bluuebunny/crossref_metadata_2025_split huggingface dataset:
‘Isolated anti‐HBc’ in blood donors: Significance after implementation of single‐unit nucleic acid amplification test?
Authors: Tiwari Aseem Kumar , Dara Ravi C. , Arora Dinesh , Aggarwal Geet , Sharma Jyoti , Chandnani Madhu , Bhardwaj Gunjan 
Published: August 2019

BackgroundThough seropositivity for anti‐HBc is high in India, neither anti‐HBc nor single‐unit NAT (ID‐NAT) is mandatory. Approximately 10% of blood transfusion services in India employ anti‐HBc (Total) testing, and approximately 50% of these also do NAT testing routinely. Adding anti‐HBc test to transfusion‐transmissible disease testing for screening donated blood remains controversial, especially after introduction of ID‐NAT testing in several centres.Materials and methodsProspective study was undertaken where anti‐HBc positive, HBsAg negative and ID‐NAT negative donor samples were investigated for HBeAg, anti‐HBe and anti‐HBs. Isolated anti‐HBc (anti‐HBc positive, HBeAg negative, anti‐HBe negative and anti‐HBs negative) samples were analysed by a sensitive polymerase chain reaction (RT‐PCR).Results955/14296 (7·6%) samples were anti‐HBc repeat reactive. While none of these were reactive for HBeAg, 696 samples were in possible convalescent phase (anti‐HBe positive) or resolution phase (anti‐HBs positive). A total of 259 were isolated anti‐HBc positive, and there were two low copy numbers (20 and 17 IU/ml) RT‐PCR positive amongst these. This finding is in agreement with several other studies with HBV DNA positivity in isolated anti‐HBc cases (0–0·91%).ConclusionAbout 0·77% DNA positivity (2/259 isolated anti‐HBc positive) by alternate PCR missed by ID‐NAT underlies the fact that anti‐HBc (Total) testing continues to be relevant in context of enhancing blood safety, especially in medium endemicity region like India. It is also possible to adopt screening algorithm of Japan Red Cross where units are considered transfusable if the anti‐HBs titre is over 100 mIU/ml, and we could have used 35·3% of repeat reactive anti‐HBc units using this approach.
Impact of gender on the career development of female traditional Korean medicine doctors: a qualitative study
Authors: Chun Se Eun , Lee Ju Hyun , Lee Ju Eun , Lee Seung Min Kathy , Leem Jungtae , Kim Hyunho 
Published: August 2019

ObjectiveThis study aims to examine the impact of gender and expected gender roles on the career development of young female traditional Korean medicine (KM) doctors.DesignWe conducted semistructured interviews to examine the experiences of study subjects regarding early career choices, employment, job performance and career moves, as well as future career aspirations, from the perspective of gender. The transcription was analysed using the Strauss and Corbin constant comparative analysis method.SettingThe interview was conducted at a quiet and comfortable place selected by the participants in South Korea.ParticipantsTen female KM doctors in their 30s participated in the study.ResultsThis study reveals that, initially, the participating female KM doctors were unaware of their gender affecting career decisions. However, after graduation and during employment, female doctors experienced direct discrimination or gender segregation while selecting areas of treatment and specialty; they found that they were preferred to work in paediatrics and dermatology departments than in departments treating musculoskeletal health problems. Furthermore, after entering the workforce, female KM doctors found that their gender significantly affects patient–doctor relationships and life events, such as pregnancy and childbirth require temporary career breaks. In addition, female KM doctors assumed stereotypical gender roles both in the workplace and at home, as well as becoming the main nurturer of their children.ConclusionGender and stereotyped gender roles affect the overall career planning, career moves and even patient–doctor relationships of female KM doctors. Female doctors were also more likely to experience specific gender roles in the workplace and at home, including both childbirth and childrearing.
Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression
Authors: Shen Jialing , Chen Mengnuo , Lee Derek , Law Cheuk-Ting , Wei Lai , Tsang Felice Ho-Ching , Chin Don Wai-Ching , Cheng Carol Lai-Hung , Lee Joyce Man-Fong , Ng Irene Oi-Lin , Wong Carmen Chak-Lui , Wong Chun-Ming 
Published: August 2019

ObjectiveFacilitates Chromatin Transcription (FACT) complex is a histone chaperone participating in DNA repair-related and transcription-related chromatin dynamics. In this study, we investigated its oncogenic functions, underlying mechanisms and therapeutic implications in human hepatocellular carcinoma (HCC).DesignWe obtained HCC and its corresponding non-tumorous liver samples from 16 patients and identified FACT complex as the most upregulated histone chaperone by RNA-Seq. We further used CRISPR-based gene activation and knockout systems to demonstrate the functions of FACT complex in HCC growth and metastasis. Functional roles and mechanistic insights of FACT complex in oxidative stress response were investigated by ChIP assay, flow cytometry, gene expression assays and 4sU-DRB transcription elongation assay. Therapeutic effect of FACT complex inhibitor, Curaxin, was tested in both in vitro and in vivo models.ResultsWe showed that FACT complex was remarkably upregulated in HCC and contributed to HCC progression. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilised NRF2 and FACT complex form a positive feedback loop; NRF2 transcriptionally activates the FACT complex, while FACT complex promotes the transcription elongation of NRF2 and its downstream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Therapeutically, Curaxin effectively suppressed HCC growth and sensitised HCC cell to sorafenib.ConclusionIn conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment.
De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy
Authors: Park Joohyun , Flores Bianca R , Scherer Katalin , Kuepper Hanna , Rossi Mari , Rupprich Katrin , Rautenberg Maren , Deininger Natalie , Weichselbaum Annette , Grimm Alexander , Sturm Marc , Grasshoff Ute , Delpire Eric , Haack Tobias B 
Published: August 2019

BackgroundCharcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT.MethodsWe evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes.ResultsWe identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes.ConclusionOur findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.
Semi-quantum secret sharing protocol using W-state
Authors: Tsai Chia-Wei , Yang Chun-Wei , Lee Narn-Yih 
Published: August 2019

Quantum secret sharing protocol, which lets a master share a secret with his/her agents and the agents can recover the master’s secret when they collaborate, is an important research issue in the quantum information field. In order to make the quantum protocol more practical, the concept of semi-quantum protocol is advanced by Boyer et al. Based on this concept, many semi-quantum secret sharing protocols have been proposed. The various entanglement states (including Bell state, GHZ state and so on) were used to be the quantum resources in these SQSS protocols, except for W-state which is the other multi-qubit entanglement state and different from GHZ states. Therefore, this study wants to use the entanglement property of W-state to propose the first three-party SQSS protocol and analyze the proposed protocol is free from the well-known attacks.
Device-guided slow breathing reduces blood pressure and sympathetic activity in young normotensive individuals of both sexes
Authors: Adler Tessa E. , Coovadia Yasmine , Cirone Domenica , Khemakhem Maha L. , Usselman Charlotte W. 
Published: August 2019

Slow breathing (SLOWB) is recommended for use as an adjuvant treatment for hypertension. However, the extent to which blood pressure (BP) responses to SLOWB differ between men and women are not well-established. Therefore, we tested the hypothesis that an acute bout of SLOWB would induce larger decreases in BP in males than in females, given that males typically have higher resting BP. We also examined autonomic contributors to reduced BP during SLOWB; that is, muscle sympathetic nerve activity and spontaneous cardiovagal (sequence method) and vascular sympathetic baroreflex sensitivity. We tested normotensive females ( n = 10, age: 22 ± 2 y, body mass index: 22 ± 2 kg/m2) and males ( n = 12, age: 23 ± 3 y, body mass index: 26 ± 4 kg/m2). Subjects were tested at baseline and during the last 5 min of a 15-min RESPeRATE-guided SLOWB session. Overall, SLOWB reduced systolic BP by 3.2 ± 0.8 mmHg (main effect, P < 0.01). Females had lower systolic BP (main effect, P = 0.02); we observed no interaction between sex and SLOWB. SLOWB also reduced muscle sympathetic nerve activity burst incidence by −5.0 ± 1.4 bursts/100 heartbeats (main effect, P < 0.01). Although females tended to have lower burst incidence (main effect, P = 0.1), there was no interaction between sex and SLOWB. Cardiovagal baroreflex sensitivity improved during SLOWB (21.0 vs. 36.0 ms/mmHg, P = 0.03) with no effect of sex. Despite lower overall BP in females, our data support a lack of basement effect on SLOWB-induced reductions in BP, as SLOWB was equally effective in reducing BP in males and females. Our findings support the efficacy of the RESPeRATE device for reducing BP in both sexes, even in young, normotensive individuals. NEW & NOTEWORTHY We provide support for the effectiveness of device-guided slow breathing for blood pressure reduction in young normotensive women and men. Despite having lower baseline blood pressure and sympathetic nerve activity, women experienced equivalent reductions in both measures in response to RESPeRATE-guided slow breathing as men. Thus, slow breathing appears to be effective in young healthy normotensive individuals of both sexes and may be an ideal preventative therapy against future hypertension.
Contraction intensity-dependent variations in the responses to brain and corticospinal tract stimulation after a single session of resistance training in men
Authors: Colomer-Poveda David , Romero-Arenas Salvador , Lundbye-Jensen Jesper , Hortobágyi Tibor , Márquez Gonzalo 
Published: August 2019

The aim of this study was to determine the effects of acute resistance training (RT) intensity on motor-evoked potentials (MEPs) generated by transcranial magnetic brain stimulation and on cervicomedullary motor-evoked potentials (CMEPs) produced by electrical stimulation of the corticospinal tract. In four experimental sessions, 14 healthy young men performed 12 sets of eight isometric contractions of the elbow flexors at 0 (Control session), 25, 50, and 75% of the maximal voluntary contraction (MVC). Before and after each session, MEPs, CMEPs, and the associated twitch forces were recorded at rest. MEPs increased by 39% ( P < 0.05 versus 25% in the control condition, Effect size (ES) = 1.04 and 1.76, respectively) after the 50% session and by 70% ( P < 0.05 vs. all other conditions, ES = 0.91–2.49) after the 75% session. In contrast, CMEPs increased similarly after the 25%, 50%, and 75% sessions with an overall increase of 27% ( P < 0.05 vs. control condition, ES = 1.34). The amplitude of maximal compound muscle action potentials (Mmax) was unchanged during the experiment. The MEP- and CMEP-associated twitch forces also increased after RT, but training intensity affected only the increases in MEP twitch forces. The data tentatively suggest that the intensity of muscle contraction used in acute bouts of RT affects cortical excitability. NEW & NOTEWORTHY Resistance training (RT) can acutely increase the efficacy of the corticospinal-motoneuronal synapse, motoneuron excitability and motor cortical excitability. We show that motor-evoked potential generated by transcranial magnetic stimulation but not cervicomedullary electrical stimulation increased in proportion to the intensity of training used during a single session of RT. The data suggest that the intensity of muscle contraction used in acute bouts of RT affects cortical excitability.
Macrophage ABHD5 Suppresses NFκB-Dependent Matrix Metalloproteinase Expression and Cancer Metastasis
Authors: Shang Shenglan , Ji Xinran , Zhang Lili , Chen Jun , Li Chuan , Shi Rongchen , Xiang Wei , Kang Xia , Zhang Dapeng , Yang Fan , Dai Rongyang , Chen Peng , Chen Shan , Chen Yongchuan , Li Yongsheng , Miao Hongming 
Published: August 2019

Abstract

Metabolic reprogramming in tumor-associated macrophages (TAM) is associated with cancer development, however, the role of macrophage triglyceride metabolism in cancer metastasis is unclear. Here, we showed that TAMs exhibited heterogeneous expression of abhydrolase domain containing 5 (ABHD5), an activator of triglyceride hydrolysis, with migratory TAMs expressing lower levels of ABHD5 compared with the nonmigratory TAMs. ABHD5 expression in macrophages inhibited cancer cell migration in vitro in xenograft models and in genetic cancer models. The effects of macrophage ABHD5 on cancer cell migration were dissociated from its metabolic function as neither triglycerides nor ABHD5-regulated metabolites from macrophages affected cancer cell migration. Instead, ABHD5 deficiency in migrating macrophages promoted NFκB p65-dependent production of matrix metalloproteinases (MMP). ABHD5 expression negatively correlated with MMP expression in TAMs and was associated with better survival in patients with colorectal cancer. Taken together, our findings show that macrophage ABHD5 suppresses NFκB-dependent MMP production and cancer metastasis and may serve as a prognostic marker in colorectal cancer.

Significance:
These findings highlight the mechanism by which reduced expression of the metabolic enzyme ABHD5 in macrophages promotes cancer metastasis.
Studying Cancer Evolution and Therapeutic Responses in Different Organs: The Pros and Cons of a Broad Focus
Authors: Pham-Danis Catherine , DeGregori James 
Published: August 2019

Abstract

Cellular adaptation brought upon by insults such as old age and therapeutic exposure is a complex phenomenon in which cells undergo adaptive phenotypic changes. Our lab has focused on understanding the mechanisms underlying adaptation during the evolution of cancer, from the early stages of development to the ability of cancer cells to escape therapeutic challenges. Our studies span hematopoietic and lung systems. Herein, we discuss the advantages and disadvantages involved in studying two vastly different organ systems. Through the use of these organ/cancer model systems, we hope to develop interventions to limit oncogenic adaptation leading to cancer development and to prevent adaptation of cancers following treatment leading to cancer relapse.
Purinostat Mesylate Is a Uniquely Potent and Selective Inhibitor of HDACs for the Treatment of BCR-ABL–Induced B-Cell Acute Lymphoblastic Leukemia
Authors: Yang Linyu , Qiu Qiang , Tang Minghai , Wang Fang , Yi Yuyao , Yi Dongni , Yang Zhuang , Zhu Zejiang , Zheng Shoujun , Yang Jianhong , Pei Heying , Zheng Li , Chen Yong , Gou Liping , Luo Liya , Deng Xing , Ye Haoyu , Hu Yiguo , Niu Ting , Chen Lijuan 
Published: August 2019

Abstract

Purpose:
This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph+ B-cell acute lymphoblastic leukemia (B-ALL).

Experimental Design:
Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph+ leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity in vitro. BL-2 secondary transplantation Ph+ B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties in vivo. BCR-ABL(T315I)–induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph+ B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph+ B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate.

Results:
Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph+ leukemia cell lines and primary Ph+ B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph+ B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph+ B-ALL, BCR-ABL(T315I)–induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph+ B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties.

Conclusions:
Purinostat mesylate provides a new therapeutic strategy for patients with Ph+ B-ALL, including those who relapse after TKI treatment.
A Novel Mitochondrial Inhibitor Blocks MAPK Pathway and Overcomes MAPK Inhibitor Resistance in Melanoma
Authors: Vashisht Gopal Y.N. , Gammon Seth , Prasad Rishika , Knighton Barbara , Pisaneschi Federica , Roszik Jason , Feng Ningping , Johnson Sarah , Pramanik Snigdha , Sudderth Jessica , Sui Dawen , Hudgens Courtney , Fischer Grant M. , Deng Wanleng , Reuben Alexandre , Peng Weiyi , Wang Jian , McQuade Jennifer L. , Tetzlaff Michael T. , Di Francesco Maria E. , Marszalek Joe , Piwnica-Worms David , DeBerardinis Ralph J. , Davies Michael A. 
Published: August 2019

Abstract

Purpose:
The purpose of this study is to determine if inhibition of mitochondrial oxidative phosphorylation (OxPhos) is an effective strategy against MAPK pathway inhibitor (MAPKi)–resistant BRAF-mutant melanomas.
Experimental Design: The antimelanoma activity of IACS-010759 (OPi), a novel OxPhos complex I inhibitor, was evaluated in vitro and in vivo. Mechanistic studies and predictors of response were evaluated using molecularly and metabolically stratified melanoma cell lines. 13C-labeling and targeted metabolomics were used to evaluate the effect of OPi on cellular energy utilization. OxPhos inhibition in vivo was evaluated noninvasively by [18F]-fluoroazomycin arabinoside (FAZA) PET imaging.

Results:
OPi potently inhibited OxPhos and the in vivo growth of multiple MAPKi-resistant BRAF-mutant melanoma models with high OxPhos at well-tolerated doses. In vivo tumor regression with single-agent OPi treatment correlated with inhibition of both MAPK and mTOR complex I activity. Unexpectedly, antitumor activity was not improved by combined treatment with MAPKi in vitro or in vivo. Signaling and growth-inhibitory effects were mediated by LKB1–AMPK axis, and proportional to AMPK activation. OPi increased glucose incorporation into glycolysis, inhibited glucose and glutamine incorporation into the mitochondrial tricarboxylic acid cycle, and decreased cellular nucleotide and amino acid pools. Early changes in [18F]-FAZA PET uptake in vivo, and the degree of mTORC1 pathway inhibition in vitro, correlated with efficacy.

Conclusions:
Targeting OxPhos with OPi has significant antitumor activity in MAPKi-resistant, BRAF-mutant melanomas, and merits further clinical investigation as a potential new strategy to overcome intrinsic and acquired resistance to MAPKi in patients.
A Phase II Trial of Vandetanib in Children and Adults with Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumor
Authors: Glod John , Arnaldez Fernanda I. , Wiener Lori , Spencer Melissa , Killian J. Keith , Meltzer Paul , Dombi Eva , Derse-Anthony Claudia , Derdak Joanne , Srinivasan Ramaprasad , Linehan W. Marston , Miettinen Markku , Steinberg Seth M. , Helman Lee , Widemann Brigitte C. 
Published: August 2019

Abstract

Purpose:
Gastrointestinal stromal tumors (GIST) are resistant to cytotoxic chemotherapy and radiotherapy. Most GIST in children are wild-type for KIT and PDGFRA (WT GIST) and deficient in expression of succinate dehydrogenase (dSDH GIST). We tested the activity of vandetanib, an oral small-molecule inhibitor of VEGFR2, EGFR, and RET, in patients with dSDH GIST.

Patients and Methods:
Phase II study of vandetanib (300 mg orally once daily to patients ≥18 years, and 100 mg/m2/dose to patients &lt; 18 years) on a continuous dosing schedule (1 cycle = 28 days) to assess the clinical activity (partial and complete response rate RECIST v1.1) in patients with dSDH GIST. A Simon optimal two-stage design (target response rate 25%, rule out 5%) was used: If ≥1 of 9 patients in stage 1 responded, enrollment would be expanded to 24 patients, and if ≥3 of 24 responded, vandetanib would be considered active.

Results:
Nine patients (7 female and 2 male; median age, 24 years; range, 11–52) with metastatic disease were enrolled. Three of the initial 5 adult patients developed treatment-modifying toxicities. After a protocol amendment, two adults received vandetanib at 200 mg/dose with improved tolerability. The two children (&lt;18 years old) enrolled did not experience treatment-modifying toxicities. No partial or complete responses were observed (median number of cycles, 4; range, 2–18).

Conclusions:
Vandetanib at a dose of 300 mg daily was not well tolerated by adults with dSDH GIST. Two of 9 patients had prolonged stable disease, but no partial or complete responses were observed, and vandetanib is thus not considered active in dSDH GIST.