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Background Comparative therapeutic benefits of combined and single neurostimulation therapies including neuromuscular electrical stimulation (NMES), pharyngeal electrical stimulation (PES), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and traditional dysphagia therapy (TDT) remain unknown in post-stroke dysphagia (PSD) rehabilitation. Therefore, we performed the first network meta-analysis (NMA) to determine comparative effectiveness of combined and single neurostimulation and traditional dysphagia therapies for PSD. Methods A frequentist NMA model was performed with therapy effect sizes presented as standardized mean differences (SMD) and corresponding 95% confidence interval (95% CI) for therapy comparisons while netrank function ranked the therapies in R-Software. Meta-regression models for study characteristics were analyzed using Bayesian NMA Model. Results Overall, 50 randomized controlled studies with 2250 participants were included. NMES + TDT 3.82 (95% CI, 1.62-6.01), tDCS + TDT 3.34 (95% CI, 1.09-5.59), rTMS + TDT 3.32 (95% CI, 1.18-5.47), NMES 2.69 (95% CI, 0.44-4.93), and TDT 2.27 (95% CI, 0.12-4.41) demonstrated very large effect in improving swallowing function. NMES + TDT −0.50 (95% CI, −0.68 to −0.32, rTMS + TDT −0.44 (95% CI, −0.67 to −0.21), TDT −0.28 (95% CI, −0.46 to −0.10), and NMES −0.19 (95% CI, −0.34 to −0.04) demonstrated medium to small effect in reducing pharyngeal transit time (PTT). rTMS −0.51 (95% CI, −0.93 to −0.08) demonstrated medium effect in reducing oral transit time (OTT). No significant therapy comparison differences were found for reducing aspiration/penetration. The highest ranked therapy was NMES + TDT for better swallowing function and reduction of PTT, rTMS for reduction of OTT, and tDCS + TDT for reduction of aspiration/penetration. Therapeutic effects of the therapies were moderated by frequency, sessions, and duration. Conclusion Combined therapies including NMES + TDT, tDCS + TDT, and rTMS + TDT demonstrate better therapeutic effect for improved swallowing function and reduction of PTT, OTT, and aspiration/penetration for PSD.

Flap endonuclease 1 (FEN1) is a critical protein in DNA repair, genomic stability, and carcinogenesis. Functional polymorphisms in FEN1 promoter -69GA (rs174538) and 3'UTR 4150GT (rs4246215), have been associated with the susceptibility to several cancers, including lung, breast, esophageal, gastric, liver, colorectal, and gallbladder cancer, as well as glioma, endometriosis, and leukemia. However, the contribution of FEN1 variant genotypes to oral cancer has never been examined. Thus, we aimed to evaluate the contribution of FEN1 rs174538 and rs4246215 genotypes to oral cancer risk in Taiwan.The contribution of FEN1 genotypes to oral cancer risk was examined in 958 oral cancer patients and 958 age- and sex-matched healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The percentages of GG, AG, and AA genotypes at FEN1 rs174538 were 34.8%, 46.0%, and 19.2% among oral cancer patients and 37.8%, 45.2%, and 17.0% among healthy controls (p for trend=0.2788). The genotypic percentages of FEN1 rs4246215 were 35.9%, 45.9%, and 18.2% among oral cancer patients and 37.6%, 45.1%, and 17.3% among healthy controls (p for trend=0.7315). Overall, FEN1 rs174538 and rs4246215 were not differently distributed between the oral cancer patient and healthy control groups. The allele frequency analysis confirmed that FEN1 rs174538 and rs4246215 were non-differentially distributed among case and control groups (OR=1.11 and 1.05, 95%CI=0.98-1.27 and 0.93-1.20, p=0.1074 and 0.4491, respectively).FEN1 may contribute to oral cancer risk determination via protein expression and/or post-transcription modification, but may not be a practical genetic marker.

The coronavirus disease 2019 (COVID-19) pandemic is an exceptional public health crisis that demands the timely creation of new therapeutics and viral detection. Owing to their high specificity and reliability, monoclonal antibodies (mAbs) have emerged as powerful tools to treat and detect numerous diseases. Hence, many researchers have begun to urgently develop Ab-based kits for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ab drugs for use as COVID-19 therapeutic agents. The detailed structure of the SARS-CoV-2 spike protein is known, and since this protein is key for viral infection, its receptor-binding domain (RBD) has become a major target for therapeutic Ab development. Because SARS-CoV-2 is an RNA virus with a high mutation rate, especially under the selective pressure of aggressively deployed prophylactic vaccines and neutralizing Abs, the use of Ab cocktails is expected to be an important strategy for effective COVID-19 treatment. Moreover, SARS-CoV-2 infection may stimulate an overactive immune response, resulting in a cytokine storm that drives severe disease progression. Abs to combat cytokine storms have also been under intense development as treatments for COVID-19. In addition to their use as drugs, Abs are currently being utilized in SARS-CoV-2 detection tests, including antigen and immunoglobulin tests. Such Ab-based detection tests are crucial surveillance tools that can be used to prevent the spread of COVID-19. Herein, we highlight some key points regarding mAb-based detection tests and treatments for the COVID-19 pandemic.

Seeking health information online has gained in popularity. However, few studies have investigated seeking health information online among U.S. pregnant women. The aim of this study was to investigate the patterns, trends, and characteristics of pregnant women in the U.S. who seek health information online. We obtained data from the National Health Interview Survey from 2009 to 2018. The study population consisted of women aged 18 to 49 years who self-reported being pregnant. Complex survey weighting and Chi-squared tests were used to evaluate trends and compare characteristics of online users and nonusers. Multivariable logistic regression analyses were used to evaluate characteristics associated with seeking health information online. Significantly more pregnant women sought health information online in 2018 compared to 2009 (72.9 percent, standard error [SE]: 3.3, 95 percent confidence interval [CI]: 66.3 percent-79.5 percent, vs. 60.7 percent, SE: 3.3, 95 percent CI: 54.0 percent-67.4 percent

Combinatorial therapies have garnered enormous interest from researchers in efficiently devastating malignant tumors through synergistic effects. To explore the combinatorial approach, multiple therapeutic agents are typically loaded in the delivery vehicles, controlling their release profiles and executing subsequent therapeutic purposes. Herein, we report the fabrication of core (silica)-shell (mesoporous silica nanoparticles, MSNs) architectures to deliver methylene blue (MB) and cupric doxorubicin (Dox) as model drugs for synergistic photodynamic therapy (PDT), chemotherapy, and chemodynamic therapy (CDT). MB, as the photosensitizer, is initially loaded and stabilized in the silica core for efficient singlet oxygen generation under light irradiation towards PDT. The most outside shell with imidazole silane-modified MSNs is immobilized with a chemotherapeutic agent of Dox molecules through the metal (Copper, Cu)-ligand coordination interactions, achieving the pH-sensitive release and triggering the production of intracellular hydrogen peroxide and subsequent Fenton-like reaction-assisted Cu-catalyzed free radicals for CDT. Further, the designed architectures are systematically characterized using various physicochemical characterization techniques and demonstrate the potent anti-cancer efficacy against skin melanoma. Together our results demonstrated that the MSNs-based core-shell nanoarchitectures have great potential as an effective strategy in synergistically ablating cancer through chemo-, chemodynamic, and photodynamic therapies.

Background The variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) harbor diverse spike (S) protein sequences, which can greatly influence the efficacies of therapeutics. Therefore, it would be of great value to develop neutralizing monoclonal antibodies (mAbs) that can broadly recognize multiple variants. Methods Using an mRNA-LNP immunization strategy, we generated several mAbs that specifically target the conserved S2 subunit of SARS-CoV-2 (B-S2-mAbs). These mAbs were assessed for their neutralizing activity with pseudotyped viruses and binding ability for SARS-CoV-2 variants. Results Among these mAbs, five exhibited strong neutralizing ability toward the Gamma variant and also recognized viral S proteins from the Wuhan, Alpha, Beta, Gamma, Delta and Omicron (BA.1, BA.2 and BA.5) variants. Furthermore, we demonstrated the broad reactivities of these B-S2-mAbs in several different applications, including immunosorbent, immunofluorescence and immunoblotting assays. In particular, B-S2-mAb-2 exhibited potent neutralization of Gamma variant (IC50 = 0.048 µg/ml) in a pseudovirus neutralization assay. The neutralizing epitope of B-S2-mAb-2 was identified by phage display as amino acid residues 1146–1152 (DSFKEEL) in the S2 subunit HR2 domain of SARS-CoV-2. Conclusion Since there are not many mAbs that can bind the S2 subunit of SARS-CoV-2 variants, our set of B-S2-mAbs may provide important materials for basic research and potential clinical applications. Importantly, our study results demonstrate that the viral S2 subunit can be targeted for the production of cross-reactive antibodies, which may be used for coronavirus detection and neutralization.

Tumor regression grade (TRG) is a measure of histopathological response of cancer to neoadjuvant chemoradiotherapy (nCRT) and is associated with outcomes. Several TRG system are used in esophageal cancer: Becker (0%,1 ~ 10%,10 ~ 50%, >50% vital residual tumor cell [VRTC]), Chirieac (0%,1 ~ 50%, >50% VRTC) and Japan TRG (0%,1 ~ 33%,33 ~ 66%, >66% VRTC). Although these methods are generally accepted, currently there is no common standard. We compared the application of three systems for assessment of TRG. Hematoxylin and eosin–stained slides from 482 resection specimens of esophageal squamous cell carcinoma following nCRT were independently reviewed by three pathologists. Interobserver agreement was analyzed by kappa statistics. The prognostic strength of each TRG system was assessed using the concordance index. Interobserver agreement for the Chirieac system showed the best kappa value (0.93) followed by the Becker (0.90) and JTRG (0.87) system. All three models predicted survival (P Chirieac system is most reproducible for the evaluation of esophageal cancer response to nCRT. However, the JTRG system seemed to be more accurate in predicting survival.

TDP-43 proteinopathies cover a range of neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Hyperphosphorylated TDP-43 was found within the inclusion bodies in disease lesions; however, the role of hyperphosphorylation and the toxic species are still ambiguous. To characterize the hyperphosphorylation effect of TDP-43, here, we employed five serine mutations implicated in the diseases at serine locations 379, 403, 404, 409, and 410 in the C-terminus to aspartate (S5D) and to alanine (S5A). We systematically characterized the conformation, liquid-liquid phase separation, oligomerization, and fibrillization of TDP-43 variants. Results revealed that the recombinant TDP-43 variants readily formed structurally similar spherical oligomers, as evidenced by circular dichroism spectroscopy, fluorescence spectroscopy, the TDP-43 oligomer-specific antibody assay, dynamic light scattering, and transmission electron microscopy. After incubation, only the phosphor-mimic S5D TDP-43 formed thioflavin-positive amyloid fibrils, whereas wild-type and S5A TDP-43 formed amorphous aggregates. We also examined membrane disruption, the cytotoxicity of human neuroblastoma, and the synaptic loss of primary neurons induced by oligomers and large aggregates of TDP-43. The results showed that all oligomeric TDP-43 variants were toxic regardless of hyperphosphorylation, but the fibrils and amorphous aggregates were not. Overall, our results demonstrated the hyperphosphorylation effect on fibril formation and the toxicity attributed from TDP-43 oligomers. This study facilitates the understanding and therapeutic development for TDP-43 proteinopathies.

The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.

Background Few prognostic factors have been proposed for patients with locally advanced renal cell carcinoma (RCC). This study aimed to investigate the possible predictive factors for disease-free survival (DFS) after curative surgery for RCC stage T3 or higher. Methods Patients with locally advanced RCC who underwent cure-intended partial or radical nephrectomy, with or without tumor thrombectomy, at our institution from April 1 st , 2005 to October 31 st , 2013 were retrospectively reviewed. Those undergoing cytoreductive nephrectomy were excluded. Preoperative data, including surgical and pathologic characteristics, were assessed for correlation with DFS. Chi-squared tests, multivariate Cox regression analysis, and Kaplan-Meier survival curve analyses were performed to determine potential predictive factors. A P-value less than 0.05 was considered statistically significant. Results A total of 159 patients were included for analysis. One hundred and nineteen (74.8%) patients remained disease-free during follow-up. Disease recurrence was found in 40 (25.2%) patients, and pathological T stage, capsule penetration, Fuhrman grade, thrombocytosis, and elevated serum alkaline phosphatase and γ-glutamyl transpeptidase levels were significantly associated with disease recurrence on univariate analysis. On multivariate analysis, capsule penetration (hazard ratio [HR] = 2.25, p = 0.038, 95% confidence interval [CI] = 1.05–4.85) and Fuhrman grade 3 or 4 (HR = 8.06, p = 0.003, 95% CI = 2.59–25.02) showed significant associations with DFS. Conclusions In patients with locally advanced RCC, capsule penetration and Fuhrman grade were associated with worse DFS after curative surgery. Urologists should closely monitor patients with capsule penetration and high Fuhrman grades, and adjuvant systemic treatments, other than targeted agents, should be considered.

This study aimed to evaluate the association between visual impairment (VI) and psychological distress (PD) among older adults in Taiwan. The present cohort study included participants aged >65 years who participated in a physical examination program. Participants were divided into two groups on the basis of whether they had PD at baseline. The association between PD and VI with other variables was compared using the two-sample t-test for continuous variables and chi-squared test for discrete variables. Cox regression analyses were used to calculate the hazard ratio (HR). Cumulative incidence of PD was analyzed using the Kaplan-Meier method, and differences among participants with different severities of VI were analyzed using the two-tailed log-rank test. Subgroup analyses were performed to calculate the HR for PD among participants with different severities of VI. The PD group showed a significantly high percentage of VI. In addition, participants with VI showed a significantly higher HR and seven-year cumulative incidence rate of PD than those without VI. VI was independently and significantly associated with a higher incidence of PD among older Asian people. Therefore, identifying and treating correctible VI is important to prevent PD and improve the overall quality of life.

Semaphorins (SEMAs) are axon guidance factors that participate in axonal connections and nerve system development. However, the functional roles of SEMAs in tumorigenesis are still largely uncovered. By using in silico data analysis, we found that SEMA6C was downregulated in pancreatic cancer, and its reduction was correlated with worse survival rates. RNA sequencing revealed that cell cycle-related genes, especially cyclin D1, were significantly altered after blockage of SEMA6C by neutralizing antibodies or ectopic expressions of SEMA6C. Mechanistic investigation demonstrated that SEMA6C acts as a tumor suppressor in pancreatic cancer by inhibiting the AKT/GSK3 signaling axis, resulting in a decrease in cyclin D1 expression and cellular proliferation. The enhancement of cyclin D1 expression and cyclin-dependent kinase activation in SEMA6C-low cancer created a druggable target of CDK4/6 inhibitors. We also elucidated the mechanism underlying SEMA6C downregulation in pancreatic cancer and demonstrated a novel regulatory role of miR-124-3p in suppressing SEMA6C. This study provides new insights of SEMA6C-mediated anti-cancer action and suggests the treatment of SEMA6C-downregulated cancer by CDK4/6 inhibitors.

Background Docetaxel has been approved by USFDA as a first-line treatment for castration-resistant prostate cancer (CRPC) patients. Patients receiving androgen deprivation therapy along with docetaxel result in superior survival, lower serum prostate specific antigen (PSA) level, and better quality of life. However, a significant proportion of these patients ultimately develop resistance to docetaxel within months. Caffeic acid phenethyl ester (CAPE), one of the main bioactive components extracted from the propolis, has been reported to be effective for repressing the tumor growth, the migration and invasion of prostate cancer (PCa) cells, as well as the downstream signaling and stability of androgen receptor (AR). We hence determined if combination treatment of docetaxel with CAPE can suppress the proliferation and the survival of docetaxel-resistant PCa cells. Methods We established docetaxel-resistant PC/DX25 and DU/DX50 CRPC cell lines from PC-3 and DU-145 human PCa cells, respectively. Proliferation assay, MTT assay, flow cytometry with Annexin V staining, Comet Assay, and nude mice xenograft model were applied to determine the effects of combination treatment on cell proliferation and survival of the docetaxel-resistant PCa cells. Micro-Western Array (MWA) and qRT-PCR were used to investigate the molecular mechanism lying underneath. Results Combination treatment effectively suppressed the proliferation, survival and tumor growth of docetaxel-resistant PCa cells both in vitro and in nude mice. Comet assay and flow cytometry indicated that combination treatment induced apoptosis in docetaxel-resistant PCa cells. MWA and Western blotting assay revealed that combination treatment suppressed protein expression of Bcl-2, AKT2, c-Myc, apoptosis and caspase activation inhibitor (AVEN), pyruvate kinase M2 (PKM2) but increased protein expression of Bax, caspase 3, cytochrome c, glucose-6-phosphate dehydrogenase (G6PD) and acylglycerol kinase (AGK). Overexpression of Bcl-2 in the docetaxel-resistant PCa cells enhanced cell proliferation of docetaxel-resistant PCa cells under combination treatment. Analysis with qRT-PCR suggested that combination treatment decreased cholesterol biosynthesis genes DHCR24 (24-dehydrocholesterol reductase) and LSS (lanosterol synthase) but increased genes involved in glycolysis and TCA cycle. Conclusions Combination treatment of docetaxel with CAPE effectively suppressed the proliferation and survival of docetaxel-resistant PCa cells via inhibition of Bcl-2 and c-Myc as well as induction of metabolism interference. Combination treatment can be beneficial for patients with docetaxel-resistant PCa.

The development of sialolithiasis is commonly related to local factors, such as the retrograde migration of foods, bacteria, or foreign bodies from the oral cavity. The association of sialolithiasis and saliva stasis resulting from decreased spontaneous secretion remains largely unexplored. The current study investigated the potential role of impaired spontaneous secretion in association with the formation of submandibular gland calculi.A retrospective cohort study.Between September 2016 and December 2017, 11 patients with unilateral submandibular gland sialolithiasis confirmed with sialendoscopy were assigned to the experimental group. Another 35 patients clinically diagnosed with parotid obstructive sialadenitis were assigned as the control group. The slope changes of the isotope count curve of the unaffected submandibular gland in the experimental group and the bilateral submandibular glands in the control group were calculated and compared to estimate the spontaneous secretion differences. The degree of spontaneous secretion was defined as the slope changes in the steady ascending stage of the scintigraphic exam.The slope decline (degree of spontaneous secretion) on the unaffected side in patients with single-gland submandibular obstructive sialadenitis was significantly lower than that in the control individuals (The spontaneous secretion of the submandibular gland in patients with submandibular sialolithiasis was decreased compared to that in patients without submandibular sialolithiasis. This phenomenon might be associated with the development of sialolithiasis.3.

Background The time from injury to surgery (TIS) is critical in the functional recovery of individuals with traumatic acute subdural hematoma (TASDH). However, only few studies have confirmed such notion. Methods The data of TASDH patients who were surgically treated in Chia-Yi Christian Hospital between January 2008 and December 2015 were collected. The significance of variables, including age, sex, traumatic mechanism, coma scale, midline shift on brain computed tomography (CT) scan, and TIS, in functional recovery was assessed using the student’s t-test, Mann-Whitney U test, chi-square test, univariate and multivariate models, and receiver operating characteristic (ROC) curve. Results A total of 37 patients achieved functional recovery (outcome scale score of 4 or 5) and 33 patients had poor recovery (outcome scale score of 1–3) after at least 1 year of follow-up. No significant difference was observed in terms of age, sex, coma scale score, traumatic mechanism, or midline shift on brain CT scan between the functional and poor recovery groups. TIS was found to be significantly shorter in the functional recovery group than in the poor recovery group (145.5 ± 27.0 vs. 181.9 ± 54.5 min, P-value = 0.002). TIS was a significant factor for functional outcomes in the univariate and multivariate regression models. The analysis of TIS with the ROC curve between these two groups showed that the threshold time for functional recovery in comatose patients and those with TASDH who were surgically treated was 2 h and 57.5 min. Conclusions TIS is an important factor l for the functional recovery of comatose TASDH patients who underwent surgery.

Our previous study showed Tai‐Chi‐Chuan (TCC) training, a moderate exercise, at school improved pulmonary function and inflammation profiles in children with mild asthma. However, habitual practice is hard to maintain with the lack of continuous family and peer support. We investigated whether parental intervention with social media could enhance children's adherence to exercise at home and improve asthmatic outcome measures. Parents were opted to attend a 12‐week TCC classroom training, supervise home practice, and report to a four‐step web‐based social media platform to stay updated and motivated through logging activity and tracking competition. Fractional exhaled nitric oxide (FeNO), FEV1/FVC and peak expiratory flow (PEF) were measured before and after 12 weeks of training. Fifty‐three asthmatic children were allocated into non‐TCC (control, n = 12), TCC groups with moderate‐to‐severe (TCC‐S, n = 26) and mild‐to‐moderate (TCC‐M, n = 15) asthma. We found both TCC groups exhibited better pulmonary function than the non‐TCC control. TCC increased FVC in mild‐to‐moderate asthma children while more pronounced improvement in FEV1, FEV1/FVC, PEF and FeNO was noticed in moderate‐to‐severe asthmatic children. All TCC subjects retained greater participation and better interaction online except for low‐ranking families who dramatically dropped their practice 9 weeks later. For asthmatic children, moderate exercise improves pulmonary functions in a severity‐dependent fashion. Parent‐based Learn‐Practice‐Persuade‐Award wheel is a useful platform to motivate children engagement in physical activity. Classical social persuasive skills could enhance general parent‐child relationship but tend to decrease in persuasiveness over time in low‐ranking families.

Neurodegenerative disorders that are triggered by injury typically have variable and unpredictable outcomes due to the complex and multifactorial cascade of events following the injury and during recovery. Hence, several factors beyond the initial injury likely contribute to the disease progression and pathology, and among these are genetic factors. Genetics is a recognized factor in determining the outcome of common neurodegenerative diseases. The role of mitochondrial genetics and function in traditional neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, is well-established. Much less is known about mitochondrial genetics, however, regarding neurodegenerative diseases that result from injuries such as traumatic brain injury and ischaemic stroke. We discuss the potential role of mitochondrial DNA genetics in the progression and outcome of injury-related neurodegenerative diseases. We present a guide for understanding mitochondrial genetic variation, along with the nuances of quantifying mitochondrial DNA variation. Evidence supporting a role for mitochondrial DNA as a risk factor for neurodegenerative disease is also reviewed and examined. Further research into the impact of mitochondrial DNA on neurodegenerative disease resulting from injury will likely offer key insights into the genetic factors that determine the outcome of these diseases together with potential targets for treatment.

Mitigation strategies of the coronavirus disease 2019 (COVID-19) pandemic have been greatly hindered by the continuous emergence of SARS-CoV-2 variants. New sensitive, rapid diagnostic tests for the wide-spectrum detection of viral variants are needed. We generated a panel of 41 monoclonal antibodies against the SARS-CoV-2 nucleocapsid protein (NP) by using mice hybridoma techniques. Of these mAbs, nine exhibited high binding activities and were applied in latex-based lateral flow immunoassays (LFIAs). The LFIAs utilizing NP-mAb-7 and -40 had the best sensitivity and lowest limit of detection: 8 pg for purified NP and 625 TCID50/mL for the authentic virus (hCoV-19/Taiwan/4/2020). The specificity tests showed that the NP-mAb-40/7 LFIA strips did not cross-react with five human coronavirus strains or 20 other common respiratory pathogens. Importantly, we found that 10 NP mutants, including alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2) variants, could be detected by NP-mAb-40/7 LFIA strips. A clinical study (n = 60) of the NP-mAb-40/7 LFIA strips demonstrated a specificity of 100% and sensitivity of 90% in infected individuals with cycle threshold (Ct) values &lt, 29.5. These anti-NP mAbs have strong potential for use in the clinical detection of SARS-CoV-2 infection, whether the virus is wild-type or a variant of concern.

We used gastric cancer cell line AGS and clinical samples to investigate the roles of mitochondrial DNA (mtDNA) alterations and mitochondrial respiratory dysfunction in gastric adenocarcinoma (GAC). A total of 131 clinical samples, including 17 normal gastric mucosa (N-GM) from overweight patients who had received sleeve gastrectomy and 57 paired non-cancerous gastric mucosae (NC-GM) and GAC from GAC patients who had undergone partial/subtotal/total gastrectomy, were recruited to examine the copy number and D310 sequences of mtDNA. The gastric cancer cell line AGS was used with knockdown (KD) mitochondrial transcription factor A (TFAM) to achieve mitochondrial dysfunction through a decrease of mtDNA copy number. Parental (PT), null-target (NT), and TFAM-KD-(A/B/C) represented the parental, control, and TFAM knocked-down AGS cells, respectively. These cells were used to compare the parameters reflecting mitochondrial biogenesis, glycolysis, and cell migration activity. The median mtDNA copy numbers of 17 N-GM, 57 NC-GM, and 57 GAC were 0.058, 0.055, and 0.045, respectively. The trend of decrease was significant (p = 0.030). In addition, GAC had a lower mean mtDNA copy number of 0.055 as compared with the paired NC-GM of 0.078 (p < 0.001). The mean mtDNA copy number ratio (mtDNA copy number of GAC/mtDNA copy number of paired NC-GM) was 0.891. A total of 35 (61.4%) GAC samples had an mtDNA copy number ratio ≤0.804 (p = 0.017) and 27 (47.4%) harbored a D310 mutation (p = 0.047), and these patients had shorter survival time and poorer prognosis. After effective knockdown of TFAM, TFAM-KD-B/C cells expressed higher levels of hexokinase II (HK-II) and v-akt murine thymoma viral oncogene homolog 1 gene (AKT)-encoded AKT, but lower levels of phosphorylated pyruvate dehydrogenase (p-PDH) than did the NT/PT AGS cells. Except for a higher level of p-PDH, the expression levels of these proteins remained unchanged in TFAM-KD-A, which had a mild knockdown of TFAM. Compared to those of NT, TFAM-KD-C had not only a lower mtDNA copy number (p = 0.050), but also lower oxygen consumption rates (OCR), including basal respiration (OCRBR), ATP-coupled respiration (OCRATP), reserve capacity (OCRRC), and proton leak (OCRPL)(all with p = 0.050). In contrast, TFAM-KD-C expressed a higher extracellular acidification rate (ECAR)/OCRBR ratio (p = 0.050) and a faster wound healing migration at 6, 12, and 18 h, respectively (all with p = 0.050). Beyond a threshold, the decrease in mtDNA copy number, the mtDNA D310 mutation, and mitochondrial dysfunction were involved in the carcinogenesis and progression of GACs. Activation of PDH might be considered as compensation for the mitochondrial dysfunction in response to glucose metabolic reprogramming or to adjust mitochondrial plasticity in GAC.

This population-based, case–control study aims to explore the relationship between prior tinnitus and the occurrence of chronic kidney disease (CKD) using a nationwide, population-based cohort study. We used data from the Taiwan National Health Insurance Research Database to explore the association of CKD with tinnitus. We identified 15,314 patients aged ≥40 years old with a first-time diagnosis of CKD as the cases. We used propensity-scored matching to select 45,942 controls (1:3 ratio). We performed multivariate logistic regression to estimate the odds ratio (OR) of a prior tinnitus diagnosis among the CKD group vs. the control group. Analysis showed that 770 (1.26%) out of the 61,256 sampled patients had previously diagnosed tinnitus. Chi-square testing revealed a significant difference in the rate of previously diagnosed tinnitus between cases and controls (3.86% vs. 0.93%, p < 0.001). Univariate logistic regression analysis showed an OR of prior tinnitus for cases of 10.249 (95% confidence interval (CI): (8.662~12.126)) relative to controls. In adjusted analysis, cases were more likely than controls to have a prior diagnosis of tinnitus (OR = 10.970, 95% CI = 9.255~13.004, p < 0.001) after adjusting for age, sex, monthly income, geographic location, urbanization level, hypertension, diabetes, coronary heart disease, hyperlipidemia, obesity, and autoimmune disease. Our study shows that CKD patients have a higher likelihood of having suffered from tinnitus before CKD was diagnosed, but we have no data suggesting that tinnitus is a predictor of subsequent CKD. Patients diagnosed with tinnitus may benefit from proactive measures to prevent CKD and detect it early through lifestyle modifications and regular renal function examinations, regardless of CKD-related symptoms.

Decellularization has emerged as a potential solution for tracheal replacement. As a fully decellularized graft failed to achieve its purposes, the de-epithelialization partial decellularization protocol appeared to be a promising approach for fabricating scaffolds with preserved mechanical properties and few immune rejection responses after transplantation. Nevertheless, a lack of appropriate concurrent epithelialization treatment can lead to luminal stenosis of the transplant and impede its eventual success. To improve re-epithelialization, autologous nasal epithelial cell sheets generated by our cell sheet engineering platform were utilized in this study under an in vivo rabbit model. The newly created cell sheets have an intact and transplantable appearance, with their specific characteristics of airway epithelial origin being highly expressed upon histological and immunohistochemical analysis. Subsequently, those cell sheets were incorporated with a partially decellularized tracheal graft for autograft transplantation under tracheal partial resection models. The preliminary results two months post operation demonstrated that the transplanted patches appeared to be wholly integrated into the host trachea with adequate healing of the luminal surface, which was confirmed via endoscopic and histologic evaluations. The satisfactory result of this hybrid scaffold protocol could serve as a potential solution for tracheal reconstructions in the future.

ALDH2 gene is coded for the aldehyde dehydrogenase (ALDH), which is an enzyme involved in alcohol metabolism. Compared to normal aldehyde dehydrogenases, a homozygous point mutation on exon 12 from G to A significantly reduces its efficiency. In this study, we have reported the generation of IBMS-iPSC-021-04, IBMS-iPSC-022-01, and IBMS-iPSC-023-03 as induced pluripotent stem cell (iPSC) lines carrying the homozygous form of ALDH2 with the rs671 genetic polymorphism (E487K mutation). These cell lines were characterized in terms of pluripotency and differentiation potential. They serve as useful platforms to study alcohol metabolism and other chronic diseases associated with alcohol consumption.

Objectives To provide a concept of measuring pressure changes under constant fluid infusion for the diagnosis of sialolithiasis, termed the sialodynamic test, in a porcine head model. Methods Using a porcine head model, a constant infusion of water into the submandibular gland of the two groups over 30 s was performed and the outlet pressure was measured. Metal beads were inserted into the salivary duct for obstruction simulation after the normal submandibular gland sialodynamic measurements were completed. Statistical analyses were performed to evaluate the differences between the measured individuals and the experimental group ( n = 3). Results The results showed no significant difference between individuals in the control group, but intergroup variation was noted in the simulated sialolithiasis group. The volume-dependent linear increase in pressure was exacerbated in the simulated sialolithiasis group compared with the control. Conclusion This study indicated that evaluating the relationship between pressure and volume changes can help to determine whether stones are present in the submandibular gland. The sialodynamic test might serve as a potential diagnostic method for salivary diseases.

This study demonstrates a novel multi-functional microfluidic system, designated three dimensional Alternative Current Electrokinetic/Surface Enhanced Raman Scattering (3D-ACEK/SERS), which can concentrate bacteria from whole blood, identify bacterial species, and determine antibiotic susceptibilities of the bacteria rapidly. The system consists of a hybrid electrokinetic mechanism, integrating AC-electroosmosis (AC-EO) and dielectrophoresis (DEP) that allows thousand-fold concentration of bacteria, including S. aureus, Escherichia coli, and Chryseobacterium indologenes, in the center of an electrode with a wide range of working distance (hundreds to thousands of μm), while exclusion of blood cells through negative DEP forces. This microchip employs SERS assay to determine the identity of the concentrated bacteria in approximately 2 min with a limit of detection of 3 CFU/ml, 5 orders of magnitude lower than that using standard centrifugation−purification process. Finally, label-free antibiotic susceptibility testing has been successfully demonstrated on the platform using both antibiotic-sensitive and multidrug-resistant bacterial strains illustrating a potential utility of the system to clinical applications.

The ALDH2 mutation (ALDH2*2) is caused by an amino acid substitution ALDH2 rs671 G>A (pE487K) which reduces ALDH2 enzyme activity. When individuals with the ALDH2 mutation consume alcohol, accumulating acetaldehyde in the blood can cause reddened face, headache, nausea, and palpitations; symptoms referred to as Alcohol Flushing Reaction. We report the production of an induced pluripotent stem cell (iPSC) line, FIRDIi001-A, developed from peripheral blood mononuclear cells of a 39-year-old male subject with the ALDH2*2 mutation. The ALDH2-pE487K iPSCs will be valuable in investigating pathogenic mechanisms involved in the link between the ALDH2 polymorphism and alcohol-related diseases.

The present study was performed to investigate root-associated bacteria from Platycodon grandiflorum, a medicinal plant commonly grown in East Asia. Isolates were obtained from the rhizosphere or root interior with various culture media, and phylogenetic analyses were performed based on their 16S rDNA sequences. In consideration of practical applications, traits related to plant growth promotion and niche adaptation were assessed in several endophytic strains with fewer biosafety concerns. The effects of a bacterial inoculation on seedling and mature plant growth were evaluated. Seventeen genera that encompassed more than 30 bacterial lineages were successfully retrieved from the roots, the majority of which have not been reported as P. grandiflorum-associated bacteria, particularly for non-negligible Proteobacteria. Although nitrogen-fixing or phosphate-solubilizing and indole acetic acid-producing activities were recorded in all of the strains selected, these strains were beneficial or detrimental to plant growth as evidenced by their influence on the length of seedlings and biomass of mature plants. Among the 4 endophytic Rhizobium species tested in the present study, the potentially novel Rhizobium sp. BF-E16, which was more compatible with the non-leguminous medicinal plant P. grandiflorum, was identified. Other than plant growth-promoting traits, characteristics such as plant constituent-hydrolyzing activities need to be taken into consideration and their roles clarified when investigating plant growth-promoting rhizobacteria.

Spontaneous cerebrospinal fluid (sCSF) leak from the skull base has been previously reported, but there are few reports of sCSF leak from the foramen rotundum due to its rare occurrence. This case report describes a 15-year-old male patient that presented with left side watery rhinorrhoea that had been present since he was 4 years of age and a history of repeated bouts of meningitis of unknown cause. A discharge sample from the nose tested positive for beta-2 transferrin. Preoperative computed tomography (CT) revealed a fistula between the cerebellopontine angle and the left sphenoid sinus. There was also a pseudo-Chiari malformation type I with ectopia of the cerebellar tonsil. Endoscopic transnasal surgery identified a leak from the foramen rotundum that was repaired using autologous material and a contralateral pedicle nasoseptal flap. At 6 months after surgery, the patient reported no recurrence of the CSF leakage. Postoperative CT imaging revealed that the cerebellar tonsil was back in the normal position, indicating that the preoperative Chiari malformation was possibly due to decreased CSF volume. This current case shows that a rare case of sCSF leak from the foramen rotundum can be effectively repaired using the endoscopic transnasal approach.

Medical devices are widely used in modern medicine, but their utilities are often limited by the biofilm formation of bacteria that are tolerant to most antibiotics. In this report, antimicrobial peptides (AMPs) were coated onto biomaterials by the aid of surfactant through hydrophobic interactions. To increase the coating efficiency, stability of AMPs in body fluids and spectrum of antimicrobial activity, pairs of AMPs were coated simultaneously onto various substrates, such as silicone, polyurethane and titanium, which are commonly used components of biomedical devices. These coated AMPs exhibited very low cytotoxicity and hemolytic activities because they were gradually released into urine or serum. The AMP pairs, such as T9W + SAAP159 and T9W + RRIKA, coated onto the silicone discs were able to inhibit in vitro bacterial adherence in urine. Most importantly, AMP pairs coated onto the silicone tubing by surfactant SDBS could prevent bacterial adherence to mouse bladder and the silicone tubing implanted within it. These results provide a promising approach towards circumventing urinary catheter-associated infections caused by bacterial adherence.

A bimetallic amperometric sensor comprising a dendritic Pt shell formed on rod-shaped Au cores (Aurod@Pt) for the rapid estimation of glucose by direct electro-oxidation under physiological conditions is reported. The materials were characterized by XRD, TEM, UV-vis, and cyclic voltammetry. The sensor was constructed by immobilizing Aurod@Pt bimetallic nanoparticles, in a Nafion film, on a glassy carbon electrode (Nafion/Aurod@Pt/GCE). The results showed that Aurod@Pt nanoparticles provided significantly higher sensitivity compared to dendritic Pt. X-ray absorption spectroscopy and X-ray photoelectron spectroscopy suggested that electron transfer, from the Au core to dendritic Pt, resulted in significant enhancement of electrocatalytic activity, due to reduction in Pt absorption of glucose oxidation intermediates and Cl− ions. In addition, Nafion/Aurod@Pt/GCE was found to exhibit a low working potential, fast amperometric response, high sensitivity, good reproducibility, good long term stability, and a high specificity to glucose with negligible interference from uric acid, ascorbic acid, acetamidophenol, or chloride ions.

Background/Purpose To evaluate the therapeutic responsiveness of office-based salivary gland ductal irrigation in patients with chronic sialoadenitis. Methods Between August 2017 and April 2019, 55 patients comprising the following three disease groups were enrolled: Sjogren’s syndrome: 39 patients; postradiotherapy sialoadenitis: ten patients; and post-RAI sialoadenitis: six patients. Quantitative salivary scintigraphy was recorded, and a formulated questionnaire including the Summated Xerostomia Inventory was utilized to assess acute/chronic symptoms. All patients received at least three serial salivary gland ductal irrigations with a one-month interval in our outpatient department. Results The general response rates for each disease groups are as follows: Sjogren’s syndrome: 61.5% (24/39); postradiotherapy: 60% (6/10); and post-RAI: 83.3% (5/6). Among the patients with Sjogren’s syndrome, the parotid scintigraphic Tmin showed a significant positive correlation with the responsiveness of salivary irrigation (P = 0.046), whereas the treatment tended to be irresponsive in patients who previously took medicine for their related discomfort (P = 0.009). In the postradiotherapy and post-RAI groups, no significant factors were found to be associated with the responsiveness of irrigation. Conclusion Simple salivary ductal irrigation without complex equipment can be performed as an outpatient procedure to alleviate glandular swelling or xerostomia in patients with Sjogren's syndrome, postradiotherapy sialoadenitis or post-RAI sialoadenitis, and it can be considered an alternative management approach for patients refractory to conventional strategies.

Objective To evaluate the association between the use of cholinesterase inhibitors (ChEIs) and incident cardiovascular events (CVEs) among older patients with Alzheimer disease (AD). Patients and Methods This retrospective cohort study was conducted with a new-user design and active-comparator design. The data source was the 2005–2014 Full Population file from the Health and Welfare Database in Taiwan. Patients were included if they were aged 50 years or older and had been diagnosed with AD between January 1, 2006, and December 31, 2010. The association between ChEI use and the risk of CVEs was investigated in patients with AD. Among the ChEI users, the risk of CVEs was further compared between patients with different cumulative doses and different ChEI treatment strategies. The propensity score method, which included matching and inverse probability of treatment weighting, was used to balance the potential confounders. A Cox proportional hazards model with competing risks was used to estimate the hazard ratio of CVEs. Results The study included 6070 patients with AD. After covariate adjustment, ChEI users had a significantly lower risk of CVEs than nonusers (hazard ratio, 0.57; 95% CI, 0.51 to 0.62). Among ChEI users, patients with a high cumulative dose had a significantly lower risk of CVEs than those with a low cumulative dose (hazard ratio, 0.82; 95% CI, 0.70 to 0.96). Conclusion The use of ChEIs was associated with a decreased risk of incident CVEs among patients with AD. The cardioprotective effect of ChEIs showed a dose-response relationship.

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials.

AIM To evaluate feasibility of establishing a clinically applicable reference value through those unaffected salivary gland on sialoscintigraphic data obtained from patients presented with obstructive sialadenitis affected a single gland. MATERIALS AND METHODS Ninety-one patients suffered from single salivary gland swelling, pain/tenderness and received sialoscintigraphic examinations were retrospectively enrolled. The quantitative data parameters, including the uptake ratio, maximal accumulation, maximal excretion, time to maximal (Tmax) and time to minimal (Tmin) activity of the affected and unaffected glands, were calculated for analysis. Data were also obtained and recorded for comparison from 50 patients who fulfill the American-European criteria for the diagnosis of Sjogren's syndrome. RESULTS The maximal excretion appeared to be the best indicator for distinguishing affected and unaffected glands of obstructive diseases, for parotid and submandibular glands (P = 0.0002 and P

Ubiquitination modulates a large repertoire of cellular functions and thus, dysregulation of the ubiquitin system results in multiple human diseases, including cancer. Ubiquitination requires an E3 ligase, which is responsible for substrate recognition and conferring specificity to ubiquitination. HUWE1 is a multifaceted HECT domain-containing ubiquitin E3 ligase, which catalyzes both mono-ubiquitination and K6-, K48- and K63-linked poly-ubiquitination of its substrates. Many of the substrates of HUWE1 play a crucial role in maintaining the homeostasis of cellular development. Not surprisingly, dysregulation of HUWE1 is associated with tumorigenesis and metastasis. HUWE1 is frequently overexpressed in solid tumors, but can be downregulated in brain tumors, suggesting that HUWE1 may possess differing cell-specific functions depending on the downstream targets of HUWE1. This review introduces some important discoveries of the HUWE1 substrates, including those controlling proliferation and differentiation, apoptosis, DNA repair, and responses to stress. In addition, we review the signaling pathways HUWE1 participates in and obstacles to the identification of HUWE1 substrates. We also discuss up-to-date potential therapeutic designs using small molecules or ubiquitin variants (UbV) against the HUWE1 activity. These molecular advances provide a translational platform for future bench-to-bed studies. HUWE1 is a critical ubiquitination modulator during the tumor progression and may serve as a possible therapeutic target for cancer treatment.

Leucine rich repeat kinase (LRRK2) is the most prevalent genetic cause for Parkinson's disease. LRRK2 p.G2385R is an Asian specific genetic risk factor for sporadic Parkinson's disease. We generated two induced pluripotent stem cells (iPSCs), IBMS-iPSC-018-09 and IBMS-iPSC-020-01, from the peripheral blood mononuclear cells of two patients carrying LRRK2 p.G2385R variant by using the Sendai-virus delivery system. These iPSCs had a normal karyotype and exhibited pluripotency, such as an embryonic stem cell-like morphology, expression of pluripotent markers, and capacity to differentiate into three germ layers. This cellular model will provide a platform for pathophysiological studies of neurodegeneration in Parkinson's disease.

The choice of medical services affects an individual’s treatment and health. However, few studies have focused on medical electronic word-of-mouth (eWOM), which has the greatest impact on such choices. This study was performed to explore the need for and general public’s attitude toward medical eWOM and provide a reference for government, media, and medical practitioners. In this study, 84% of the respondents had experience using online evaluation platforms to search for eWOM, and those who were satisfied with the online evaluation platforms substantially outnumbered those who were dissatisfied. The respondents generally believed that there is a need for physician evaluation platforms, although a difference remained between respondents who needed the online evaluation platforms (72.0%) and were willing to reference them (72.0%) and those who trusted them (46.5%) and were willing to provide their opinions (55.0%). These results could signify that despite the public’s need, the public remains doubtful of the information provided by these online evaluation platforms.

The requesting of detailed information on new drugs including drug-drug interactions or targets is often unavailable and resource-intensive in assessing adverse drug events. To shorten the common evaluation process of drug-drug interactions, we present a machine learning framework-HAINI to predict DDI types for histamine antagonist drugs using simplified molecular-input line-entry systems (SMILES) combined with interaction features based on CYP450 group as inputs. The data used in our research consisted of approved drugs of histamine antagonists that are connected to 26,344 DDI pairs from the DrugBank database. Various classification algorithms such as Naive Bayes, Decision Tree, Random Forest, Logistic Regression, and XGBoost were used with 5-fold cross-validation to approach a large-scale DDIs prediction among histamine antagonist drugs. The prediction performance shows that our model outperformed previously published works on DDI prediction with the best precision of 0.788, a recall of 0.921, and an F1-score of 0.838 among 19 given DDIs types. An important finding of the study is that our prediction is based solely on the SMILES and CYP450 and thus can be applied at the early stage of drug development.

Sensorineural hearing loss (SNHL) is a prevalent form of deafness commonly arising from damage to the cochlear sensory hair cells and degeneration of the spiral ganglion neurons. In this study, Sendai virus was used to generate an induced pluripotent stem cell (iPSC) line from a 39-year-old female patient diagnosed with severe-to-profound, non-syndromic SNHL. The patient also carries a A1555G mutation in the mitochondrial 12S ribosome RNA gene (MTRNR1). This iPSC line was verified to express pluripotent markers, possess normal karyotype, harbor the specific mutation and demonstrated the capacity to differentiate into three germ layers.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly inherited forms of polycystic kidney disease, and is characterized by the growth of numerous cysts in both kidneys. Here we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a 63-year-old female ADPKD patient carrying an R803X mutation in the PKD2 gene using the Sendai-virus delivery system. Downstream characterization of these iPSCs showed that they possessed normal karyotyping, were free of genomic integration, retained the disease-causing PKD2 mutation, expressed pluripotency markers and could differentiate into three germ layers.

Growing body of evidence shows that extra adiposity influences on the progression of multiple cancers, including breast cancer. The aim of this study is to investigate whether obesity correlates with mammary tumor development in vitro and in vivo. We found that obesity-related mediators, 3T3-L1 adipocyte conditioned medium, enhanced formation of cancerous foci induced by the carcinogen 7,12-Dimethylbenz[a]anthracene (DMBA) in NIH/3T3 fibroblasts, in vitro. Additionally, we tested the effect of obesity in mouse model of DMBA-induced breast cancer. C57BL/6J female mice were fed a low fat (LF), or high fat (HF) diet, and DMBA was administered by oral gavage (LF plus DMBA [LFD] and HF plus DMBA [HFD]). Our results indicated that HFD mouse developed a tumor which weight was 169mg, whereas the LFD mouse developed a tumor weight of 77mg. Histological analysis of the mammary tumor from HFD group showed morphological aggressiveness and multiple cell type infiltration compared to LFD group. The epididymal adipose tissue from the DMBA groups showed more macrophage infiltration, polarized towards an M1 phenotype compared to the non-DMBA mice. HF mice showed less accumulation of M2 macrophages in the adipose tissue. In summary, obese mediators enhanced DMBA induced tumorigenesis in vitro and in vivo.

Food allergy occurs due to IgE- and mast cell-dependent intestinal inflammation. Previously, we showed that histamine-releasing factor (HRF), a multifunctional protein secreted during allergy, interacts with a subset of IgE molecules and that the HRF dimer activates mast cells in an HRF-reactive IgE-dependent manner. In this study, we investigated whether HRF plays any role in food allergy. Specifically, we determined that prophylactic and therapeutic administration of HRF inhibitors that block HRF-IgE interactions reduces the incidence of diarrhea and mastocytosis in a murine model of food allergy. Food allergy-associated intestinal inflammation was accompanied by increased secretion of the HRF dimer into the intestine in response to proinflammatory, Th2, and epithelial-derived cytokines and HRF-reactive IgE levels at the elicitation phase. Consistent with these data, patients with egg allergy had higher blood levels of HRF-reactive IgE compared with individuals that were not hypersensitive. Successful oral immunotherapy in egg-allergy patients and food-allergic mice reduced HRF-reactive IgE levels, thereby suggesting a pathological role for HRF in food allergy. Together, these results suggest that antigen and HRF dimer amplify intestinal inflammation by synergistically activating mast cells and indicate that HRF has potential as a therapeutic target in food allergy.

Epithelial-mesenchymal transition (EMT) is a process through which epithelial cells are transformed into mesenchymal cells; EMT diminishes cell polarity and cell-cell adhesion in cancer cells, leading to enhanced migratory and invasive properties. In this experiment, zymography, cell invasion, and migration assays were performed. Results indicated that Duchesnea indica extracts (DIE) inhibited highly metastatic A549 and H1299 cells by reducing the secretions of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Cell adhesion assay also demonstrated that DIE reduced the cell adhesion properties. Western blot analysis showed that DIE down-regulated the expression of N-cadherin, fibronectin, and vimentin, which are mesenchymal markers, and enhanced that of E-cadherin, which is an epithelial marker. In vivo study showed that tumor growth was significantly reduced in BALB/c nude mouse xenograft model administered with oral gavage of DIE. Therefore, DIE could be exhibits potential as a phytochemical-based platform for prevention and treatment of lung cancer. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2053-2063, 2017.

Heparin-binding hemagglutinin (HBHA) is a 199 amino acid virulence factor at the envelope of Mycobacterium tuberculosis that contributes to latent tuberculosis. The binding of HBHA to respiratory epithelial cells, which leads to extrapulmonary dissemination of the pathogen, is mediated by cell-surface heparan sulfate (HS). We report the structural characterization of the HBHA/HS complex by NMR spectroscopy. To develop a model for the molecular recognition, the first chemically synthesized uniformly 13 C- and 15 N-labeled HS octasaccharide and a uniformly 13 C- and 15 N-labeled form of HBHA were prepared. Residues 180-195 at the C-terminal region of HBHA show large chemical shift perturbation upon association with the octasaccharide. Molecular dynamics simulations conforming to the multidimensional NMR data revealed key electrostatic and even hydrophobic interactions between the binding partners that may aid in the development of agents targeting the binding event.

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by a trinucleotide repeat (CAG) expansion in the coding region of ATXN3 gene resulting in production of ataxin-3 with an elongated polyglutamine tract. Here, we generated induced pluripotent stem cells (iPSCs) from the peripheral blood mononuclear cells of a male patient with SCA3 by using the Sendai-virus delivery system. The resulting iPSCs had a normal karyotype, retained the disease-causing ATXN3 mutation, expressed pluripotent markers and could differentiate into the three germ layers. Potentially, the iPSCs could be a useful tool for the investigation of disease mechanisms of SCA3.

Estimating the volume of a convex body is a central problem in convex geometry and can be viewed as a continuous version of counting. We present a quantum algorithm that estimates the volume of an $n$-dimensional convex body within multiplicative error $\epsilon$ using $\tilde{O}(n^{3}+n^{2.5}/\epsilon)$ queries to a membership oracle and $\tilde{O}(n^{5}+n^{4.5}/\epsilon)$ additional arithmetic operations. For comparison, the best known classical algorithm uses $\tilde{O}(n^{4}+n^{3}/\epsilon^{2})$ queries and $\tilde{O}(n^{6}+n^{5}/\epsilon^{2})$ additional arithmetic operations. To the best of our knowledge, this is the first quantum speedup for volume estimation. Our algorithm is based on a refined framework for speeding up simulated annealing algorithms that might be of independent interest. This framework applies in the setting of "Chebyshev cooling", where the solution is expressed as a telescoping product of ratios, each having bounded variance. We develop several novel techniques when implementing our framework, including a theory of continuous-space quantum walks with rigorous bounds on discretization error. To complement our quantum algorithms, we also prove that volume estimation requires $\Omega(\sqrt n+1/\epsilon)$ quantum membership queries, which rules out the possibility of exponential quantum speedup in $n$ and shows optimality of our algorithm in $1/\epsilon$ up to poly-logarithmic factors., Comment: 61 pages, 8 figures. v2: Quantum query complexity improved to $\tilde{O}(n^{3}+n^{2.5}/\epsilon)$ and number of additional arithmetic operations improved to $\tilde{O}(n^{5}+n^{4.5}/\epsilon)$. v3: Improved Section 4.3.3 on nondestructive mean estimation and Section 6 on quantum lower bounds; various minor changes

Overproduction of reactive oxygen species (ROS) is known to mediate glutamate excitotoxicity in neurological diseases. However, how ROS burdens can influence neural circuit integrity remains unclear. Here, we investigate the impact of excitotoxicity induced by depletion of Drosophila Eaat1, an astrocytic glutamate transporter, on locomotor central pattern generator (CPG) activity, neuromuscular junction architecture, and motor function. We show that glutamate excitotoxicity triggers a circuit-dependent ROS feedback loop to sculpt the motor system. Excitotoxicity initially elevates ROS, thereby inactivating cholinergic interneurons and consequently changing CPG output activity to overexcite motor neurons and muscles. Remarkably, tonic motor neuron stimulation boosts muscular ROS, gradually dampening muscle contractility to feedback-enhance ROS accumulation in the CPG circuit and subsequently exacerbate circuit dysfunction. Ultimately, excess premotor excitation of motor neurons promotes ROS-activated stress signaling that alters neuromuscular junction architecture. Collectively, our results reveal that excitotoxicity-induced ROS can perturb motor system integrity through a circuit-dependent mechanism.