tbuckley/cabot-search huggingface dataset:
Pooled RCTs: Early goal-directed therapy does not reduce mortality more than usual care in early septic shock
Authors: Brian M. Fuller, Christopher R. Carpenter
Journal: Annals of Internal Medicine (2017)

ACP Journal Club18 July 2017Pooled RCTs: Early goal-directed therapy does not reduce mortality more than usual care in early septic shockBrian M. Fuller, MD, MSCI, Christopher R. Carpenter, MD, MScBrian M. Fuller, MD, MSCIWashington University in St. Louis, St. Louis, Missouri, USA (B.M.F., C.R.C.)Search for more papers by this author, Christopher R. Carpenter, MD, MScWashington University in St. Louis, St. Louis, Missouri, USA (B.M.F., C.R.C.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2017-167-2-006 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationThe PRISM Investigators. Early, goal-directed therapy for septic shock—a patient-level meta-analysis. N Engl J Med. 2017 Mar 21. [Epub ahead of print]. https://pubmed.ncbi.nlm.nih.gov/28320242Clinical Impact RatingsEmergency Med: Infectious Disease: Critical Care: References1 Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-77. [PMID: 11794169] Google Scholar2 The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370:1683-93. [PMID: 24635773] Google Scholar3 The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371:1496-506. [PMID: 25272316] Google Scholar4 Mouncey PR, Osborn TM, Power GS, et al; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372:1301-11. [PMID: 25776532] Google Scholar5 Nguyen HB, Jaehne AK, Jayaprakash N, et al. Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. Crit Care. 2016;20:160. [PMID: 27364620] Google Scholar6 Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a “trial effect”. J Clin Epidemiol. 2001;54:217-24. [PMID: 11223318] Google Scholar Author, Article, and Disclosure InformationAffiliations: Washington University in St. Louis, St. Louis, Missouri, USA (B.M.F., C.R.C.)This article was published at Annals.org on 4 July 2017. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 18 July 2017Volume 167, Issue 2Page: JC6KeywordsAntibioticsEmergency departmentMortalityObservational studiesPatientsResearch assessmentResuscitationSepsisShockVasopressors ePublished: 18 July 2017 Issue Published: 18 July 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Androgen receptor activation in HER2-negative breast cancer liver metastases.
Authors: Corinne Ramos, Mariaelena Pierobon, Nicholas N Hoke, Lance A. Liotta, Ahmad Abdelfattah Al-Hader, Maren K Levin, Bryant Dunetz, Emanuel Petricoin, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2016)

11527 Background: The androgen receptor (AR) is expressed in the majority of breast cancers (BC) and its signaling may contribute to the development of BC metastases. The expression pattern of AR, its phosphorylated (p) form, and correlations with other BC growth and survival pathways was evaluated by protein pathway activation mapping in primary and metastatic (met) BC tissues. Methods: Group 1: 72 human BC primary and metastatic tissues underwent phosphoproteomic analysis using the TheraLink Assay, a reverse phase protein array (RPPA)-based method at a CLIA-certified laboratory (Theranostics Health). Immunostaining with 24 antibodies was directed against AR, pAR, pMet, and total and pHER1/2/3 pathway proteins. Spearman correlation was performed. Group 2: 25 met BC tissues from the SideOut Foundation-sponsored clinical trial (#NCT01919749) were analyzed by RPPA at GMU. Results: Group 1: 34 were primary BCs (55%); 38 were mets (45%). Sites of mets: liver (n = 24); lung (n = 7); chest wall (n = 7). AR expression was increased in chest wall (1.7-fold) and liver (1.3-fold) compared to primary BCs. pAR was increased in liver (2.3-fold) and chest wall (1.8-fold) compared to primary BCs. Liver mets showed a negative correlation between pAR and HER2 (p = 0.014), pAR and pHER2 (p = 0.001), and pAR and pmTOR (p = 0.046); this was observed in the 17 liver mets that were HER2–. A strong positive correlation was seen in these HER2– liver mets between total AR and pAKT (p = 0.012), pAR and p4EBP1 (p = 0.029), pAR and pMek1/2 (p = 0.006), pAR and pMet (p = 0.005), and pMet and pHER3 (p = 0.071). Group 2: Sites of mets: liver (n = 10), skin/chest wall (n = 7), lymph node (n = 3), intra-abdominal masses (n = 3), lung (n = 2). High expression levels of pAR were seen in 4/10 (40%) of the liver mets whereas 2/15 (13%) of the other mets had any measurable pAR. Conclusions: 2 independent sets of HER2 metBC tissues showed strong liver-specific activation of AR along with activation of cMet/HER3 signaling. These results suggest a possible role of AR in the growth of HER2 liver mets. Clinical trials inhibiting AR as well as HER3 or cMet kinase activity in patients with liver mets would be of interest.
Abstract 4: Porcine Parthenotes as a Model to Evaluate Developmental Potential of Human Inducible Pluripotent Stem Cells
Authors: Naoko Koyano-Nakagawa, James Dutton, Mary G Garry, Daniel J Garry
Journal: Circulation Research (2015)

The use of human induced pluripotent stem cells (hiPSCs) has tremendous potential for regenerative medicine by providing an unlimited source of personalized cells. A number of protocols have been established for efficient differentiation of hiPSCs to the desired lineage in vitro, such as cardiomyocytes and blood. However, the field lacks an in vivo system to evaluate the differentiation potential and quality of hiPSCs. Developmental potential of stem cells derived from experimental animals can be readily assessed by generating blastocyst chimeras and examination of the contribution to the embryos, or by the potential of teratoma formation. However, this is not possible in the case of humans. As a potential solution for this issue, we examined whether porcine parthenotes could be used as an experimental model to test the developmental potential of the hiPSCs. Parthenotes are generated by electrical activation of the oocytes collected at the abattoir and will develop up to gestational day 53 if transferred to a pseudo-pregnant sow. The embryonic culture conditions have also been established and the zygotes can develop normally to the expanded blastocyst stage (day 7 post fertilization/activation), in vitro. We took advantage of this in vitro system and examined the ability of hiPSCs to proliferate and integrate into the parthenogenetic embryos. Parthenogenetic embryos were injected with ten undifferentiated hiPSCs at day 4 (8 cell ~ morula stage) and cultured up to 72 hours. During this period, parthenotes underwent blastocoel cavity formation and hatching. Cell tracing experiments demonstrated that hiPSCs proliferated and integrated into the parthenotes. They retained pluripotency marker expression during this period. hiPSCs and their derivatives were found both in trophoectoderm and embryo proper. We further observed that the hiPSCs underwent cellular proliferation and promoted developmental progression of the parthenote in vitro. In summary, the porcine parthenote model system is an efficient high throughput system to examine the developmental capacity of human stem cell populations.
Telemedicine for management of inflammatory bowel disease (myIBDcoach): a pragmatic, multicentre, randomised controlled trial
Authors: Marin J de Jong, Andrea E van der Meulen-de Jong, Mariëlle J Romberg-Camps, Marco C Becx, Jeroen P Maljaars, Mia Cilissen, Ad A van Bodegraven, Nofel Mahmmod, Tineke Markus, Wim M Hameeteman, Gerard Dijkstra, Ad A Masclee, Annelies Boonen, Bjorn Winkens, Astrid van Tubergen, Daisy M Jonkers, Marie J Pierik
Journal: The Lancet (2017)
Novel tyrosine kinase inhibitor therapy (NTKI) prior to allogeneic stem cell transplantation (ASCT) in patients (pts) with chronic myeloid leukemia (CML): No evidence for increased transplant-related toxicity
Authors: M. J. De Lima, E. Jabbour, J. E. Cortes, H. Kantarjian, S. Giralt, B. S. Andersson, R. E. Champlin
Journal: Journal of Clinical Oncology (2006)

16515 Background: Patients undergoing ASCT for CML are increasingly likely to have received a NTKI after failing imatinib mesylate. It is unknown whether the use of these NTKIs prior to ASCT increases transplant-related toxicity. Methods: We retrospectively analyzed the outcome of 8 patients with CML (1 chronic, 4 accelerated, and 3 in blastic) who received dasatinib (n = 2) or AMN-107 (n = 6) prior to ASCT. Results: The median time on treatment was 85 days, and the median time from the end of NTKI therapy to HSCT was 37 days. Preparative regimen was ablative in 5 patients and non-ablative in 3. All patients engrafted within 13 days. There was no significant early transplant-related toxicity. Five patients achieved a molecular response after a median follow-up of 8 months; three complete and two major (Q-PCR &lt; 0.05%). Three patients relapsed within 3 months. Two patients died of disease progression, and extensive GVHD, respectively. Conclusions: Previous treatment with NTKI did not increase transplant-related toxicity in this preliminary experience. Further follow-up and larger number of patients will be necessary to confirm these observations. No significant financial relationships to disclose.
Abstract #SY14-2: What can we learn about self renewal and drug resistance from the isolation of epithelial tumor stem cells?
Authors: Michael Clarke
Journal: Cancer Research (2009)

Most common cancers, such as cancers of the breast and colon, arise in organs such as the breast that contain a small population of stem cells that constantly replenish the mature cells of the tissue. Stem cells are defined by the ability to divide and give rise to a new stem cell (self-renewal), as well as the ability to give rise to the differentiated cells of an organ, and thus are the only long-lived cell population in many tissues[1]. Epithelial tumors consist of a heterogeneous population of cancer cells that differ in their apparent state of differentiation, suggesting that solid tumors might represent aberrant organs containing a cancer stem cell population that maintains the ability to self-renew. Indeed, using a xenograft model of human breast, colon and head and neck cancers, a phenotypically-distinct subset of the cancer cells (cancer stem cells) has been found to have the exclusive ability to form tumors[2-4]. The remaining cancer cells, which often form the bulk of the tumor, are unable to self-renew or sustain tumorigenesis. Recently, it has become apparent that some oncogenes and tumor suppressor genes also regulate self-renewal, the process by which both normal and malignant stem cells maintain themselves. The process of self-renewal is de-regulated in cancer stem cells resulting in tumor formation. Extensive molecular and cellular analyses of normal and malignant mouse and human breast, head and neck, and colon stem cells will be discussed[5, 6]. These analyses have revealed new pathways that regulate self renewal as well as resistance to cytotoxic therapies in normal and cancer stem cells. 1.%9Akala, O.O. and M.F. Clarke, Hematopoietic stem cell self-renewal. Curr Opin Genet Dev, 2006. 16(5): p. 496-501. 2.%9Al-Hajj, M., et al., Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A, 2003. 100(7): p. 3983-8. 3.%9Prince, M.E., et al., Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A, 2007. 104(3): p. 973-8. 4.%9Dalerba, P., et al., Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A, 2007. 104(24): p. 10158-63. 5.%9Cho, R.W., et al., Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-Wnt-1 Murine Breast Tumors. Stem Cells, 2007. 6.%9Liu, R., et al., The Prognostic Role of a Gene Signature from Tumorigenic Breast-Cancer Cells. N Engl J Med, 2007. 356(3): p. 217-226.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr SY14-2.
Assessment of progress towards universal health coverage for people with disabilities in Afghanistan: a multilevel analysis of repeated cross-sectional surveys
Authors: Jean-Francois Trani, Praveen Kumar, Ellis Ballard, Tarani Chandola
Journal: The Lancet Global Health (2017)

Since 2002, Afghanistan has made much effort to achieve universal health coverage. According to the UN Sustainable Development Goal 3, target eight, the provision of quality care to all must include usually underserved groups, including people with disabilities. We investigated whether a decade of international investment in the Afghan health system has brought quality health care to this group.We used data from two representative household surveys, one done in 2005 and one in 2013, in 13 provinces of Afghanistan, that included questions about activity limitations and functioning difficulties, socioeconomic factors, perceived availability of health care, and experience with coverage of health-care needs. We used multilevel modelling and tests for interaction to investigate factors associated with differences in perception between timepoints and whether village remoteness affected changes in perception.The 2005 survey included 334 people, and the 2013 survey included 961 people. Mean age, employment, and asset levels of participants with disabilities increased slightly between 2005 and 2013, but the level of education decreased. Formal education and higher asset level were associated with improved availability of health care and positive experience with coverage of health-care needs, whereas being employed was only associated with the latter. Perceived availability of health care and positive experience with coverage of health-care needs significantly worsened in 2013 compared with in 2005 (227 [69%] perceived that services were available in 2005 vs 405 [44%] in 2013, p<0·0001; 255 [78%] perceived a positive experience in 2005 vs 410 [45%] in 2013, p<0·0001). Village remoteness increased in 2013 (no connectivity by paved road 186 [57%] in 2005 vs 797 [87%] in 2013, p<0·0001; mean time to reach health-care facility 64·3 min [SD 167·7] vs 84·4 min [107·7], p<0·0001) and negatively affected perception of health-care availability.Perceived availability of health care and experience with health-care coverage have not greatly improved for people with disabilities in Afghanistan, particularly in remote areas. Health policy in Afghanistan will need to address attitudinal, social, and accessibility barriers to health care.Swedish International Development Agency.
Long-term treatment of refractory severe chronic urticaria by omalizumab: analysis of two cases
Authors: Maddalena Vacca, Irene Fiorino, Filomena Loconte, Anna Simona Rucco, Andrea Nico, Elisabetta Damiani, Eustachio Nettis, Maria Filomena Caiaffa, Luigi Macchia
Journal: Allergy (2014)
DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8
Authors: Chunyuan Guo, Lirong Pei, Xiao Xiao, Qingqing Wei, Jian-Kang Chen, Han-Fei Ding, Shuang Huang, Guoping Fan, Huidong Shi, Zheng Dong
Journal: Kidney International (2017)
Effects of risk-reducing surgery on libido, self-image, and psychological status among <i>BRCA</i> mutation carriers.
Authors: Olga Ivanov, Aileen Caceres, Cynthia Buffington, Karen Wiercinski, Nicole Centers
Journal: Journal of Clinical Oncology (2016)

1505 Background: BRCA mutation carriers often have risk-reducing surgery (mastectomy, bilateral salpingo-oophorectomy; BSO, hysterectomy) for prevention and treatment of breast and ovarian cancer. These surgeries may have an adverse effect on sexuality, contributing to a loss of libido, reduction in sexual activity, and a poor self-image. In this study we have: surveyed a large population of BRCA mutation carriers to examine the effects of risk-reducing surgery on sexuality and libido and studied, in a subpopulation, contributors to impaired sexual inactivity and associated effects on psychological status. Methods: The study population included 763 BRCA1 or 2 mutation carriers (53% previvors, 48% cancer survivors) who completed an online survey and a smaller subset of BRCA positive patients (n=122 + 26 non-BRCA controls) who participated in a lifestyle study that examined sexual activity, causes for reduced sexuality, and psychosocial status (Beck Anxiety Index, RAND-36 Quality of Life). Results: According to survey findings, the percentage of BRCA mutation carriers having had a mastectomy, a BSO, or hysterectomy was a respective 60%, 59%, and 41% for previvors and a respective 87%, 77% and 62% for survivors. Among those BRCA positive patients having risk-reducing surgery, 72% reported a problem with sexuality and libido and 79% considered low libido to be a major concern. In the subset population, 33% of previvors and 44% of survivors were sexually inactive, in comparison to only 12.5% of the non-BRCA mutation controls. Causes for sexual inactivity included poor body image (48%), vaginal dryness (46%), reduced desire (63%), and a change in relationships (17%). Individuals who were sexually inactive, as compared to those who were active, had significantly (p<0.05) greater anxiety and lower (p<0.0001) emotional and physical quality of life inactivity. Conclusions: The majority of BRCA mutation carriers undergo risk-reducing surgery for prevention of cancer occurrence/recurrence which contributes significantly to a loss of libido. Reduced sexual activity among BRCA positive survivors occurs in association with low libido, poor self-image and a deterioration of psychological status.
Mechanical Thrombectomy After Intravenous Thrombolysis vs Mechanical Thrombectomy Alone in Acute Stroke
Authors: Pierre Seners, Catherine Oppenheim, Jean-Claude Baron
Journal: JAMA Neurology (2017)

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Drug policy isn’t working, medical leaders and lawmakers agree
Authors: Richard Hurley
Journal: BMJ (2017)

UK policy is failing to prioritise the health of people who use drugs, medical and political leaders agreed at a dinner at the House of Commons on 11 July. Diners heard that the public’s respect for doctors, and their authority, made them ideal advocates to lead calls for reform on behalf of vulnerable drug users.

The four organisations that hosted the dinner— The BMJ , the BMA, the Royal Society for Public Health, and the Royal College of Physicians’ Faculty of Public Health—have all stated recently that criminal punishment for drug users had not prevented drug taking but instead encouraged stigma, driving vulnerable patients away from treatment.

In the week that saw the government publish its strategy for dealing with use of drugs such as cannabis, cocaine, and heroin,1 the dinner, sponsored by Ronnie Cowan, the …
Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study
Authors: Khurum Khan, Mihaela Rata, David Cunningham, Dow-Mu Koh, Nina Tunariu, Jens C Hahne, George Vlachogiannis, Somaieh Hedayat, Silvia Marchetti, Andrea Lampis, Mahnaz Darvish Damavandi, Hazel Lote, Isma Rana, Anja Williams, Suzanne A Eccles, Elisa Fontana, David Collins, Zakaria Eltahir, Sheela Rao, David Watkins, Naureen Starling, Jan Thomas, Eleftheria Kalaitzaki, Nicos Fotiadis, Ruwaida Begum, Maria Bali, Massimo Rugge, Eleanor Temple, Matteo Fassan, Ian Chau, Chiara Braconi, Nicola Valeri
Journal: Gut (2017)

Objective Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. Design Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (K trans ), enhancing fraction (EF) and their product KEF (summarised median values of K trans × EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. Results Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, &gt;70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06). Conclusions Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.