tbuckley/cabot-search huggingface dataset:
Age exerts a continuous effect in the outcomes of Asian breast cancer patients treated with breast-conserving therapy
Authors: Fuh Yong Wong, Wei Ying Tham, Wen Long Nei, Cindy Lim, Hui Miao
Journal: Cancer Communications (2018)

Asians are diagnosed with breast cancer at a younger age than Caucasians are. We studied the effect of age on locoregional recurrence and the survival of Asian breast cancer patients treated with breast-conserving therapy.Medical records of 2492 patients treated with breast-conserving therapy between 1989 and 2012 were reviewed. The Kaplan-Meier method was used to estimate locoregional recurrence, breast cancer-free survival, and breast cancer-specific survival rates. These rates were then compared using log-rank tests. Outcomes and age were modeled by Cox proportional hazards. Fractional polynomials were then used to test for non-linear relationships between age and outcomes.Patients ≤ 40 years old were more likely to have locoregional recurrence than were older patients (Hazard ratio [HR] = 2.32, P < 0.001). Locoregional recurrence rates decreased year-on-year by 4% for patients with luminal-type breast cancers, compared with 8% for those with triple-negative cancers. Similarly, breast cancer-free survival rates increased year-on-year by 4% versus 8% for luminal-type and triple-negative cancers, respectively. Breast cancer-specific survival rates increased with age by 5% year-on-year. Both breast cancer-free survival and breast cancer-specific survival rates in patients with luminal cancers exhibited a non-linear ("L-shaped") relationship-where decreasing age at presentation was associated with escalating risks of relapse and death. The influence of age on overall survival was confounded by competing non-cancer deaths in older women, resulting in a "U-shaped" relationship.Young Asian breast cancer patients have a continuous year-on-year increase in rates of disease relapse and cancer deaths compared with older patients with no apparent threshold.
Aberrant activation of the type I interferon system may contribute to the pathogenesis of anti‐melanoma differentiation‐associated gene 5 dermatomyositis
Authors: S.H. Zhang, Y. Zhao, Q.B. Xie, Y. Jiang, Y.K. Wu, B. Yan
Journal: British Journal of Dermatology (2018)

Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM) is a distinctive subtype of DM that carries a significant risk of interstitial lung disease (ILD). The mechanisms remain elusive.To explore the role of the type I interferon (IFN) system in the pathogenesis of anti-MDA5 DM.Twenty patients with anti-MDA5 DM were studied and compared with patients with anti-aminoacyl-tRNA synthetase (ARS) DM (n = 10) and autoantibody-negative patients with DM (n = 20). The levels of inflammatory cytokines, B-cell-activating factor (BAFF) and Krebs von den Lungen (KL)-6 in blood were tested by enzyme-linked immunosorbent assay and multiplex assays. Expressions of transcripts for IFN-associated sensors and type I IFN-inducible genes in peripheral blood mononuclear cells (PBMCs) were detected by real-time polymerase chain reaction. Expressions of the signal transducer and activator of transcription (STAT)1, interferon-stimulated gene (ISG)15 and MxA proteins in skin lesions were analysed by immunohistochemistry.Plasma IFN-α levels were significantly increased in patients with anti-MDA5 DM. PBMCs from patients with anti-MDA5 DM showed significant upregulation of the TLR3, TLR7, IFIH1 and DDX58 genes, as well as serial IFN-inducible genes. Skin biopsies from patients with anti-MDA5 DM were characterized by strong expression of the STAT1, ISG15 and MxA proteins. In the patients with anti-MDA5 DM and ILD with high IFN-α production, there was a positive quantitative correlation between IFN-α and BAFF (rs = 0·63, P = 0·044). In addition, the higher levels of BAFF paralleled the higher concentrations of KL-6 (rs = 0·86, P = 0·0012).Our data confirm the aberrant activation of the type I IFN system in anti-MDA5 DM. Overproduction of IFN-α linked with BAFF may be implicated in the development of ILD.
Abstract 4814: Adaptation of uveal melanoma cells to MEK inhibition can be overcome through HDAC inhibition
Authors: Fernanda Faião-Flores, Silvya S. Maria-Engler, Zeynep Eroglu, Keiran S. Smalley
Journal: Cancer Research (2018)

Abstract Uveal melanoma is the most common adult cancer of the eye. Although uveal melanoma has a low incidence, it has a high capability to develop metastases, mainly to the liver. Mortality rates are high and new therapeutic strategies are urgently needed. 85-90% of all uveal melanomas harbor driver mutations in GNAQ or GNA11 leading to constitutive activation of many signaling pathways, including the MAPK pathway. Although MEK inhibitors have been evaluated clinically for metastatic uveal melanoma, responses are short-lived, and the mechanisms of adaptation are not well delineated. In the current study we performed mass spectrometry-based proteomics to define the adaptive response of uveal melanoma cells to MEK inhibition at a systems level with the hope of identifying the key escape pathways. These analyses identified MEK inhibition to lead to increased histone phosphorylation and histone deacetylase (HDAC) activity, as well as reorganization of the cytoskeleton associated with cortactin phosphorylation. MEK inhibition also increased receptor tyrosine kinase (RTK) signaling (through ROR1 and IGFIR) and enhanced AKT phosphorylation. Use of pan-HDAC inhibitors sensitized the uveal melanoma cells to MEK inhibition leading to enhanced apoptosis and decreased cell invasion. Mechanistic studies showed the MEK+HDAC inhibitor combination inhibited MAPK, PI3K/AKT and the Hippo signaling, an effect associated with increased cell death inhibition of cell invasion. Chronic MEK inhibitor treatment led to acquired resistance that was associated with increased RTK signaling and the adoption of an invasive phenotype. Studies are ongoing to identify the key HDAC isoform required for the adaptation to MEK inhibitor therapy as well as the anti-invasive potential of the cortactin knockdown with the goal of developing novel combination therapies that can be evaluated clinically. Citation Format: Fernanda Faião-Flores, Silvya S. Maria-Engler, Zeynep Eroglu, Keiran S. Smalley. Adaptation of uveal melanoma cells to MEK inhibition can be overcome through HDAC inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4814.
Acute Cardiac Effects of Severe Pre-Eclampsia
Authors: Arthur Jason Vaught, Lara C. Kovell, Linda M. Szymanski, Susan A. Mayer, Sara M. Seifert, Dhananjay Vaidya, Jamie D. Murphy, Cynthia Argani, Anna O’Kelly, Sarah York, Pamela Ouyang, Monica Mukherjee, Sammy Zakaria
Journal: Journal of the American College of Cardiology (2018)
Effect of antiviral therapy in reducing perinatal transmission of hepatitis B virus and maternal outcomes after discontinuing them
Authors: Kwang Il Seo, Si Hyun Bae, Pil Soo Sung, Chung-Hwa Park, Hae Lim Lee, Hee Yeon Kim, Hye Ji Kim, Bo Hyun Jang, Jeong Won Jang, Seung Kew Yoon, Jong Young Choi, In-Yang Park, Juyoung Lee, Hyun Seung Lee, Sa-Jin Kim, Jung Hyun Kwon, U Im Chang, Chang Wook Kim, Se Hyun Jo, Young Lee, Fisseha Tekle, Jong-Hyun Kim
Journal: Clinical and Molecular Hepatology (2018)

Background/Aims There have been numerous efforts to reduce mother-to-child transmission (MTCT) of hepatitis B virus (HBV) with antiviral agents during pregnancy. However, there are limited data regarding the outcomes of pregnant women after delivery. This study was performed to evaluate the efficacy of antiviral agents in preventing MTCT of HBV and maternal long-term outcomes. Methods The HBV-infected pregnant women treated with antiviral agents to prevent MTCT were retrospectively reviewed. Forty-one pregnant women who received telbivudine or tenofovir during late pregnancy (28-34 week) were analyzed. Hepatitis B virus surface antibody (HBsAb) positivity was tested in 43 infants after 7 months of birth. Eleven mothers were followed >1 year after delivery. Results The mean HBV DNA titer before antiviral therapy was 8.67 (6.60â9.49) log copies/mL, and the median age at delivery was 32 years (range, 22â40). Eleven patients were treated with tenofovir and 30 with telbivudine. The median duration was 57 days (range, 23â100), and the median HBV DNA titer at birth was 5.06 log copies/mL (range, 2.06â6.50). Antiviral treatments were associated with significant HBV DNA reduction (P<0.001). Among 43 infants (two cases of twins), HBsAb was not detected in two, subsequently confirmed to have HBV infection. Biochemical flare was observed in two of 11 mothers followed >12 months, and an antiviral agent was administered. Conclusions Antiviral treatment during late pregnancy effectively reduced MTCT. Long-term follow-up should be required in such cases. In addition, given that maternal biochemical flare occurred in 18% of mothers, re-administration of antiviral agents might be required. Keywords: Mother-to-child transmission; Hepatitis B virus; Pregnancy; Antiviral agents; Postpartum
The COPII cargo adapter SEC24C is essential for neuronal homeostasis
Authors: Bo Wang, Joung Hyuck Joo, Rebecca Mount, Brett J. W. Teubner, Alison Krenzer, Amber L. Ward, Viraj P. Ichhaporia, Elizabeth J. Adams, Rami Khoriaty, Samuel T. Peters, Shondra M. Pruett-Miller, Stanislav S. Zakharenko, David Ginsburg, Mondira Kundu
Journal: Journal of Clinical Investigation (2018)

SEC24 family members are components of the coat protein complex II (COPII) machinery that interact directly with cargo or with other adapters to ensure proper sorting of secretory cargo into COPII vesicles. SEC24C is 1 of 4 mammalian SEC24 paralogs (SEC24A-D), which segregate into 2 subfamilies on the basis of sequence homology (SEC24A/SEC24B and SEC24C/SEC24D). Here, we demonstrate that postmitotic neurons, unlike professional secretory cells in other tissues, are exquisitely sensitive to loss of SEC24C. Conditional KO of Sec24c in neural progenitors during embryogenesis caused perinatal mortality and microcephaly, with activation of the unfolded protein response and apoptotic cell death of postmitotic neurons in the murine cerebral cortex. The cell-autonomous function of SEC24C in postmitotic neurons was further highlighted by the loss of cell viability caused by disrupting Sec24c expression in forebrain neurons of mice postnatally and in differentiated neurons derived from human induced pluripotent stem cells. The neuronal cell death associated with Sec24c deficiency was rescued in knockin mice expressing Sec24d in place of Sec24c. These data suggest that SEC24C is a major cargo adapter for COPII-dependent transport in postmitotic neurons in developing and adult brains and that its functions overlap at least partially with those of SEC24D in mammals.
Abstract 2639: Prognostic significance of non-small cell lung cancer and response to EGFR-TKI of EGFR mutated lung cancer besed on PD-L1 expression
Authors: Kenichi Kobayashi, Masahiro Seike, Rintaro Noro, Shinobu Hemmi, Akihiko Gemma
Journal: Cancer Research (2018)

Abstract Background: Recent clinical trials have shown that immune checkpoint blockades that target either PD-1 or PD-L1 yield remarkable responses in a subgroup of non-small cell lung cancer (NSCLC) patients. Materials and Methods: We retrospectively examined, by immunohistochemical analysis, 211 NSCLC patients who had undergone complete surgical resection. Using 32 independent samples, we also evaluated PD-L1 expression in 32 NSCLC patients with epidermal growth factor receptor (EGFR) mutations treated by EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Results: Overall survival of PD-L1 positive surgical NSCLC patients with stages I-III and stage I disease were significantly shorter than those of PD-L1 negative NSCLC patients (P &amp;lt;0.01 and P = 0.02, respectively). In 86 squamous cell carcinoma (SQ) cases, PD-L1 positive patients showed significantly poorer survival than PD-L1 negative patients (P = 0.01). In stage I NSCLC patients, gender and PD-L1 expression were found to be independent predictors of death after multivariate analysis (Hazard ratio [HR] 3.57, P &amp;lt;0.01 and HR 2.05, P = 0.04, respectively). In SQ patients, p-stage and PD-L1 expression were independent predictors of death (HR 2.53, P &amp;lt;0.01 and HR 2.26, P = 0.02, respectively). Response to EGFR-TKIs, progression-free survival and overall survival were not significantly different between PD-L1 positive and negative NSCLC patients with EGFR mutations. Conclusion: PD-L1 positive expression in a tumor was a significant independent predictor of poor outcome in patients with lung SQ and in stage I NSCLC patients. Based on PD-L1 expression, the clinical response to EGFR-TKIs and prognosis did not differ in EGFR-mutated NSCLC patients. Citation Format: Kenichi Kobayashi, Masahiro Seike, Rintaro Noro, Shinobu Hemmi, Akihiko Gemma. Prognostic significance of non-small cell lung cancer and response to EGFR-TKI of EGFR mutated lung cancer besed on PD-L1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2639.
Ethical Issues Related to Breastfeeding for US Physicians Who are Mothers—Reply
Authors: Nelya Melnitchouk, Rebecca E. Scully, Jennifer S. Davids
Journal: JAMA Internal Medicine (2018)

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TRIMming TGF-β signals in Th17 cells
Authors: Aaron S. Rapaport, Wenjun Ouyang
Journal: The Journal of Experimental Medicine (2018)

The precise downstream mediators of TGF-β signaling in Th17 and T reg cells remain unclear. In this issue of JEM, Tanaka et al. report that Trim33 transduces TGF-β signals in Th17 cells to generate an optimal proinflammatory cytokine profile.
Late mortality after allogeneic blood or marrow transplantation in childhood for leukemia: a report from the Blood or Marrow Transplant Survivor Study-2
Authors: Anna Sällfors Holmqvist, Yanjun Chen, Jessica Wu, Michelle Kung, Emily Ness, Mariel Parman, Liton Francisco, Lindsey Hageman, Kevin Battles, Ravi Bhatia, Donna Salzman, Jeanette Falck Winther, Joseph Rosenthal, Stephen J. Forman, Daniel J. Weisdorf, Saro H. Armenian, Mukta Arora, Smita Bhatia
Journal: Leukemia (2018)
Proposal of a new scoring formula for the Dermatology Life Quality Index in psoriasis
Authors: F. Rencz, L. Gulácsi, M. Péntek, A.K. Poór, M. Sárdy, P. Holló, A. Szegedi, É. Remenyik, V. Brodszky
Journal: British Journal of Dermatology (2018)

'Not relevant' responses (NRRs) on the Dermatology Life Quality Index (DLQI) may occur in up to 40% of patients with psoriasis. As these responses are scored as the item of the questionnaire having no impact on the patients' lives at all, it is more difficult for these patients to fulfil the DLQI > 10 criterion required by clinical guidelines to become candidates for systemic treatment including biologics.We propose a new scoring system for the DLQI that corrects for the bias in the NRR option and test its construct validity in a sample of patients with psoriasis.Data from 242 patients (104 of whom marked at least one NRR) from two earlier cross-sectional surveys were reanalysed. For each patient, the DLQI score was calculated in two ways: (i) according to the original scoring and (ii) by applying a new scoring formula (DLQI-R) that adjusts the total score for the number of NRRs. The construct validity of the DLQI-R was tested against the Psoriasis Area and Severity Index (PASI) and EQ-5D-3L.The mean DLQI and DLQI-R scores were 9·99 ± 7·52 and 11·0 ± 8·02, respectively. The DLQI-R allowed eight more patients (3·3%) to achieve the 'PASI > 10 and DLQI > 10' threshold. The results were robust when limiting the maximum number of NRRs allowed to two or three. Compared with the DLQI, DLQI-R correlated slightly better with PASI (rs = 0·59 vs. 0·57) and EQ-5D-3L index scores (rs = -0·58 vs. -0·54).The DLQI-R seems to be a valid scoring system for avoiding the bias in the NRR option and can help to improve patients' access to biologics.
Effect of Repetitive Transcranial Magnetic Stimulation on Treatment-Resistant Major Depression in US Veterans
Authors: Jerome A. Yesavage, J. Kaci Fairchild, Zhibao Mi, Kousick Biswas, Anne Davis-Karim, Ciaran S. Phibbs, Steven D. Forman, Michael Thase, Leanne M. Williams, Amit Etkin, Ruth O’Hara, Gerald Georgette, Tamara Beale, Grant D. Huang, Art Noda, Mark S. George
Journal: JAMA Psychiatry (2018)

Treatment-resistant major depression (TRMD) in veterans is a major clinical challenge given the high risk for suicidality in these patients. Repetitive transcranial magnetic stimulation (rTMS) offers the potential for a novel treatment modality for these veterans.To determine the efficacy of rTMS in the treatment of TRMD in veterans.A double-blind, sham-controlled randomized clinical trial was conducted from September 1, 2012, to December 31, 2016, in 9 Veterans Affairs medical centers. A total of 164 veterans with TRD participated.Participants were randomized to either left prefrontal rTMS treatment (10 Hz, 120% motor threshold, 4000 pulses/session) or to sham (control) rTMS treatment for up to 30 treatment sessions.The primary dependent measure of the intention-to-treat analysis was remission rate (Hamilton Rating Scale for Depression score ≤10, indicating that depression is in remission and not a clinically significant burden), and secondary analyses were conducted on other indices of posttraumatic stress disorder, depression, hopelessness, suicidality, and quality of life.The 164 participants had a mean (SD) age of 55.2 (12.4) years, 132 (80.5%) were men, and 126 (76.8%) were of white race. Of these, 81 were randomized to receive active rTMS and 83 to receive sham. For the primary analysis of remission, there was no significant effect of treatment (odds ratio, 1.16; 95% CI, 0.59-2.26; P = .67). At the end of the acute treatment phase, 33 of 81 (40.7%) of those in the active treatment group achieved remission of depressive symptoms compared with 31 of 83 (37.4%) of those in the sham treatment group. Overall, 64 of 164 (39.0%) of the participants achieved remission.A total of 39.0% of the veterans who participated in this trial experienced clinically significant improvement resulting in remission of depressive symptoms; however, there was no evidence of difference in remission rates between the active and sham treatments. These findings may reflect the importance of close clinical surveillance, rigorous monitoring of concomitant medication, and regular interaction with clinic staff in bringing about significant improvement in this treatment-resistant population.ClinicalTrials.gov Identifier: NCT01191333.
BMA calls for end to period poverty
Authors: Abi Rimmer
Journal: BMJ (2018)

All patients in hospital should have access to sanitary products, and the government should provide them more widely for free, doctors have said.

Delegates at the BMA annual representative meeting in Brighton on 26 June supported a call for the association to help to end period poverty by ensuring that sanitary products were freely available.

Eleanor Wilson, the medical student who proposed the motion, said that access to sanitary products was fundamental to the human rights, health, and wellbeing of the population. She called on the BMA “to campaign for the eradication of period poverty and for the provision of sanitary products in hospital and community settings.”

“We do not ask patients to bring in toilet paper or food …
Is right heart catheterisation still a fundamental part of the follow-up assessment of pulmonary arterial hypertension? The argument against
Authors: Luke S. Howard
Journal: European Respiratory Journal (2018)

<b>Noninvasive assessment of pulmonary arterial hypertension is adequate to provide a risk assessment in the majority of cases. Patients need to be managed in high-volume, expert centres with access to invasive haemodynamics for selected use in follow-up</b>http://ow.ly/lXrq30koXZV
Abstract 331: Therapeutic co-targeting of WEE1 and ATM has synergistic effects and contributes to downregulation of PD-L1 expression in pancreatic cancer
Authors: Meihua Jin, Ah-Rong Nam, Ji Eun Park, Ju Hee Bang, Yung-Jue Bang, Do-Youn Oh
Journal: Cancer Research (2018)

Abstract Background: Currently, targeting DNA damage response (DDR) is one of strategies for new cancer drug development. DDR pathway involves DNA damage repair, cell cycle progression, apoptosis, and regulate the immune system. In pancreatic cancer (PC), one of the most fatal disease, TP53 mutation was found in approximately 78% of cases and BRCA pathway alteration including BRCA1, BRCA2, the ataxia telangiectasia mutated (ATM) and PALB2 was observed in 5% (germline) and 12% (somatic) of patients. The purpose of this study is to evaluate the DDR-targeting strategy using Wee1 inhibitor and ATM inhibitor in PC. Methods: Using a total of 11 kinds of PC cell lines (AsPC-1, Capan-1, Capan-2, MIA PaCa-2, PANC-1, SNU213, SNU324, SNU410, SNU2822, SNU2913, and SNU2918), AZD1775 (Wee1 inhibitor) and AZD0156 (ATM inhibitor) were tested. Results: AZD1775 significantly inhibited cell proliferation in all of the PC cell lines. AZD1775 monotherapy induced apoptosis and S phase arrest, and decreased Wee1/ p-wee1/ p-CDC2 expression. An increase of rH2AX and caspase-7 cleavage were occurred by AZD1775. When the cells were treated with AZD1775, upregulation of p-ATM was observed. The combination of AZD1775 and AZD0156, the synergism was found. P-wee1 and p-CDC2 were downregulated more obviously in co-treated cells compared with monotherapy. In some cells, PD-L1 was increased after AZD1775 treatment. Interestingly the combination of AZD1775 and AZD0156 synergistically reduced PD-L1 protein level in the cancer cells, especially in SNU213 and SNU2913 cells. Conclusion: Therapeutic WEE1 and ATM co-targeting strategy demonstrated promising anti-cancer effect in pancreatic cancer cells. Moreover, this co-treatment blocked PD-L1 expression. Taken together, this supports further clinical development of DDR targeting strategy in pancreatic cancer. Citation Format: Meihua Jin, Ah-Rong Nam, Ji Eun Park, Ju Hee Bang, Yung-Jue Bang, Do-Youn Oh. Therapeutic co-targeting of WEE1 and ATM has synergistic effects and contributes to downregulation of PD-L1 expression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 331.