tbuckley/cabot-search huggingface dataset:
LncRNA-MTA2TR functions as a promoter in pancreatic cancer via driving deacetylation-dependent accumulation of HIF-1α
Authors: Zhu Zeng, Feng-yu Xu, Hai Zheng, Ping Cheng, Qing-yong Chen, Zeng Ye, Jian-xin Zhong, Shi-jiang Deng, Ming-liang Liu, Kang Huang, Qiang Li, Wei Li, Yu-hang Hu, Fan Wang, Chun-you Wang, Gang Zhao
Journal: Theranostics (2019)

Rationale: Hypoxia has been proved to contribute to aggressive phenotype of cancers, while functional and regulatory mechanism of long noncoding RNA (lncRNA) in the contribution of hypoxia on pancreatic cancer (PC) tumorigenesis is incompletely understood.The aim of this study was to uncover the regulatory and functional roles for hypoxia-induced lncRNA-MTA2TR (MTA2 transcriptional regulator RNA, AF083120.1) in the regulation of PC tumorigenesis. Methods:A lncRNA microarray confirmed MTA2TR expression in tissues of PC patients.The effects of MTA2TR on proliferation and metastasis of PC cells and xenograft models were determined, and the key mechanisms by which MTA2TR promotes PC were further dissected.Furthermore, the expression and regulation of MTA2TR under hypoxic conditions in PC cells were assessed.We also assessed the correlation between MTA2TR expression and PC patient clinical outcomes.Results: We found that metastasis associated protein 2 (MTA2) transcriptional regulator lncRNA (MTA2TR) was overexpressed in PC patient tissues relative to paired noncancerous tissues.Furthermore, we found that depletion of MTA2TR significantly inhibited PC cell proliferation and invasion both in vitro and in vivo.We further demonstrated that MTA2TR transcriptionally upregulates MTA2 expression by recruiting activating transcription factor 3 (ATF3) to the promoter area of MTA2.Consequentially, MTA2 can stabilize the HIF-1α protein via deacetylation, which further activates HIF-1α transcriptional activity.Interestingly, our results revealed that MTA2TR is transcriptionally regulated by HIF-1α under hypoxic conditions.Our clinical samples further indicated that the overexpression of MTA2TR was correlated with MTA2 upregulation, as well as with reduced overall survival (OS) in PC patients. Conclusions:These results suggest that feedback between MTA2TR and HIF-1α may play a key role in regulating PC tumorigenesis, thus potentially highlighting novel avenues PC treatment.
Progression to type 2 diabetes mellitus and associated risk factors after hyperglycemia first detected in pregnancy: A cross-sectional study in Cape Town, South Africa
Authors: Tawanda Chivese, Shane A. Norris, Naomi S. Levitt
Journal: PLoS Medicine (2019)

Background Global data indicate that women with a history of hyperglycemia first detected in pregnancy (HFDP) are at up to 7 times risk of progressing to type 2 diabetes mellitus (T2DM) compared with their counterparts who have pregnancies that are not complicated by hyperglycemia. However, there are no data from the sub-Saharan African region, which has the highest projected rise in diabetes prevalence globally. The aim of this study was to determine the proportion of women who progress to T2DM and associated risk factors 5 to 6 years after HFDP in Cape Town, South Africa. Methods and findings All women with HFDP, at a major referral hospital in Cape Town, were followed up 5 to 6 years later using a cross-sectional study. Each participant had a 75 g oral glucose tolerance test; anthropometric measurements and a survey were administered. A total of 220 participants were followed up. At this time, their mean age was 37.2 years (SD 6.0). Forty-eight percent (95% CI 41.2–54.4) progressed to T2DM, 5.5% (95% CI 3.1–9.4) had impaired fasting glucose, and 10.5% (95% CI 7.0–15.3) had impaired glucose tolerance. Of the participants who progressed to T2DM, 47% were unaware of their diabetes status. When HFDP was categorized post hoc according to WHO 2013 guidelines, progression in the diabetes in pregnancy (DIP) group was 81% (95% CI 70.2–89.0) and 31.3% (95% CI 24.4–39.3) in the gestational diabetes mellitus (GDM) category. Factors associated with risk of progression to T2DM were; at follow-up: waist circumference (odds ratios [OR] 1.1, 95% CI 1.0–1.1, p = 0.007), hip circumference (OR 0.9, 95% CI 0.8–1.0, p = 0.001), and BMI (OR 1.1, 95% CI 1.0–1.3, p = 0.001), and at baseline: insulin (OR 25.8, 95% CI 3.9–171.4, p = 0.001) and oral hypoglycaemic treatment during HFDP (OR 4.1, 95% CI 1.3–12.9, p = 0.018), fasting (OR 2.7, 95% CI 1.5–4.8, p = 0.001), and oral glucose tolerance test 2-hour glucose concentration at HFDP diagnosis (OR 4.3, 95% CI 2.4–7.7, p < 0.001). Our findings have limitations in that we did not include a control group of women without a history of HFDP. Conclusions The progression to T2DM in women with previous HFDP found in this study highlights the need for interventions to delay or prevent progression to T2DM after HFDP. In addition, interventions to prevent HFDP may also contribute to reducing the risk of T2DM.
Menopausal Estrogen-Alone Therapy and Health Outcomes in Women With and Without Bilateral Oophorectomy
Authors: JoAnn E. Manson, Aaron K. Aragaki, Shari S. Bassuk, Rowan T. Chlebowski, Garnet L. Anderson, Jacques E. Rossouw, Barbara V. Howard, Cynthia A. Thomson, Marcia L. Stefanick, Andrew M. Kaunitz, Carolyn J. Crandall, Charles B. Eaton, Victor W. Henderson, Simin Liu, Juhua Luo, Thomas Rohan, Aladdin H. Shadyab, Gretchen Wells, Jean Wactawski-Wende, Ross L. Prentice
Journal: Annals of Internal Medicine (2019)

Background: Whether health outcomes of menopausal estrogen therapy differ between women with and without bilateral salpingo-oophorectomy (BSO) is unknown. Objective: To examine estrogen therapy outcomes by BSO status, with additional stratification by 10-year age groups. Design: Subgroup analyses of the randomized Women's Health Initiative Estrogen-Alone Trial. (ClinicalTrials.gov: NCT00000611) Setting: 40 U.S. clinical centers. Participants: 9939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status. Intervention: Conjugated equine estrogens (CEE) (0.625 mg/d) or placebo for a median of 7.2 years. Measurements: Incidence of coronary heart disease and invasive breast cancer (the trial's 2 primary end points), all-cause mortality, and a "global index" (these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture) during the intervention phase and 18-year cumulative follow-up. Results: The effects of CEE alone did not differ significantly according to BSO status. However, age modified the effect of CEE in women with prior BSO. During the intervention phase, CEE was significantly associated with a net adverse effect (hazard ratio for global index, 1.42 [95% CI, 1.09 to 1.86]) in older women (aged ≥70 years), but the global index was not elevated in younger women (P trend by age = 0.016). During cumulative follow-up, women aged 50 to 59 years with BSO had a treatment-associated reduction in all-cause mortality (hazard ratio, 0.68 [CI, 0.48 to 0.96]), whereas older women with BSO had no reduction (P trend by age = 0.034). There was no significant association between CEE and outcomes among women with conserved ovaries, regardless of age. Limitations: The timing of CEE in relation to BSO varied; several comparisons were made without adjustment for multiple testing. Conclusion: The effects of CEE did not differ by BSO status in the overall cohort, but some findings varied by age. Among women with prior BSO, in those aged 70 years or older, CEE led to adverse effects during the treatment period, whereas women randomly assigned to CEE before age 60 seemed to derive mortality benefit over the long term. Primary Funding Source: The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs.
Interaction between Molecular Subtypes and Stromal Immune Infiltration before and after Treatment in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy
Authors: Anne-Sophie Hamy, Hélène Bonsang-Kitzis, Diane De Croze, Enora Laas, Lauren Darrigues, Lucian Topciu, Emmanuelle Menet, Anne Vincent-Salomon, Florence Lerebours, Jean-Yves Pierga, Etienne Brain, Jean-Guillaume Feron, Gabriel Benchimol, Giang-Thanh Lam, Marick Laé, Fabien Reyal
Journal: Clinical Cancer Research (2019)

High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC.We assessed stromal TIL levels in 716 pre- and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group.Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, P = 0.001). This was observed in luminal tumors and TNBCs, but not in HER2-positive breast cancers (PInteraction = 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs (P = 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, P < 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels (r = -0.80, P < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (P < 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive breast cancers (HR, 1.04; confidence interval, 1.02-1.06; P = 0.001), but not in luminal tumors or TNBCs (PInteraction = 0.04).The associations of pre- and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.
Associations Between Time Spent Using Social Media and Internalizing and Externalizing Problems Among US Youth
Authors: Kira E. Riehm, Kenneth A. Feder, Kayla N. Tormohlen, Rosa M. Crum, Andrea S. Young, Kerry M. Green, Lauren R. Pacek, Lareina N. La Flair, Ramin Mojtabai
Journal: JAMA Psychiatry (2019)

Social media use may be a risk factor for mental health problems in adolescents. However, few longitudinal studies have investigated this association, and none have quantified the proportion of mental health problems among adolescents attributable to social media use.
What’s hot that the other lot got
Authors: Lydia Spurr
Journal: Thorax (2019)

Accurate and efficient diagnostic pathways are essential in non-small cell lung cancer (NSCLC) staging as site and spread of disease typically dictate therapeutic options. Taylor et al ( Lancet Respir Med 2019;7:523) prospectively evaluated the diagnostic accuracy for metastatic disease of staging pathways based on whole-body MRI (WB-MRI), compared with standard multimodality pathway in cases of newly diagnosed, but potentially radically treatable NSCLC. The Streamline L trial was implemented in 16 UK centres which screened 976 patients, recruiting 353 with 187 completing the trial protocol. Participants underwent WB-MRI in addition to standard staging investigations. Radiologists blinded to patients’ clinical history (other than suspected cancer diagnosis) and contemporaneous imaging reported on local tumour stage and distant metastases. The local multidisciplinary team made the first major treatment decision based on standard investigations. The WB-MRI was then reviewed as if it were the initial staging investigation: any additional investigations deemed necessary were performed or reviewed to stage disease and decide on treatment. Compared with a reference standard established from a multidisciplinary consensus panel there was no significant difference in sensitivity for metastatic disease (n=52; WB-MRI 50% (95% CI 37 to 63), standard 54% (41 to 67), difference −4% …
Detection of free radical formation in human skin upon systemic application of chemotherapeutics.
Authors: Alexa Patzelt, Leonhard Zastrow, Maxim E. Darvin, Radoslav Chekerov, Jalid Sehouli, Juergen Lademann
Journal: Journal of Clinical Oncology (2013)

e20689 Background: A wide variety of chemotherapeutics is available for systemic therapy of cancers some of which, e.g., pegylated liposomal doxorubicin (PLD), paclitaxel, docetaxel, and capecetabin may induce dermal side effects (DSE). PLD is most prominent for its risk to induce palmar plantar erythrodysethesia (PPE). Recent investigations have shown that PLD escapes onto the skin surface with the sweat, and penetrates into deeper dermal layers like topically applied destroying the tissue via radical forming processes. PPE seems to be avoidable if antioxidant-containing ointments are applied previous and during therapy. To which extent this prevention strategy is feasible also for other chemotherapeutics was investigated in the presented study. Methods: The investigations were performed on 20 patients aged between 53 and 72 years who underwent their 2 nd cycle of therapy with any of the aforementioned therapeutics. These volunteers exhibited no or only a mild form (grade I) of PPE at the timepoint of investigation. Using an optical skin scanner, the radical formation was indirectly measured via the decline of the antioxidant concentration immediately before and 2-4 h after the chemotherapy, respectively. Results: In about 50% of the volunteers treated with paclitaxel and in about 30% treated with capecetabin, the antioxidant concentration distinctly declined during chemotherapyThis decline was predominantly found in patients with a weak initial antioxidative protection system. Conclusions: Thus, the application of an antioxidant-containing ointment seems to be also a reasonable prevention measure for patients under therapy with other chemotherapeutics. Analyzing the antioxidant concentration with the optical skin scanner is a simple, non-invasive option to investigate any chemotherapeutic for radical forming processes in the skin during patient treatment.
Adherence to the Prevailing Sepsis Definition Is Quintessential to Subphenotype Identification
Authors: Souvik Maitra, Sulagna Bhattacharjee
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

We read the article "Identifying Novel Sepsis Subphenotypes Using Temperature Trajectories" by Bhavani and colleagues (1) with great interest.The authors identified four subphenotypes of patients with sepsis from temperature trajectories and found a significant variability in clinical outcomes and inflammatory markers.However, there are a few concerns that we believe need to be mentioned.The authors included hospitalized patients with infection according to Rhee's criteria and did not adhere to the current Sepsis-3 definition (2) or the previous American College of Chest Physicians/Society of Critical Care Medicine sepsis definition (3).Sepsis-3 defines sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection."We believe that this has incurred a significant bias that may be reflected as lower in-hospital mortality rates in both the derivation and validation cohorts.The authors reported an overall in-hospital mortality of 6% in the derivation cohort and 6.1% in the validation cohort.On the other hand, a U.S. nationwide inpatient database analysis revealed that in-hospital mortality declined from 23.7% to 18.4% between 2007 and 2011 (4).In that study, the authors identified sepsis, severe sepsis, and septic shock according to ICD-9 coding.Significant heterogeneity in the mortality rate among patients with septic shock is already known.We believe that the patients included in this study had "suspected infection" rather than sepsis.As we understand it, the authors used the quick Sequential Organ Failure Assessment (qSOFA) score as an indicator of disease severity; however, qSOFA is known to be inferior to SOFA for predicting in-hospital mortality in patients in both ICU and non-ICU settings (5).Therefore, the role of baseline disease severity as an independent predictor of mortality cannot be ruled out in four temperature trajectory groups when qSOFA is used.
State Strategies to Address Opioid Use Disorder Among Pregnant and Postpartum Women and Infants Prenatally Exposed to Substances, Including Infants with Neonatal Abstinence Syndrome
Authors: Charlan D. Kroelinger, Marion E. Rice, Shanna Cox, Hadley R. Hickner, Mary Kate Weber, Lisa Romero, Jean Y. Ko, Donna Addison, Trish Mueller, Carrie Shapiro-Mendoza, S. Nicole Fehrenbach, Margaret A. Honein, Wanda D. Barfield
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Since 1999, the rate of opioid use disorder (OUD) has more than quadrupled, from 1.5 per 1,000 delivery hospitalizations to 6.5 (1), with similar increases in incidence of neonatal abstinence syndrome (NAS) observed for infants (from 2.8 per 1,000 live births to 14.4) among Medicaid-insured deliveries (2). CDC's response to the opioid crisis involves strategies to prevent opioid overdoses and related harms by building state capacity and supporting providers, health systems, and payers.* Recognizing systems gaps in provision of perinatal care and services, CDC partnered with the Association of State and Territorial Health Officials (ASTHO) to launch the Opioid Use Disorder, Maternal Outcomes, and Neonatal Abstinence Syndrome Initiative Learning Community (OMNI LC). OMNI LC supports systems change and capacity building in 12 states.† Qualitative data from participating states were analyzed to identify strategies, barriers, and facilitators for capacity building in state-defined focus areas. Most states focused on strategies to expand access to and coordination of quality services (10 of 12) or increase provider awareness and training (nine of 12). Fewer states focused on data, monitoring, and evaluation (four of 12); financing and coverage (three of 12); or ethical, legal, and social considerations (two of 12). By building capacity to strengthen health systems, state-identified strategies across all focus areas might improve the health trajectory of mothers, infants, and families affected by the U.S. opioid crisis.
Comparison of non‐myeloablative and reduced‐intensity allogeneic stem cell transplantation in older patients with myelodysplastic syndromes
Authors: Madlen Jentzsch, Christine Döhring, Richard Linke, Andrea Hille, Juliane Grimm, Wolfram Pönisch, Vladan Vucinic, Georg‐Nikolaus Franke, Gerhard Behre, Dietger Niederwieser, Sebastian Schwind
Journal: American Journal of Hematology (2019)

Abstract Allogeneic stem cell transplantation (HSCT) remains the only curative treatment for myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. The introduction of reduced intensity (RIC) and non‐myeloablative (NMA) conditioning enabled HSCT in older or comorbid individuals representing the majority of patients. Studies comparing RIC and NMA conditioning are limited. We retrospectively analyzed 151 MDS or MDS/MPN patients older than 50 years who received NMA‐ or RIC‐HSCT. Patients younger or older than 65 years at HSCT were analyzed separately. Patients receiving RIC‐HSCT or NMA‐HSCT were balanced in factors reflecting disease aggressiveness and the HCT‐CI comorbidity score. The NMA conditioned patients had a higher incidence of graft rejection and chronic graft‐vs‐host disease. Cumulative incidence of relapse (CIR), non‐relapse mortality (NRM) and overall survival (OS), did not differ significantly with regard to the conditioning regime in the whole cohort. In patients &lt;65 years at HSCT, NMA conditioning associated with higher NRM and shorter OS by trend, while CIR was similar in both groups. In multivariable analyzes, the conditioning regimen remained a prognostic factor for NRM and OS in patients &lt;65 years at HSCT. In MDS patients NMA and RIC conditioning result in similar disease control, but especially patients &lt;65 years may benefit from RIC‐HSCT.
Author Correction: Leveraging European infrastructures to access 1 million human genomes by 2022
Authors: Gary Saunders, Michael Baudis, Regina Becker, Sergi Beltran, Christophe Béroud, Ewan Birney, Cath Brooksbank, Søren Brunak, Marc Van den Bulcke, Rachel Drysdale, Salvador Capella-Gutierrez, Paul Flicek, Francesco Florindi, Peter Goodhand, Ivo Gut, Jaap Heringa, Petr Holub, Jef Hooyberghs, Nick Juty, Thomas M. Keane, Jan O. Korbel, Ilkka Lappalainen, Brane Leskosek, Gert Matthijs, Michaela Th. Mayrhofer, Andres Metspalu, Arcadi Navarro, Steven Newhouse, Tommi Nyrönen, Angela Page, Bengt Persson, Aarno Palotie, Helen Parkinson, Jordi Rambla, David Salgado, Erik Steinfelder, Morris A. Swertz, Alfonso Valencia, Susheel Varma, Niklas Blomberg, Serena Scollen
Journal: Nature Reviews Genetics (2019)
Deeper Molecular Response in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia Chronic Phase (CML-CP) Patients Receiving Radotinib 300 Mg BID or Imatinib: Rerise 36 Months Follow-up
Authors: Young Rok Do, Hawk Kim, Jae-Yong Kwak, Jeong-A Kim, Hyeoung-Joon Kim, Joon Seong Park, Jooseop Chung, Ho-Jin Shin, Sung-Hyun Kim, Udomsak Bunworasate, Chul Won Choi, Narcisa Sonia Cornejo Comia, Dae Young Zang, Sukjoong Oh, Saengsuree Jootar, Ary Harryanto Reksodiputro, Won-Sik Lee, Yeung-Chul Mun, Jee Hyun Kong, Priscilla B. Caguioa, Jinny Park, Chul W. Jung, Dong-Wook Kim
Journal: Blood (2017)