Efficacy and acceptability of noninvasive brain stimulation for treating posttraumatic stress disorder symptoms: A network meta-analysis of randomized controlled trials.

INTRODUCTION: Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management. METHODS: We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason). RESULTS: We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity. CONCLUSIONS: This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms. TRIAL REGISTRATION: PROSPERO CRD42023391562.

Efficacy and acceptability of different probiotic products plus laxatives for pediatric functional constipation: a network meta-analysis of randomized controlled trials.

The prevalence of pediatric constipation ranges from 0.7 to 29.6% across different countries. Functional constipation accounts for 95% of pediatric constipation, and the efficacy of pharmacotherapy is limited, with a success rate of 60%. Several randomized controlled trials (RCTs) have shown the benefits of probiotic supplements in treating this condition. However, the reported strains of probiotics varied among the RCTs. We aimed to compare the efficacy and acceptability of different probiotic supplements for pediatric functional constipation. The current frequentist model-based network meta-analysis (NMA) included RCTs of probiotic supplements for functional constipation in children. The primary outcome was changes in bowel movement or stool frequency; acceptability outcome was all-cause discontinuation. Nine RCTs were included (N = 710; mean age = 5.5 years; 49.4% girls). Most probiotic products, used either alone or combined with laxatives, were associated with significantly better improvement in bowel movement or stool frequency than placebo/control. Protexin plus laxatives (standardized mean difference (SMD) = 1.87, 95% confidence interval (95% CI) = 0.85 to 2.90) were associated with the greatest improvement in bowel movement or stool frequency among all the investigated probiotic products. For the single probiotic interventions, only Lactobacillus casei rhamnosus Lcr35 was associated with significant efficacy compared to placebo/control treatments (SMD = 1.37, 95% CI: 0.32 to 2.43). All the investigated probiotic products had fecal incontinence and patient drop-out rates similar to those of placebo/control treatments.  Conclusion: The results of our NMA support the application of an advanced combination of probiotics and laxatives for pediatric functional constipation if there is no concurrent contraindication.  Registration: PROSPERO (CRD42022298724). What is Known: • Despite of the high prevalence of pediatric constipation, which ranges from 0.7% to 29.6%, the efficacy of pharmacotherapy is limited, with a success rate of 60%. Several randomized controlled trials (RCTs) have shown the benefits of probiotic supplements in treating this condition. However, the reported strains of probiotics varied among the RCTs. The widely heterogeneous strains of probiotics let the traditional meta-analysis, which pooled all different strains into one group, be nonsense and insignificant. What is New: • By conducting a comprehensive network meta-analysis, we aimed to compare the efficacy and acceptability of different strains of probiotic supplements for pediatric functional constipation. Network meta-analysis of nine randomized controlled trials revealed that the most probiotic products, used either alone or combined with laxatives, were associated with significantly better improvement in bowel movement or stool frequency than placebo/control. Protexin plus laxatives was associated with the greatest improvement in bowel movement or stool frequency among all the investigated probiotic products. For the single probiotic interventions, only Lactobacillus casei rhamnosus Lcr35 was associated with significant efficacy compared to placebo/control treatments. All the investigated probiotic products had fecal incontinence and patient drop-out rates similar to those of placebo/control treatments.

Anti-cancer activity and cellular uptake of 7,3',4'- and 7,8,4'-trihydroxyisoflavone in HepG2 cells under hypoxic conditions.

Transarterial chemoembolisation (TACE) is used for unresectable hepatocellular carcinoma (HCC) treatment, but TACE-induced hypoxia leads to poor prognosis. The anti-cancer effects of soybean isoflavones daidzein derivatives 7,3',4'-trihydroxyisoflavone (734THIF) and 7,8,4'-trihydroxyisoflavone (784THIF) were evaluated under hypoxic microenvironments. Molecular docking of these isomers with cyclooxygenase-2 (COX-2) and vascular endothelial growth factor receptor 2 (VEGFR2) was assessed. About 40 µM of 734THIF and 784THIF have the best effect on inhibiting the proliferation of HepG2 cells under hypoxic conditions. At a concentration of 40 µM, 784THIF significantly inhibits COX-2 expression in pre-hypoxia conditions compared to 734THIF, with an inhibition rate of 67.73%. Additionally, 40 µM 784THIF downregulates the expression of hypoxic, inflammatory, and metastatic-related proteins, regulates oxidative stress, and inhibits the expression of anti-apoptotic proteins. The uptake by HepG2 confirmed higher 784THIF level and slower degradation characteristics under post- or pre-hypoxic conditions. In conclusion, our results showed that 784THIF had better anti-cancer effects and cellular uptake than 734THIF.

Clinical effectiveness of oral antiviral agents in older patients with COVID-19 based on real-world data.

Several randomized controlled trials and real-world cohort studies have demonstrated the efficacies of nirmatrelvir plus ritonavir (NMV-r) and molnupiravir (MOV) in at-risk patients with COVID-19; however, the effectiveness of antisevere acute respiratory syndrome-coronavirus 2 treatments on older patients (≥65 years) remains unclear. This retrospective cohort study aimed to assess the clinical effectiveness of the oral antiviral agents, MOV and NMV-r, in older patients (≥65 years) infected with severe acute respiratory syndrome-coronavirus 2. Nonhospitalized older patients with COVID-19 between January 1, 2022, and December 31, 2022, were recruited from the TriNetX Research Network. Propensity score matching (PSM) was used to match patients who received either NMV-r or MOV treatment with those who did not receive any oral antiviral agents. Hazard ratios (HRs) for composite all-cause hospitalization or death during the 30-day follow-up period were calculated. PSM revealed two cohorts with 28 824 patients each having balanced baseline characteristics. The antiviral group was associated with significantly lower risk of the primary composite outcome of all-cause hospitalization or death than the control group (241 vs. 801; HR, 0.307; 95% confidence interval (CI), 0.27-0.36) during the follow-up period. For the secondary outcome, the antiviral group had a significantly lower risk of all-cause hospitalization (288 vs. 725; HR, 0.322; 95% CI, 0.28-0.37) and mortality (16 vs. 94; HR, 0.176; 95% CI, 0.10-0.30) than the control group. Moreover, the reduced risk of all-cause hospitalization or death remained consistent in patients receiving NMV-r (HR, 0.279; 95% CI, 0.24-0.33) and MOV (HR, 0.279; 95% CI, 0.21-0.38). Our results revealed that NMV-r and MOV decreased the all-cause hospitalization and death rates among older patients with COVID-19, supporting the use of antivirals in this vulnerable population.

Efficacy and acceptability of anti-inflammatory eicosapentaenoic acid for cognitive function in Alzheimer's dementia: A network meta-analysis of randomized, placebo-controlled trials with omega-3 fatty acids and FDA-approved pharmacotherapy.

Alzheimer's dementia (AD) is a major contributor to global disability, and effective therapies to modify disease progression are currently lacking. The neuro-inflammatory theory is a potential etiology underlying this neurodegenerative disease. Previous randomized, controlled trials (RCTs) have provided inconclusive results regarding efficacy of omega-3 polyunsaturated fatty acids (PUFAs) regimens, which might provide anti-inflammatory benefits in the management of AD, in improving cognitive function among participants with AD. The objective of this frequentist-model based network meta-analysis (NMA) was to evaluate the potential advantages of omega-3 PUFAs and currently FDA-approved medications for AD on overall cognitive function in AD individuals. The primary outcomes were: (1) changes in cognitive function, and (2) acceptability, which refers to all-cause discontinuation. Additionally, secondary outcomes included quality of life, behavioral disturbances and safety/tolerability, which was assessed through the frequency of any reported adverse event. This NMA included 52 RCTs (6 with omega-3 PUFAs and 46 with FDA-approved medications) involving 21,111 participants. The results showed that long-term high-dose (1500-2000 mg/day) of eicosapentaenoic acid (EPA)-dominant omega-3 PUFAs augmented with anti-oxidants had the highest potential for cognitive improvement among all investigated treatments [standardized mean difference = 3.00, 95% confidence intervals (95 %CIs) = 1.84-4.16]. Compared to placebo, omega-3 PUFAs had similar acceptability [odds ratio (OR) = 0.46, 95 %CIs = 0.04 to 5.87] and safety profiles (OR = 1.24, 95 %CIs = 0.66 to 2.33)o. These findings support the potential neurotherapeutic effects of high dosage EPA-dominant omega-3 PUFAs for the amelioration of cognitive decline in patients with AD. Future large-scale, long-term RCTs should focus on different dosages of EPA-dominant omega-3 PUFAs regimens on improving cognitive dysfunction in patients with AD at different levels of inflammatory status and psychopathology.

Low expression of ZSCAN4 predicts unfavorable outcome in urothelial carcinoma of upper urinary tract and urinary bladder.

BACKGROUND: With the advance in genome-wide analyses, genetic alternations have been found to play an important role in carcinogenesis and aggressiveness of UC. Through bioinformatic analysis of gene expression profiles of urinary bladder urothelial carcinoma (UBUC) from publicly available GEO dataset (GSE31684), Zinc finger and SCAN domain containing 4 (ZSCAN4) was identified as a significant downregulated gene in muscle-invasive bladder cancer when compared with non-muscle-invasive bladder cancer. METHODS: The expression of ZSCAN4 was evaluated by immunohistochemistry in 340 upper urinary tract urothelial carcinomas (UTUCs) and 295 UBUCs. The expression profiles of ZSCAN4 and potential signaling pathways were analyzed bioinformatically. RESULTS: In UTUC, low expression of ZSCAN4 was significantly associated with advanced primary pT stage (P = 0.011), increased nodal metastasis (P = 0.002) and increased vascular invasion (P = 0.019). In UBUC, low expression of ZSCAN4 was significantly correlated with advanced primary pT stage (P < 0.001), increased nodal metastasis (P = 0.001), high histological grade (P = 0.003) and increased vascular invasion (P = 0.003). In survival analysis, low expression of ZSCAN4 acted as an independent negative prognostic factor for disease-specific survival and metastasis-free survival both in UTUC and UBUC. Gene ontology analysis showed that ZSCAN4 mRNA and its co-downregulated genes are associated with the mitotic cell cycle. CONCLUSIONS: Low expression of ZSCAN4 predicted worse outcome in urothelial carcinoma and might have potential regulatory role in cell mitosis.

Placebo effects on all-cause mortality of patients with COVID-19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta-analysis.

AIM: Many randomized controlled trials (RCTs) have investigated the use of interleukin 6 antagonists for the treatment of coronavirus disease 2019 (COVID-19), yielding inconsistent results. This network meta-analysis (NMA) aimed to identify the source of these inconsistent results by reassessing whether participants treated with standard of care (SoC) plus placebo have different all-cause mortality from those treated with SoC alone and to reevaluate the efficacy of interleukin 6 antagonists in the treatment of COVID-19. METHODS: We conducted a systematic search for relevant RCTs from the inception of electronic databases through 1 September 2022. The primary outcome was all-cause mortality. The secondary outcomes were the incidences of major medical events, secondary infections, all-cause discontinuation, and serious adverse events. RESULTS: The results of NMA of 33 RCTs showed that patients with COVID-19 treated with SoC plus placebo had lower odds of all-cause mortality than those who received SoC alone (OR, 0.75 [95% confidence interval, 0.58-0.97]). This finding remained consistent after excluding studies with no incident deaths. In addition, when we consider the impact of the widely promoted COVID-19 vaccination and newly developed antiviral treatment strategy, the results from the analysis of the RCT published in 2021 and 2022 remained similar. CONCLUSION: These findings suggest the potential influence of placebo effects on the treatment outcomes of COVID-19 in RCTs. When evaluating the efficacy of treatment strategies for COVID-19, it is crucial to consider the use of placebo in the design of clinical trials.

Effectiveness and acceptability of noninvasive brain and nerve stimulation techniques for migraine prophylaxis: a network meta-analysis of randomized controlled trials.

BACKGROUND: Current pharmacologic prophylactic strategies for migraine have exhibited limited efficacy, with response rates as low as 40%-50%. In addition to the limited efficacy, the acceptability of those pharmacologic prophylactic strategies were unacceptable. Although noninvasive brain/nerve stimulation strategies may be effective, the evidence has been inconsistent. The aim of this network meta-analysis (NMA) was to compare strategies of noninvasive brain/nerve stimulation for migraine prophylaxis with respect to their effectiveness and acceptability. METHODS: The PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov , ClinicalKey, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov databases were systematically searched to date of June 4th, 2021 for randomized controlled trials (RCTs). Patients with diagnosis of migraine, either episodic migraine or chronic migraine, were included. All NMA procedures were conducted under the frequentist model. RESULTS: Nineteen RCTs were included (N = 1493; mean age = 38.2 years; 82.0% women). We determined that the high frequency repetitive transcranial magnetic stimulation (rTMS) over C3 yielded the most decreased monthly migraine days among all the interventions [mean difference = - 8.70 days, 95% confidence intervals (95%CIs): - 14.45 to - 2.95 compared to sham/control groups]. Only alternating frequency (2/100 Hz) transcutaneous occipital nerve stimulation (tONS) over the Oz (RR = 0.36, 95%CIs: 0.16 to 0.82) yielded a significantly lower drop-out rate than the sham/control groups did. CONCLUSIONS: The current study provided a new direction for the design of more methodologically robust and larger RCTs based on the findings of the potentially beneficial effect on migraine prophylaxis in participants with migraine by different noninvasive brain/nerve stimulation, especially the application of rTMS and tONS. TRIAL REGISTRATION: CRD42021252638. The current study had been approval by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29).

O6-methylguanine-DNA methyltransferase modulates cisplatin-induced DNA double-strand breaks by targeting the homologous recombination pathway in nasopharyngeal carcinoma.

BACKGROUND: The homologous recombination (HR) pathway is involved in DNA damage response (DDR), which is crucial to cancer cell survival after treatment with DNA damage agents. O6-methylguanine DNA methyltransferase (MGMT) is associated with cisplatin (CDDP) resistance in cancer cells; however, the underlying mechanisms remain unclear. Here, we explored the interactions between MGMT and the HR pathway in CDDP-activated DDR and their clinical implications in nasopharyngeal carcinoma (NPC). METHODS: Human NPC cells were assessed using loss-of-function approaches in vitro. The expression correlations between MGMT and major proteins of the HR pathway were analyzed through Western blotting, quantitative real-time PCR, and bioinformatic analysis by using a public database. The physical interactions between MGMT and HR proteins were studied using co-immunoprecipitation and immunofluorescence analyses. Cell comet tails and γ-H2AX expression levels were examined to evaluate double-strand break (DSB) formation. Established immunofluorescence and reporter analyses were conducted to measure HR activity. Xenograft and cell viability studies were used to assess the therapeutic potential of MGMT inhibition in combination with CDDP and poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. RESULTS: Among major proteins of the HR pathway, MGMT suppression inhibited CDDP-induced RAD51 expression. Bioinformatic analyses showed a positive correlation between MGMT and RAD51 expression in patients with NPC. Moreover, MGMT physically interacted with BRCA1 and regulated CDDP-induced BRCA1 phosphorylation (ser 988). In functional assays, MGMT inhibition increased CDDP-induced DSB formation through attenuation of HR activity. NPC xenograft studies demonstrated that MGMT inhibition combined with CDDP treatment reduced tumor size and downregulated RAD51 expression and BRCA1 phosphorylation. Furthermore, MGMT suppression increased PARP inhibitor-induced cell death and DSB formation in NPC cells. CONCLUSION: MGMT is crucial in the activation of the HR pathway and regulates DDR in NPC cells treated with CDDP and PARP inhibitor. Thus, MGMT is a promising therapeutic target for cancer treatments involving HR-associated DDR.

High glycosyltransferase 8 domain containing two protein levels contribute to poor prognosis in urothelial carcinoma.

OBJECTIVE: To examine the expression levels of the glycosyltransferase 8 domain containing protein 2 and its clinical implications in urothelial carcinoma patients. METHODS: Data mining, immunohistochemistry together with H-score calculation was carried out to evaluate the glycosyltransferase 8 domain containing protein 2 levels on tissue specimens from urothelial carcinoma patients, retrospectively. Correlations between glycosyltransferase 8 domain containing protein 2 H-score and imperative clinicopathological factors were measured. The indication of glycosyltransferase 8 domain containing protein 2 level on disease-specific and metastasis-free survivals were next analyzed. RESULTS: In upper tract urothelial carcinomas (n = 340) and bladder urothelial carcinomas (n = 295), 170 (50%) and 148 (50%) patients, respectively, were identified to have high glycosyltransferase 8 domain containing protein 2 expression. The glycosyltransferase 8 domain containing protein 2 levels were correlated to several clinicopathological characteristics and patient survival. Upregulation of the glycosyltransferase 8 domain containing protein 2 was correlated to primary tumor (P < 0.001), nodal metastasis (P < 0.001), histological grade (P < 0.001), vascular invasion (P < 0.001), perineural invasion (P < 0.05) and mitotic rate (P < 0.001). High glycosyltransferase 8 domain containing protein 2 levels independently predicted poor disease-specific survival (P = 0.049) and metastasis-free survival (P = 0.008) in upper tract urothelial carcinoma and urinary bladder urothelial carcinoma, respectively. Gene Ontology enrichment analysis additionally showed that multiple biological processes were enriched including "ECM organization" (Gene Ontology:0030198), "extracellular structure organization" (Gene Ontology:0043062), "biological adhesion" (Gene Ontology:0022610), "cell adhesion" (Gene Ontology:0007155), "collagen fibril organization" (Gene Ontology:0030199) and "vasculature development" (Gene Ontology:0001944). CONCLUSIONS: The present findings suggest that upregulation of the glycosyltransferase 8 domain containing protein 2 is an independent and disadvantageous prognosticator in urothelial carcinoma. High glycosyltransferase 8 domain containing protein 2 level might play a crucial role in progression of urothelial carcinoma.

ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of SKP2 at Both Transcriptional and Post-Translational Levels.

The objective was to investigate the anti-cancer effects and underlying molecular mechanisms of cytostasis which were activated by an anti-microtubule drug, ABT-751, in two urinary bladder urothelial carcinoma (UBUC)-derived cell lines, BFTC905 and J82, with distinct genetic backgrounds. A series of in vitro assays demonstrated that ABT-751 induced G2/M cell cycle arrest, decreased cell number in the S phase of the cell cycle and suppressed colony formation/independent cell growth, accompanied with alterations of the protein levels of several cell cycle regulators. In addition, ABT-751 treatment significantly hurdled cell migration and invasion along with the regulation of epithelial-mesenchymal transition-related proteins. ABT-751 triggered autophagy and apoptosis, downregulated the mechanistic target of rapamycin kinase (MTOR) and upregulated several pro-apoptotic proteins that are involved in extrinsic and intrinsic apoptotic pathways. Inhibition of autophagosome and autolysosome enhanced apoptosis was also observed. Through the inhibition of the NFκB signaling pathway, ABT-751 suppressed S-phase kinase associated protein 2 (SKP2) transcription and subsequent translation by downregulation of active/phospho-AKT serine/threonine kinase 1 (AKT1), component of inhibitor of nuclear factor kappa B kinase complex (CHUK), NFKB inhibitor alpha (NFKBIA), nuclear RELA proto-oncogene, NFκB subunit (RELA) and maintained a strong interaction between NFKBIA and RELA to prevent RELA nuclear translocation for SKP2 transcription. ABT-751 downregulated stable/phospho-SKP2 including pSKP2(S64) and pSKP2(S72), which targeted cyclin-dependent kinase inhibitors for degradation through the inactivation of AKT. Our results suggested that ABT-751 may act as an anti-cancer drug by inhibiting cell migration, invasion yet inducing cell cycle arrest, autophagy and apoptosis in distinct UBUC-derived cells. Particularly, the upstream molecular mechanism of its anticancer effects was identified as ABT-751-induced cytostasis through the inhibition of SKP2 at both transcriptional and post-translational levels to stabilize cyclin dependent kinase inhibitor 1A (CDKN1A) and CDKN1B proteins.

High G protein subunit beta 4 protein level is correlated to poor prognosis of urothelial carcinoma.

Data mining on a public domain detected eight potential transcripts which were upregulated in advanced UBUCs, suggesting that they may take part in UC development or/and progression. Retrospectively, immunohistochemistry along with H-score recording was carried out to evaluate the GNB4 protein levels on tissues from UC patients. Correlations between GNB4 H-score and imperative clinicopathological factors, as well as the implication of GNB4 protein level on disease-specific and metastasis-free survivals were assessed. In UTUCs (n = 340) and UBUCs (n = 295), 170 (50.0%) and 148 (50.0%) cases, respectively, were identified to be of high GNB4 expression. The GNB4 protein levels were correlated to numerous clinicopathological features and patients' survivals. Upregulation of the GNB4 protein was significantly associated with primary tumor, nodal metastasis, histological grade, vascular invasion and mitotic rate. High GNB4 protein levels independently and significantly predicted poor disease-specific and metastasis-free in UTUC and UBUC, respectively. Ingenuity pathway analysis furthermore showed that multiple signaling pathways were enriched including 'Communication between Innate and Adaptive Immune Cells' and 'NFκB Signaling'. Our findings demonstrated that the upregulation of the GNB4 protein is an independent unfavorable prognosticator in UC. High GNB4 gene expression plays an important role in UC progression.

High EREG Expression Is Predictive of Better Outcomes in Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy.

BACKGROUND/AIM: A great proportion of patients with rectal cancer initially present with locally advanced disease and can potentially benefit from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before surgery. However, risk and clinical outcome stratification remain a great challenge. We aimed to find the potential biomarker to predict the effect of neoadjuvant CCRT on rectal cancer. METHODS: We identified epiregulin (EREG) as the most significant predictive marker for neoadjuvant CCRT response from the published rectal cancer transcriptome data set GSE35452. We collected 172 biopsy specimens from rectal cancer patients who received neoadjuvant CCRT followed by radical proctectomy, performed EREG immunohistochemistry, and analyzed the H-scores. We further examined the correlations between the expression level of EREG and clinicopathological features, tumor regression grade, and survival, including disease-specific survival (DSS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MeFS). RESULTS: High EREG expression was significantly related to early pretreatment (pre-Tx) and posttreatment (post-Tx) tumor status (T1, T2, p = 0.047 and p < 0.001), pre-Tx and post-Tx negative nodal status (N0, p < 0.001 and p = 0.004), less vascular and perineurial invasion (p = 0.015 and p = 0.023), and higher tumor regression grade (p < 0.001). In the survival analysis, high EREG expression was significantly associated with better DSS (p < 0.0001), LRFS (p = 0.0004), and MeFS (p < 0.0001). In the multivariate analysis, high EREG expression remained prognostically significant for better DSS (p = 0.003; hazard ratio: 5.599). CONCLUSION: These data suggest that EREG is a potential predictive marker and therapeutic target in rectal cancer patients receiving neoadjuvant CCRT.

The association between melatonin and episodic migraine: A pilot network meta-analysis of randomized controlled trials to compare the prophylactic effects with exogenous melatonin supplementation and pharmacotherapy.

Although exogenous melatonin supplementation has been suggested to be effective for episodic migraine prophylaxis, there is no conclusive evidence comparing the efficacy of exogenous melatonin supplementation to the other FDA-approved pharmacotherapy for episodic migraine prophylaxis. The aim of the current network meta-analysis (NMA) was to compare the efficacy of exogenous melatonin supplementation in patients with episodic migraine. The randomized placebo-controlled trials or randomized controlled trials (RCTs) incorporating a placebo in the study designs were included in our analyses. All of the NMA procedures were conducted under the frequentist model. The primary outcome was changes in frequency of migraine days and response rate after migraine prophylaxis with melatonin supplementation or pharmacological interventions. We included 25 RCTs in total with 4499 patients (mean age = 36.0 years, mean female proportion = 78.9%). The NMA demonstrated that migraine prophylaxis with oral melatonin 3 mg/d (immediate-release) at bedtime was associated with the greatest improvement in migraine frequency [mean difference = -1.71 days, 95% confidence interval (CI): -3.27 to -0.14 days compared to placebo] and the second highest response rate (odds ratio = 4.19, 95% CI = 1.46 to 12.00 compared to placebo). Furthermore, oral melatonin 3 mg (immediate-release) at bedtime was the most preferred pharmacological intervention among all of the investigated interventions when improvements in migraine frequency, response rate, dropout rate, and rates of any adverse events were taken into account. This pilot NMA suggests the potential prophylactic role of exogenous melatonin supplementation in patients with episodic migraine.

Inhibition of the formation of autophagosome but not autolysosome augments ABT-751-induced apoptosis in TP53-deficient Hep-3B cells.

The objective was to investigate the upstream mechanisms of apoptosis which were triggered by a novel antimicrotubule drug, ABT-751, in a tumor protein p53 ( TP53)-deficient hepatocellular carcinoma-derived Hep-3B cells. A series of in vitro assays indicated that ABT-751 caused the disruption of the mitotic spindle structure, collapse of mitochondrial membrane potential, generation of reactive oxygen species, DNA damage, G 2 /M cell cycle arrest, inhibition of anchorage-independent cell growth and apoptosis in Hep-3B cells accompanied by alteration of the expression levels of several DNA damage checkpoint proteins and cell cycle regulators. Subsequently, ABT-751 triggered apoptosis along with markedly upregulated several proapoptotic proteins involving in extrinsic, intrinsic, and caspase-mediated apoptotic pathways. A pan-caspase inhibitor suppressed ABT-751-induced apoptosis. ABT-751 also induced autophagy soon after the occurrence of apoptosis through the suppression of AKT serine/threonine kinase/mechanistic target of rapamycin signaling pathway. Exogenous expression of the TP53 gene significantly incurred both apoptosis and autophagy in Hep-3B cells. Pharmacological inhibition of autophagosome (early autophagy) but not autolysosome (late autophagy) enhanced ABT-751-induced apoptosis in TP53-deficient Hep-3B cells. Our study provided a new strategy to augment ABT-751-induced apoptosis in TP53-deficient cells.

Differential clinical significance of COL5A1 and COL5A2 in tongue squamous cell carcinoma.

BACKGROUND: Type V collagen (COL5), in the functional heterotrimer [α1(V)2 α2(V)] isoform, participates in the malignancies of various cancers. However, its role in tongue squamous cell carcinoma (TSCC) remains unclear. MATERIALS AND METHODS: The expression levels of COL5A1 and COL5A2 polypeptide chains were examined using the tissue microarray from 245 TSCC patients with immunohistochemistry. Paired t test and Wilcoxon signed-rank test were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan-Meier method and compared with log-rank tests. A Cox proportional hazards model was used to evaluate the impact of protein expression level on survival rate. RESULTS: Expression level of COL5A1 was significantly increased in tumor tissues (P < 0.001) compared to that in corresponding adjacent normal tissues. High expression level of COL5A1 was associated with advanced pathological stage (III, IV, P = 0.015) and lymph node metastasis (P = 0.005) of TSCC patients. High expression level of COL5A1 was also correlated with poor disease-specific survival (DSS, P = 0.001) and disease-free survival (DFS, P = 0.003) in TSCC patients. However, high expression level of COL5A2 was correlated with better DFS in TSCC patients (P = 0.043). Moreover, co-expression level of high (COL5A1)2 /low (COL5A2) heterotrimer was correlated with worse DSS (P = 0.004) and DFS (P = 0.004). CONCLUSION: COL5A1 is an unfavorable factor for tumorigenesis, clinicopathological outcomes, and prognosis, whereas COL5A2 is only a favorable factor for prognosis in TSCC. The co-expression of high (COL5A1)2/low (COL5A2) heterotrimer is a more potential unfavorable factor for prognosis in TSCC.

Vein Pattern Locating Technology for Cannulation: A Review of the Low-Cost Vein Finder Prototypes Utilizing near Infrared (NIR) Light to Improve Peripheral Subcutaneous Vein Selection for Phlebotomy.

One of the most common means for diagnosis is through medical laboratory testing, which primarily uses venous blood as a sample. This requires an invasive method by cannulation that needs proper vein selection. The use of a vein finder would help the phlebotomist to easily locate the vein, preventing possible pre-analytical error in the specimen collection and even more discomfort and pain to the patient. This paper is a review of the scientific publications on the different developed low-cost vein finder prototypes utilizing camera assisted near infrared (NIR) light technology. Methods: Electronic databases were searched online, these included PubMed (PMC), MEDLINE, Science Direct, ResearchGate, and Institute of Electrical and Electronics Engineers (IEEE) Xplore digital library. Specifically, publications with the terms vein finder prototype, NIR technology, vein detection, and infrared imaging were screened. In addition, reference lists were used to further review related publications. Results: Cannulation challenges medical practitioners because of the different factors that can be reduced by the utilization of a vein finder. A limited number of publications regarding the assessment of personnel performing cannulation were observed. Moreover, variations in methodology, number of patients, type of patients according to their demographics and materials used in the assessment of the developed prototypes were noted. Some studies were limited with regard to the actual human testing of the prototype. Conclusions: The development of a low-cost effective near infrared (NIR) vein finder remains in the phase of improvement. Since, it is being challenged by different human factors, increasing the number of parameters and participants/human for actual testing of the prototypes must also be taken into consideration for possible commercialization. Finally, it was noted that publications regarding the assessment of the performance of phlebotomists using vein finders were limited.

Prediction of progression in skull base meningiomas: additional benefits of apparent diffusion coefficient value.

A subset of benign (WHO grade I) skull base meningiomas show early progression/recurrence (P/R) in the first years after surgical resection. Besides, complete surgical resection may be difficult to achieve safely in skull base meningiomas due to complex neurovascular structures. The one main challenge in the treatment of skull base meningiomas is to determine factors that correlate with P/R. We retrospectively investigated the preoperative CT and MR imaging features for the prediction of P/R in skull base meningiomas, with emphasis on quantitative ADC values. Only patients had postoperative MRI follow-ups for more than 1 year (at least every 6 months) were included. From October 2006 to December 2015, total 73 patients diagnosed with benign (WHO grade I) skull base meningiomas were included (median follow-up time 41 months), and 17 (23.3%) patients had P/R (median time to P/R 28 months). Skull base meningiomas with spheno-orbital location, adjacent bone invasion, high DWI, and lower ADC value/ratio were significantly associated with P/R (P < 0.05). The cut-off points of ADC value and ADC ratio for prediction of P/R are 0.83 × 10- 3 mm2/s and 1.09 respectively, with excellent area under curve (AUC) values (0.86 and 0.91) (P < 0.05). In multivariate logistic regression, low ADC values (< 0.83 × 10- 3 mm2/s) and adjacent bone invasion are high-risk factors of P/R (P < 0.05), with odds ratios of 31.53 and 17.59 respectively. The preoperative CT and MRI features for prediction of P/R offered clinically vital information for the planning of treatment in skull base meningiomas.

The influence of disease-modifying anti-rheumatic drugs and corticosteroids on the association between rheumatoid arthritis and skin cancer: a nationwide retrospective case-control study in Taiwan.

OBJECTIVES: To investigate the influence of corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs, including conventional synthetic and biologic DMARDs) treatment on the association between rheumatoid arthritis (RA) and non-melanoma skin cancer (NMSC). METHODS: This nationwide retrospective case-control study retrieved data from Taiwan National Health Insurance Research Database during 1995-2013. Cases with newly-diagnosed NMSC (n=19,603) were matched with control without NMSC in a 1:1 ratio according to age, sex, and reference date. The aforementioned association was analysed using conditional logistic regression and adjustments for age, sex, residential regions, occupations, and co-morbidities. Causality cannot be inferred by case-control study. RESULTS: Compared to patients without RA, the patients with RA had a significantly higher association with NMSC (adjusted odds ratio (AOR)=2.23, 95% confidence interval (CI) 1.6-3.1, p<0.001), especially those using cyclosporine (AOR=5.7, 95%CI 2.2-14.86; ≥65 years: AOR=7.28, 95%CI 2.16-24.56), etanercept (AOR=5.27, 95%CI 1.15-24.27; ≥65 years: AOR=8.95, 95%CI 1.12-71.85), and d-penicillamine (AOR=4.79, 95%CI 1.63-14.12; ≥65 years: AOR=3.81, 95%CI 1.26-11.52); those using higher cumulative doses of corticosteroids and methotrexate (corticosteroids: >10g: AOR=2.96, 95%CI 1.67-5.22; >10g and ≥65years: AOR=3.5, 95%CI 1.77-6.92; methotrexate: 1-3g: AOR=2.57, 95%CI 1.13-5.82; >3g: AOR=4.64, 95%CI 1.74-12.4; >3g and ≥65 years: AOR=10.17, 95%CI 2.34-44.26); and those using more kinds of DMARDs (any 3: AOR=3.72, 95%CI 1.67-8.26; any 5: AOR=2.81, 95%CI 1.13-7.04; any 6: AOR=5.23, 95%CI 1.14-24.14; 7-8: AOR=4.06, 95%CI 1.14-14.49). CONCLUSIONS: The patients with RA had significantly increased associations with NMSC, especially those receiving cyclosporine, etanercept, and d-penicillamine; higher cumulative doses of corticosteroids and methotrexate; or more kinds of DMARDs in combination or in sequence. The aforementioned associations were much stronger in the elderly.