tbuckley/cabot-search huggingface dataset:
Roll-out of first HIV pre-exposure prophylaxis services in the Democratic Republic of the Congo
Authors: Halli Olsen, William Reidy, Nadine Mushimbele, Richted Tenda, Serge Matumaini Kayembe, Guy Mukari, Tania Tchissambou, Felix Ndagije, Faustin Malele Bazola, Gaston Djomand, Trista Bingham, Jacob Dee, Elie Mukinda, Julie Franks
Journal: The Lancet Global Health (2019)

BackgroundIn the Democratic Republic of the Congo (DR Congo), HIV prevalence is highest in key populations, specifically female sex workers and men who have sex with men, with estimates of 7% and 18%, respectively, compared with 1·2% in the general population. Pre-exposure prophylaxis (PrEP) is an evidence-based intervention to reduce HIV incidence in populations who are at substantial risk of acquiring HIV. Building the capacity of clinics and outreach programmes serving key populations is a critical first step in scaling-up PrEP services. Here, we describe a programme from the DR Congo's National AIDS Control Programme, US Centers for Disease Control and Prevention (CDC), and ICAP at Columbia University to initiate 350 clients from key population on PrEP in 2018.MethodsWith support from the National AIDS Control Programme and CDC, ICAP facilitated PrEP implementation at seven HIV care and treatment facilities in DR Congo. Capacity-building activities included: guidance on national planning; establishment of a national PrEP technical working group; and the development of PrEP training material for multidisciplinary facility teams to provide and monitor PrEP services. Training addressed: PrEP eligibility screening, initiation, and follow-up; PrEP retention and follow-up activities; and monitoring and evaluation of PrEP services. ICAP also provided ongoing on-site mentorship of clinic staff, and continuous evaluation of clinic procedures to ensure standardised PrEP service delivery across all facilities.FindingsBy February, 2018, 38 clinical staff and 48 peer outreach workers had completed a 6-day PrEP training course using ICAP's PrEP training curriculum; participant and facilitator manuals; job aids; and monitoring, evaluation, and reporting tools. Following the training, four sites in Kinshasa and three sites in Lubumbashi initiated PrEP services for the first time, resulting in successful achievement of the national PrEP targets.InterpretationCollaboration between national and global stakeholders resulted in the successful introduction of PrEP in DR Congo. PrEP implementation required extensive clinic training, tailoring of existing outreach activities to improve PrEP retention, inclusion of peer workers to help educate patients about PrEP, comprehensive monitoring and evaluation reporting, and ongoing mentoring of clinic staff. Lessons learned in DR Congo will be shared with other programmes in African countries that work with populations at risk of HIV. Project findings will also support the endorsement of national PrEP guidelines and the scale-up of PrEP in DR Congo.FundingUS Centers for Disease Control and Prevention.
Preventing Preeclampsia by Silencing Soluble Flt-1?
Authors: Sarah A. Robertson
Journal: New England Journal of Medicine (2019)

Soluble Flt-1 (sFlt-1) is a known mediator of vascular events that cause preeclampsia. A recent study showed that suppressing the synthesis of sFlt-1 in mouse and baboon models of preeclampsia resulted in normalization of blood pressure, although the birth weights of baboon infants tended to be low.
Comparison of common pretransplant assessment scores: A single institution experience.
Authors: Hayder M. Saeed, Swati Yalamanchi, Meng Liu, Emily (Van Meter) Dressler, Syed Noman Haider, Zartash Gul, Gregory P. Monohan, Roger Herzig
Journal: Journal of Clinical Oncology (2015)

e18004 Background: With the most recent incorporation of age variable in the hematopoietic stem cell transplant comorbidity index (HSCT-CI/Age), we sought to evaluate its usefulness in comparison to pretransplant assessment of mortality (PAM) score in our patient population. Methods: We performed a retrospective analysis of adult patients who underwent allogeneic stem cell transplant in our institution 2010-2014. Clinicopathologic data from pretransplant evaluation and post-transplant course was studied. The study end points were non-relapse mortality (NRM) and overall survival (OS) at 2 years. Cumulative incidence and K-M methods were used to compare events for all risk groups. Pearson correlations were calculated between HSCT-CI/Age and PAM scores. Results: A total of 114 evaluable patients were found, with a median age of 53 (range 20-69), 75% were older than 40. Patients with reduced DLCO (<80%) represented 58.5% (see table). There was a moderate correlation between PAM and HSCT-CI/Age, correlation coefficient (r=0.42, p<0.001). NRM and OS for the low risk PAM score of <24 was (36.1 % and 49.4% respectively), trended towards improved outcome compared to high risk score of ≥24 (50.7% and 43%), although neither reached statistical significance (both p>0.19). Subjects with low HSCT-CI/Age score (0-4) had a NRM 36.2% and OS 52.4%, which was statistically different from the high risk score (5-7) (75.6% and 23.8% respectively) (both p<0.004). In multivariate analysis, HSCT-CI/Age was the strongest predictor of OS with a hazard ratio of 2.2 (95% confidence interval 1.1-4.1) (p=0.023). Conclusions: In this single institution retrospective review, pretransplant decision-making needs to be tailored to different populations’ characteristics until a more universally validated method is acceptable. Variables N % Age <40 28 24.6 ≥40 86 75.4 Gender Male 60 52.6 Female 54 47.4 CMV patient Positive 70 61.4 Negative 27 23.7 Unknown 17 14.9 CMV donor Positive 50 43.9 Negative 46 40.4 Unknown 18 15.8 HSCT-CI/Age score 0-4 92 80.7 5-7 22 19.3 PAM Score 17-23 44 39.6 ≥24 67 60.4 aGvHD Grade 0-1 71 62.3 2-4 43 37.7 cGvHD Grade None-Mild 86 75.5 Moderate-Severe 28 24.5
Plk3 functions as a tumor suppressor and is a negative regulator of HIF-1α under hypoxic conditions
Authors: Yali Yang, Rulong Sheng, Jeffery Winkles, Wei Dai
Journal: Cancer Research (2008)

2042  Polo-like kinase 3 (Plk3) is an important mediator of the cellular responses to genotoxic stresses. In mammals, the Plk family consists of four members; namely, Plk1, Plk2, Plk3 (also termed Prk and Fnk), and Plk4. Besides the kinase domain at the amino-terminus, Plks share a highly conserved amino acid sequence at the carboxyl terminus termed the Polo-box domain (PBD). To understand the role of Plk3 in controlling cell proliferation and oncogenesis, we generated and characterized Plk3 knockout mice. Whereas there was no significant difference in body weight between newborn Plk3-/- mice and their wild-type littermates, Plk3-/- mice displayed an increase in weight and developed tumors in various organs at advanced age. Plk3-/- mouse embryonic fibroblasts (MEFs) were hyper-sensitive to the induction of HIF-1α under hypoxic conditions or by nickel and cobalt ion treatments. Ectopic expression of the Plk3 kinase domain, but not its polo-box domain or a Plk3 kinase domain mutant, suppressed the nuclear accumulation of HIF-1α induced by nickel or cobalt ions. Moreover, hypoxia-induced HIF-1α expression was tightly associated with a significant down-regulation of Plk3 expression in HeLa cells. Given the importance of HIF-1α in mediating the activation of the survival machinery in cancer cells, these studies strongly suggest that enhanced tumorigenesis in Plk3-null mice is at least partially mediated by a deregulated HIF-1 pathway. Further studies on the mode of action of Plk3 will provide additional mechanistic insights that can guide the design of anti-cancer drugs tailored against the HIF-VHL pathway.
Could autologous adipose-derived stromal vascular fraction turn out an unwanted source of profibrotic myofibroblasts in systemic sclerosis?
Authors: Mirko Manetti
Journal: Annals of the Rheumatic Diseases (2019)

With great interest, I read the recent publication by Magalon et al 1 in the Annals of the Rheumatic Diseases . The results of this study are placed in the scenario of a quite complex disease featuring vasculopathy, autoimmunity and extensive multiorgan fibrosis whose life-threatening nature is well testified by a 5-year mortality of 30%–50% in a subset of patients with diffuse cutaneous systemic sclerosis (SSc) and internal organ involvement.2 Although substantial basic/translational and clinical research progresses have been achieved over the past decade, current treatments are mainly organ based and do not result in a cure which highlights the urgent need of developing new potentially disease-modifying therapies and personalised medicine approaches.2 

In this context, the adipose-derived stromal vascular fraction (ADSVF) has recently gained attention as an innovative biotherapy because of its abundance of mesenchymal-like stem/stromal cells (referred to as adipose-derived stem cells; ADSC), accessibility and ease of harvest. The same research team has previously reported encouraging results from a phase I clinical trial showing a good safety profile and a potential efficacy of local injection of autologous ADSVF to treat hand disability in patients with SSc. …
Abstract P082: Mortality in NSTEMI With Tachycardia is Influenced by Diabetes
Authors: Ebenezer Oni, Adegbola Oluwole, Behnam Bozorgnia
Journal: Circulation (2019)

Background: The presence of arrhythmias has been shown to predict mortality in patients presenting with Acute coronary syndrome. We evaluated if the association of Tachycardia and Mortality in Non-ST Elevation myocardial infarction (NSTEMI) patients was independent of the presence of diabetes. Methods: Our study population included patients admitted for NSTEMI in a single center between 08/01/2016 and 09/30/2012. Diabetes (DM) was defined by a documented diagnosis or use of diabetic medication. Tachycardia was defined as heart rate (HR) &gt;100 bpm. Results: A total of 543 patients were included in this analysis. The mean age was 66 ± 0.6 years, 50% (n-269) were diabetics, and mortality was 10% (n=54). In an unadjusted logistic regression, Tachycardia increased the odds of mortality, OR 2.05 (CI 1.15-3.65), p=0.016. After adjusting for all the risk factors and confounding variables, the relationship was no longer significant. This was however different after stratifying by the presence of diabetes. Diabetics had about four times the probability odds of death compared to non-diabetics in the fully adjusted model. See Table 1. Conclusion: The association of tachycardia and mortality in patients who presented with NSTEMI was dependent on the presence of diabetes. The study emphases the impact of diabetes on cardiovascular disease.
Predicting overall survival (OS) in patients (pts) with penile squamous cell carcinoma (PSCC) undergoing regional lymph node dissection (LND) ± multimodal therapy.
Authors: Andrea Necchi, Luigi Mariani, Yao Zhu, Ding-Wei Ye, Salvatore Lo Vullo, Antonio Augusto Ornellas, Nick Watkin, Michael Ager, Oliver W Hakenberg, Axel Heidenreich, Daniele Raggi, Mario Catanzaro, Roberto Salvioni, Juan Chipollini, Mounsif Azizi, Philippe E. Spiess
Journal: Journal of Clinical Oncology (2019)

512 Background: Advances in prognostic allocation of pts with PSCC receiving regional LND are needed, along with an assessment of the role of perioperative treatments. Methods: An international, multicenter, retrospective database was queried for all pts with PSCC who had received inguinal ± pelvic LND from 1980 to 2017. We classified or re-classified pts according to the 2009 TNM classification system. The primary endpoint was OS. Survival analysis methods were adopted for the purpose of detecting and modeling putative prognostic factors, and develop a prognostic stratification tool. The analysis was performed in two steps: first, we modeled outcome data and covariates by resorting to a random forest (RF) method (an “ensemble” machine-learning approach, with an ad hoc approach incorporating missing data imputation). Second, data was modeled using Cox proportional hazard regression. In addition, a Cox model was fit including pre-specified variables that were deemed to be clinically relevant. Results: There were 743 pts who received LND at seven referral centers from Europe, the USA, Brazil, and China. Of these pts, 689 were analyzed: 86 (12.5%) received neoadjuvant chemotherapy (NAC); 171 (24.8%) received adjuvant chemotherapy (AC), and 74 (10.7%) received adjuvant radiotherapy. The variables significantly associated with OS were age (p &lt; 0.001), the pathologically involved/total removed LN ratio (p &lt; 0.001), pN stage (overall p &lt; 0.001) and NAC (HR: 1.58, 95%CI: 1.10-2.26, p = 0.013). NAC and AC were ineffective or detrimental in N1-2 patients, whereas they provided OS improvements in N3 patients. OS improvement reached statistical significance for AC in pelvic LN-positive pts (p = 0.046). Finally, we developed a nomogram predicting 12- and 24-month OS based on pre-specified variables (c-index: 0.75). The study is limited by its retrospective nature. Conclusions: We propose a post-treatment prognostic tool that can be offered as an aid to physicians to enhance decision-making, clinical research, and patient counseling after LND in PSCC. Administration of NAC and AC should be restricted to N3 patients.
Targeting VE-PTP phosphatase protects the kidney from diabetic injury
Authors: Isabel A. Carota, Yael Kenig-Kozlovsky, Tuncer Onay, Rizaldy Scott, Benjamin R. Thomson, Tomokazu Souma, Christina S. Bartlett, Yanyang Li, Daniele Procissi, Veronica Ramirez, Shinji Yamaguchi, Antoine Tarjus, Christine E. Tanna, Chengjin Li, Vera Eremina, Dietmar Vestweber, Sunday S. Oladipupo, Matthew D. Breyer, Susan E. Quaggin
Journal: The Journal of Experimental Medicine (2019)

Diabetic nephropathy is a leading cause of end-stage kidney failure. Reduced angiopoietin-TIE2 receptor tyrosine kinase signaling in the vasculature leads to increased vascular permeability, inflammation, and endothelial cell loss and is associated with the development of diabetic complications. Here, we identified a mechanism to explain how TIE2 signaling is attenuated in diabetic animals. Expression of vascular endothelial protein tyrosine phosphatase VE-PTP (also known as PTPRB), which dephosphorylates TIE2, is robustly up-regulated in the renal microvasculature of diabetic rodents, thereby reducing TIE2 activity. Increased VE-PTP expression was dependent on hypoxia-inducible factor transcriptional activity in vivo. Genetic deletion of VE-PTP restored TIE2 activity independent of ligand availability and protected kidney structure and function in a mouse model of severe diabetic nephropathy. Mechanistically, inhibition of VE-PTP activated endothelial nitric oxide synthase and led to nuclear exclusion of the FOXO1 transcription factor, reducing expression of pro-inflammatory and pro-fibrotic gene targets. In sum, we identify inhibition of VE-PTP as a promising therapeutic target to protect the kidney from diabetic injury.
Correction to: Secukinumab: A Review in Ankylosing Spondylitis
Authors: Hannah A. Blair
Journal: Drugs (2019)

The article Secukinumab: A Review in Ankylosing Spondylitis, written by Hannah A. Blair, was originally published Online First without open access. After online publication Novartis Pharma AG requested that the article be Open Choice to make the article an open access publication.
The enigmatic morula: mechanisms of development, cell fate determination, self-correction and implications for ART
Authors: Giovanni Coticchio, Cristina Lagalla, Roger Sturmey, Francesca Pennetta, Andrea Borini
Journal: Human Reproduction Update (2019)

Assisted reproduction technology offers the opportunity to observe the very early stages of human development. However, due to practical constraints, for decades morphological examination of embryo development has been undertaken at a few isolated time points at the stages of fertilisation (Day 1), cleavage (Day 2-3) and blastocyst (Day 5-6). Rather surprisingly, the morula stage (Day 3-4) has been so far neglected, despite its involvement in crucial cellular processes and developmental decisions.The objective of this review is to collate novel and unsuspected insights into developmental processes occurring during formation of the morula, highlighting the key importance of this stage for a better understanding of preimplantation development and an improvement of ART.PubMed was used to search the MEDLINE database for peer-reviewed English-language original articles and reviews concerning the morula stage in mammals. Searches were performed by adopting 'embryo', 'morula', 'compaction', 'cell fate' and 'IVF/assisted reproduction' as main terms, in association with other keywords expressing concepts relevant to the subject (e.g. cell polarity). The most relevant publications, i.e. those concerning major phenomena occurring during formation of the morula in established experimental models and the human species, were assessed and discussed critically.Novel live cell imaging technologies and cell biology studies have extended our understanding of morula formation as a key stage for the development of the blastocyst and determination of the inner cell mass (ICM) and the trophectoderm (TE). Cellular processes, such as dynamic formation of filopodia and cytoskeleton-mediated zippering cell-to-cell interactions, intervene to allow cell compaction (a geometrical requisite essential for development) and formation of the blastocoel, respectively. At the same time, differential orientation of cleavage planes, cell polarity and cortical tensile forces interact and cooperate to position blastomeres either internally or externally, thereby influencing their cellular fate. Recent time lapse microscopy (TLM) observations also suggest that in the human the process of compaction may represent an important checkpoint for embryo viability, through which chromosomally abnormal blastomeres are sensed and eliminated by the embryo.In clinical embryology, the morula stage has been always perceived as a 'black box' in the continuum of preimplantation development. This has dictated its virtual exclusion from mainstream ART procedures. Recent findings described in this review indicate that the morula, and the associated process of compaction, as a crucial stage not only for the formation of the blastocyst, but also for the health of the conceptus. This understanding may open new avenues for innovative approaches to embryo manipulation, assessment and treatment.
The role of interferon gamma and NK cells in the eradication of pulmonary osteosarcoma metastases by IL-12
Authors: Lisa Mills, Gangxiong Huang, Laura L. Worth
Journal: Cancer Research (2005)

6009  Osteosarcoma is a primary bone tumor that occurs predominantly in adolescents and young adults. Despite aggressive chemotherapy and surgical intervention, the 2- year disease-free survival of 60% has not changed significantly in the past 20 years. Salvage chemotherapeutic regimes has had little efficacy. Consequently, new approaches are needed. We are interested in stimulating the body’s own immune system to eradicate pulmonary metastases, and have previously demonstrated in mice that gene therapy with IL-12 resulted in a dramatic decrease in the size and number of pulmonary metastases. The purpose of this study is to identify the molecular and immunological events responsible for the eradication of pulmonary metastases in mice treated intranasally with an adenoviral vector containing the IL-12 gene. Balb/c mice were injected intra-osseously or intravenously (i.v.) with K7M3 cells, which resulted in the development of spontaneous, or experimental, pulmonary metastases, respectively. To assess the role of NK cell activation by IL-12 in this model, mice were treated with 50μl of asialoGM-1 antibody (this antibody inactivates NK cell function) or saline intraperitoneally twice weekly for 4 weeks. Mice then received AdmIL-12, Ad Bgal (control viral vector), or saline intranasally two times per week for 4 - 6 weeks. Analysis of the number of pulmonary metastases at the end of therapy demonstrated a two-fold increase in the size and number of pulmonary metastases in saline treated mice compared to IL-12 treated mice whose NK cell activity was blocked. Interestingly, the number of metastases in the IL-12 group (anti-asialo GM treated) was similar to control groups not receiving the antibody. These results suggest that NK cells are essential and partially responsible for the IL-12 induced eradications of pulmonary OS metastases. In another series of experiments, the role of IL-12 induction of interferon-gamma (IFNγ) was assessed. Some of IFNγ activities include inducing anti-angiogenic activity, activating macrophage iNOS activity, activation of NK cells, and IFN-γ dependent induction of Th1 cell differentiation and activation of T cells. IFNγ activation by IL-12 therapy was blocked using 100μg of anti-IFNγ intraperitoneally twice weekly. The mice received intranasal gene therapy with mIL-12, Ad Bgal, or saline as described above. Blocking IL-12’s induction of IFNγ resulted in a greater than two fold increase in the size and number of metastases compared to the group receiving intranasal mIL-12 and a control antibody intraperitoneally. In addition, in the IL-12 treated mice a five-fold increase in CD4+ T cells were recruited to the lungs day 3 after i.v. injection compared to control mice. In mice treated with anti-IFNγ, no significant difference in CD4+ T cell recruitment was noted between groups.
Patients with an extremely high prostate-specific antigen at prostate cancer diagnosis: A single institution analysis.
Authors: Qian Qin, Krishna Bikkasani, William K. Oh, Bobby Chi-Hung Liaw, Matt D. Galsky, Che-Kai Tsao
Journal: Journal of Clinical Oncology (2019)

309 Background: High prostate specific antigen (PSA) at diagnosis is associated with worse outcomes in patients (pt) with prostate cancer. However, treatment selection and clinical outcome in those diagnosed with an extremely high PSA (&gt; 500 ng/ml) are not well characterized, and we aim to better study this unique pt population. Methods: Using the Mount Sinai Genitourinary (GU) Cancer Biorepository, an IRB approved database containing all consented GU cancer pts seen between 2010-2018, we identified 23 pts with a PSA &gt;500 at prostate cancer diagnosis. Descriptive analysis was performed to capture clinical characteristics, treatment selection and response, and outcomes in this cohort. Results: The median age and PSA at diagnosis were 64 (54-85) and 1057 ng/ml (528-11,418). At presentation, 1 pt had localized versus 22 pts had metastatic disease, 3 were asymptomatic, and sites of metastasis included lymph nodes (LN) only (n=3), bone only (n=8), or LNs and bone (n=11). Pts were initiated on either first line androgen deprivation (ADT) or ADT plus docetaxel if seen after 2015 (1 refused). All pts had &gt;90% PSA response to first line therapy, with median PSA nadir 4.38 ng/ml (0.06-153), duration of response 6 months (1-33), and time to castration-resistant prostate cancer (CRPC) 14.5 months (5-99). There are differences in treatment selection and outcomes for pts treated with ADT vs. ADT plus docetaxel first line (see table). Conclusions: In pts with PSA &gt;500 at prostate cancer diagnosis, we have observed significant heterogeneity in clinical presentation and response to treatment. In pts treated with first line ADT plus docetaxel, we observed 2 of 7 pts with extended treatment response (&gt; 42 months). Differences in disease biology may account for this observation, and molecular characterization will be needed to better understand this subset. [Table: see text]