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Background: To systematically review and assess the efficacy and safety of hydroxychloroquine (HCQ) for treating primary Sjogren's syndrome (pSS).Methods: Five electronic databases (Pubmed, EMBASE, Web of science, Ovid, Cochrane Library) were searched for randomized controlled trials and retrospective or prospective studies published in English that reported the effect of HCQ on pSS. The subjective symptoms (sicca symptoms, fatigue and pain) and the objective indexes (erythrocyte sedimentation rate and Schirmer test) were assessed as main outcome measures. A meta-analysis and descriptive study on the efficacy and safety of HCQ were conducted. The estimate of the effect of HCQ treatment was expressed as a proportion together with 95% confidence interval, and plotted on a forest plot.Results: Four trials with totals of 215 SS patients, including two randomized controlled trials, one double blind crossover trial and one retrospective open-label study, were analyzed in this review. For dry mouth and dry eyes, the effectiveness of HCQ treatment was essentially the same as placebo treatment. For fatigue, the effectiveness of HCQ was lower than placebo. The efficacy of HCQ in treating pain associated with pSS was superior to that of the placebo. There was no significant difference between HCQ-treated groups and controls in terms of Schirmer test results, but HCQ could reduce the erythrocyte sedimentation rate compare with placebo. A descriptive safety assessment showed that gastrointestinal adverse effects were the most common adverse effects associated with HCQ.Conclusions: This systematic review showed that there is no significant difference between HCQ and placebo in the treatment of dry mouth and dry eye in pSS. Well-designed, randomized, controlled trials are needed to provide higher-quality evidence to confirm our findings, and future studies should focus on some other index or extraglandular measures, such as cutaneous manifestations, to further explore the therapeutic effect of HCQ in pSS. [ABSTRACT FROM AUTHOR]

Background: Gastric epithelial hyper-proliferation was reported in patients with Helicobacter pylori (H. pylori)-infected gastric mucosa with intestinal metaplasia (IM) changes. In patients with gastric ulcer (GU) and IM, the GU may have a different healing rate in comparison to patients without IM. This study aimed to compare the difference in GU healing between H. pylori-infected patients with IM and those without IM.Methods: We retrospectively analyzed patients at the Keelung Chung Gung Memorial Hospital during the period from March 2005 to January 2011. The inclusion criteria were: 1) endoscopic findings of GU and biopsy histological examination plus rapid urease test indicating H. pylori infection; 2) gastric IM adjacent to a GU but with no atrophic gastritis changes; 3) patients receiving H. pylori eradication triple therapy and 8 weeks of maintenance therapy with a proton pump inhibitor; and 4) patients receiving follow-up endoscopy within the 3rd and the 4th months after treatment.Results: In total, 327 patients with GU and H. pylori infection (136 with IM and 191 without IM) were included. Patients with IM had a higher GU healing rate than those without IM (91.9% vs. 84.3%, P = 0.040). Multivariate logistical regression analysis revealed that failure of H. pylori eradication (Odds = 4.013, 95% CI: 1.840-8.951, P < 0.001) and gastric IM (Odds = 0.369, 95% CI: 0.168-0.812, P = 0.013) were the predictors of non-healing GU following treatment.Conclusions: Patient with gastric IM change may have a higher GU healing rate than those without gastric IM. However, successful H. pylori eradication is a more important factor for GU healing than gastric IM. [ABSTRACT FROM AUTHOR]

Background: Reperfusion ventricular arrhythmia (RA) associated with hypothermic ischaemic storage is increasingly recognized as a substantial contributor to adverse consequences after heart transplantation. Ischemia- or hypothermia-induced gap junction (GJ) remodelling is closely linked to RA. Reducing GJ remodelling contributes to RA attenuation and is important in heart transplantation. However, sevoflurane has an antiarrhythmic effect associated with the connexin 43 (Cx43) protein that has not yet been fully established. Methods: Hearts were divided into two groups according to a random number table: all hearts were arrested by an infusion of histidine-tryptophan-ketoglutarate (HTK) solution (4 °C) followed by (1) storage in HTK solution (4 °C) alone for 6 h (n = 8, Control group) or (2) storage in HTK solution supplemented with sevoflurane (2.5%) (4 °C) for 6 h (n = 8, Sevo-HTK group). First, the total Cx43 level and the phosphorylation of Cx43 at Ser368 (Cx43-pS368) were assessed by Western blotting, and the distribution of Cx43 was assessed by immunohistochemistry. Second, programmed electrical stimulation (PES) and monophasic action potential (MAP) recording were used to analyse the MAP duration (MAPD), conduction velocity (CV) and transmural repolarization dispersion (TDR). In addition, haematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-dUTP nick end labelling (TUNEL) staining were individually used to investigate the degree of myocardial pathological damage and cell apoptosis. Finally, bipolar electrograms were used to record the graft re-beating time and monitor RA during reperfusion for 15 to 30 min. Results: Sevo-HTK solution relatively increased the total Cx43 (P < 0.01) and Cx43-pS368 (P < 0.01) levels and prevented Cx43 redistribution (P < 0.05) and CV slowing (P < 0.001) but did not change TDR (P > 0.05). Additionally, the Cx43-pS368/total Cx43 ratio (P>0.05) was similar in the two groups. However, with Sevo-HTK solution, the graft re-beating times were shortened, myocardial pathological damage was ameliorated, and the number of apoptotic cells was markedly decreased. Conclusion: The reduction in hypothermia and ischaemia-induced reperfusion arrhythmias by the addition of sevoflurane to HTK solution may be related to the phosphorylation of Cx43 at serine 368. [ABSTRACT FROM AUTHOR]

Background: The age-related osteoporosis is an increasing risk severely threatening the live quality of aged people. Human parathyroid hormone (hPTH) is applied to the therapy of osteoporosis successfully, however, the mechanism, especially the signaling pathway activated in the healing fracture by PTH is still unknown.Methods: The once daily injections of hPTH(1-34) and GR (1-34) (the PLC deficient analog) into the orchiectomized male mice with bone fracture, were started at the second day after fracture and lasted for 4 weeks. To explore the role of phospholipase C signaling in the androgen-deficient fracture healing, the fracture healing were evaluated via radiography, micro-CT, biomechanics testing, serum biochemistry, bone marrow cell culture and gene expression quantification.Results: After two weeks of fracture, both peptides significantly increased bone mineral density (BMD), bone mass content (BMC) and bone volume (BV/TV) in the healing area. However, compared to hPTH(1-34), GR(1-34) induced more woven bones, the higher BMC and BMD, as well as the less serum TRAP and osteoclasts. After four weeks of treatment, the effects of hPTH(1-34) on fracture healing showed no difference to those of GR(1-34). Consistently, GR(1-34) induced the similar osteogenesis but less osteoclastogenesis under the ex vivo condition immediately after administration compared to hPTH(1-34), which was verified by the weaker activation of RANKL, NFATC1, TRAP and Cathepsin K in GR(1-34) treatment.Conclusion: These results indicated that the PLC signaling activated by the intermittent injection of hPTH(1-34) leads to the bone resorption by rapidly activating the osteoclastogenesis in the fracture healing zone. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is a global disease with growing prevalence that is difficult to cure.Rosa roxburghii Tratt is an edible and medicinal plant, and modern pharmacological studies have shown that it has potential anti-diabetic activity. This is the first study to explore the active components and potential mechanisms of Rosa roxburghii Tratt fruit for treating T2DM based on UPLC-Q-Exactive Orbitrap/MS and network pharmacology. Methods: The active components of Rosa roxburghii Tratt fruit were obtained from UPLC-Q-Exactive Orbitrap/MS analysis and retrieval in the SciFinder, PubMed, Web of Science, and CNKI databases. The potential targets of the active components were obtained from the SwissTargetPrediction and PharmMapper databases. The disease targets for T2DM were obtained from GeneCards, OMIM, TTD, DisGENent, and GEO databases. The intersection of the two datasets was used to obtain the potential targets of Rosa roxburghii Tratt fruit against T2DM. The target protein interaction network was constructed using the String database and Cytoscape software. The R software ClusterProfiler package was used for target enrichment analysis and the Cytoscape CytoNCA plug-in was used to screen core targets. Molecular docking and result visualization were performed using PyMOL and Autodock Vina software. Results: We obtained 20 bioactive ingredients, including alphitolic acid, quercetin, and ellagic acid, as well as 13 core targets, such as AKT1, TNF, SRC, and VEGFA. All bioactive ingredients in Rosa roxburghii Tratt fruit were active against T2DM-related therapeutic targets. Rosa roxburghii Tratt fruit may play a therapeutic role in T2DM by regulating the PI3K/AKT, RAS, AGE-RAGE, and other signaling pathways. Conclusions: This study explored the active components and potential mechanisms of Rosa roxburghii Tratt fruit in the treatment of T2DM, laying the foundation for a further experimental study based on pharmacodynamic substances and their mechanisms of action. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma multiforme, the most aggressive and malignant primary brain tumor, is characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma. Our previous studies delineated a crosstalk between PI3K/Akt and JNK signaling pathways, and a moderate anti-glioblastoma synergism caused by the combined inhibition of PI3K p110β (PI3Kβ) isoform and JNK. However, this combination strategy is not potent enough. MLK3, an upstream regulator of ERK and JNK, may replace JNK to exert stronger synergism with PI3Kβ. Methods: To develop a new combination strategy with stronger synergism, the expression pattern and roles of MLK3 in glioblastoma patient's specimens and cell lines were firstly investigated. Then glioblastoma cells and xenografts in nude mice were treated with the PI3Kβ inhibitor AZD6482 and the MLK3 inhibitor URMC-099 alone or in combination to evaluate their combination effects on tumor cell growth and motility. The combination effects on cytoskeletal structures such as lamellipodia and focal adhesions were also evaluated. Results: MLK3 protein was overexpressed in both newly diagnosed and relapsing glioblastoma patients' specimens. Silencing of MLK3 using siRNA duplexes significantly suppressed migration and invasion, but promoted attachment of glioblastoma cells. Combined inhibition of PI3Kβ and MLK3 exhibited synergistic inhibitory effects on glioblastoma cell proliferation, migration and invasion, as well as the formation of lamellipodia and focal adhesions. Furthermore, combination of AZD6482 and URMC-099 effectively decreased glioblastoma xenograft growth in nude mice. Glioblastoma cells treated with this drug combination showed reduced phosphorylation of Akt and ERK, and decreased protein expression of ROCK2 and Zyxin. Conclusion: Taken together, combination of AZD6482 and URMC-099 showed strong synergistic anti-tumor effects on glioblastoma in vitro and in vivo. Our findings suggest that combined inhibition of PI3Kβ and MLK3 may serve as an attractive therapeutic approach for glioblastoma multiforme. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma multiforme, the most aggressive and malignant primary brain tumor, is characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma. Our previous studies delineated a crosstalk between PI3K/Akt and JNK signaling pathways, and a moderate anti-glioblastoma synergism caused by the combined inhibition of PI3K p110β (PI3Kβ) isoform and JNK. However, this combination strategy is not potent enough. MLK3, an upstream regulator of ERK and JNK, may replace JNK to exert stronger synergism with PI3Kβ. Methods: To develop a new combination strategy with stronger synergism, the expression pattern and roles of MLK3 in glioblastoma patient's specimens and cell lines were firstly investigated. Then glioblastoma cells and xenografts in nude mice were treated with the PI3Kβ inhibitor AZD6482 and the MLK3 inhibitor URMC-099 alone or in combination to evaluate their combination effects on tumor cell growth and motility. The combination effects on cytoskeletal structures such as lamellipodia and focal adhesions were also evaluated. Results: MLK3 protein was overexpressed in both newly diagnosed and relapsing glioblastoma patients' specimens. Silencing of MLK3 using siRNA duplexes significantly suppressed migration and invasion, but promoted attachment of glioblastoma cells. Combined inhibition of PI3Kβ and MLK3 exhibited synergistic inhibitory effects on glioblastoma cell proliferation, migration and invasion, as well as the formation of lamellipodia and focal adhesions. Furthermore, combination of AZD6482 and URMC-099 effectively decreased glioblastoma xenograft growth in nude mice. Glioblastoma cells treated with this drug combination showed reduced phosphorylation of Akt and ERK, and decreased protein expression of ROCK2 and Zyxin. Conclusion: Taken together, combination of AZD6482 and URMC-099 showed strong synergistic anti-tumor effects on glioblastoma in vitro and in vivo. Our findings suggest that combined inhibition of PI3Kβ and MLK3 may serve as an attractive therapeutic approach for glioblastoma multiforme. [ABSTRACT FROM AUTHOR]

Background: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. Nonspecific symptoms make the diagnosis elusive. In addition, locating the responsible tumor(s) is challenging. The aim of this study was to investigate the clinical management and outcomes of TIO.Methods: The clinical features, diagnostic procedures, treatment, and outcomes of 12 patients were reviewed retrospectively.Results: The cohort comprised six men and six women (mean age 45.5 ± 9.9 years, range 23-61 years). The mean duration of disease was 3.7 ± 2.6 years. All patients manifested progressive bone pain, muscle weakness, and/or difficulty walking. Serum phosphorus concentrations were low in all patients (mean 0.42 ± 0.12 mmol/L). Technetium-99m octreotide scintigraphy was performed in 11 patients and showed lesions in the right distal femur, left femoral head, and right tibial plateau, respectively, in three patients. Magnetic resonance imaging (MRI) was negative for lesions in one patient. Two patients underwent biopsies that showed negative histopathology. Two patients, at 2 years and 8 months, respectively, after having negative technetium-99m octreotide studies, underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (CT), which revealed lesions in the sacrum and soft tissue of the left palm, respectively. One tumor was detected by CT and MRI. Overall, lesion sites were the head (two patients, 16.7%), thoracic and lumbar region (two, 16.7%), pelvis (three, 25%), lower limbs (four, 33.3%), and upper limbs (one, 8.3%). All patients underwent surgery, and histopathology showed phosphaturic mesenchymal tumors in each. Postoperatively, serum phosphorus concentrations normalized within 2-7 days in 11 patients. With follow-ups of 1-41 months, surgery was effective in 10 patients. One patient developed local recurrence and another had metastases.Conclusions: Locating tumors responsible for tumor-induced osteomalacia is often challenging. Although complete tumor resection confers a good prognosis in most patients, surveillance for recurrence and metastasis is necessary. Before surgery or when surgery is not indicated, oral phosphate can alleviate symptoms and metabolic imbalance. [ABSTRACT FROM AUTHOR]

Background: We conducted a prospective randomized study of an adjuvant oxaliplatin-based regimen plus orally administered tegafur-uracil in patients with stage III colon cancer after radical resection to evaluate the feasibility of this drug combination in cancer clinical outcomes, acute toxicity, disease-free survival (DFS), and overall survival (OS) in Taiwan.Methods/design: This is an open-label, randomized, comparative, double-arm, multicenter, phase III study to assess DFS, OS, and safety profiles of the aforementioned drug combination as maintenance therapy for 1 year in patients with stage III colon cancer after radical resection in Taiwan. Following the completion of an adjuvant oxaliplatin-based regimen for 3 weeks with no evident disease recurrence, all eligible patients will be randomly assigned to either arm A (maintenance therapy) or arm B (observation arm) in a 2:1 ratio (364 and 182 patients in the tegafur-uracil and observation groups, respectively). Treatment in arm A will be started within 7 days of randomization. If the patients reported disease recurrence, intolerable toxicity, withdrew consent or the investigator determined that the patient should be withdrawn during the study period, they were withdrawn from the study. If a patient was discontinued from the study, the corresponding data were not reused, and the patient was not allowed to re-enter the study.Discussion: A unique characteristic of this intervention was that the adjuvant chemotherapy with oxaliplatin and tegafur-uracil was anticipated to be safe and has high treatment efficacy, with the advantage of yielding a favorable response rate and tolerable toxicity profile.Trial Registration: ClinicalTrials.gov, identifier: NCT02836977 . Registered on 18 July 2016. [ABSTRACT FROM AUTHOR]

Background: This study investigates differences in depression and anxiety between patients with chronic hepatitis C who are treated with peginterferon alpha-2a (PegIFN-a-2a) plus ribavirin and those who are treated with peginterferon alpha-2b (PegIFN-a-2b) plus ribavirin. Methods: In this 24 week, non-randomized, observational, prospective study, 55 patients with chronic hepatitis C were treated with PegIFN-α-2a plus ribavirin (Group 1), and 26 patients were treated with PegIFN-α-2b plus ribavirin (Group 2). All patients underwent assessment using the Hospital Anxiety and Depression Scale (HADS) at the baseline and at weeks 4, 12 and 24. Patients with depression scores (HADS-D) = 8 and anxiety scores (HADS-A) = 8 were defined as having depression and anxiety, respectively. The factors that were associated with depression and anxiety during the 24 week antiviral treatment were determined. Results: During the 24 week antiviral treatment, the proportion of patients with depression significantly increased over time in both groups (Group 1: p = 0.048; Group 2: p = 0.044). The proportion of patients with anxiety did not significantly change during the follow-up period in either group. Incidences of depression or anxiety did not differ significantly between Group 1 and Group 2. A history of alcohol use disorder was an independent predictor of depression at week 12 (p < 0.001) and week 24 (p < 0.001), and a poor virological response to treatment was associated with depression at week 24 (p = 0.029). Patients who had more physical comorbidities were more likely to suffer from anxiety at week 12 (p = 0.038). Conclusions: This study did not identify significant differences in depression or anxiety between in patients with chronic hepatitis C who underwent a 24 week antiviral treatment regimen with PegIFN-α-2a plus ribavirin and those who underwent a regiment with PegIFN-α-2b plus ribavirin. Future research with larger samples and a randomized, controlled design are required to verify the findings in this study. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a lethal disease without effective treatments at present. It ranks as s as 4th and 5th in cancer-related mortality in the western countries and worldwide. Locally advanced pancreatic duct carcinoma (PDAC) and metastatic PDAC, usually found the metastases over liver, peritoneum, or lung, have been shown to be with dismal prognosis. Brain metastasis is a rare entity and most cases reported before were found post-mortem. Intraductal papillary mucinous neoplasms of the pancreas (IPMN) has been deemed as a precursor of PDAC with very slow progression rate. Here we reported a case diagnosed with IPMN-derived PDAC with brain metastasis. After surgeries for PDAC and brain metastasis, subsequent chemotherapy and radiotherapy were also given. One and half year after surgery, this patient is still living with good performance status, which may warrant individualization of therapeutic strategy for PDAC with only brain metastasis. [ABSTRACT FROM AUTHOR]

Background: Malignant insulinoma is extremely rare and accounts for only 10% of total insulinoma cases. The goal of this study is to retrospectively analyze clinical data from 15 patients with malignant insulinoma treated at Peking Union Medical College Hospital (PUMCH) from 1984 to April 2017. Methods: "Malignant insulinoma" was used as the keywords in the PUMCH medical record retrieval system to search and obtain patients' clinical information. We identified subjects diagnosed with malignant insulinoma based on clinical or surgical pathological signs and subsequently analyzed their clinical data. Results: Eight males and seven females with a median age at diagnosis of 40 years (38–54 years) were included. Eight patients (53%) had developed metastases at diagnosis, while the others (46.67%) developed metastases during the follow-up visits. The major sites of metastasis were the liver (86.7%), local tissues and blood vessels (33%) and abdominal lymph nodes (13%). All patients displayed neuroglycopenic (100%) and/or autonomic (60%) symptoms, mostly during fasting periods (73.3%), with an average blood glucose level of 1.66 ± 0.51 mmol/L. A total of 93% of the patients had one primary pancreatic lesion, 53% had a lesion in the head of the pancreas, and 47% had a lesion in the tail of the pancreas, with diameters ranging between 0.9 and 6.0 cm. Most liver metastases were multiple lesions. Selective celiac arteriography yielded 100% sensitivity for both primary pancreatic lesions and liver metastases. Most patients received synthetical treatments, including surgery, chemoembolization, and octreotide. Conclusions: Malignant insulinomas have a similar diagnostic process to that of benign insulinomas but require far more comprehensive therapies to alleviate hypoglycemic symptoms and extend patients' survival. [ABSTRACT FROM AUTHOR]