bluuebunny/crossref_metadata_2025_split huggingface dataset:
Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation
Authors: Dixit Pragyesh , Kokate Shrikant B. , Poirah Indrajit , Chakraborty Debashish , Smoot Duane T. , Ashktorab Hassan , Rout Niranjan , Singh Shivaram P. , Bhattacharyya Asima 
Published: February 2021

Abstract
Background
Helicobacter pylori-mediated gastric carcinogenesis is initiated by a plethora of signaling events in the infected gastric epithelial cells (GECs). The E3 ubiquitin ligase seven in absentia homolog 2 (Siah2) is induced in GECs in response to H. pylori infection. Posttranslational modifications of Siah2 orchestrate its function as well as stability. The aim of this study was to evaluate Siah2 phosphorylation status under the influence of H. pylori infection and its impact in gastric cancer progression.

Methods
H. pylori-infected various GECs, gastric tissues from H. pylori-infected GC patients and H. felis-infected C57BL/6 mice were evaluated for Siah2 phosphorylation by western blotting or immunofluorescence microscopy. Coimmunoprecipitation assay followed by mass spectrometry were performed to identify the kinases interacting with Siah2. Phosphorylation sites of Siah2 were identified by using various plasmid constructs generated by site-directed mutagenesis. Proteasome inhibitor MG132 was used to investigate proteasome degradation events. The importance of Siah2 phosphorylation on tumorigenicity of infected cells were detected by using phosphorylation-null mutant and wild type Siah2 stably-transfected cells followed by clonogenicity assay, cell proliferation assay, anchorage-independent growth and transwell invasion assay.

Results
Siah2 was phosphorylated in H. pylori-infected GECs as well as in metastatic GC tissues at residues serine6 (Ser6) and threonine279 (Thr279). Phosphorylation of Siah2 was mediated by MRCKβ, a Ser/Thr protein kinase. MRCKβ was consistently expressed in uninfected GECs and noncancer gastric tissues but its level decreased in infected GECs as well as in metastatic tissues which had enhanced Siah2 expression. Infected murine gastric tissues showed similar results. MRCKβ could phosphorylate Siah2 but itself got ubiquitinated from this interaction leading to the proteasomal degradation of MRCKβ and use of proteasomal inhibitor MG132 could rescue MRCKβ from Siah2-mediated degradation. Ser6 and Thr279 phosphorylated-Siah2 was more stable and tumorigenic than its non-phosphorylated counterpart as revealed by the proliferation, invasion, migration abilities and anchorage-independent growth of stable-transfected cells.

Conclusions
Increased level of Ser6 and Thr279-phosphorylated-Siah2 and downregulated MRCKβ were prominent histological characteristics of Helicobacter-infected gastric epithelium and metastatic human GC. MRCKβ-dependent Siah2 phosphorylation stabilized Siah2 which promoted anchorage-independent survival and proliferative potential of GECs. Phospho-null mutants of Siah2 (S6A and T279A) showed abated tumorigenicity.
High GFPT1 expression predicts unfavorable outcomes in patients with resectable pancreatic ductal adenocarcinoma
Authors: Gong Yitao , Qian Yunzhen , Luo Guopei , Liu Yu , Wang Ruijie , Deng Shengming , Cheng He , Jin Kaizhou , Ni Quanxing , Yu Xianjun , Wu Weiding , Liu Chen 
Published: January 2021

Abstract
Background
Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which plays a pivotal role in the progression of pancreatic ductal adenocarcinoma (PDAC). Therefore, we investigated the prognostic significance of GFPT1 expression in patients with resectable PDAC.

Methods
We analyzed public datasets to compare GFPT1 expression in tumor tissues and normal/adjacent pancreatic tissues. We measured the relative GFPT1 expression of 134 resected PDAC specimens in our institution, using real-time polymerase chain reaction (PCR). Survival was compared between high and low GFPT1 expression groups using Kaplan-Meier curves and log-rank tests. Multivariate analyses were estimated using Cox regression and logistic regression models.

Results
GFPT1 is generally upregulated in PDAC tissues, according to the analysis of public datasets. The data from our institution shows that high GFPT1 expression was correlated with a high rate of lymph node (LN) metastasis (p = 0.038) and was an independent risk factor for LN metastasis (odds ratio (OR) = 3.14, 95% confidence interval (CI) = 1.42 to 6.90, P = 0.005). High GFPT1 expression was significantly associated with poor overall survival (OS; P = 0.019) in patients with resected PDAC. The multivariable-adjusted hazard ratio (HR) for mortality when comparing patients with high and low GFPT1 expression was 2.54 (95% CI = 1.35 to 4.79, P = 0.004).

Conclusions
GFPT1 is generally upregulated in PDAC tissue and is associated with a high risk of LN metastasis and an unfavorable outcome in patients with resectable PDAC, suggesting its crucial role in PDAC progression.
Hsa_circ_0025202 suppresses cell tumorigenesis and tamoxifen resistance via miR-197-3p/HIPK3 axis in breast cancer
Authors: Li Hongjuan , Li Qing , He Shan 
Published: February 2021

Abstract
Background
The involvement of circular RNAs (circRNAs) in tamoxifen (TAM) resistance has been identified. Herein, we aimed to identify the role and novel mechanisms of hsa_circ_0025202 in tamoxifen resistance in breast cancer (BC).

Methods
The levels of hsa_circ_0025202, microRNA (miR)-197-3p, and homeodomain-interacting protein kinase 3 (HIPK3) were tested using quantitative real-time polymerase chain reaction and western blot. IC50 value of TAM, cell proliferation, cell cycle, cell invasion, migration, apoptosis, western blot, and mouse xenograft assays was used to demonstrate the effects of hsa_circ_0025202, miR-197-3p, and HIPK3 on BC cell tumorigenesis and TAM resistance. Dual-luciferase report and RNA immunoprecipitation assays were applied to explore the potential interaction between miR-197-3p and hsa_circ_0025202 or HIPK3.

Results
Hsa_circ_0025202 was decreased in BC tissues and TAM resistant BC cells, and knockdown of hsa_circ_0025202 elevated the IC50 value of cells to TAM, led to the promotion of cell proliferation, invasion and migration, mediated cell cycle progression, and inhibited cell apoptosis in BC in vitro. Besides, the upregulation of hsa_circ_0025202 hindered tumor growth and promoted TAM sensitivity in vivo. In a mechanical study, hsa_circ_0025202 targeted miR-197-3p, and silencing of miR-197-3p reversed the regulatory effects of hsa_circ_0025202 knockdown on TAM resistance and malignant phenotypes. Additionally, HIPK3 was a target of miR-197-3p, and miR-197-3p overexpression enhanced TAM resistance and promoted cell malignant biological behaviors in BC by targeting HIPK3.

Conclusion
Hsa_circ_0025202 repressed cell tumorigenesis and TAM resistance via miR-197-3p/HIPK3 axis in BC, suggesting a potential therapeutic strategy to overcome chemoresistance in BC patients.
Neoadjuvant therapy of BRCA1-driven ovarian cancer by combination of cisplatin, mitomycin C and doxorubicin
Authors: Gorodnova Tatiana V. , Sokolenko Anna P. , Kotiv Khristina B. , Sokolova Tatiana N. , Ivantsov Alexandr O. , Guseynov Konstantin D. , Nekrasova Ekaterina A. , Smirnova Olga A. , Berlev Igor V. , Imyanitov Evgeny N. 
Published: February 2021

Abstract
Background
Cisplatin, mitomycin C and anthracyclines demonstrate high activity in BRCA1-deficient tumors. This study aimed to evaluate the efficacy of the triplet combination of these drugs in BRCA1-driven high-grade serous ovarian carcinomas (HGSOCs).

Methods
Ten HGSOC patients with germ-line BRCA1 mutation received neoadjuvant chemotherapy (NACT) consisting of mitomycin C 10 mg/m2 (day 1), doxorubicin 30 mg/m2 (days 1 and 8) and cisplatin 80 mg/m2 (day 1), given every 4 weeks (MAP regimen). The comparator group included 16 women, who received standard NACT combination of paclitaxel 175 mg/m2 and carboplatin (6 AUC), given every 3 weeks (TCbP scheme).

Results
None of the patients treated by the MAP scheme demonstrated complete pathologic response in ovaries, while 4 women showed absence of tumor cells in surgically excised omental specimens. When chemotherapy response scores (CRS) were considered, poor responsiveness (CRS 1) was not observed in the MAP group, but was common for the TCbP regimen (6/16 (38 %) for ovaries and 5/16 (31 %) for omentum; p = 0.05 and 0.12, respectively). Median treatment-free interval (TFI) was not reached in women treated by the MAP, but was 9.5 months for the TCbP scheme (p = 0.1). The rate of the recurrence within 1 year after the completion of the treatment was 4/10 (40 %) for the MAP and 10/13 (77 %) for the TCbP (p = 0.1).

Conclusions
The attempt to intensify NACT by administering combination of 3 drugs did not result in high rate of complete pathologic responses. However, there was a trend towards higher efficacy of the MAP regimen versus conventional TCbP scheme with regard to CRS and clinical outcomes.
Cannabinoid treatment for autism: a proof-of-concept randomized trial
Authors: Aran Adi , Harel Moria , Cassuto Hanoch , Polyansky Lola , Schnapp Aviad , Wattad Nadia , Shmueli Dorit , Golan Daphna , Castellanos F. Xavier 
Published: February 2021

Abstract
Background
Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5–21 years) with ASD.

Methods
We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and Δ9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and Δ9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability.
Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI).

Results
Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94).
Limitations
Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results.

Conclusions
This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended.
Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226
Mimickers of novel coronavirus disease 2019 (COVID-19) on chest CT: spectrum of CT and clinical features
Authors: Elmokadem Ali H. , Batouty Nihal M. , Bayoumi Dalia , Gadelhak Basma N. , Abdel-Wahab Rihame M. , Zaky Mona , Abo-Hedibah Sherif A. , Ehab Ahmed , El-Morsy Ahmed 
Published: February 2021

AbstractCOVID-19 (coronavirus disease 2019) is a recently emerged pulmonary infection caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2). It started in Wuhan, China, in December 2019 and led to a highly contagious disease. Since then COVID-19 continues to spread, causing exponential morbidity and mortality and threatening economies worldwide. While the primary diagnostic test for COVID-19 is the reverse transcriptase–polymerase chain reaction (RT-PCR) assay, chest CT has proven to be a diagnostic tool of high sensitivity. A variety of conditions demonstrates CT features that are difficult to differentiate from COVID-19 rendering CT to be of low specificity. Radiologists and physicians should be aware of imaging patterns of these conditions to prevent an erroneous diagnosis that could adversely influence management and patients’ outcome. Our purpose is to provide a practical review of the conditions that mimic COVID-19. A brief description of the forementioned clinical conditions with their CT features will be included.
Chemotherapy-related striate melanonychia: a case report
Authors: Hussain Fazleenah , Gnanappiragasam Dushyanth , Shaffrali Freida 
Published: January 2021

AbstractBackgroundChemotherapy medications are reported to cause discoloration of the nails known as melanonychia. Depending on the nail structure affected and the severity of the insult, the clinical features can be variable. There are a great deal of unreported cases of pigmentary nail changes associated with chemotherapy treatment. By sharing our knowledge, we hope to raise the awareness of these nail changes amongst clinicians. Early recognition is crucial to allay anxiety among patients and avoid any unnecessary investigations.Case presentationWe present a case of 36-year-old woman of south Asian origin, who developed dark pigmentation in the left thumb nail during neoadjuvant chemotherapy with 5-fluorouracil, epirubicin, cyclophosphamide, and docetaxel (FEC-D) for triple negative breast cancer. Upon examination, the left thumb nail pigmentation was strikingly linear, uniform, and well demarcated extending from proximal nail fold to free margin. Despite the reassuring clinical features, the patient was understandably anxious that this could be a presentation of acral melanoma and was referred to the plastic surgeons for a nail matrix biopsy. Biopsy reassuringly was reported as melanosis and a diagnosis of striate melanonychia was made. The patient was discharged after 2-year follow-up.ConclusionChemotherapy medications have improved survival rates and patient outcomes. It is important for clinicians to be aware of the association of melanonychia with certain chemotherapy medications to reduce anxiety and allow successful management of these patients without delay. Striate melanonychia in this patient was felt most likely due to the synergistic effect of chemotherapy drugs compounded with racial predisposition. Chemotherapy agents most likely to have contributed include cyclophosphamide, docetaxel, and 5-fluorouracil.
Electrospun fibers enhanced the paracrine signaling of mesenchymal stem cells for cartilage regeneration
Authors: Kadir Nurul Dinah , Yang Zheng , Hassan Afizah , Denslin Vinitha , Lee Eng Hin 
Published: February 2021

Abstract
Background
Secretome profiles of mesenchymal stem cells (MSCs) are reflective of their local microenvironments. These biologically active factors exert an impact on the surrounding cells, eliciting regenerative responses that create an opportunity for exploiting MSCs towards a cell-free therapy for cartilage regeneration. The conventional method of culturing MSCs on a tissue culture plate (TCP) does not provide the physiological microenvironment for optimum secretome production. In this study, we explored the potential of electrospun fiber sheets with specific orientation in influencing the MSC secretome production and its therapeutic value in repairing cartilage.

Methods
Conditioned media (CM) were generated from MSCs cultured either on TCP or electrospun fiber sheets of distinct aligned or random fiber orientation. The paracrine potential of CM in affecting chondrogenic differentiation, migration, proliferation, inflammatory modulation, and survival of MSCs and chondrocytes was assessed. The involvement of FAK and ERK mechanotransduction pathways in modulating MSC secretome were also investigated.

Results
We showed that conditioned media of MSCs cultured on electrospun fiber sheets compared to that generated from TCP have improved secretome yield and profile, which enhanced the migration and proliferation of MSCs and chondrocytes, promoted MSC chondrogenesis, mitigated inflammation in both MSCs and chondrocytes, as well as protected chondrocytes from apoptosis. Amongst the fiber sheet-generated CM, aligned fiber-generated CM (ACM) was better at promoting cell proliferation and augmenting MSC chondrogenesis, while randomly oriented fiber-generated CM (RCM) was more efficient in mitigating the inflammation assault. FAK and ERK signalings were shown to participate in the modulation of MSC morphology and its secretome production.

Conclusions
This study demonstrates topographical-dependent MSC paracrine activities and the potential of employing electrospun fiber sheets to improve the MSC secretome for cartilage regeneration.
MicroRNA-205 mediates endothelial progenitor functions in distraction osteogenesis by targeting the transcription regulator NOTCH2
Authors: Jiang Weidong , Zhu Peiqi , Zhang Tao , Liao Fengchun , Yu Yangyang , Liu Yan , Shen Huijuan , Zhao Zhenchen , Huang Xuanping , Zhou Nuo 
Published: February 2021

Abstract
Background
Distraction osteogenesis (DO) is a highly efficacious form of reconstructive bone regeneration, but its clinical utility is limited by the prolonged period required for bone consolidation to occur. Understanding the mechanistic basis for DO and shortening this consolidation phase thus represent promising approaches to improving the clinical utility of this procedure.

Methods
A mandibular DO (MDO) canine model was established, after which small RNA sequencing was performed to identify relevant molecular targets genes. Putative miRNA target genes were identified through bioinformatics and confirmed through qPCR, Western blotting, and dual-luciferase reporter assays. Peripheral blood samples were collected to isolate serum and endothelial colony-forming cells (ECFCs) in order to measure miR-205, NOTCH2, and angiogenic cytokines expression levels. Lentiviral constructs were then used to inhibit or overexpress miR-205 and NOTCH2 in isolated ECFCs, after which the angiogenic activity of these cells was evaluated in migration, wound healing, proliferation, tube formation, and chick chorioallantoic membrane (CAM) assay. Autologous ECFCs transfected to knockdown miR-205 and were injected directly into the distraction callus. On days 14, 28, 35 and 42 after surgery, bone density was evaluated via CBCT, and callus samples were collected and evaluated via histological staining to analyze bone regeneration and remodeling.

Results
MiR-205 was identified as being one of the miRNAs that was most significantly downregulated in MDO callus samples. Downregulation of miR-205 was also observed in DO-ECFCs and serum of animals undergoing MDO. Inhibiting miR-205 markedly enhanced angiogenesis, whereas overexpressing miR-205 had the opposite effect in vitro. Importantly, NOTCH2, which is a unique regulator in bone angiogenesis, was identified as a miR-205 target gene. Consistent with this regulatory relationship, knocking down NOTCH2 suppressed angiogenesis, and transduction with a miR-205 inhibitor lentivirus was sufficient to rescue angiogenic activity. When ECFCs in which miR-205 had been inhibited were transplanted into the MDO callus, this significantly bolstered osteogenesis, and remodeling in vivo.

Conclusions
MiR-205 is a significant regulator of the MDO process, and inhibiting this miRNA can accelerate MDO-related mineralization. Overall, these results offer new insights into the mechanistic basis for this procedure, highlighting potential targets for therapeutic clinical intervention.
Mesenchymal stem cell-derived exosomes: therapeutic opportunities and challenges for spinal cord injury
Authors: Liu Wen-zhao , Ma Zhan-jun , Li Jie-ru , Kang Xue-wen 
Published: February 2021

AbstractSpinal cord injury (SCI) often leads to serious motor and sensory dysfunction of the limbs below the injured segment. SCI not only results in physical and psychological harm to patients but can also cause a huge economic burden on their families and society. As there is no effective treatment method, the prevention, treatment, and rehabilitation of patients with SCI have become urgent problems to be solved. In recent years, mesenchymal stem cells (MSCs) have attracted more attention in the treatment of SCI. Although MSC therapy can reduce injured volume and promote axonal regeneration, its application is limited by tumorigenicity, a low survival rate, and immune rejection. Accumulating literature shows that exosomes have great potential in the treatment of SCI. In this review, we summarize the existing MSC-derived exosome studies on SCI and discuss the advantages and challenges of treating SCI based on exosomes derived from MSCs.
Perioperative risk factors for recovery room delirium after elective non-cardiovascular surgery under general anaesthesia
Authors: Wu Jiayi , Gao Shaojie , Zhang Shuang , Yu Yao , Liu Shangkun , Zhang Zhiguo , Mei Wei 
Published: February 2021

AbstractBackgroundAlthough postoperative delirium is a frequent complication of surgery, little is known about risk factors for delirium occurring in the post-anaesthesia care unit (PACU). The aim of this study was to determine pre- and intraoperative risk factors for the development of recovery room delirium (RRD) in patients undergoing elective non-cardiovascular surgery.MethodsRRD was diagnosed according to the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). We collected perioperative data in 228 patients undergoing elective non-cardiovascular surgery under general anaesthesia and performed univariate and multivariate logistic regression to identify risk factors related to RRD. PACU and postoperative events were recorded to assess the outcome of RRD.ResultsFifty-seven patients (25%) developed RRD. On multivariate analysis, maintenance of anaesthesia with inhalation anaesthetic agents (OR = 6.294, 95% CI 1.4–28.8, corrected p= 0.03), malignant primary disease (OR = 3.464, 95% CI = 1.396–8.592, corrected p= 0.018), American Society of Anaesthesiologists Physical Status (ASA-PS) III–V (OR = 3.389, 95% CI = 1.401–8.201, corrected p= 0.018), elevated serum total or direct bilirubin (OR = 2.535, 95% CI = 1.006–6.388, corrected p= 0.049), and invasive surgery (OR = 2.431, 95% CI = 1.103–5.357, corrected p= 0.035) were identified as independent risk factors for RRD. RRD was associated with higher healthcare costs (31,428 yuan [17,872–43,674] versus 16,555 yuan [12,618–27,788], corrected p= 0.002), a longer median hospital stay (17 days [12–23.5] versus 11 days [9–17], corrected p= 0.002), and a longer postoperative stay (11 days [7–15] versus 7 days [5–10], corrected p= 0.002]).ConclusionsIdentifying patients at high odds for RRD preoperatively would enable the formation of more timely postoperative delirium management programmes.