CircDUSP22 Overexpression Restrains Pancreatic Cancer Development via Modulating miR-1178-3p and Downstream BNIP3.

Aberrant expression of circular RNAs (circRNAs) is important in carcinogenesis, however, many differentially expressed circRNAs have not been functionally characterized. This study aimed to unveil the role of circRNA-dual specificity phosphatase 22 (circDUSP22) in pancreatic cancer (PaCa). Expression analyses of circDUSP22, miR-1178-3p and BCL2 interacting protein 3 (BNIP3) were carried out using quantitative real-time PCR (qRT-PCR) or western blotting. Cell growth was assessed by MTT, EdU and colony formation assays. Cell cycle distribution and cell apoptosis were investigated using flow cytometry assay. The assumed binding relationship between miR-1178-3p and circDUSP22 or BNIP3 was testified by dual-luciferase reporter and pull-down assays. The effect of circDUSP22 in vivo was identified by animal studies. The decreased expression of circDUSP22 was observed in PaCa samples and cells. CircDUSP22 ectopic expression in vitro blocked PaCa cell proliferation, arrested cell cycle and provoked cell apoptosis. CircDUSP22 targeted miR-1178-3p, whose expression was reinforced in PaCa. The inhibitory cell growth caused by circDUSP22 ectopic expression was reversed by miR-1178-3p enrichment. In addition, miR-1178-3p targeted BNIP3, whose expression was declined in PaCa. The inhibitory cell growth caused by circDUSP22 ectopic expression was reversed by BNIP3 knockdown. CircDUSP22 overexpression in vivo decelerated tumor growth. CircDUSP22 upregulation blocked PaCa development partly by targeting miR-1178-3p and increasing BNIP3, implying the potential implication of circDUSP22 in targeted therapy of PaCa.

A ß-ketoacyl carrier protein reductase confers heat tolerance via the regulation of fatty acid biosynthesis and stress signaling in rice.

Heat stress is a major environmental threat affecting crop growth and productivity. However, the molecular mechanisms associated with plant responses to heat stress are poorly understood. Here, we identified a heat stress-sensitive mutant, hts1, in rice. HTS1 encodes a thylakoid membrane-localized ß-ketoacyl carrier protein reductase (KAR) involved in de novo fatty acid biosynthesis. Phylogenetic and bioinformatic analysis showed that HTS1 probably originated from streptophyte algae and is evolutionarily conserved in land plants. Thermostable HTS1 is predominantly expressed in green tissues and strongly induced by heat stress, but is less responsive to salinity, cold and drought treatments. An amino acid substitution at A254T in HTS1 causes a significant decrease in KAR enzymatic activity and, consequently, impairs fatty acid synthesis and lipid metabolism in the hts1 mutant, especially under heat stress. Compared to the wild-type, the hts1 mutant exhibited heat-induced higher H2 O2 accumulation, a larger Ca2+ influx to mesophyll cells, and more damage to membranes and chloroplasts. Also, disrupted heat stress signaling in the hts1 mutant depresses the transcriptional activation of HsfA2s and the downstream target genes. We suggest that HTS1 is critical for underpinning membrane stability, chloroplast integrity and stress signaling for heat tolerance in rice.

Efficacy and safety of carisbamate in patients with diabetic neuropathy or postherpetic neuralgia: results from 3 randomized, double-blind placebo-controlled trials.

The results of 3 proof-of-concept studies to evaluate carisbamate's efficacy and safety in treating neuropathic pain are presented. In studies 1 (postherpetic neuralgia, n = 91) and 2 (diabetic neuropathy, n = 137), patients received carisbamate 400 mg/day or placebo for 4 weeks and then crossed over to the other treatment for 4 weeks. In study 3 (diabetic neuropathy, higher carisbamate doses), patients (n = 386) were randomized (1:1:1:1) to receive either carisbamate 800 mg/day, 1200 mg/day, pregabalin 300 mg/day or placebo for 15 weeks. Primary efficacy end point was the mean of the last 7 average daily pain scores obtained on days the study drug was taken, for all 3 studies. Least square mean (95% CI) differences between carisbamate and placebo groups on the primary end point were as follows: study 1: -0.512 (-1.32, 0.29) carisbamate 400 mg/day; study 2: -0.307 (-0.94, 0.33) carisbamate 400 mg/day; and study 3: -0.51 (-1.10, 0.08), carisbamate 800 mg/day; -0.55 (-1.13, 0.04), carisbamate 1200 mg/day; and -0.43 (-1.01, 0.15), pregabalin 300 mg/day. Neither carisbamate (all 3 studies) nor pregabalin (study 3) significantly differed from placebo, although multiple secondary end points showed significant improvement in efficacy with carisbamate in studies 1 and 2. Dizziness was the only treatment-emergent adverse event occurring at ≥10% difference in carisbamate groups versus placebo (study 1: 12% vs. 1%; study 3: 14% vs. 4%; study 2: 1% vs. 2%). Carisbamate, although well tolerated, did not demonstrate efficacy in neuropathic pain across these studies, nor did the active comparator pregabalin (study 3).

Effects of Mesalamine Combined with Live Combined Bifidobacterium, Lactobacillus and Enterococcus Capsules on Intestinal Mucosa Barrier Function and Intestinal Microbiota in Mildly Active Crohn's Disease Patients.

Objective: This study is aimed at investigating the impact of mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules on intestinal mucosa barrier function and intestinal microbiota in mildly active Crohn's disease patients.Methods: Ninety-six Crohn's disease patients in mild activity period were randomized into the control group (treated with mesalamine) and the observation group (treated with mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules) (n = 48). After 4 wk of treatment, the patients were evaluated for their clinical efficacy. Intestinal microbiota counts, serum inflammatory factors, T lymphocyte subsets, and mucosal barrier function indicators in both groups were assessed.Results: After 4 wk of treatment, the total clinical effective rate of the observation group was higher than that of the control group. The number of Lactobacillus acidophilus (L. acidophilus) and Bifidobacterium Longum (B. longum) in the intestinal tract, serum IL-10 levels, and peripheral blood CD4+ and CD4+/CD8+ levels were higher, and the number of Bacteroides vulgatus (B. vulgatus), the levels of TNF-α, IL-6, CRP, CD8+, ET, D-lactate, DAO, and urine L/M ratio were lower in the observation group in comparison to those in the control group (all p < 0.05).Conclusion: Mesalamine combined with Live combined Bifidobacterium, Lactobacillus and Enterococcus capsules are more effective in treating mildly active Crohn's disease.

Association between serum potassium and Parkinson's disease in the US (NHANES 2005-2020).

Background: Evaluating the correlation between serum potassium and Parkinson's disease (PD) in US adults. Methods: A cross-sectional study was conducted on 20,495 adults aged 40 years or older using NHANES data from 2005 to 2020. The study utilized one-way logistic regression and multifactorial logistic regression to examine the correlation between serum potassium levels and PD. Additionally, a smoothed curve fitting approach was employed to assess the concentration-response relationship between serum potassium and PD. Stratified analyses were carried out to investigate potential interactions between serum potassium levels and PD with variables such as age, sex, race, marital status, education, BMI, smoking and medical conditions like coronary, stroke, diabetes, hypertension, and hypercholesterolemia. Results: In this study, a total of 20,495 participants, comprising 403 PD and 20,092 non-PD individuals, were included. After adjusted for covariates, multivariable logistic regression revealed that high serum potassium level was an independent risk factor for PD (OR:1.86, 95% CI:1.45 ~ 2.39, p < 0.01).The linear association between serum potassium and PD was described using fitted smoothing curves. Age, sex, race, education, marital, BMI, coronary, stroke, diabetes, hypertension and hypercholesterolemia were not significantly correlated with this positive connection, according to subgroup analysis and interaction testing (P for interaction >0.05). Conclusion: Serum potassium levels are elevated in patients with Parkinson's disease compared to non-PD patients. Additional prospective studies are required to explore the significance of serum potassium levels in individuals with Parkinson's disease.

Disease progression model in subjects with mild cognitive impairment from the Alzheimer's disease neuroimaging initiative: CSF biomarkers predict population subtypes.

AIM: The objective is to develop a semi-mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS-cog scores from the Alzheimer's disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for 3 years. METHOD: Various covariates were tested on disease progression parameters and these variables fell into six categories: imaging volumetrics, biochemical, genetic, demographic, cognitive tests and CSF biomarkers. RESULTS: CSF biomarkers were associated with both baseline disease score and disease progression rate in subjects with MCI. Baseline disease score was also correlated with atrophy measured using hippocampal volume. Progression rate was also predicted by executive functioning as measured by the Trail B-test. CONCLUSION: CSF biomarkers have the ability to discriminate MCI subjects into sub-populations that exhibit markedly different rates of disease progression on the ADAS-cog scale. These biomarkers can therefore be utilized for designing clinical trials enriched with subjects that carry the underlying disease pathology.

State-of-the-art polyetheretherketone three-dimensional printing and multifunctional modification for dental implants.

Polyetheretherketone (PEEK) is a high-performance thermoplastic polymer with an elastic modulus close to that of the jawbone. PEEK has the potential to become a new dental implant material for special patients due to its radiolucency, chemical stability, color similarity to teeth, and low allergy rate. However, the aromatic main chain and lack of surface charge and chemical functional groups make PEEK hydrophobic and biologically inert, which hinders subsequent protein adsorption and osteoblast adhesion and differentiation. This will be detrimental to the deposition and mineralization of apatite on the surface of PEEK and limit its clinical application. Researchers have explored different modification methods to effectively improve the biomechanical, antibacterial, immunomodulatory, angiogenic, antioxidative, osteogenic and anti-osteoclastogenic, and soft tissue adhesion properties. This review comprehensively summarizes the latest research progress in material property advantages, three-dimensional printing synthesis, and functional modification of PEEK in the fields of implant dentistry and provides solutions for existing difficulties. We confirm the broad prospects of PEEK as a dental implant material to promote the clinical conversion of PEEK-based dental implants.

Utility of clinical metagenomics in diagnosing malignancies in a cohort of patients with Epstein-Barr virus positivity.

Backgrounds: Differentiation between benign and malignant diseases in EBV-positive patients poses a significant challenge due to the lack of efficient diagnostic tools. Metagenomic Next-Generation Sequencing (mNGS) is commonly used to identify pathogens of patients with fevers of unknown-origin (FUO). Recent studies have extended the application of Next-Generation Sequencing (NGS) in identifying tumors in body fluids and cerebrospinal fluids. In light of these, we conducted this study to develop and apply metagenomic methods to validate their role in identifying EBV-associated malignant disease. Methods: We enrolled 29 patients with positive EBV results in the cohort of FUO in the Department of Infectious Diseases of Huashan Hospital affiliated with Fudan University from 2018 to 2019. Upon enrollment, these patients were grouped for benign diseases, CAEBV, and malignant diseases according to their final diagnosis, and CNV analysis was retrospectively performed in 2022 using samples from 2018 to 2019. Results: Among the 29 patients. 16 of them were diagnosed with benign diseases, 3 patients were diagnosed with CAEBV and 10 patients were with malignant diseases. 29 blood samples from 29 patients were tested for mNGS. Among all 10 patients with malignant diagnosis, CNV analysis suggested neoplasms in 9 patients. Of all 19 patients with benign or CAEBV diagnosis, 2 patients showed abnormal CNV results. The sensitivity and specificity of CNV analysis for the identification for tumors were 90% and 89.5%, separately. Conclusions: The application of mNGS could assist in the identification of microbial infection and malignancies in EBV-related diseases. Our results demonstrate that CNV detection through mNGS is faster compared to conventional oncology tests. Moreover, the convenient collection of peripheral blood samples adds to the advantages of this approach.

Detection of Bartonella vinsonii subsp. berkhoffii in an HIV patient using metagenomic Next-Generation Sequencing.

Bartonella species are fastidious, aerobic bacteria that are transmitted by blood-sucking arthropods. Bartonella spp. are responsible for cat scratch disease, Carrion's disease, bacillary angiomatosis and trench fever. On the other hand, Bartonella vinsonii is rarely reported in the literature and there exist a few reports of systemic infection caused by Bartonella vinsonii in patients with acquired immunodeficiency syndrome. A 31-year-old male (diagnosed with AIDS six years ago) had persistent fever and ulceration in the right knee. The elevated levels of inflammatory markers suggested an infectious aetiology. Despite the negative findings of blood culture, metagenomic Next-Generation Sequencing of plasma detected Bartonella vinsonii. The polymerase chain reaction of whole blood and Sanger sequencing confirmed the mNGS findings. Immunohistochemical staining had later suggested bacillary angiomatosis, which was consistent with Bartonella infection. Following antibiotic treatment, the ulcers subsided significantly, but a high fever persisted. The patient died due to sudden respiratory failure.

Diffuse Large B-Cell Lymphoma of the Mandible Diagnosed by Metagenomic Sequencing: A Case Report.

Introduction: Non-Hodgkin lymphoma (NHL) has a much higher incidence rate than Hodgkin lymphoma. Approximately 40% NHL occurs in extranodal tissues or organs, and its clinical manifestations are often nonspecific. Primary bone NHL involving the mandible is an uncommon NHL that is characterized by fever, gum swelling and toothache. Therefore, it is often misdiagnosed as oral diseases. Case Presentation: A 52-year-old female had recurrent fever for more than 1 month, with numbness in her left jaw and toothache. PET/CT showed an uptake area in the left mandible, suggesting microbial infections. However, antibacterial, and antiviral treatment were ineffective. Furthermore, metagenomic sequencing of plasma reported no pathogens, but instead showed significant copy number variations of multiple chromosomes, which highly suggested the existence of tumor. Finally, diffuse large B-cell lymphoma (DLBCL) was diagnosed by mandibular biopsy, and the patient was transferred to Hematology department for chemotherapy. Conclusion: mNGS not only assists rapid etiological diagnosis, but also helps rule out infection and diagnose malignant neoplasm.

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.

Importance: Atabecestat, a nonselective oral ß-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. Interventions: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). Main Outcomes and Measures: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. Results: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups. Conclusions and Relevance: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02569398.

Analysis of safety and tolerability data obtained from over 1,500 patients receiving topiramate for migraine prevention in controlled trials.

OBJECTIVE: Topiramate is an effective and generally well-tolerated migraine preventive therapy, as shown in three large, randomized, double-blind, placebo-controlled registration trials. Based upon efficacy/tolerability, topiramate 100 mg/day (50 mg BID) is the recommended target dose for most patients with migraine. To further assess the safety and tolerability of topiramate for migraine prevention, we analyzed safety data from 1,580 patients who participated in the three pivotal registration trials or an earlier pilot, randomized, double-blind, placebo-controlled trial. METHODS: The safety population consisted of all patients who took >or=1 dose of study medication during the double-blind phase (topiramate 50 mg/day [N = 235], 100 mg/day [N = 386], 200 mg/day [N = 514], or placebo [N = 445]). Safety assessments included adverse event (AE) reports, physical examination, and clinical laboratory tests. RESULTS: Paresthesia was the most common topiramate-associated AE (35%, 51%, and 49% of patients receiving topiramate 50 mg/day, 100 mg/day, or 200 mg/day, respectively [6% on placebo]). The most common topiramate-associated AE were generally mild or moderate in severity and occurred at consistently higher rates during the titration period, compared with the maintenance period of the double-blind phase. AEs leading to withdrawal from the recommended dose of topiramate 100 mg/day included paresthesia (8%), fatigue (5%), nausea (2%), and difficulty with concentration (2%). Serious AEs were infrequent, occurring in 2% of 1,135 topiramate-treated patients and 3% of 445 placebo-treated patients. Patients on topiramate experienced significant decreases in mean body weight compared with placebo. CONCLUSIONS: Topiramate is generally safe and reasonably well tolerated for the prevention of migraine in adults. The most common topiramate-associated AEs were mild or moderate in severity and occurred more frequently during titration to target doses.

Comprehensive review of visual defects reported with topiramate.

OBJECTIVE: The objective of this study was to analyze clinical patterns of visual field defects (VFDs) reported with topiramate treatment and assess possible mechanism of action (MOA) for antiepileptic drug (AED) associated VFDs. METHODS: A comprehensive topiramate database review included preclinical data, sponsor's clinical trials database, postmarketing spontaneous reports, and medical literature. All treatment-emergent adverse events (TEAEs) suggestive of retinal dysfunction/damage were summarized. Relative risk (RR) was computed from topiramate double-blind, placebo-controlled trials (DBPCTs) data. RESULTS: Preclinical studies and medical literature review suggested that despite sharing gamma-aminobutyric acid (GABA)-ergic MOA with other AEDs, topiramate treatment was not associated with VFDs. TEAEs suggestive of retinal dysfunction/damage were observed in 0.3%-0.7% of adults and pediatric patients with topiramate (N=4,679) versus ≤0.1% with placebo (N=1,834) in DBPCTs for approved indications (epilepsy and migraine prophylaxis); open-label trials (OLTs) and DBPCTs for investigational indications had similar incidence. Overall, 88% TEAEs were mild or moderate in severity. Serious TEAEs were very rare (DBPCTs: 0%; OLTs: ≤0.1%), and most were not treatment limiting, and resolved. The most common visual TEAEs (approved indications) were VFD, scotoma, and optic atrophy. The incidence of TEAEs in DBPCTs (approved and investigational indications) was higher in topiramate-treated (N=9,169) versus placebo-treated patients (N=5,023; 0.36% vs 0.24%), but the RR versus placebo-treated patients was not significant (RR: 1.51 [95% confidence interval: 0.78, 2.91]). CONCLUSION: VFDs do not appear to be a class effect for AEDs with GABA-ergic MOA. The RR for VFDs is not significantly different between topiramate and placebo treatment.

A novel subject synchronization clinical trial design for Alzheimer's disease.

One of the challenges in developing a viable therapy for Alzheimer's disease has been demonstrating efficacy within a clinical trial. Using this as motivation, we sought to re-examine conventional clinical trial practices in order to determine whether efficacy can be better shown through alternative trial designs and novel analysis methods. In this work, we hypothesize that the confounding factors which hamper the ability to discern a treatment signal are the variability in observations as well as the insidious nature of the disease. We demonstrate that a two-phase trial design in which drug dosing is administered after a certain level of disease severity has been reached, coupled with a method to account more accurately for the progression of the disease, may allow us to compensate for these factors, and thus enable us to make treatment effects more apparent. Utilizing data from two previously failed trials which involved the evaluation of galantamine for indication in mild cognitive impairment, we were able to demonstrate that a clear treatment effect can be realized through both visual and statistical means, and propose that future trials may be more likely to show success if similar methods are utilized.

Safety and tolerability of tegaserod in patients with irritable bowel syndrome and diarrhea symptoms.

OBJECTIVES: Tegaserod is a selective serotonin (5-HT4) receptor partial agonist effective in providing relief from abdominal pain, bloating, and constipation in patients with irritable bowel syndrome. Tegaserod therapy may be associated with early transient diarrhea, which is related to its mechanism of action. This study was performed in patients with irritable bowel syndrome and symptoms of diarrhea to further assess the safety of tegaserod. METHODS: After a 2-wk baseline, patients were randomized (2:2:1) in a double-blind manner to receive 4 mg of tegaserod a day (n = 35), 12 mg of tegaserod a day (n = 34), or placebos (n = 17) for 8 wk. Patients had to fulfill > or =2 Rome diarrhea criteria > or =25% of the time. Adverse events were recorded. RESULTS: Diarrhea, abdominal pain, headache, flatulence, and fatigue were the most frequently reported adverse events. The frequency rates of diarrhea were 49%, 18%, and 35% for the 4 mg/day, 12 mg/day, and placebo groups, respectively; when the tegaserod data were pooled, the frequency of diarrhea was similar to that of the placebo group (33% and 35%, respectively). No complications of diarrhea (e.g., dehydration and electrolyte abnormalities) were reported. Five patients (6%), all from the tegaserod groups, discontinued study participation because of diarrhea and/or abdominal pain. No serious adverse events were reported. CONCLUSIONS: In this study, tegaserod at doses of 4 and 12 mg/day was safe and not associated with complications of diarrhea or serious adverse events.