tbuckley/cabot-search huggingface dataset:
Abstract P2-01-14: Adipocytes and cancer cell interactions promote leptin receptor expression and drive β-catenin-mediated progression in triple negative breast cancer
Authors: Z Feng, Z Tao, X Hu
Journal: Cancer Research (2019)

Abstract Background Triple negative breast cancer (TNBC) patients suffer from poor prognosis due to short-term recurrence and/or metastasis. Obesity is reported to predict poor prognosis of TNBC. However, the mechanisms connecting obesity to progression of TNBC remain unclarified. Methods We co-cultured TNBC model cells with adipocytes differentiated from human adipose-derived mesenchymal stem cells (hMSC-ad) and TNBC patients derived primary adipocytes to examine migration, invasion and metastasis abilities using Transwell assays and tail vein injection xenograft mouse model, respectively. Expression levels of leptin receptor (LEPR) , epithelial-mesenchymal transition (EMT) markers and β-catenin signaling pathway related molecules in the control and co-cultured TNBC model were analyzed by real time quantitative polymerase chain reaction (RT-qPCR) and western blot assays. Downregulation of LEPR by LEPR specific short hairpin RNA (shRNA) and upregulation of the downstream pathway with continuous activated β-catenin were applied to access their roles in adipocytes and cancer cell interactions. Degree of adipocytes infiltration in tumor tissue was evaluated by histopathology. LEPR mRNA expression level in breast cancer and corresponding patients' information was retrieved from The Cancer Genome Atlas (TCGA) database. Results Here we first reported that both hMSC-ad- and patients-derived adipocytes promoted migration and invasion of TNBC model cells in vitro and lung metastasis in vivo. Adipocytes were then confirmed to induce upregulation of LEPR in each TNBC model cell compared to the control groups (p&amp;lt;0.0001), resulting in higher expression of EMT markers and molecules related to β-catenin signaling pathway.Afterwards, LEPR knockdown led to decreased migration, invasion and metastasis capacities, as well as reduced expression of EMT markers and molecules related to ?-catenin signaling pathway, while activation of ?-catenin could restore robust EMT and metastatic abilities of TNBC model cells. Last, clinical specimen analyses showed that infiltration of adipocytes to tumor tissue was significantly associated with shorter DFS of TNBC patients (p&amp;lt;0.05) and upregulated LEPR in breast cancer tissue indicated poor prognosis (median OS of 7.43 vs 10.81 years of the LEPR-low group, p &amp;lt; 0.05). Conclusions To our knowledge, adipocytes are first shown to promote progression of TNBC via previously uncharacterized LEPR-β-catenin signaling pathway. Citation Format: Feng Z, Tao Z, Hu X. Adipocytes and cancer cell interactions promote leptin receptor expression and drive β-catenin-mediated progression in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-14.
A sudden headache
Authors: Michael Kinney, Melvyn Ang, Paula Scullin
Journal: BMJ (2011)

A 55 year old woman attended the emergency department with a headache that had started suddenly at the back of her head 12 hours earlier. It had reached its peak intensity (10/10 in severity) within minutes and spread across her whole head. It was exacerbated by coughing, stooping forward, and movement of her head. She had no neck stiffness, photophobia, or limb or facial weakness. She experienced no sensory symptoms, and her vision was unaffected.

On systems review, she last felt well two months before her current presentation. She had a persistently sore throat and a dry cough, despite completing her fourth course of antibiotics, during that time. The preceding day she had noticed swelling of the face, neck, and breasts, with some visible veins on the chest wall. She reported no wheeze, shortness of breath, or symptoms consistent with urticaria. She had no fever, rash, weight loss, or night sweats.

She was a smoker of 40 pack years. Her history was non-contributory. Her family history showed her mother had died of metastatic lung cancer at the age of 66. She had no drug allergies.

On examination, she was haemodynamically stable, saturating at 91% on room air, …
Abstract P3-06-05: Whole genome sequence analysis of 77 breast cancer patients reveal increased somatic transposable element insertions responsible for early onset of cancer
Authors: R Paul, JP Solzak, M Radovich
Journal: Cancer Research (2019)

Abstract More than 50% of the human genome consists of transposable elements (TE). However only certain classes of retrotransposons (ALU, SVA, ERV and L1) are believed to be active. They transpose using an RNA intermediate causing target-site duplications along with a poly-A tail. They can also insert into intronic regions and disrupt normal transcription of protein-coding genes. However, most TEs are repressed using various epigenetic mechanisms such as DNA methylation, histone modifications and RNA silencing. The piRNA pathway also plays an important role in retrotransposon silencing by establishing a repressive chromatin state. In this study, somatic and germline TE insertions in 77 TCGA breast cancer cases were characterized. These studies have revealed that somatic TEs can insert into intronic regions of tumor suppressor genes such as LRP1B, RAD51B and WNK2. Characterization of germline TE insertions, reveal insertions in intronic regions of predisposition genes such as CDH1 and BRCA2. Analysis of germline SNPs in high somatic TE patients reveals the presence of deleterious variants in genes such as NRDE2, RAD51C and DDX3X which are known to regulate TEs using RNA silencing via the piRNA pathway and other DNA-damage response mechanisms. Patients having high somatic TE insertions were found to have lower age of diagnosis suggesting a role in the early onset of cancer (median age of patients with high TE=43.37yrs; low TE=59.77yrs, Wilcoxan p=0.023). Further comparison of somatic TE insertion burden against somatic point-mutation burden revealed an inverse correlation suggesting analysis of TE insertions is indispensable to get the complete mutation profile of breast cancer genomes. Citation Format: Paul R, Solzak JP, Radovich M. Whole genome sequence analysis of 77 breast cancer patients reveal increased somatic transposable element insertions responsible for early onset of cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-05.
Group Purchasing Organizations and Costs—Reply
Authors: William E. Bruhn, Elizabeth A. Fracica, Martin A. Makary
Journal: JAMA (2019)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Abstract 18105: Mice Lacking OPA1 in Adipose Tissue Are Resistant to Diet-Induced Obesity and Insulin Resistance
Authors: Renata O Pereira, Jeffrey White, Shi Fang, Angela Olvera, Rana Hewezi, Rose McGlauflin, Matthew J Potthoff, E. Dale Abel
Journal: Circulation (2017)

OPA1 (Optic Atrophy 1) is a mitochondrial GTPase that regulates mitochondrial dynamics, cristae structure and respiratory capacity. Changes in mitochondrial dynamics can alter brown adipocyte metab...
The blame game
Authors: Neil Chanchlani
Journal: BMJ (2010)

Our drawer has it all at the moment—codeine for my dad’s back pain, spare insulin for my diabetes, diazepam for when my mum’s nerves play up, and even leftover fluoxetine (Prozac) from when my sister had a tragic loss. All prescriptive and all within a finger’s reach.

The past decade has seen a definite rise in not only dispensing prescription drugs but also misusing them. The National Health Service managed to spend £1.3bn (€1.5bn; $2.1bn) on prescriptions alone last year. From students who take nootropic memory enhancers to get …
It is good to feel better, but better to feel good: whether a patient finds treatment ‘successful’ or not depends on the questions researchers ask
Authors: Ewa M Roos, Eleanor Boyle, Richard B Frobell, L Stefan Lohmander, Lina Holm Ingelsrud
Journal: British Journal of Sports Medicine (2019)

Introduction In sports physiotherapy, medicine and orthopaedic randomised controlled trials (RCT), the investigators (and readers) focus on the difference between groups in change scores from baseline to follow-up. Mean score changes are difficult to interpret (‘is an improvement of 20 units good?’), and follow-up scores may be more meaningful. We investigated how applying three different responder criteria to change and follow-up scores would affect the ‘outcome’ of RCTs. Responder criteria refers to participants’ perceptions of how the intervention affected them. Methods We applied three different criteria—minimal important change (MIC), patient acceptable symptom state (PASS) and treatment failure (TF)—to the aggregate Knee injury and Osteoarthritis Outcome Score (KOOS 4 ) and the five KOOS subscales, the primary and secondary outcomes of the KANON trial ( ISRCTN84752559 ). This trial included young active adults with an acute ACL injury and compared two treatment strategies: exercise therapy plus early reconstructive surgery, and exercise therapy plus delayed reconstructive surgery, if needed. Results MIC: At 2 years, more than 90% in the two treatment arms reported themselves to be minimally but importantly improved for the primary outcome KOOS 4 . PASS: About 50% of participants in both treatment arms reported their KOOS 4 follow-up scores to be satisfactory. TF: Almost 10% of participants in both treatment arms found their outcomes so unsatisfactory that they thought their treatment had failed. There were no statistically significant or meaningful differences between treatment arms using these criteria. Conclusion We applied change criteria as well as cross-sectional follow-up criteria to interpret trial outcomes with more clinical focus. We suggest researchers apply MIC, PASS and TF thresholds to enhance interpretation of KOOS and other patient-reported scores. The findings from this study can improve shared decision-making processes for people with an acute ACL injury.
Low cardiac lipolysis reduces mitochondrial fission and prevents lipotoxic heart dysfunction in Perilipin 5 mutant mice
Authors: Stephanie Kolleritsch, Benedikt Kien, Gabriele Schoiswohl, Clemens Diwoky, Renate Schreiber, Christoph Heier, Lisa Katharina Maresch, Martina Schweiger, Thomas O Eichmann, Sarah Stryeck, Petra Krenn, Tamara Tomin, Matthias Schittmayer, Dagmar Kolb, Thomas Rülicke, Gerald Hoefler, Heimo Wolinski, Tobias Madl, Ruth Birner-Gruenberger, Guenter Haemmerle
Journal: Cardiovascular Research (2019)

Lipotoxic cardiomyopathy in diabetic and obese patients typically encompasses increased cardiac fatty acid (FA) uptake eventually surpassing the mitochondrial oxidative capacity. Lowering FA utilization via inhibition of lipolysis represents a strategy to counteract the development of lipotoxic heart dysfunction. However, defective cardiac triacylglycerol (TAG) catabolism and FA oxidation in humans (and mice) carrying mutated ATGL alleles provokes lipotoxic heart dysfunction questioning a therapeutic approach to decrease cardiac lipolysis. Interestingly, decreased lipolysis via cardiac overexpression of Perilipin 5 (Plin5), a binding partner of ATGL, is compatible with normal heart function and lifespan despite massive cardiac lipid accumulation. Herein, we decipher mechanisms that protect Plin5 transgenic mice from the development of heart dysfunction.We generated mice with cardiac-specific overexpression of Plin5 encoding a serine-155 to alanine exchange (Plin5-S155A) of the protein kinase A phosphorylation site, which has been suggested as a prerequisite to stimulate lipolysis and may play a crucial role in the preservation of heart function. Plin5-S155A mice showed a substantial increase in cardiac TAG and ceramide levels, which was comparable to mice overexpressing non-mutated Plin5. Lipid accumulation was compatible with normal heart function even under mild stress. Plin5-S155A mice showed reduced cardiac FA oxidation but normal ATP production and changes in the Plin5-S155A phosphoproteome compared to Plin5 transgenic mice. Interestingly, mitochondrial recruitment of dynamin-related protein 1 (Drp1) was markedly reduced in cardiac muscle of Plin5-S155A and Plin5 transgenic mice accompanied by decreased phosphorylation of mitochondrial fission factor, a mitochondrial receptor of Drp1.This study suggests that low cardiac lipolysis is associated with reduced mitochondrial fission and may represent a strategy to combat the development of lipotoxic heart dysfunction.
Employment pressure and the burden of publication in China
Authors: Jiaywei Tsauo
Journal: BMJ (2013)

Although the pressure to publish might seem to be one that affects medical students and doctors everywhere, in China it is generally considered a “must have” for employment by large hospitals. This requirement, however, affects not only the credibility of China’s body of scientific research.1 but also the career paths of China’s young doctors, and access to healthcare for China’s rural population. An article by Yuan and …
Metabolic characterization of human IDH mutant and wild type gliomas using simultaneous pH- and oxygen-sensitive molecular MRI
Authors: Jingwen Yao, Ararat Chakhoyan, David A Nathanson, William H Yong, Noriko Salamon, Catalina Raymond, Sergey Mareninov, Albert Lai, Phioanh L Nghiemphu, Robert M Prins, Whitney B Pope, Richard G Everson, Linda M Liau, Timothy F Cloughesy, Benjamin M Ellingson
Journal: Neuro-Oncology (2019)

Isocitrate dehydrogenase 1 (IDH1) mutant gliomas are thought to have distinct metabolic characteristics, including a blunted response to hypoxia and lower glycolytic flux. We hypothesized that non-invasive quantification of abnormal metabolic behavior in human IDH1 mutant gliomas could be performed using a new pH- and oxygen-sensitive molecular MRI technique. Simultaneous pH- and oxygen-sensitive MRI was obtained at 3T using amine CEST-SAGE-EPI. The pH-dependent measure of the magnetization transfer ratio asymmetry (MTRasym) at 3 ppm and oxygen-sensitive measure of R2' were quantified in 90 patients with gliomas. Additionally, stereotactic, image-guided biopsies were performed in 20 patients for a total of 52 samples. The association between imaging measurements and hypoxia-inducible factor 1 alpha (HIF1α) expression was identified using Pearson correlation analysis. IDH1 mutant gliomas exhibited significantly lower MTRasym at 3 ppm, R2', and MTRasymxR2' (P = 0.007, P = 0.003, and P = 0.001, respectively). MTRasymxR2' could identify IDH1 mutant gliomas with a high sensitivity (81.0%) and specificity (81.3%). HIF1α was positively correlated with MTRasym at 3 ppm, R2' and MTRasymxR2' in IDH1 wild type (r = 0.610, P = 0.003; r = 0.667, P = 0.008; r = 0.635, P = 0.006), but only MTRasymxR2' in IDH1 mutant gliomas (r = 0.727, P = 0.039). IDH1 mutant gliomas have distinct metabolic and microenvironment characteristics compared with wild type gliomas. An imaging biomarker combining tumor acidity and hypoxia (MTRasymxR2') can differentiate IDH1 mutation status and is correlated with tumor acidity and hypoxia.
Homeostasis of the sebaceous gland and mechanisms of acne pathogenesis
Authors: R.W. Clayton, K. Göbel, C.M. Niessen, R. Paus, M.A.M. Steensel, X. Lim
Journal: British Journal of Dermatology (2019)

Sebaceous glands (SGs) are appendages of mammalian skin that produce a mixture of lipids known as sebum. Acne vulgaris is an exceptionally common skin condition, characterized by elevated sebum production, altered sebum composition, and the formation of infundibular cysts, called comedones. Comedo-associated SGs are atrophic, suggesting that comedo formation involves abnormal differentiation of progenitor cells that generate the SG and infundibulum: the 'comedo switch'. Understanding the biological processes that govern SG homeostasis promises to highlight potential aetiological mechanisms underlying acne and other SG-associated skin disorders.In this review, we discuss the clinical data, genetic mouse models and in vitro research that have highlighted major hormones, paracrine factors, transcription factors and signalling pathways that control SG homeostasis. These include, but are not limited to androgens, progestogens and oestrogens; retinoids; receptor tyrosine kinases such as ErbB family receptors, fibroblast growth factor receptor 2 and insulin/insulin-like growth factor 1 receptors; peroxisome proliferator-activated receptor γ; aryl hydrocarbon receptor; and the Wnt signalling pathway. Where possible, the cellular and molecular mechanisms by which these regulatory factors control SG biology are indicated, along with considerations as to how they might contribute to acne pathogenesis.Future research should seek to establish the relative importance, and causative relationships, of altered sebum production, sebum composition, inflammation and abnormal differentiation of sebaceous progenitors to the process of comedo formation in acne. Such an understanding will allow for therapeutic targeting of regulatory factors that control SG homeostasis, with the aim of treating acne.
The Importance of Outcome and Precise Evaluation in Economic Analysis of Cancer Drugs
Authors: Jason Chesney, Igor Puzanov, Merrick Ross
Journal: JAMA Dermatology (2019)

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 Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Dermatology journal
Anhedonia Reduction and the Association Between Left Ventral Striatal Reward Response and 6-Month Improvement in Life Satisfaction Among Young Adults
Authors: Kristen L. Eckstrand, Erika E. Forbes, Michele A. Bertocci, Henry W. Chase, Tsafrir Greenberg, Jeanette Lockovich, Ricki Stiffler, Haris A. Aslam, Simona Graur, Genna Bebko, Mary L. Phillips
Journal: JAMA Psychiatry (2019)

Anhedonia is a symptom of multiple psychiatric conditions in young adults that is associated with poorer mental health and psychosocial function and abnormal ventral striatum reward processing. Aberrant function of neural reward circuitry is well documented in anhedonia and other psychiatric disorders. Longitudinal studies to identify potential biomarkers associated with a reduction in anhedonia are necessary for the development of novel treatment targets.To identify neural reward-processing factors associated with improved psychiatric symptoms and psychosocial function in a naturalistic, observational context.A longitudinal cohort follow-up study was conducted from March 1, 2014, to June 5, 2018, at the University of Pittsburgh Medical Center after baseline functional magnetic resonance imaging in 52 participants between the ages of 18 and 25 years who were experiencing psychological distress.Participants were evaluated at baseline and 6 months. At baseline, participants underwent functional magnetic resonance imaging during a card-guessing monetary reward task. Participants completed measures of affective symptoms and psychosocial function at each visit. Neural activation during reward prediction error (RPE), a measure of reward learning, was determined using Statistical Parametric Mapping software. Neural reward regions with significant RPE activation were entered as regions associated with future symptoms in multiple linear regression models.A total of 52 young adults (42 women and 10 men; mean [SD] age, 21.4 [2.2] years) completed the study. Greater RPE activation in the left ventral striatum was associated with a decrease in anhedonia symptoms during a 6-month period (β = -6.152; 95% CI, -11.870 to -0.433; P = .04). The decrease in anhedonia between baseline and 6 months mediated the association between left ventral striatum activation to RPE and improvement in life satisfaction between baseline and 6 months (total [c path] association: β = 0.245; P = .01; direct [c' path] association: β = 0.133; P = .16; and indirect [ab path] association: 95% CI, 0.026-0.262). Results were not associated with psychotropic medication use.Greater left ventral striatum responsiveness to RPE may serve as a biomarker or potential target for novel treatments to improve the severity of anhedonia, overall mental health, and psychosocial function.
Preventing medication-related osteonecrosis of the jaw
Authors: Lara Zebic, Vinod Patel
Journal: BMJ (2019)

### What you need to know

Osteonecrosis of the jaw is a severe adverse effect reported with certain drugs commonly used in the treatment of cancers and osteoporosis. Although rare, it can severely impair quality of life.1 The number and type of drugs associated with osteonecrosis of the jaw continue to increase, as do their indications. With greater life expectancy and more people living with cancer as a chronic disease, the pool of those “at risk” is increasing.

Management can be costly, invasive, and difficult.2 Clinicians can play a pivotal role in prevention of medication-related osteonecrosis of the jaw by informing patients of the risks when they prescribe these drugs and discussing ways to minimise the risk. In this article we describe the risks associated with different therapies and provide guidance on prevention for non-specialists.

### Data sources and selection

We have drawn on the recommendations from the American Association of Oral and Maxillofacial Surgeons and the Scottish Dental Clinical Effectiveness Programme, with relevant citations identified from their content. We supplemented this with literature from our personal archive of references which includes randomised controlled trials, prospective and retrospective studies as well as case reports. In discussing the risk of medication-related osteonecrosis of the …