bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly
Authors: Shi Qing , Zhu Yasheng , Ma Jian , Chang Kun , Ding Dongling , Bai Yang , Gao Kun , Zhang Pingzhao , Mo Ren , Feng Kai , Zhao Xiaying , Zhang Liang , Sun Huiru , Jiao Dongyue , Chen Yingji , Sun Yinghao , Zhao Shi-min , Huang Haojie , Li Yao , Ren Shancheng , Wang Chenji 
Published: November 2019

Abstract
Background
The gene encoding the E3 ubiquitin ligase substrate-binding adaptor SPOP is frequently mutated in primary prostate cancer, but how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. Stress granules (SG) assembly is an evolutionarily conserved strategy for survival of cells under stress, and often upregulated in human cancers. We investigated the role of SPOP mutations in aberrant activation of the SG in prostate cancer and explored the relevanve of the mechanism in therapy resistance.

Methods
We identified SG nucleating protein Caprin1 as a SPOP interactor by using the yeast two hybrid methods. A series of functional analyses in cell lines, patient samples, and xenograft models were performed to investigate the biological significance and clinical relevance of SPOP regulation of SG signaling in prostate cancer.

Results
The cytoplasmic form of wild-type (WT) SPOP recognizes and triggers ubiquitin-dependent degradation of Caprin1. Caprin1 abundance is elevated in SPOP-mutant expressing prostate cancer cell lines and patient specimens. SPOP WT suppresses SG assembly, while the prostate cancer-associated mutants enhance SG assembly in a Caprin1-dependent manner. Knockout of SPOP or expression of prostate cancer-associated SPOP mutants conferred resistance to death caused by SG inducers (e.g. docetaxel, sodium arsenite and H2O2) in prostate cancer cells.

Conclusions
SG assembly is aberrantly elevated in SPOP-mutated prostate cancer. SPOP mutations cause resistance to cellular stress induced by chemtherapeutic drug such as docetaxel in prostate cancer.
LncRNA H19 induced by helicobacter pylori infection promotes gastric cancer cell growth via enhancing NF-κB-induced inflammation
Authors: Zhang Yifeng , Yan Jin , Li Chao , Wang Xiaoyong , Dong Yu , Shen Xiaoran , Zhang Ximei 
Published: November 2019

Abstract
Background
The aim of this study was to investigate the role of long non-coding RNA (lncRNA) H19 in gastric cancer (GC) with Helicobacter pylori (H. pylori).

Methods
H19 expression in peripheral blood from H. pylori+/− GC patients and healthy donors (control) as well as in GC tissues and cells were detected by qRT-PCR. Cell proliferation was evaluated by CCK-8 assay. Cell migration and invasion were evaluated by Transwell assay. The levels of pro-inflammatory cytokines were determined by ELISA. The protein levels of IκBα, p-IκBα and p65 were determined by western blotting.

Results
H19 expression was upregulated in H. pylori-infected GC tissues and cells. Furthermore, H. pylori promoted GC cell viability, migration, invasion and inflammatory response. Moreover, H19 overexpression promoted the proliferation, migration and invasion of H. pylori-infected GC cells via enhancing NF-κB-induced inflammation.

Conclusions
LncRNA H19 promotes H. pylori-induced GC cell growth via enhancing NF-κB-induced inflammation.
Mono-institutional phase 2 study of innovative Stereotactic Body RadioTherapy targeting PArtial Tumor HYpoxic (SBRT-PATHY) clonogenic cells in unresectable bulky non-small cell lung cancer: profound non-targeted effects by sparing peri-tumoral immune microenvironment
Authors: Tubin Slavisa , Khan Mohammad K. , Salerno Gerardo , Mourad Waleed F. , Yan Weisi , Jeremic Branislav 
Published: November 2019

Abstract
Background
Radiotherapy-induced lymphopenia may be limiting the success of therapy and could also negatively affect the ability of immune system in mediating the bystander (BE) and abscopal effects (AE). A novel SBRT-based PArtial Tumor irradiation of HYpoxic clonogenic cells (SBRT-PATHY) for induction of the tumoricidal BE and AE by sparing the peritumoral immune microenvironment and regional circulating lymphocytes has been developed to enhance the radiotherapy therapeutic ratio of advanced lung cancer. The aim of this retrospective review of prospectively collected mono-institutional phase 2 study was to compare the outcomes between unconventional SBRT-PATHY and standard of care in unresectable stage IIIB/IV bulky NSCLC.

Materials and methods
Sixty patients considered inoperable or unsuitable for radical radio-chemotherapy were enrolled and treated using the following 3 regimens: SBRT-PATHY (group I, n = 20 patients), recommended standard of care chemotherapy (group II, n = 20 patients), and institutional conventional palliative radiotherapy (group III, n = 20 patients).

Results
Median follow-up was 13 months. The 1-year overall survival was 75, 60, and 20% in groups 1, 2 and 3, respectively (p = 0.099). The 1-year cancer specific survival was 90, 60, and 20% in groups 1, 2, and 3, respectively (p = 0.049). Bulky tumor control rate was 95% for SBRT-PATHY compared with 20% in the other two groups. BE and AE were seen by SBRT-PATHY in 95 and 45% of patients, respectively. Multi-variate analysis for cancer specific survival was significant for treatment effect with SBRT-PATHY (p < 0.001) independent of age, sex, performance status, histology, stage, treated bulky site and tumor diameter. SBRT-PATHY resulted in lower toxicity (p = 0.026), and improved symptom control (p = 0.018) when compared to other two treatment options.

Conclusion
SBRT-PATHY improved treatment outcomes in unresectable NSCLC and should be investigated in larger trials.
Present study has been retrospectively registered on 8th of August 2019 by the ethic committee for Austrian region „Kärnten “in Klagenfurt (AUT), under study number A 31/19.
Incontinentia pigmenti burden scale: designing a family burden questionnaire
Authors:   the Filière Maladies Rares en Dermatologie, Taieb Charles , Hadj-Rabia Smail , Monnet Jacques , Bennani Mohammed , Bodemer Christine 
Published: November 2019

AbstractBackgroundIncontentia pigmenti (IP) is a rare multisystem disorder of ectodermal origin comprising skin, dental, ocular and central nervous system features. Symptomatic treatments are adapted to each family according to the patient’s disability. Due to its rarity, the family IP burden in its broadest sense (psychological, social, economic and physical) has not yet been evaluated.AimTo design a questionnaire allowing assessing the family burden of IP (F’BoIP).MethodA questionnaire was developed using a standardized methodology for designing quality of life questionnaires according to the following steps: conception, development, and validation. A multidisciplinary working group was designed, including experts in questionnaire development, dermatologists specialised in IP patient care and representatives of the French IP association. A cultural and linguistic validation into US English was conducted, based on the original French version.ResultsA 20-item conceptual questionnaire was generated. Subsequent confirmatory analyses produced a 20-item questionnaire grouped into four domains, demonstrating internal consistency (Cronbach’s alpha: 0.93), reproducibility and high reliability. The F’BoIP questionnaire significantly correlated with other validated questionnaires: Family Dermatology Life Quality Index (F-DLQI), Perceived Stress Scale (PSS) and SF-12 mental and SF12 physical scores, indicating good external validity.ConclusionThe F’BoIP questionnaire is the first specific tool to assess the family burden of IP and can be used by both family members of IP patients and by health care professionals. It is a valuable tool which evaluates medical and nonmedical strategies to improve the daily life of families affected by this orphan disease.
The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?
Authors: Ghelli Luserna di Rorà Andrea , Martinelli Giovanni , Simonetti Giorgia 
Published: November 2019

AbstractMitosis is the process whereby an eukaryotic cell divides into two identical copies. Different multiprotein complexes are involved in the fine regulation of cell division, including the mitotic promoting factor and the anaphase promoting complex. Prolonged mitosis can result in cellular division, cell death, or mitotic slippage, the latter leading to a new interphase without cellular division. Mitotic slippage is one of the causes of genomic instability and has an important therapeutic and clinical impact. It has been widely studied in solid tumors but not in hematological malignancies, in particular, in acute leukemia. We review the literature data available on mitotic regulation, alterations in mitotic proteins occurring in acute leukemia, induction of prolonged mitosis and its consequences, focusing in particular on the balance between cell death and mitotic slippage and on its therapeutic potentials. We also present the most recent preclinical and clinical data on the efficacy of second-generation mitotic drugs (CDK1-Cyclin B1, APC/CCDC20, PLK, Aurora kinase inhibitors). Despite the poor clinical activity showed by these drugs as single agents, they offer a potential therapeutic window for synthetic lethal combinations aimed to selectively target leukemic cells at the right time, thus decreasing the risk of mitotic slippage events.
DNMT3b/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6/STAT3 regulation
Authors: Lai Ssu-Chuan , Su Yu-Ting , Chi Ching-Chi , Kuo Yung-Che , Lee Kam-Fai , Wu Yu-Chih , Lan Pei-Chi , Yang Muh-Hwa , Chang Te-Sheng , Huang Yen-Hua 
Published: November 2019

AbstractBackgroundThe inflammatory cytokine interleukin-6 (IL-6) is critical for the expression of octamer-binding transcription factor 4 (OCT4), which is highly associated with early tumor recurrence and poor prognosis of hepatocellular carcinomas (HCC). DNA methyltransferase (DNMT) family is closely linked with OCT4 expression and drug resistance. However, the underlying mechanism regarding the interplay between DNMTs and IL-6-induced OCT4 expression and the sorafenib resistance of HCC remains largely unclear.MethodsHCC tissue samples were used to examine the association between DNMTs/OCT4 expression levels and clinical prognosis. Serum levels of IL-6 were detected using ELISA assays (n = 144). Gain- and loss-of-function experiments were performed in cell lines and mouse xenograft models to determine the underlying mechanism in vitro and in vivo.ResultsWe demonstrate that levels of DNA methyltransferase 3 beta (DNMT3b) are significantly correlated with the OCT4 levels in HCC tissues (n = 144), and the OCT4 expression levels are positively associated with the serum IL-6 levels. Higher levels of IL-6, DNMT3b, or OCT4 predicted early HCC recurrence and poor prognosis. We show that IL-6/STAT3 activation increases DNMT3b/1 and OCT4 in HCC. Activated phospho-STAT3 (STAT-Y640F) significantly increased DNMT3b/OCT4, while dominant negative phospho-STAT3 (STAT-Y705F) was suppressive. Inhibiting DNMT3b with RNA interference or nanaomycin A (a selective DNMT3b inhibitor) effectively suppressed the IL-6 or STAT-Y640F-induced increase of DNMT3b-OCT4 and ALDH activity in vitro and in vivo. The fact that OCT4 regulates the DNMT1 expressions were further demonstrated either by OCT4 forced expression or DNMT1 silence. Additionally, the DNMT3b silencing reduced the OCT4 expression in sorafenib-resistant Hep3B cells with or without IL-6 treatment. Notably, targeting DNMT3b with nanaomycin A significantly increased the cell sensitivity to sorafenib, with a synergistic combination index (CI) in sorafenib-resistant Hep3B cells.ConclusionsThe DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. Findings from this study highlight the significance of IL-6-DNMT3b–mediated OCT4 expressions in future therapeutic target for patients expressing cancer stemness-related properties or sorafenib resistance in HCC.
Impact of rewarming rate on the mortality of patients with accidental hypothermia: analysis of data from the J-Point registry
Authors: Watanabe Makoto , Matsuyama Tasuku , Morita Sachiko , Ehara Naoki , Miyamae Nobuyoshi , Okada Yohei , Jo Takaaki , Sumida Yasuyuki , Okada Nobunaga , Nozawa Masahiro , Tsuruoka Ayumu , Fujimoto Yoshihiro , Okumura Yoshiki , Kitamura Tetsuhisa , Ohta Bon 
Published: November 2019

AbstractBackgroundAccidental hypothermia (AH) is defined as an involuntary decrease in core body temperature to < 35 °C. The management of AH has been progressing over the last few decades, and numerous techniques for rewarming have been validated. However, little is known about the association between rewarming rate (RR) and mortality in patients with AH.MethodThis was a multicentre chart review study of patients with AH visiting the emergency department of 12 institutions in Japan from April 2011 to March 2016 (Japanese accidental hypothermia network registry, J-Point registry). We retrospectively registered patients using the International Classification of Diseases, Tenth Revision code T68: ‘hypothermia’. We excluded patients whose body temperatures were unknown or ≥ 35 °C, who could not be rewarmed, whose rewarmed temperature or rewarming time was unknown, those aged < 18 years, or who or whose family members had refused to join the registry. RR was calculated based on the body temperature on arrival at the hospital, time of arrival at the hospital, the documented temperature during rewarming, and time of the temperature documentation. RR was classified into the following five groups: ≥2.0 °C/h, 1.5–< 2.0 °C/h, 1.0–< 1.5 °C/h, 0.5–< 1.0 °C/h, and < 0.5 °C/h. The primary outcome of this study was in-hospital mortality. The association between RR and in-hospital mortality was evaluated using multivariate logistic regression analysis.ResultDuring the study, 572 patients were registered in the J-Point registry, and 481 patients were included in the analysis. The median body temperature on arrival to the hospital was 30.7 °C (interquartile range [IQR], 28.2 °C–32.4 °C), and the median RR was 0.85 °C/h (IQR, 0.53 °C/h–1.31 °C/h). The in-hospital mortality rates were 19.3% (11/57), 11.1% (4/36), 14.4% (15/104), 20.1% (35/175), and 34.9% (38/109) in the ≥2.0 °C/h, 1.5–< 2.0 °C/h, 1.0–< 1.5 °C/h, 0.5–< 1.0 °C/h, and < 0.5 °C/h groups, respectively. Multivariate regression analysis revealed that in-hospital mortality rate increased with each 0.5 °C/h decrease in RR (adjusted odds ratio, 1.49; 95% confidence interval, 1.15–1.94;Ptrend < 0.01).ConclusionThis study showed that slower RR is independently associated with in-hospital mortality.
Unique fine scale village spatial-temporal distributions of Anopheles farauti differ by physiological state and sex
Authors: Pollard Edgar J. M. , Russell Tanya L. , Apairamo Allan , Burkot Thomas R. 
Published: November 2019

AbstractBackgroundThe ecology of many mosquitoes, includingAnopheles farauti, the dominant malaria vector in the southwest Pacific including the Solomon Islands, remains inadequately understood. Studies to map fine scale vector distributions are biased when trapping techniques use lures that will influence the natural movements of mosquitoes by attracting them to traps. However, passive collection methods allow the detailed natural distributions of vector populations by sex and physiological states to be revealed.MethodsThe barrier screen, a passive mosquito collection method along with human landing catches were used to recordAn. farautidistributions over time and space in two Solomon Island villages from May 2016 to July 2017.ResultsTemporal and spatial distributions of over 15,000 mosquitoes, including males as well as unfed, host seeking, blood-fed, non-blood fed and gravid females were mapped. These spatial and temporal patterns varied by species, sex and physiological state. Sugar-fedAn. farautiwere mostly collected between 10–20 m away from houses with peak activity from 18:00 to 19:00 h. MaleAn. farautiwere mostly collected greater than 20 m from houses with peak activity from 19:00 to 20:00 h.ConclusionsAnopheles farautisubpopulations, as defined by physiological state and sex, are heterogeneously distributed in Solomon Island villages. Understanding the basis for these observed heterogeneities will lead to more accurate surveillance of mosquitoes and will enable spatial targeting of interventions for greater efficiency and effectiveness of vector control.
Effects of enriched endogenous omega-3 fatty acids on age-related hearing loss in mice
Authors: Honkura Yohei , Suzuki Jun , Sakayori Nobuyuki , Inada Hitoshi , Kawase Tetsuaki , Katori Yukio , Osumi Noriko 
Published: November 2019

Abstract
Objective
Dietary intervention is a practical prevention strategy for age-related hearing loss (AHL). Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) may be effective in prevention of AHL due to their anti-inflammatory and tissue-protective functions. Age-related changes in the hearing function of wild-type and Fat-1 transgenic mice derived from the C57BL/6N strain, which can convert omega-6 PUFAs to n-3 PUFAs and consequently produce enriched endogenous n-3 PUFAs, were investigated to test the efficacy of n-3 PUFAs for AHL prevention.

Results
At 2 months, the baseline auditory brainstem response (ABR) thresholds were the same in Fat-1 and wild-type mice at 8–16 kHz but were significantly higher in Fat-1 mice at 4 and 32 kHz. In contrast, the ABR thresholds of Fat-1 mice were significantly lower at 10 months. Moreover, the ABR thresholds of Fat-1 mice at low-middle frequencies were significantly lower at 13 months (12 kHz). Body weights were significantly reduced in Fat-1 mice at 13 months, but not at 2, 10, and 16–17 months. In conclusion, enriched endogenous n-3 PUFAs produced due to the expression of the Fat-1 transgene partially alleviated AHL in male C57BL/6N mice.
Cytotoxic T-lymphocyte antigen-4 +49A/G polymorphisms in Sudanese adults with type 1 diabetes and latent autoimmune diabetes
Authors: Alshareef Shimos A. , Omar Saeed M. , Hamdan Hamdan Z. , Adam Ishag 
Published: November 2019

Abstract
Objectives
This study was conducted to assess the association of T-lymphocyte-associated protein 4 (CTLA-4 +49A/G) variant with Latent autoimmune diabetes in adults (LADA) in Eastern Sudan. The study included 24 LADA, 240 patients with type 1 diabetes mellitus (T1DM), and 240 healthy controls. Genotyping for CTLA-4 +49A/G was done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP).

Results
Genotypes distribution of CTLA-4 in controls was in accordance with the HWE (P > 0.05). The frequency of mutation (both homozygous and heterozygous) of CTLA-4 +49A/G (AG + GG) was significantly higher in LADA compared with T1DM and the controls [19 (79.1%) vs. 100 (41.7%) vs. 78 (32.5%), P < 0.001]. It was significantly higher when LADA was compared with T1DM [19 (79.1%) vs. 100 (41.7%), P = 0.018, OR = 3.21, 95% CI 1.16–8.89] and when LADA was compared with the controls [19 (79.1%) vs. 78 (32.5%), P = 0.001, OR = 4.49, 95% CI 1.62–12.42]. The rate of heterozygous mutation of the CTLA-4 +49A/G (AG) was significantly higher in LADA compared with T1DM and the controls [16 (66.7%) vs. 85 (35.4%) vs. 70 (29.2%), P < 0.001]. It was significantly higher when LADA was compared with T1DM [16 (66.7%) vs. 85 (35.4%), P = 0.002, OR = 3.64, 95% CI 1.49–8.87] and when LADA was compared with the controls [16 (66.6%) vs. 85 (35.4%), P = 0.001, OR = 4.85, 95% CI 1.98–11.86].
The utility of PAX8 and SATB2 immunohistochemical stains in distinguishing ovarian mucinous neoplasms from colonic and appendiceal mucinous neoplasm
Authors: Aldaoud Najla , Erashdi Madiha , AlKhatib Sohaib , Abdo Nour , Al-Mohtaseb Alia , Graboski-Bauer Ashley 
Published: November 2019

AbstractObjectivesIt is challenging to distinguish between primary ovarian mucinous tumors and metastatic mucinous neoplasms from the lower gastrointestinal tract, including appendiceal tumors. A combination of PAX8 and SATB2 immunohistochemical stains can be used as a diagnostic tool to distinguish between these cases.ResultsImmunostaining for SATB2, PAX8, CK7, CK20 and CDX2 was performed on 50 ovarian mucinous neoplasms (OMN) (39 cystadenomas, 4 borderline and 7 adenocarcinomas), 63 mucinous colorectal carcinoma (CRC), and 9 appendiceal mucinous neoplasms (AMN) [8 low grade appendiceal mucinous neoplasms (LAMN) and 1 adenocarcinoma]. PAX8 was positive in 32% of OMN and negative in all CRC and AMN cases. SATB2 was expressed in 2.0% of OMN, 77.8% of AMN, and 49.2% of CRC cases. CK7 was positive in 78.0% of OMN, 33.3% of AMN, and 9.5% of CRC cases. CK20 was expressed in 24.0% of OMN, 88.9% of OMN, and 87.3% of CRC cases. CDX2 was positive in 14.0% of OMN, 100% of AMN, and 90.5% of CRC cases. PAX8 can differentiate between OMN and AMN with high specificity but low sensitivity. CDX2 is the most sensitive marker for CRC and AMN, whereas SATB2 has better specificity.
Perturbations in imprinted methylation from assisted reproductive technologies but not advanced maternal age in mouse preimplantation embryos
Authors: Kindsfather Audrey J. , Czekalski Megan A. , Pressimone Catherine A. , Erisman Margaret P. , Mann Mellissa R. W. 
Published: November 2019

Abstract
Background
Over the last several decades, the average age of first-time mothers has risen steadily. With increasing maternal age comes a decrease in fertility, which in turn has led to an increase in the use of assisted reproductive technologies by these women. Assisted reproductive technologies (ARTs), including superovulation and embryo culture, have been shown separately to alter imprinted DNA methylation maintenance in blastocysts. However, there has been little investigation on the effects of advanced maternal age, with or without ARTs, on genomic imprinting. We hypothesized that ARTs and advanced maternal age, separately and together, alter imprinted methylation in mouse preimplantation embryos. For this study, we examined imprinted methylation at three genes, Snrpn, Kcnq1ot1, and H19, which in humans are linked to ART-associated methylation errors that lead to imprinting disorders.

Results
Our data showed that imprinted methylation acquisition in oocytes was unaffected by increasing maternal age. Furthermore, imprinted methylation was normally acquired when advanced maternal age was combined with superovulation. Analysis of blastocyst-stage embryos revealed that imprinted methylation maintenance was also not affected by increasing maternal age. In a comparison of ARTs, we observed that the frequency of blastocysts with imprinted methylation loss was similar between the superovulation only and the embryo culture only groups, while the combination of superovulation and embryo culture resulted in a higher frequency of mouse blastocysts with maternal imprinted methylation perturbations than superovulation alone. Finally, the combination of increasing maternal age with ARTs had no additional effect on the frequency of imprinted methylation errors.

Conclusion
Collectively, increasing maternal age with or without superovulation had no effect of imprinted methylation acquisition at Snrpn, Kcnq1ot1, and H19 in oocytes. Furthermore, during preimplantation development, while ARTs generated perturbations in imprinted methylation maintenance in blastocysts, advanced maternal age did not increase the burden of imprinted methylation errors at Snrpn, Kcnq1ot1, and H19 when combined with ARTs. These results provide cautious optimism that advanced maternal age is not a contributing factor to imprinted methylation errors in embryos produced in the clinic. Furthermore, our data on the effects of ARTs strengthen the need to advance clinical methods to reduce imprinted methylation errors in in vitro-produced embryos.