described their observations on pulmonary arterial blood pressure in the hypoxic cat [1], scientists have been dedicated to better understand the pulmonary vascular response to hypoxia. It is generally accepted that the endothelial cell plays a central role in hypoxic sensing [2], and that hypoxic sensing involves changing levels of reactive oxygen species (ROS) – although the direction of this change (up or down) continues to be debated [3, 4]. Mitochondria and NADPH oxidase (Nox) are considered as the major sources of ROS production in the pulmonary vasculature [5]. Hypoxic pulmonary vasoconstriction, mediated by p22phox, is a double-edged sword in COPD <http://ow.ly/QiaC30cMgPZ>
Redefine statistical significance
Authors: Daniel J. Benjamin, James O. Berger, Magnus Johannesson, Brian A. Nosek, E.-J. Wagenmakers, Richard Berk, Kenneth A. Bollen, Björn Brembs, Lawrence Brown, Colin Camerer, David Cesarini, Christopher D. Chambers, Merlise Clyde, Thomas D. Cook, Paul De Boeck, Zoltan Dienes, Anna Dreber, Kenny Easwaran, Charles Efferson, Ernst Fehr, Fiona Fidler, Andy P. Field, Malcolm Forster, Edward I. George, Richard Gonzalez, Steven Goodman, Edwin Green, Donald P. Green, Anthony G. Greenwald, Jarrod D. Hadfield, Larry V. Hedges, Leonhard Held, Teck Hua Ho, Herbert Hoijtink, Daniel J. Hruschka, Kosuke Imai, Guido Imbens, John P. A. Ioannidis, Minjeong Jeon, James Holland Jones, Michael Kirchler, David Laibson, John List, Roderick Little, Arthur Lupia, Edouard Machery, Scott E. Maxwell, Michael McCarthy, Don A. Moore, Stephen L. Morgan, Marcus Munafó, Shinichi Nakagawa, Brendan Nyhan, Timothy H. Parker, Luis Pericchi, Marco Perugini, Jeff Rouder, Judith Rousseau, Victoria Savalei, Felix D. Schönbrodt, Thomas Sellke, Betsy Sinclair, Dustin Tingley, Trisha Van Zandt, Simine Vazire, Duncan J. Watts, Christopher Winship, Robert L. Wolpert, Yu Xie, Cristobal Young, Jonathan Zinman, Valen E. Johnson
Journal: Nature Human Behaviour (2017)
Leukemia Fusion Gene Detection in the Clinical Molecular Laboratory Using RNA-Based Targeted Next-Generation Sequencing
Authors: Kevin E. Fisher, Jacquelyn Reuther, Hadi Sayeed, Erica Fang Tam, Vijetha Kumar, Lizmery Suarez Ferguson, Jyotinder Nain Punia, Maria Monica Gramatges, Rachel E. Rau, Karen R. Rabin, Dolores H. Lopez-Terrada, Angshumoy Roy
Journal: Blood (2016)
Evaluation of in vitro hematotoxicity of c-1311, mitoxantrone and oxaliplatin to FU-GM committed neutrophil-monocyte progenitors from human and rat.
Authors: Charles K. Grieshaber, Brian Leyland-Jones, Jesse Paterson, Nezha Alami, Ralph E. Parchment
Journal: Cancer Research (2004)

2110   C-1311 is a member of the relatively large and as yet underutilized imidazoacridinone anticancer drug family. Its structure is closely related to mitoxantrone (Novantrone) and losoxantrone (DuP-941). Xanthus Life Sciences Inc. has advanced C-1311 to phase I clinical trials in solid tumor patients. This study characterizes the in vitro sensitivity of committed neutrophil progenitors from rat and human bone marrow (named CFU-GM) to the toxic effects of continuous exposure C-1311. Human and rat CFU-GM exhibited equivalent susceptibility to C-1311 toxicity: IC 90 ±SD for human CFU-GM was 7.8±1.5 ng/mL and for rat 5.8±0.3 ng/mL (p=0.12). Toxicity of two positive control compounds was also evaluated: mitoxantrone as a positive control for C-1311’s therapeutic class and oxaliplatin (Eloxatin) as a positive control for a successful cytotoxic drug for colon carcinoma in man. Mitoxantrone showed greater toxicity to human than rat CFU-GM than was expected from MTD differentials, which may indicate higher plasma protein binding in man than rat. The IC 90 ±SD for human CFU-GM was 0.23±0.05 ng/mL and for rat 1.69±0.023 ng/mL (p=0.00080). Human CFU-GM tolerated higher concentrations of oxaliplatin than rat CFU-GM, which explains its surprisingly good clinical effectiveness: IC 90 ±SD for human CFU-GM was 2332±269 ng/mL and for rat 211±9 ng/mL (p=0.0052). Mitoxantrone and oxaliplatin are FDA approved drugs, proving that differential sensitivity between human and animal CFU-GM is not the sole determinant of clinical success or failure. In the past, the CFU-GM assay has consistently identified cytotoxic anticancer agents that are more toxic in man than mouse. Equivalent susceptibility of human and rat CFU-GM to C-1311 toxicity indicates that the structural modifications made in the anthracenedione pharmacophore to generate C-1311 improved CFU-GM tolerability more in man than rat and eliminated the species difference in tolerance seen with mitoxantrone. CFU-GM testing predicts a clinical MTD for C-1311 of 81 mg/m 2 /d qdx5 (range 20–320, given ±4-fold accuracy of the model), assuming neutropenia will be dose-limiting in both species; C-1311, not a biologically active metabolite, will be the marrow toxicant; and plasma protein binding will be equivalent in rat and man. If neutropenia is not dose-limiting in man, then the predicted human MTD from the in vitro data will become the upper limit on human tolerability. Recent studies demonstrating that C-1311 has superior efficacy over oxaliplatin in preclinical models suggest C-1311 might fare well in head-to-head clinical trials in colorectal carcinoma, where oxaliplatin doses would be higher than in rodent models, but C-1311 doses would likely not be any higher.
A novel genetic variant of Streptococcus pneumoniae serotype 11A discovered in Fiji
Authors: S. Manna, B.D. Ortika, E.M. Dunne, K.E. Holt, M. Kama, F.M. Russell, J. Hinds, C. Satzke
Journal: Clinical Microbiology and Infection (2017)

ObjectivesAs part of annual cross-sectional Streptococcus pneumoniae carriage surveys in Fiji (2012–2015), we detected pneumococci in over 100 nasopharyngeal swabs that serotyped as '11F-like' by microarray. We examined the genetic basis of this divergence in the 11F-like capsular polysaccharide (cps) locus compared to the reference 11F cps sequence. The impact of this diversity on capsule phenotype, and serotype results using genetic and serologic methods were determined.MethodsGenomic DNA from representative 11F-like S. pneumoniae isolates obtained from the nasopharynx of Fijian children was extracted and subject to whole genome sequencing. Genetic and phylogenetic analyses were used to identify genetic changes in the cps locus. Capsular phenotypes were evaluated using the Quellung reaction and latex agglutination.ResultsCompared to published 11F sequences, the wcwC and wcrL genes of the 11F-like cps locus are phylogenetically divergent, and the gct gene contains a single nucleotide insertion within a homopolymeric region. These changes within the DNA sequence of the 11F-like cps locus have modified the antigenic properties of the capsule, such that 11F-like isolates serotype as 11A by Quellung reaction and latex agglutination.ConclusionsThis study demonstrates the ability of molecular serotyping by microarray to identify genetic variants of S. pneumoniae and highlights the potential for discrepant results between phenotypic and genotypic serotyping methods. We propose that 11F-like isolates are not a new serotype but rather are a novel genetic variant of serotype 11A. These findings have implications for invasive pneumococcal disease surveillance as well as studies investigating vaccine impact.