tbuckley/cabot-search huggingface dataset:
Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges
Authors: Hernandez Moura Silva, André Báfica, Gabriela Flavia Rodrigues-Luiz, Jingyi Chi, Patricia d’Emery Alves Santos, Bernardo S. Reis, David P. Hoytema van Konijnenburg, Audrey Crane, Raquel Duque Nascimento Arifa, Patricia Martin, Daniel Augusto G.B. Mendes, Daniel Santos Mansur, Victor J. Torres, Ken Cadwell, Paul Cohen, Daniel Mucida, Juan J. Lafaille
Journal: The Journal of Experimental Medicine (2019)

Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monocyte-derived CD11c+CD64+ double-positive (DP) macrophage eWAT population with a predominant anti-inflammatory/detoxifying gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that ATM populations dynamically adapt to metabolic stress and inflammation, suggesting an important role for these cells in maintaining tissue homeostasis.
Effect of the ERα agonist, GTx-758 (250 mg daily), on total and free testosterone, and PSA, in men with castration resistant prostate cancer (CRPC) maintained on LHRH therapy.
Authors: Evan Y. Yu, Michael L. Hancock, Tamas Babicz, William J. Aronson, Zsuzsanna Papai, Lajos Geczi, Robert H. Getzenberg
Journal: Journal of Clinical Oncology (2015)

e16020 Background: LHRH agents used for androgen deprivation therapy (ADT) were intended to lower total testosterone (T) levels to those achieved by orchiectomy. Studies have now demonstrated that a significant percentage of men do not reach orchiectomy equivalent levels and that lower serum T levels correlate with improved outcomes. GTx-758 (Capesaris) is an oral estrogen receptor α agonist that has the potential to increase sex hormone binding globulin (SHBG), lower T levels, and ameliorate estrogen deficiency side effects associated with ADT. Methods: In an ongoing Phase 2 open label study (G200712, NCT01615120), men with high risk nmCRPC and mCRPC were continued on their current form of ADT along with either 125 mg or 250 mg of GTx-758 daily, for at least 90 days. The primary endpoint of this trial is the proportion of men with a PSA decline ≥ 50%, while secondary endpoints include serum total and free T, SHBG, bone turnover and hot flashes. Results: As of February 2015, the 250 mg cohort of GTx-758 has completed enrollment of 33 patients, 25 of which (1 nmCRPC and 24 mCRPC) are evaluable, having been on study ≥ 90 days. 250 mg GTx-758 impacts T levels in an additive fashion to LHRH agents, as while on study, 3/3 subjects with total T levels > 20 ng/dL have fallen below that level and 11/13 subjects with serum free T levels > 0.7 pg/ml have fallen below that level. The median serum free T level on day 1 is 1.20 ± 1.71 pg/ml whereas at day 90, the level is 0.40 ± 0.49 pg/ml, a 58% decrease from baseline (p < .0001). A major mechanism of drug action, induction of SHBG is confirmed in these subjects, with median SHBG levels increasing to 268% of baseline. Seven of the 25 (28%) subjects have exhibited a ≥ 50% decrease in PSA levels while 11/25 (44%) had PSA declines of ≥ 30%. 250 mg of GTx-758 has been well tolerated with one reported possibly drug related SAE (VTE). Conclusions: While the Phase 2 clinical trial is ongoing, these preliminary findings indicate that 250 mg of GTx-758 is generally well tolerated and has activity in men with CRPC on LHRH agents to further decrease total and free T, increase SHBG, and lower PSA. Clinical trial information: NCT01615120.
Changes in quality of care and perinatal outcomes after implementation of perinatal death audit in Uganda, 2008–15: a prospective study
Authors: Victoria Nakibuuka, M Aminu, J Dewez, R Byaruhanga, P Okong, Nnyke Renke van den Broek
Journal: The Lancet Global Health (2019)

BackgroundEvery year, an estimated 2·7 million neonatal deaths and stillbirths occur worldwide. Neonatal mortality in Uganda has been 27 deaths per 1000 births between 2008 and 2018, despite an increase in the rate of institutional deliveries from 59% to 74% over this time. Suboptimal care still occurs in hospitals, resulting in maternal and neonatal morbidity. Globally, perinatal death audit has been shown to reduce perinatal mortality by 30%. However, there is paucity of data on the effect of audit on perinatal outcomes in Uganda. Here, we describe perinatal outcomes after introduction of perinatal death audit in a tertiary hospital in Kampala, Uganda.MethodsWe undertook a prospective review of deaths between January, 2008, and December, 2015. Cause of death was identified through consensus between midwives, intern doctors, postgraduates, paediatricians, and neonatologists. We assessed standard of care against existing guidelines. We used data on outcomes from January, 2006, to December, 2007, for comparison and recorded changes to clinical practice that were implemented in response to cause-of-death data.FindingsA total of 58 997 births and 2616 perinatal deaths occured between 2008 and 2015. Of these, 603 [23%] perinatal deaths were selected for audit. Perinatal mortality decreased from 48·4 deaths per 1000 births before the intervention to 43 per 1000 births in 2015; stillbirths decreased from 32·9 per 1000 births to 22 per 1000 births. The proportion of neonatal deaths reduced from 11·2% to 4·9%. The most common causes of death in the study period were: hypoxia (186, 35·4%) and unknown (227, 43·2%). Interventions included: neonatal resuscitation training; building of a new maternity theatre; partograph training; increased human resource for maternity and the newborn care unit; and provision of equipment such as ambubags, bubble continuous positive air way pressure (CPAP) machines, and radiant warmers. Skills introduced included: kangaroo mother care; and use of antenatal steroids, CPAP, surfactant, and phototherapy. Case fatality rates decreased for hypoxia (21·1% to 15·5%) and complications of prematurity (26·4% to 11·1%) but increased for infections (1·9% to 5·7%).InterpretationPerinatal death audits are feasible in Uganda. Furthermore, the data from audits can inform decisions about new training and interventions and might lead to improved perinatal outcomes.FundingNone.
In adults in the emergency department with nausea, neither droperidol nor ondansetron improved symptoms
Authors: Christopher Sampson
Journal: Annals of Internal Medicine (2019)

Source Citation Meek R, Mee MJ, Egerton-Warburton D, et al. Randomized placebo-controlled trial of droperidol and ondansetron for adult emergency department patients with nausea. Acad Emerg Med. 2018. [Epub ahead of print.] 30368981
Pembrolizumab in Combination with Standard RCHOP Therapy for Previously Untreated Diffuse Large B-Cell Lymphoma
Authors: Stephen D. Smith, Ryan C. Lynch, Brian G. Till, Andrew J. Cowan, Qian V. Wu, Jenna M. Voutsinas, Mazyar Shadman, Katie Blue, Andrei R. Shustov, Sandra Kanan, Lauren Low, Ryan D. Cassaday, Jonathan R. Fromm, Ajay K. Gopal
Journal: Blood (2018)
Genomic analysis of circulating cell-free DNA (cfDNA) to investigate mechanisms of primary and acquired resistance to enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Arun Azad, Alexander Wyatt, Stanislav Volik, Anne Haegert, Fan Mo, Stephane Le Bihan, Robert H Bell, Shawn A Anderson, Brian McConeghy, Robert Shukin, Martin Edwin Gleave, Colin Collins, Kim N. Chi
Journal: Journal of Clinical Oncology (2015)

5015 Background: ENZ is a potent androgen receptor (AR) antagonist that prolongs survival in mCRPC patients (pts). However, factors driving resistance to ENZ are incompletely understood. Genomic analysis of cfDNA is a promising, minimally invasive approach for interrogating mechanisms of therapeutic resistance in mCRPC. Methods: Baseline plasma samples were collected from 57 mCRPC pts commencing ENZ. In 37 pts, additional samples at 12-weeks +/- end-of-treatment were obtained. DNA was extracted and subjected to array Comparative Genomic Hybridization (aCGH) for chromosome copy number (CN) analysis and AR gene (exon 2-8) sequencing (MiSeq) for mutation analysis. Endpoints were i) PSA50 or PSA30 response rates (RR) (PSA decline ≥ 50% or 30% for ≥ 3 weeks); and ii) radiographic/clinical progression-free survival (PFS). Results: On aCGH, the most frequent CN changes in baseline samples (n = 57) were 8p loss (25%), 8q gain (35%), MYC gain (26%) and AR gain/amp (33%). Compared to pts with no AR gain/amp, pts with pre-treatment AR gain/amp had lower PSA50 (39% vs. 21%, P= 0.16; Χ2) and PSA30 RR (44% vs. 25%, P= 0.059; Χ2) and shorter median PFS (4.5 vs. 2.2 months, P= 0.002; log-rank). On multivariate analysis, pre-treatment AR gain/amp (HR 2.56 P= 0.01) was confirmed as an independent prognostic factor for PFS. In pts with 12-week +/- end-of-treatment samples, 14% (5/37) had a change in AR CN status from baseline with 3 pts converting from no AR gain to AR gain and 2 pts from AR gain to AR amp. Median PFS in these 5 pts was 2.8 months. AR gene sequencing was performed on a subset of 4 pts with 4 high-frequency mutations detected in 3 pts including H874Y (n = 2) and L702H (n = 2), the latter of which converts glucocorticoids to AR agonists. Notably, both L702H mutations were found in end-of-treatment samples from pts who progressed rapidly on ENZ (2.9 months PFS each). Neither of these pts was on glucocorticoids at progression, potentially implicating L702H in ENZ resistance. Conclusions: Our data indicate that AR gene aberrations may be key biomarkers of primary and acquired resistance to ENZ in mCRPC. Complete AR gene sequencing data will be presented.
Micro-Optical Coherence Tomography for Endothelial Cell Visualization in the Coronary Arteries
Authors: Kensuke Nishimiya, Biwei Yin, Zhonglie Piao, Jiheun Ryu, Hany Osman, Hui Min Leung, Gargi Sharma, Chia Pin Liang, Joseph A. Gardecki, Hui Zheng, Hiroaki Shimokawa, Guillermo J. Tearney
Journal: JACC. Cardiovascular imaging (2019)
Abstract 18725: Predictors of Adverse Outcomes in Peripartum Cardiomyopathy
Authors: Andrew Peters, Malka Caroline, Huaqing Zhao, Emily Tsai
Journal: Circulation (2015)

Introduction: Peripartum cardiomyopathy (PPCM) is a devastating condition leading to heart failure (HF) in the final trimester of pregnancy or within five months postpartum. Nearly half of women with PPCM suffer chronic HF, and some progress towards advanced HF requiring cardiac transplantation. While risk factors for developing PPCM have been identified, predictors of poor long-term outcome are not well defined. Hypothesis: We believe that right heart failure may predict adverse outcomes in PPCM. Methods: We performed a single-center retrospective cohort study of patients with at least one pregnancy and live birth and diagnosis of PPCM between 1994 and 2014. The primary outcome was a lack of improvement in LVEF and NYHA, and the secondary outcome was cardiac transplantation within 5 years. We used univariate logistic regression to assess associations between these outcomes and various clinical and echocardiographic characteristics at the time of PPCM diagnosis. Results: Of the 57 subjects who met inclusion criteria, 19 (33%) showed no improvement in NYHA class and LVEF and 10 (18%) underwent cardiac transplantation. Median (IQR) follow-up period was 4.9 (2.9-5.8) years; 2-year mortality was 4%. Diabetes was associated with no improvement in LVEF and NYHA (OR 5.0 [95% CI 1.3 to 19.7]). LVEF &lt;30% at diagnosis was associated with no improvement in LVEF and NYHA class (OR 22.5 [95% CI 2.6 to 194]). LV internal diameter at end-diastole (LVIDd) ≥56mm was associated with no improvement in LVEF and NYHA class (OR 11.1 [95% CI 1.2 to 99]). Every 1 mm increase in LVIDd above 50 mm was associated with 22% greater odds of no improvement in LVEF and NYHA class (OR 1.22 [95% CI 1.07 to 1.38]). RV dysfunction was associated with lack of improvement in LVEF and NYHA class (OR 10.5 [95% CI 2.0 to 54]). Moderate to severe RV dysfunction was associated with cardiac transplantation (OR 4.38 [95% CI 1.0 to 19.3]). Conclusions: Diabetes is associated with chronic heart failure in PPCM. PPCM patients at risk for adverse long-term outcomes, including cardiac transplantation, may be identified by LVEF &lt;30%, LVIDd≥56mm, and RV dysfunction at time of diagnosis. Such high-risk PPCM patients could benefit from early referral to advanced heart failure specialty programs.
Evaluation of therapeutic efficiency about the combination therapy of rAd-p53 with chemotherapy for the treatment of recurrent uterine sarcomas.
Authors: Xia Yu, Xinyan Wang, Xiuqin Li
Journal: Journal of Clinical Oncology (2015)

e16528 Background: In spite of the early stage of Sarcoma, 80% of them will be local recurrence and distant metastasis. Because of the non-sensitivity to neither radiotherapy nor chemotherapy, the ratio of satisfactory tumor resection is less than 10%. Five-year survival rate is less than 30%. So, the oncologists should pay more attention to improve the survival of these patients. Methods: Retrospective analysis of 21 patients with recurrent uterine sarcomas treated in our hospital was studied. These patients were divided into two groups based on the treatment protocols, rAd-p53 combined with chemotherapy vs. chemotherapy only. In combination therapy group, rAd-p53 was intratumorally injected. After 72 hours, bleomycin 30 mg was also intratumorally injected. At the same time, cisplatin, ifosfamide and epirubicin were used intravenously. The above combination therapy was repeated 21 days later. In control group, the same chemotherapy was used only. After 2-3 courses of treatment, the total response rate (CR+PR), efficacy rate (CR+PR+SD) and progress-free survival rate (PFS) were evaluated by RESIST 1.1 system. Results: The total response rate and efficacy rate in combination group were 63.6% and 91.0%, whereas these two data were 10% and 20% (P＜0.05) respectively in control group. The PFS in combination group is 13.48 months which is 4.4 month longer than that in control group (P＜0.05). Three patients who could not accept operation because of the huge volume of tumor or the pelvic viscera extensive adhesion in combination group achieved complete remission (CR) with surgery after the combination therapy. Conclusions: This study proved that the therapeutic effect of rAd-p53 combined with chemotherapy in treatment of recurrent uterine sarcomas is much better than chemotherapy alone. The combined therapy can slow down the disease progression. It can also be a means of preoperative neo-adjuvant therapy for those patients with huge tumor recurrence and create the opportunity of surgery for patients with recurrent uterine sarcomas.
Clinical outcome with concurrent or layered treatment with radium-223 and abiraterone: A retrospective study of real-world experience with patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Daniel J. George, Cora N. Sternberg, A. Oliver Sartor, Fred Saad, Bertrand F. TOMBAL, Kurt Miller, Jan Kalinovsky, XiaoLong Jiao, Krishna Tangirala, Celestia S. Higano
Journal: Journal of Clinical Oncology (2019)

253 Background: Limited data exist on Ra-223 use in combination with Abi in a real-world setting. This retrospective study evaluated clinical outcomes in pts with mCRPC who received concurrent or layered Ra-223 + Abi treatment. Methods: This study used the Flatiron prostate cancer registry of electronic health records of pts with mCRPC treated with Ra-223 in US cancer clinics between 1/01/2013 and 6/30/2017. Two sub-cohorts were defined: pts treated with Ra-223 + Abi in a concurrent (both started within 30 days) or layered fashion (one of the two started over 30 days later). Descriptive analysis was done for baseline (BL) characteristics (prior to start of Ra-223), prior therapies, and clinical outcomes including skeletal-related events (SREs) and overall survival (OS). Results: 625 pts were treated with Ra-223; 136 (21.8%) received Ra-223 + Abi. Most received layered therapy (n = 97, 71%); concurrent start was less common (n = 39, 29%) [Table]. Conclusions: Prior to the start of Ra-223 therapy, half of the pts had prior SREs; almost one-fifth had prior pathologic fractures. Pts treated with Ra-223 + Abi had also received prior chemo and/or enzalutamide. SRE occurrence seems higher for concurrent treatment, but results should be cautiously interpreted due to low concurrent cohort size. OS in both cohorts exceeded the OS in the Phase III ALSYMPCA study (14.9 mo).[Table: see text]
Challenges in Research on Suicide Prevention
Authors: Jean Kim, Michael Davis, Tiffany Farchione
Journal: JAMA (2019)

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Impact of predictive medicine on therapeutic decision making: a randomized controlled trial in congenital heart disease
Authors: Huseyin Naci, Maximilian Salcher-Konrad, Alistair Mcguire, Felix Berger, Titus Kuehne, Leonid Goubergrits, Vivek Muthurangu, Ben Wilson, Marcus Kelm
Journal: npj Digital Medicine (2019)

Computational modelling has made significant progress towards clinical application in recent years. In addition to providing detailed diagnostic data, these methods have the potential to simulate patient-specific interventions and to predict their outcome. Our objective was to evaluate to which extent patient-specific modelling influences treatment decisions in coarctation of the aorta (CoA), a common congenital heart disease. We selected three cases with CoA, two of which had borderline indications for intervention according to current clinical guidelines. The third case was not indicated for intervention according to guidelines. For each case, we generated two separate datasets. First dataset included conventional diagnostic parameters (echocardiography and magnetic resonance imaging). In the second, we added modelled parameters (pressure fields). For the two cases with borderline indications for intervention, the second dataset also included pressure fields after virtual stenting simulations. All parameters were computed by modelling methods that were previously validated. In an online-administered, invitation-only survey, we randomized 178 paediatric cardiologists to view either conventional (control) or add-on modelling (experimental) datasets. Primary endpoint was the proportion of participants recommending different therapeutic options: (1) surgery or catheter lab (collectively, "intervention") or (2) no intervention (follow-up with or without medication). Availability of data from computational predictive modelling influenced therapeutic decision making in two of three cases. There was a statistically significant association between group assignment and the recommendation of an intervention for one borderline case and one non-borderline case: 94.3% vs. 72.2% (RR: 1.31, 95% CI: 1.14-1.50, p = 0.00) and 18.8% vs. 5.1% (RR: 3.09, 95% CI: 1.17-8.18, p = 0.01) of participants in the experimental and control groups respectively recommended an intervention. For the remaining case, there was no difference between the experimental and control group and the majority of participants recommended intervention. In sub-group analyses, findings were not affected by the experience level of participating cardiologists. Despite existing clinical guidelines, the therapy recommendations of the participating physicians were heterogeneous. Validated patient-specific computational modelling has the potential to influence treatment decisions. Future studies in broader areas are needed to evaluate whether differences in decisions result in improved outcomes (Trial Registration: NCT02700737).
Patient-reported Quality of Life Following Stereotactic Body Radiotherapy and Conventionally Fractionated External Beam Radiotherapy Compared with Active Surveillance Among Men with Localized Prostate Cancer
Authors: Dominic H. Moon, Ram S. Basak, Deborah S. Usinger, Gregg A. Dickerson, David E. Morris, Mark Perman, Maili Lim, Turner Wibbelsman, Jerry Chang, Zachary Crawford, James R. Broughman, Paul A. Godley, Ronald C. Chen
Journal: European Urology (2019)