tbuckley/cabot-search huggingface dataset:
Neoadjuvant capecitabine and oxaliplatin (CAPOX) followed by chemoradiation (CRT) in high-risk rectal cancer: A single-institution experience.
Authors: Saif Ahmad, Deepak Parashar, Catherine Rachel Jephcott, Hugo Ford, Charles Wilson
Journal: Journal of Clinical Oncology (2012)

e14100 Background: Total Mesorectal Excision (TME) is standard of care in early rectal cancer. Pre-operative CRT facilitates microscopic complete resection (R0), improving outcome in high risk disease. Recent Phase 2 studies investigated the role of neoadjuvant CAPOX chemotherapy pre-CRT with promising results. We have adopted this strategy in high risk cancers with threatened circumferential resection margin (CRM) on MRI, and report our institution’s early outcome data. Methods: Retrospective data was collected on 37 patients with high risk disease treated March 2007 to December 2011. Patients received 12 weeks oxaliplatin (130mg/m2) and capecitabine (1000mg/m2 BD for 14 days) every 3 weeks, followed by CRT (45 Gy/ 25 #) with concurrent capecitabine (800mg/m2 BD). 11/37 patients had a 5.4 Gy/ 3 # boost with CRT. 4 patients were in a clinical trial, 2 of whom had cetuximab in addition to CAPOX. Patients deemed operable on repeat MRI had TME and 4 cycles of adjuvant CAPOX. Results: Median age was 64 (33-78) and male: female ratio 2.1:1. Median follow-up was 22 months (1.9-53.7). 2 patients did not complete 4 cycles neoadjuvant CAPOX due to toxicity. Median time to surgery post CRT was 6.6 weeks (4.7-10 weeks). 1 patient had an embolic event and femoral embolectomy. 7/31 (23%) patients had no post-operative chemotherapy (4 wound; 2 previous toxicity; 1 comorbidity). Radiological response rates post CRT were 26/34 (76%). 2 patients progressed and were unable to have radical surgery. 1 further patient was found to have unsuspected metastatic disease (liver) at time of surgery. 28/35 (80%) patients had R0 resection and pathological complete response (pCR) was 6/37 (16%). 2 year DFS and OS was 89% and 91.3%. Conclusions: Our outcomes, within an unselected cohort, reflect outcomes consistent with published trial data and support routine use of pre-operative CAPOX and CRT in high risk rectal cancers. This strategy is feasible in a non-trial population, and offers the benefit of early sterilisation of micrometastases, better prediction of chemotherapy response and facilitates the incorporation of novel agents within neoadjuvant window studies.
Working as a doctor in Canada
Authors: Helen Jones
Journal: BMJ (2019)

For the past four years, Canada has been ranked as the best country in the world for quality of life, a measure that covers everything from housing to education and the environment. With its wide open spaces, sophisticated cities, and active lifestyle, it is a popular destination for doctors seeking new challenges abroad and a better work-life balance.

Canada has an ongoing shortage of locally trained medical staff which is likely to continue for some time. Statistics Canada estimates that 4.5 million people across the country are without a family doctor and the Canadian health authorities are actively recruiting overseas doctors to fill the gaps.

Nova Scotia, the Canadian province with the most acute shortage, has sent representatives from the College of Physicians and Surgeons of Nova Scotia together with provincial immigration officials to medical recruitment fairs in the UK.

Canada suffers from …
Physical Activity and Breast Cancer: Focusing on High-Risk Subgroups and Putting Recommendations in Context
Authors: Nicole M. Niehoff, Alexandra J. White, Dale P. Sandler
Journal: Cancer Research (2020)

Abstract While it is well-established that physical activity is associated with a decreased risk of breast cancer, most studies have been conducted in populations at an average underlying breast cancer risk. In this issue of Cancer Research, Kehm and colleagues present compelling evidence that adulthood physical activity is beneficial across the risk spectrum, including among women with BRCA1 and BRCA2 mutations. These findings are significant because women who are at a higher baseline risk are not engaging in sufficient physical activity to meet current guidelines but may be more motivated to do so knowing that they, like women in the general population, may benefit. See related article by Kehm et al., p. 116
How should we assess the clinical and cost effectiveness of histology independent cancer drugs?
Authors: Sophie Cooper, Jacoline C Bouvy, Lawrence Baker, Francois Maignen, Pall Jonsson, Peter Clark, Stephen Palmer, Meindert Boysen, Nick Crabb
Journal: BMJ (2020)

Sophie Cooper, Jacoline Bouvy and colleagues discuss the challenges that histology independent cancer drugs will pose for NICE and the NHS
Perspectives in allergen immunotherapy: 2019 and beyond
Authors: Oliver Pfaar, Ioana Agache, Frédéric de Blay, Sergio Bonini, Adam M. Chaker, Stephen R. Durham, Radoslaw Gawlik, Peter W. Hellings, Marek Jutel, Jörg Kleine‐Tebbe, Ludger Klimek, Matthias V. Kopp, Andreas Nandy, Ronald L. Rabin, Ronald van Ree, Harald Renz, Graham Roberts, Anne‐Marie Salapatek, Carsten B. Schmidt‐Weber, Mohamed H. Shamji, Gunter J. Sturm, J. Christian Virchow, Ulrich Wahn, Christoph Willers, Petra Zieglmayer, Cezmi A. Akdis
Journal: Allergy (2019)

Abstract The seventh “Future of the Allergists and Specific Immunotherapy (FASIT)” workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the “Therapy Allergen Ordinance” in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.
PU.1 Enforces Hematopoietic Stem Cell Quiescence during Chronic Inflammation
Authors: James Chavez, Jennifer L Rabe, Kelly Higa, Dirk Loeffler, Ahmed Nouraiz, Taylor Mills, Beau M Idler, Brett M. Stevens, Courtney Fleenor, Claus Nerlov, Hideaki Nakajima, James Hagman, Timm Schroeder, Hyun Min Kim, Craig T Jordan, James DeGregori, Eric Pietras
Journal: Blood (2019)
Abstract 18211: Notched P Wave Component is a New Electrocardiographic Marker for Recurrence of Atrial Fibrillation After Electrical Cardioversion
Authors: Yuhi Fujimoto, Kenji Yodogawa, Eiichiro Oka, Kenta Takahashi, Teppei Yamamoto, Yu-ki Iwasaki, Meiso Hayashi, Wataru Shimizu
Journal: Circulation (2017)

BACKGROUND: Early recurrence of atrial fibrillation (AF) is common following successful electrical cardioversion (ECV). Predictor of early recurrence of AF after successful ECV is still uncertain. ...
SREBP1 siRNA enhance the docetaxel effect based on a bone-cancer dual-targeting biomimetic nanosystem against bone metastatic castration-resistant prostate cancer
Authors: Jiyuan Chen, Zhenjie Wu, Weihong Ding, Chengwu Xiao, Yu Zhang, Shen Gao, Yuan Gao, Weimin Cai
Journal: Theranostics (2020)

Until recently, there have been limited options for patients with bone metastatic castration-resistant prostate cancer (BmCRPC) following the failure of or development of resistance to docetaxel (DTX), which is one of the frontline treatments.Sterol regulatory element-binding protein 1 (SREBP1) is reported to regulate abnormal lipid metabolism and to promote the progression and metastasis of prostate cancer (PCa).The siRNA interferes SREBP1 may provide an efficient treatment when combined with DTX.Methods: In this study, lipoic acid (LA) and cross-linked peptide-lipoic acid micelles were cross-linked (LC) for DTX and siSREBP1 delivery (LC/D/siR).Then, cell membrane of PCa cells (Pm) and bone marrow mesenchymal stem cells (Bm) were fused for cloaking LC/D/siR (PB@LC/D/siR).Finally, the synthesized PB@LC/D/siR was evaluated in vitro and in vivo.Results: PB@LC/D/siR is internalized in PCa cells by a mechanism of lysosome escape.Tumor targeting and bone homing studies are evaluated using bone metastatic CRPC (BmCRPC) models, both in vitro and in vivo.Moreover, the enhanced anti-proliferation, anti-migration and anti-invasion capacities of DTX-and siSREBP1-loaded PB@LC (PB@LC/D/siR) were observed in vitro.Furthermore, PB@LC/D/siR was able to suppress the growth of the tumor effectively with deep tumor penetration, high safety and good protection of the bone at the tumor site.Additionally, the mRNA levels and protein levels of SREBP1 and SCD1 were able to be significantly downregulated by PB@LC/D/siR. Conclusion:This study presented a bone-cancer dual-targeting biomimetic nanodelivery system for bone metastatic CRPC.
Impairment of spermatogenesis and sperm motility by the high-fat diet-induced dysbiosis of gut microbes
Authors: Ning Ding, Xin Zhang, Xue Di Zhang, Jun Jing, Shan Shan Liu, Yun Ping Mu, Li Li Peng, Yun Jing Yan, Geng Miao Xiao, Xin Yun Bi, Hao Chen, Fang Hong Li, Bing Yao, Allan Z Zhao
Journal: Gut (2020)

High-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally influence spermatogenesis and sperm motility.Faecal microbes derived from the HFD-fed or normal diet (ND)-fed male mice were transplanted to the mice maintained on ND. The gut microbes, sperm count and motility were analysed. Human faecal/semen/blood samples were collected to assess microbiota, sperm quality and endotoxin.Transplantation of the HFD gut microbes into the ND-maintained (HFD-FMT) mice resulted in a significant decrease in spermatogenesis and sperm motility, whereas similar transplantation with the microbes from the ND-fed mice failed to do so. Analysis of the microbiota showed a profound increase in genus Bacteroides and Prevotella, both of which likely contributed to the metabolic endotoxaemia in the HFD-FMT mice. Interestingly, the gut microbes from clinical subjects revealed a strong negative correlation between the abundance of Bacteroides-Prevotella and sperm motility, and a positive correlation between blood endotoxin and Bacteroides abundance. Transplantation with HFD microbes also led to intestinal infiltration of T cells and macrophages as well as a significant increase of pro-inflammatory cytokines in the epididymis, suggesting that epididymal inflammation have likely contributed to the impairment of sperm motility. RNA-sequencing revealed significant reduction in the expression of those genes involved in gamete meiosis and testicular mitochondrial functions in the HFD-FMT mice.We revealed an intimate linkage between HFD-induced microbiota dysbiosis and defect in spermatogenesis with elevated endotoxin, dysregulation of testicular gene expression and localised epididymal inflammation as the potential causes.NCT03634644.
OGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism
Authors: Weiqi Dai, Ling Xu, Xiangnan Yu, Guangcong Zhang, Hongying Guo, Hailin Liu, Guangqi Song, Shuqiang Weng, Ling Dong, Jimin Zhu, Taotao Liu, Chuanyong Guo, Xizhong Shen
Journal: Journal of Hepatology (2019)
Sweetening the hallmarks of cancer: Galectins as multifunctional mediators of tumor progression
Authors: María Romina Girotti, Mariana Salatino, Tomás Dalotto-Moreno, Gabriel A. Rabinovich
Journal: The Journal of Experimental Medicine (2019)

Hanahan and Weinberg have proposed 10 organizing principles that enable growth and metastatic dissemination of cancer cells. These distinctive and complementary capabilities, defined as the “hallmarks of cancer,” include the ability of tumor cells and their microenvironment to sustain proliferative signaling, evade growth suppressors, resist cell death, promote replicative immortality, induce angiogenesis, support invasion and metastasis, reprogram energy metabolism, induce genomic instability and inflammation, and trigger evasion of immune responses. These common features are hierarchically regulated through different mechanisms, including those involving glycosylation-dependent programs that influence the biological and clinical impact of each hallmark. Galectins, an evolutionarily conserved family of glycan-binding proteins, have broad influence in tumor progression by rewiring intracellular and extracellular circuits either in cancer or stromal cells, including immune cells, endothelial cells, and fibroblasts. In this review, we dissect the role of galectins in shaping cellular circuitries governing each hallmark of tumors, illustrating relevant examples and highlighting novel opportunities for treating human cancer.
Abstract A35: Microenvironmental adaptations drive obesity-associated pancreatic cancer
Authors: Katherine Minjee Chung, Jaffarguribal Singh, Lauren Lawres, Kimberly Judith Dorans, Rebecca Robbins, Arjun Bhutkar, Ana Babic, Sara A. Vayrynen, Andressa D. Costa, Jonathan A. Nowak, Daniel T. Chang, Richard F. Dunne, Aram F. Hezel, Albert C. Koong, Joshua J. Wilhelm, Melena D. Bellin, Vibe Nylander, Anna L. Gloyn, Mark I. McCarthy, Brian M. Wolpin, Tyler Jacks, Charles S. Fuchs, Mandar Deepak Muzumdar
Journal: Cancer Research (2019)

Abstract Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how obesity contributes to pancreatic cancer development is not well understood. Moreover, whether and at what point weight loss or other obesity-related interventions may impact PDAC progression remains largely unexplored, with significant implications for prevention and treatment. Leveraging an autochthonous genetically engineered model of PDAC, we demonstrate that obesity plays a stage-specific causal and reversible role in early PDAC progression. Molecular and histologic analyses reveal prominent microenvironmental alterations in tumors from obese mice, including increased inflammation and fibrosis and evidence for marked pancreatic islet cell adaptation. In particular, we identify aberrant expression of the peptide hormone cholecystokinin (CCK) in pancreatic islets in tumors as an adaptive response to obesity and show that islet CCK expression promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Together, these studies link obesity, changes in the local microenvironment, and tumorigenesis and implicate islet-derived hormones beyond insulin in PDAC development. Furthermore, the reversible nature of these adaptations supports the potential of antiobesity strategies to intercept PDAC early during progression. Citation Format: Katherine Minjee Chung, Jaffarguribal Singh, Lauren Lawres, Kimberly Judith Dorans, Rebecca Robbins, Arjun Bhutkar, Ana Babic, Sara A. Vayrynen, Andressa D. Costa, Jonathan A. Nowak, Daniel T. Chang, Richard F. Dunne, Aram F. Hezel, Albert C. Koong, Joshua J. Wilhelm, Melena D. Bellin, Vibe Nylander, Anna L. Gloyn, Mark I. McCarthy, Brian M. Wolpin, Tyler Jacks, Charles S. Fuchs, Mandar Deepak Muzumdar. Microenvironmental adaptations drive obesity-associated pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A35.
Breakdown of spatial coding and interneuron synchronization in epileptic mice
Authors: Tristan Shuman, Daniel Aharoni, Denise J. Cai, Christopher R. Lee, Spyridon Chavlis, Lucia Page-Harley, Lauren M. Vetere, Yu Feng, Chen Yi Yang, Irene Mollinedo-Gajate, Lingxuan Chen, Zachary T. Pennington, Jiannis Taxidis, Sergio E. Flores, Kevin Cheng, Milad Javaherian, Christina C. Kaba, Naina Rao, Mimi La-Vu, Ioanna Pandi, Matthew Shtrahman, Konstantin I. Bakhurin, Sotiris C. Masmanidis, Baljit S. Khakh, Panayiota Poirazi, Alcino J. Silva, Peyman Golshani
Journal: Nature Neuroscience (2020)
Characteristics of successful programmes targeting gender inequality and restrictive gender norms for the health and wellbeing of children, adolescents, and young adults: a systematic review
Authors: Jessica K Levy, Gary L Darmstadt, Caitlin Ashby, Mary Quandt, Erika Halsey, Aishwarya Nagar, Margaret E Greene
Journal: The Lancet Global Health (2019)

BackgroundIn the context of the Sustainable Development Goals and the shifting global burden of disease, this systematic review analyses the evidence from rigorously evaluated programmes that seek to transform the gendered social norms undermining the health and wellbeing of children, adolescents, and young adults. The aim of this study was threefold: to describe the landscape of gender-transformative programmes that attempt to influence health-related outcomes; to identify mechanisms through which successful programmes work; and to highlight where gaps might exist in implementation and evaluation.MethodsWe systematically reviewed rigorous evaluations published between Jan 1, 2000, and Nov 1, 2018 of programmes that sought to decrease gender inequalities and transform restrictive gender norms to improve the health and wellbeing of 0–24 year olds. We included rigorously evaluated health programmes that met the Interagency Gender Working Group definition of gender-transformative programming, regardless of where in the world they were implemented and what area of health they focused on.FindingsAmong 22 993 articles identified by our search, 61 evaluations of 59 programmes met review criteria. Programmes were concentrated in sub-Saharan Africa (25 [42%]), south Asia (13 [22%]), and North America (13 [22%]) and mainly measured health indicators related to reproductive health (29 [48%]), violence (26 [43%]), or HIV (18 [30%]). Programmes most frequently focused on improving the individual power of the beneficiaries, rather than working on broader systems of inequality. 45 (74%) of the evaluations measured significant improvements in health-related and gender-related indicators; however, only ten (16%) showed evidence of, or potential for, broader norm change. These ten programmes worked with sectors beyond health, included multiple stakeholders, implemented diversified strategies, and fostered critical awareness and participation among affected community members.InterpretationThis review can accelerate efforts to improve global health by leading to more strategic investment in programmes that promote gender equality and target restrictive gender norms among young people. Such programmes can lead to a lifetime of improved health and wellbeing by challenging not only attitudes and behaviours related to gender at an early age, but also the gendered systems that surround them.FundingBill & Melinda Gates Foundation.
A bioceramic scaffold composed of strontium-doped three-dimensional hydroxyapatite whiskers for enhanced bone regeneration in osteoporotic defects
Authors: Rui Zhao, Siyu Chen, Wanlu Zhao, Long Yang, Bo Yuan, Voicu Stefan Ioan, Antoniac Vasile Iulian, Xiao Yang, Xiangdong Zhu, Xingdong Zhang
Journal: Theranostics (2020)

Reconstruction of osteoporotic bone defects is a clinical problem that continues to inspire the design of new materials.
Diagnosis and Management of Heavy Menstrual Bleeding and Bleeding Disorders in Adolescents
Authors: Claudia Borzutzky, Julie Jaffray
Journal: JAMA Pediatrics (2019)

<h3>Importance</h3> Heavy menstrual bleeding is a common cause of anemia and reduced quality of life in adolescents. There is a higher prevalence of bleeding disorders in girls with heavy menstrual bleeding than in the general population. Pediatricians should be comfortable with the initial evaluation of heavy menstrual bleeding and the indications for referral to subspecialty care. <h3>Observations</h3> The most common cause of heavy menstrual bleeding in adolescents is ovulatory dysfunction, followed by coagulopathies. The most common inherited bleeding disorder is von Willebrand disease, and its incidence in adolescents with heavy menstrual bleeding is high. Distinguishing the etiology of heavy menstrual bleeding will guide treatment, which can include hemostatic medications, hormonal agents, or a combination of both. Among hormonal agents, the 52-mg levonogestrel intrauterine device has been shown to be superior in its effect on heavy menstrual bleeding and is safe and effective in adolescents with bleeding disorders. <h3>Conclusions and Relevance</h3> Anemia, need for transfusion of blood products, and hospitalization may be avoided with prompt recognition, diagnosis, and treatment of heavy menstrual bleeding, especially when in the setting of bleeding disorders. Safe and effective treatment methods are available and can greatly improve quality of life for affected adolescents. A multidisciplinary approach to the treatment of girls with bleeding disorders and history of heavy menstrual bleeding is optimal.
Epigenetic Targeting of <i>TERT</i>-Associated Gene Expression Signature in Human Neuroblastoma with <i>TERT</i> Overexpression
Authors: Min Huang, Jasmine Zeki, Nathan Sumarsono, Garry L. Coles, Jordan S. Taylor, Enrico Danzer, Matias Bruzoni, Florette K. Hazard, Norman J. Lacayo, Kathleen M. Sakamoto, James C.Y. Dunn, Sheri L. Spunt, Bill Chiu
Journal: Cancer Research (2020)

Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-sequencing data from 498 patients with neuroblastoma and revealed a differentially overexpressed gene signature in MYCN nonamplified neuroblastomas with telomerase reverse transcriptase (TERT) gene overexpression and coordinated activation of oncogenic signaling pathways, including E2Fs, Wnt, Myc, and the DNA repair pathway. Promoter rearrangement of the TERT gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis in neuroblastoma, but TERT-associated oncogenic signaling remains unclear. ChIP-seq analysis of the human CLB-GA neuroblastoma cells harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. Brd4 and cyclin-dependent kinases (CDK) had critical regulatory roles in the expression and chromatin activation of TERT and multiple TERT-associated genes. Epigenetically targeting Brd4 or CDKs with their respective inhibitors suppressed the expression of TERT and multiple TERT-associated genes in neuroblastoma with TERT overexpression or MYCN amplification. ChIP-seq and ChIP-qPCR provided evidence that the CDK inhibitor directly inhibited Brd4 recruitment to activate chromatin globally. Therefore, inhibiting Brd4 and CDK concurrently with AZD5153 and dinaciclib would be most effective in tumor growth suppression, which we demonstrated in neuroblastoma cell lines, primary human cells, and xenografts. In summary, we describe a unique mechanism in neuroblastoma with TERT overexpression and an epigenetically targeted novel therapeutic strategy. SIGNIFICANCE: Epigenetically cotargeting Brd4 and Cdks suppresses human neuroblastoma with TERT overexpression by inhibiting the TERT-associated gene expression networks.
Traditional, Not the Usual: On Misrepresenting Acute Respiratory Distress Syndrome Network Lower Tidal Volume Trial (ARMA)
Authors: Peter Shiu-Hwa Tsu
Journal: The American Journal of Bioethics (2020)

Macklin and Natanson (2020) maintain that in recent “comparative effectiveness” research, where the “usual care” is compared with alternative treatments for effectiveness, the “usual care” (i.e., “...