Prognostic assessment of 18F-boronophenylalanine positron emission tomography (BPA-PET) in salvage boron neutron capture therapy for malignant brain tumors.

Background: Boron neutron capture therapy (BNCT) stands out as a propitious anti-cancer modality. 18F-boronophenylalanine positron emission tomography (BPA-PET) holds the potential to ascertain the concentration of BPA within the tumor, enabling meticulous treatment planning and outcome evaluation. However, no studies have been conducted on comparing the outcomes of those treated with BNCT to those who did not undergo this therapy. This study endeavors to analyze the correlation between BPA-PET and BNCT in the context of malignant brain tumors, and assess the survival outcomes following BNCT. Methods: A cohort study was performed on patients who underwent BPA-PET between February 2017 and April 2022 in our hospital. Patients were stratified into two groups: those subjected to BNCT (Group 1) and those not (Group 2). The tumor to normal tissue (T/N) ratio derived from BPA-PET was set at 2.5. The findings were scrutinized based on clinical follow-up. Student's t-test and Chi-squared test were employed to discern differences between the groups. A cumulative survival curve was constructed employing the Kaplan-Meier method. Differences were considered statistically significant at P<0.05. Results: In total, 116 patients with T/N ratios obtained from BPA-PET were enrolled. BNCT was administered to 58 patients, while mortality was observed in 100 patients. The median overall survival (OS) for the two groups was 8.5 and 6.0 months, respectively. The cumulative OS exhibited no significant discrepancy between the two groups, nor in their T/N ratios. Within Group 1, 44 out of 58 (75.9%) patients exhibited T/N ratios exceeding 2.5. Excluding 3 patients who expired within 3 months, 55 out of 58 patients were evaluated for response after BNCT. The objective response rate (ORR) was 30.9%. Patients achieving ORR displayed substantially higher survival rates compared to those without (median OS 13.5 vs. 8.3 months, P=0.0021), particularly when T/N ratio exceeded 2.5 (median OS 14.8 vs. 9.0 months, P=0.0199). Conclusions: BNCT does not appear indispensable for prolonging the survival of patients afflicted with malignant brain tumors. Nevertheless, it proves advantageous when ORR is attained, a condition closely linked to the values of T/N ratio derived from BPA-PET.

Survival outcomes of radium-223 therapy for metastatic castration-resistant prostate cancer following national health insurance reimbursement in Taiwan.

BACKGROUND: Radium-223 dichloride (Ra-223) prolongs overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) with symptomatic bone metastases. However, there is considerable variation in outcomes among individuals. We aimed to evaluate the prognostic determinants associated with patient survival following National Health Insurance (NHI) reimbursement for Ra-223 therapy in Taiwan. METHODS: Patients with mCRPC who underwent Ra-223 treatment at Taipei Veterans General Hospital were retrospectively enrolled. Each intravenous Ra-223 dose was administered at 55 kBq/kg at 4-week intervals. Clinical outcomes were obtained from medical records; potential prognostic factors for survival were assessed. Kaplan-Meier analysis was used to generate cumulative survival curves; between-group differences were evaluated using the Chi-squared test. Statistical significance was set at p < 0.05. RESULTS: Seventy-six patients underwent Ra-223 therapy; 62 patients received NHI reimbursement and the remainder self-paid. Fifty patients (65.8%) completed six cycles of treatment; 26 (34.2%) received 1 to 5 cycles. Mortality occurred in 47 patients. Factors significantly associated with survival included ≤five bone metastases ( p = 0.0018), baseline prostate-specific antigen (PSA) ≤36 ng/mL ( p = 0.0004), baseline alkaline phosphate (ALP) <115 U/L ( p = 0.0007), and baseline hemoglobin (Hb) >12 g/dL ( p = 0.0029). Patients who completed six cycles of treatment achieved significantly higher OS compared to those who did not ( p < 0.0001). There has been a 4.4-fold increase in the number of patients since reimbursement began; there was no significant difference in OS between patients who received NHI reimbursement and those who self-paid. CONCLUSION: Administration of Ra-223 demonstrates considerable potential to extend the survival of patients with mCRPC. Survival outcomes may be influenced by various prognostic factors. However, no significant difference in OS was observed subsequent to reimbursement of Ra-223 therapy for mCRPC through the NHI system in Taiwan.

Proteomics of human platelet lysates and insight from animal studies on platelet protein diffusion to hippocampus upon intranasal administration.

Human platelet lysates (HPLs) from allogeneic platelet concentrates (PCs) are biomaterials, which are rich in various trophic factors, increasingly used in regenerative medicine and biotherapy. Understanding how preparation methods influence the HPL protein profile, biological function, and clinical outcomes is crucial. Our study sheds light on the proteomes and functionality of different HPLs, with the aim of advancing their scientifically grounded clinical applications. To achieve this, PCs suspended in plasma underwent three distinct processing methods, resulting in seven HPL types. We used three characterization techniques: label-free proteomics and tandem mass tag (TMT)-based quantitative proteomics, both before and after the immunodepletion of abundant plasma proteins. Bioinformatic tools assessed the proteome, and western blotting validated our quantitative proteomics data. Subsequent pre-clinical studies with fluorescent labeling and label-free proteomics were used as a proof of concept for brain diffusion. Our findings revealed 1441 proteins detected using the label-free method, 952 proteins from the TMT experiment before and after depletion, and 1114 proteins from the subsequent TMT experiment on depleted HPLs. Most detected proteins were cytoplasmic, playing key roles in catalysis, hemostasis, and immune responses. Notably, the processing methodologies significantly influenced HPL compositions, their canonical pathways, and, consequently, their functionality. Each HPL exhibited specific abundant proteins, providing valuable insight for tailored clinical applications. Immunoblotting results for selected proteins corroborated our quantitative proteomics data. The diffusion and differential effects to the hippocampus of a neuroprotective HPL administered intranasally to mice were demonstrated. This proteomics study advances our understanding of HPLs, suggesting ways to standardize and customize their production for better clinical efficacy in regenerative medicine and biotherapy. Proteomic analyses also offered objective evidence that HPPL, upon intranasal delivery, not only effectively diffuses to the hippocampus but also alters protein expression in mice, bolstering its potential as a treatment for memory impairments.

On-chip fabrication and in-flow 3D-printing of microgel constructs: from chip to scaffold materials in one integral process.

Bioprinting has evolved into a thriving technology for the fabrication of cell-laden scaffolds. Bioinks are the most critical component for bioprinting. Recently, microgels have been introduced as a very promising bioink, enabling cell protection and the control of the cellular microenvironment. However, the fabrication of the bioinks involves the microfluidic production of the microgels, with a subsequent multistep process to obtain the bioink, which so far has limited its application potential. Here we introduce a direct coupling of microfluidics and 3D-printing for the continuous microfluidic production of microgels with direct in-flow printing into stable scaffolds. The 3D-channel design of the microfluidic chip provides access to different hydrodynamic microdroplet formation regimes to cover a broad range of droplet and microgel diameters. After exiting a microtubing the produced microgels are hydrodynamically jammed into thin microgel filaments for direct 3D-printing into two- and three-dimensional scaffolds. The methodology enables the continuous on-chip encapsulation of cells into monodisperse microdroplets with subsequent in-flow cross-linking to produce cell-laden microgels. The method is demonstrated for different cross-linking methods and cell lines. This advancement will enable a direct coupling of microfluidics and 3D-bioprinting for scaffold fabrication.

Assisted technology in Parkinson's disease gait: what's up?

BACKGROUND: Gait disturbances are prevalent and debilitating symptoms, diminishing mobility and quality of life for Parkinson's disease (PD) individuals. While traditional treatments offer partial relief, there is a growing interest in alternative interventions to address this challenge. Recently, a remarkable surge in assisted technology (AT) development was witnessed to aid individuals with PD. OBJECTIVE: To explore the burgeoning landscape of AT interventions tailored to alleviate PD-related gait impairments and describe current research related to such aim. METHODS: In this review, we searched on PubMed for papers published in English (2018-2023). Additionally, the abstract of each study was read to ensure inclusion. Four researchers searched independently, including studies according to our inclusion and exclusion criteria. RESULTS: We included studies that met all inclusion criteria. We identified key trends in assistive technology of gait parameters analysis in PD. These encompass wearable sensors, gait analysis, real-time feedback and cueing techniques, virtual reality, and robotics. CONCLUSION: This review provides a resource for guiding future research, informing clinical decisions, and fostering collaboration among researchers, clinicians, and policymakers. By delineating this rapidly evolving field's contours, it aims to inspire further innovation, ultimately improving the lives of PD patients through more effective and personalized interventions.

ANTECEDENTES: Os distúrbios da marcha são sintomas prevalentes e debilitantes, diminuindo muito a mobilidade e a qualidade de vida dos indivíduos com doença de Parkinson (DP). Embora os tratamentos tradicionais ofereçam alívio parcial, há um interesse crescente em intervenções alternativas para enfrentar esse desafio. Recentemente, um aumento notável no desenvolvimento de tecnologia assistida (TA) foi testemunhado para ajudar indivíduos com DP. OBJETIVO: Explorar o cenário crescente de intervenções de TA adaptadas para aliviar deficiências de marcha relacionadas à DP e descrever as pesquisas atuais para esse fim. MéTODOS: Nessa revisão, pesquisamos artigos em inglês publicados no PubMed de 2018 a 2023. Além disso, os resumos de cada trabalho foram lidos para assegurar a sua inclusão. Quatro pesquisadores buscaram independentemente os artigos de acordo com os critérios de inclusão e exclusão. RESULTADOS: Incluímos trabalhos que preencheram os critérios de inclusão. Identificamos as tendências em tecnologia assistiva na análise dos parâmetros da marcha em DP. Esses compreendem os sensores portáteis, análise da marcha, retroalimentação em tempo real e técnicas de pista, realidade virtual e robótica. CONCLUSãO: Essa revisão é um recurso para orientar pesquisas futuras, informar decisões clínicas e promover a colaboração entre pesquisadores, médicos e formuladores de políticas. Ao delinear os contornos deste campo em rápida evolução, pretende inspirar mais inovação, melhorando em última análise a vida dos pacientes com DP através de intervenções mais eficazes e personalizadas.

Development of antibody-detection ELISA based on beta-bungarotoxin for evaluation of the neutralization potency of equine plasma against Bungarus multicinctus in Taiwan.

Animal testing has been the primary approach to assess the neutralization potency of antivenom for decades. However, the necessity to sacrifice large numbers of experimental animals during this process has recently raised substantial welfare concerns. Furthermore, the laborious and expensive nature of animal testing highlights the critical need to develop alternative in vitro assays. Here, we developed an antibody-detection enzyme-linked immunosorbent assay (ELISA) technique as an alternative approach to evaluate the neutralization potency of hyperimmunized equine plasma against B. multicinctus, a medically important venomous snake in Taiwan. Firstly, five major protein components of B. multicinctus venom, specifically, α-BTX, ß-BTX, γ-BTX, MTX, and NTL, were isolated. To rank their relative medical significance, a toxicity score system was utilized. Among the proteins tested, ß-BTX presenting the highest score was regarded as the major toxic component. Subsequently, antibody-detection ELISA was established based on the five major proteins and used to evaluate 55 hyperimmunized equine plasma samples with known neutralization potency. ELISA based on ß-BTX, the most lethal protein according to the toxicity score, exhibited the best sensitivity (75.6 %) and specificity (100 %) in discriminating between high-potency and low-potency plasma, supporting the hypothesis that highly toxic proteins offer better discriminatory power for potency evaluation. Additionally, a phospholipase A2 (PLA2) competition process was implemented to eliminate the antibodies targeting toxicologically irrelevant domains. This optimization greatly enhanced the performance of our assay, resulting in sensitivity of 97.6 % and specificity of 92.9 %. The newly developed antibody-detection ELISA presents a promising alternative to in vivo assays to determine the neutralization potency of antisera against B. multicinctus during the process of antivenom production.

Predicting long-term time to cardiovascular incidents using myocardial perfusion imaging and deep convolutional neural networks.

Myocardial perfusion imaging (MPI) is a clinical tool which can assess the heart's perfusion status, thereby revealing impairments in patients' cardiac function. Within the MPI modality, the acquired three-dimensional signals are typically represented as a sequence of two-dimensional grayscale tomographic images. Here, we proposed an end-to-end survival training approach for processing gray-scale MPI tomograms to generate a risk score which reflects subsequent time to cardiovascular incidents, including cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke (collectively known as Major Adverse Cardiovascular Events; MACE) as well as Congestive Heart Failure (CHF). We recruited a total of 1928 patients who had undergone MPI followed by coronary interventions. Among them, 80% (n = 1540) were randomly reserved for the training and 5- fold cross-validation stage, while 20% (n = 388) were set aside for the testing stage. The end-to-end survival training can converge well in generating effective AI models via the fivefold cross-validation approach with 1540 patients. When a candidate model is evaluated using independent images, the model can stratify patients into below-median-risk (n = 194) and above-median-risk (n = 194) groups, the corresponding survival curves of the two groups have significant difference (P < 0.0001). We further stratify the above-median-risk group to the quartile 3 and 4 group (n = 97 each), and the three patient strata, referred to as the high, intermediate and low risk groups respectively, manifest statistically significant difference. Notably, the 5-year cardiovascular incident rate is less than 5% in the low-risk group (accounting for 50% of all patients), while the rate is nearly 40% in the high-risk group (accounting for 25% of all patients). Evaluation of patient subgroups revealed stronger effect size in patients with three blocked arteries (Hazard ratio [HR]: 18.377, 95% CI 3.719-90.801, p < 0.001), followed by those with two blocked vessels at HR 7.484 (95% CI 1.858-30.150; p = 0.005). Regarding stent placement, patients with a single stent displayed a HR of 4.410 (95% CI 1.399-13.904; p = 0.011). Patients with two stents show a HR of 10.699 (95% CI 2.262-50.601; p = 0.003), escalating notably to a HR of 57.446 (95% CI 1.922-1717.207; p = 0.019) for patients with three or more stents, indicating a substantial relationship between the disease severity and the predictive capability of the AI for subsequent cardiovascular inciidents. The success of the MPI AI model in stratifying patients into subgroups with distinct time-to-cardiovascular incidents demonstrated the feasibility of proposed end-to-end survival training approach.

Mechanisms and functions of SUMOylation in health and disease: a review focusing on immune cells.

SUMOylation, which is a type of post-translational modification that involves covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to target substrates, regulates various important molecular and cellular processes, including transcription, the cell cycle, cell signaling, and DNA synthesis and repair. Newly synthesized SUMO is immature and cleaved by the SUMO-specific protease family, resulting in exposure of the C-terminal Gly-Gly motif to become the mature form. In the presence of ATP, mature SUMO is conjugated with the activating enzyme E1 through the cysteine residue of E1, followed by transfer to the cysteine residue of E2-conjugating enzyme Ubc9 in humans that recognizes and modifies the lysine residue of a substrate protein. E3 SUMO ligases promote SUMOylation. SUMOylation is a reversible modification and mediated by SUMO-specific proteases. Cumulative studies have indicated that SUMOylation affects the functions of protein substrates in various manners, including cellular localization and protein stability. Gene knockout studies in mice have revealed that several SUMO cycling machinery proteins are crucial for the development and differentiation of various cell lineages, including immune cells. Aberrant SUMOylation has been implicated in several types of diseases, including cancers, cardiovascular diseases, and autoimmune diseases. This review summarizes the biochemistry of SUMO modification and the general biological functions of proteins involved in SUMOylation. In particular, this review focuses on the molecular mechanisms by which SUMOylation regulates the development, maturation, and functions of immune cells, including T, B, dendritic, and myeloid cells. This review also discusses the underlying relevance of disruption of SUMO cycling and site-specific interruption of SUMOylation on target proteins in immune cells in diseases, including cancers and infectious diseases.

Gut butyrate-producers confer post-infarction cardiac protection.

The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response.

Methanovulcanius yangii gen. nov., sp. nov., a hydrogenotrophic methanogen, isolated from a submarine mud volcano in the offshore area of southwestern Taiwan.

A novel mesophilic, hydrogenotrophic methanogen, strain CYW5T, was isolated from a sediment sample of a piston core collected from submarine mud volcano MV5 located in the offshore area of southwestern Taiwan. Cells of strain CYW5T were irregular coccids, 0.5-1.0 µm in diameter and lysed easily by 0.01 % sodium dodecyl sulphate (SDS) treatment. Strain CYW5Tutilized formate or hydrogen plus carbon dioxide as catabolic substrates for methanogenesis. The optimal growth conditions were 37 °C, 0.043-0.085 M NaCl and pH 6.02-7.32. The genomic DNA G+C content calculated from the genome sequence of strain CYW5T was 56.2 mol%. The results of phylogenetic analysis of 16S rRNA gene sequences indicated that strain CYW5T represented a member of the family Methanomicrobiaceae in the order Methanomicrobiales, and was closely related to the members of the genus Methanogenium. The most closely related species was Methanogenium cariaci JR1T (94.9 % of 16S rRNA gene sequence identity). The average nucleotide identity and average amino acid identity values between strain CYW5T and members of the family Methanomicrobiaceae were 74.7-78.5 % and 49.1-64.9%, respectively. Although many of the morphological and physiological characteristics of strain CYW5T and the species of the genus Methanogenium were similar, they were distinguishable by the differences in genomic G+C content and temperature, NaCl and pH ranges for growth. Based on these phenotypic, phylogenetic and genomic results, we propose that strain CYW5T represents a novel species, of a novel genus, named Methanovulcanius yangii gen. nov., sp. nov. The type strain is CYW5T (=BCRC AR10048T=DSM 100756T=NBRC 111404T).

Multi-omics profiling of chemotactic characteristics of brain microglia and astrocytoma.

Brain cancer is a deadly disease with low survival rates for over 70 % of patients. Therefore, there is a critical need to develop better treatment methods and strategies to improve patient outcomes. In this study, we explored the tumor microenvironment and discovered unique characteristics of microglia to interact with astrocytoma cells and promote proliferation and migration of collisions. The conditioned medium from the collisions expressed cell chemoattraction and anti-inflammatory responses. To further understand the interactions between microglia and astrocytoma cells, we used flow sorting and protein analysis found that the protein alterations were related to biogenesis in the astrocytoma cells and metabolic processes in the microglia. Both types of cells were involved in binding and activity in cell-cell interactions. Using STRING to demonstrate the protein cross-interaction between the cells. Furthermore, PHB and RDX interact with oncogenic proteins, which were significantly expressed in patients with Glioblastoma Multiforme (GBM) and low-grade glioma (LGG) according to GEPIA. To study the role of RDX in chemoattraction, the inhibitor-NSC668394 suppressed collision formation and migration in BV2 cells in vitro by down-regulating F-actin. Additionally, it suppressed macrophage infiltration in infiltrating islands in vivo of intracranial tumor-bearing mice. These findings provide evidence for the role of resident cells in mediating tumor development and invasiveness and suggest that potential interacting molecules may be a strategy for controlling tumor growth by regulating the infiltration of tumor-associated microglia in the brain tumor microenvironment.

Identification of INFG/STAT1/NOTCH3 as γ-Mangostin's potential targets for overcoming doxorubicin resistance and reducing cancer-associated fibroblasts in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer characterized by drug resistance and distant metastasis. Cancer stem cells (CSCs) are considered a major contributor to TNBC's drug resistance. Thus targeting and eliminating CSCs have been vigorously researched. However, the precise targetable molecular networks responsible for CSC genesis remain unclear; this conundrum is mainly due to the high heterogeneity of the TNBC tumor microenvironment (TME). The cancer-associated fibroblasts (CAFs) are one of the most abundant cellular components of the TME. Emerging studies indicate that CAFs facilitate TNBC's progression by establishing a pro-tumor TME. Hence, identifying the molecular networks involved in CAF transformation and CAF-associated oncogenesis are essential areas to be explored. Through a bioinformatics approach, we identified INFG/STAT1/NOTCH3 as a molecular link between CSCs and CAF. DOX-resistant TNBC cell lines showed increased expression of INFG/STAT1/NOTCH3 and CD44 and were associated with increased self-renewal ability and CAF-transformative ability. Downregulation of STAT1 significantly reduced the tumorigenic properties of MDA-MB-231 and -468 cells and their CAF-transforming potential. Our molecular docking analysis suggested that gamma mangostin (gMG), a xanthone, formed complexes with INFG/STAT1/NOTCH3 better than celecoxib. We then demonstrated that gMG treatment reduced the tumorigenic properties similarly observed in STAT1-knocked down conditions. Finally, we utilized a DOX-resistant TNBC tumoroid-bearing mouse model to demonstrate that gMG treatment significantly delayed tumor growth, reduced CAF generation, and improved DOX sensitivity. Further investigations are warranted for clinical translation.

Preparation of Medical Supply for Prehospital Emergencies and Disasters: An Internet-Based Simulation Drill.

Background: Mass casualties caused by natural disasters and man-made events may overwhelm local emergency medical services and healthcare systems. Logistics is essential to a successful emergency medical response. Drills have been used in disaster preparedness to validate plans, policies, procedures, and agreements, and identify resource gaps. The application of the internet to facilitate the conduct of exercise was still limited. This study aimed to investigate the optimal preparation of medical supplies by medical emergency response teams (MERTs) during emergencies and disasters using an internet-based drill. Methods: An internet-based drill based on real-life mass casualty incidents (MCIs) was developed and conducted in Taiwan from June 2017 to July 2018. The drill involved an MCI with 50 events delivered under two scenarios: (1) reduced transfer capacity and well-functioning local healthcare facilities (emergency module); (2) severely reduced transfer capacity and dysfunctional local healthcare facilities (disaster module). For each event, medical supplies commonly prepared by local MERTs in Taiwan were listed in structured questionnaires and participants selected the supplies they would use. Results: Forty-three senior medical emergency responders participated in the survey (responding rate of 47.3%). Resuscitation-related supplies increased from emergency to disaster module (e.g., intubation from 9.1% to 13.9%; dopamine from 3.2% to 5.0%; all p < 0.001). In the subgroup analysis of events with life-threatening injuries, the utilization of resuscitation-related supplies (e.g., intubation from 46.6% to 65.3%; p < 0.001) remained higher in the disaster than in the emergency module. Compared to emergency medical technicians, physicians and nurses are more likely to use intravenous/intramuscular analgesics. Conclusions: The severity of scenarios and the professional background of emergency responders have a different utilization of medical supplies in the simulation drill. The internet-based drill may contribute to optimizing the preparedness of medical response to prehospital emergencies and disasters.

A Vocal Hygiene Program for Mitigating the Effects of Occupational Vocal Demand in Primary School Teachers.

PURPOSE: Teachers are occupational voice users with significant vocal demand. This study examined if a vocal hygiene program could mitigate the effects of occupational vocal demand in primary school teachers across 1 month. METHOD: Sixty female teachers participated, with 30 in an experimental group receiving vocal hygiene education plus daily home practice for 1 month and 30 in a control group with no intervention. Their vocal changes across the month were quantified with (a) acoustic measures on fundamental frequency (fo), vocal intensity, jitter and shimmer, harmonics-to-noise ratio, and smoothed cepstral peak prominence and (b) Voice Handicap Index (VHI-10) and Vocal Fatigue Index (VFI) scores. RESULTS: Analysis of covariance showed significantly larger changes (significant decreases) in conversational fo and in jitter for the experimental group relative to the control group. Post hoc pairwise comparisons following repeated-measures analysis of variance showed significant decreases in conversational fo and in jitter across the month for the experimental group. No significant differences in VHI-10 and VFI scores were found between the groups. CONCLUSIONS: Vocal demand-related changes in acoustic measures could be partially mitigated with the vocal hygiene program. Future studies with a more refined intervention program and more long-term follow-up are recommended to better understand the long-term benefits of vocal hygiene programs on primary school teachers.

Preclinical Evaluation of a Novel Small Molecule LCC-21 to Suppress Colorectal Cancer Malignancy by Inhibiting Angiogenic and Metastatic Signatures.

Colorectal cancer (CRC) is one of the most common cancers, and it frequently metastasizes to the liver and lymph nodes. Despite major advances in treatment modalities, CRC remains a poorly characterized biological malignancy, with high reported cases of deaths globally. Moreover, cancer stem cells (CSCs) and their microenvironment have been widely shown to promote colon cancer development, progression, and metastasis. Therefore, an understanding of the underlying mechanisms that contribute to the maintenance of CSCs and their markers in CRC is crucial in efforts to treat cancer metastasis and develop specific therapeutic targets for augmenting current standard treatments. Herein, we applied computational simulations using bioinformatics to identify potential theranostic markers for CRC. We identified the overexpression of vascular endothelial growth factor-α (VEGFA)/ß-catenin/matrix metalloproteinase (MMP)-7/Cluster of Differentiation 44 (CD44) in CRC to be associated with cancer progression, stemness, resistance to therapy, metastasis, and poor clinical outcomes. To further investigate, we explored in silico molecular docking, which revealed potential inhibitory activities of LCC-21 as a potential multitarget small molecule for VEGF-A/CTNNB1/MMP7/CD44 oncogenic signatures, with the highest binding affinities displayed. We validated these finding in vitro and demonstrated that LCC-21 inhibited colony and sphere formation, migration, and invasion, and these results were further confirmed by a Western blot analysis in HCT116 and DLD-1 cells. Thus, the inhibitory effects of LCC-21 on these angiogenic and onco-immunogenic signatures could be of translational relevance as potential CRC biomarkers for early diagnosis.

Distinct features of the host-parasite interactions between nonadherent and adherent Trichomonas vaginalis isolates.

Cytoadherence of Trichomonas vaginalis to human vaginal epithelial cells (hVECs) was previously shown to involve surface lipoglycans and several reputed adhesins on the parasite. Herein, we report some new observations on the host-parasite interactions of adherent versus nonadherent T. vaginalis isolates to hVECs. The binding of the TH17 adherent isolate to hVECs exhibited an initial discrete phase followed by an aggregation phase inhibited by lactose. T. vaginalis infection immediately induced surface expression of galectin-1 and -3, with extracellular amounts in the spent medium initially decreasing and then increasing thereafter over the next 60 min. Extracellular galectin-1 and -3 were detected on the parasite surface but only the TH17 adherent isolate could uptake galectin-3 via the lysosomes. Only the adherent isolate could morphologically transform from the round-up flagellate with numerous transient protrusions into a flat amoeboid form on contact with the solid surface. Cytochalasin D challenge revealed that actin organization was essential to parasite morphogenesis and cytoadherence. Real-time microscopy showed that parasite exploring and anchoring on hVECs via the axostyle may be required for initial cytoadherence. Together, the parasite cytoskeleton behaviors may collaborate with cell surface adhesion molecules for cytoadherence. The nonadherent isolate migrated faster than the adherent isolate, with motility transiently increasing in the presence of hVECs. Meanwhile, differential histone acetylation was detected between the two isolates. Also, TH17 without Mycoplasma symbiosis suggests that symbiont might not determine TH17 innate cytoadherence. Our findings regarding distinctive host-parasite interactions of the isolates may provide novel insights into T. vaginalis infection.

Immunoprofiling of Equine Plasma against Deinagkistrodon acutus in Taiwan: Key to Understanding Differential Neutralization Potency in Immunized Horses.

Snakebite envenoming is a public health issue linked to high mortality and morbidity rates worldwide. Although antivenom has been the mainstay treatment for envenomed victims receiving medical care, the diverse therapeutic efficacy of the produced antivenom is a major limitation. Deinagkistrodon acutus is a venomous snake that poses significant concern of risks to human life in Taiwan, and successful production of antivenom against D. acutus envenoming remains a considerable challenge. Among groups of horses subjected to immunization schedules, few or none subsequently meet the quality required for further scale-up harvesting. The determinants underlying the variable immune responses of horses to D. acutus venom are currently unknown. In this study, we assessed the immunoprofiles of high-potency and low-potency horse plasma against D. acutus venom and explored the conspicuous differences between these two groups. Based on the results of liquid chromatography with tandem mass spectrometry (LC-MS/MS), acutolysin A was identified as the major component of venom proteins that immunoreacted differentially with the two plasma samples. Our findings indicate underlying differences in antivenoms with variable neutralization efficacies, and may provide valuable insights for improvement of antivenom production in the future.

Multiomics Study of a Novel Naturally Derived Small Molecule, NSC772864, as a Potential Inhibitor of Proto-Oncogenes Regulating Cell Cycle Progression in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most prevalent malignant tumors, and it contributes to high numbers of deaths globally. Although advances in understanding CRC molecular mechanisms have shed significant light on its pathogenicity, current treatment options, including combined chemotherapy and molecular-targeted agents, are still limited due to resistance, with almost 25% of patients developing distant metastasis. Therefore, identifying novel biomarkers for early diagnosis is crucial, as they will also influence strategies for new targeted therapies. The proto-oncogene, c-Met, a tyrosine kinase that promotes cell proliferation, motility, and invasion; c-MYC, a transcription factor associated with the modulation of the cell cycle, proliferation, apoptosis; and cyclin D1 (CCND1), an essential regulatory protein in the cell cycle, all play crucial roles in cancer progression. In the present study, we explored computational simulations through bioinformatics analysis and identified the overexpression of c-Met/GSK3ß/MYC/CCND1 oncogenic signatures that were associated with cancer progression, drug resistance, metastasis, and poor clinical outcomes in CRC. We further demonstrated the anticancer activities of our newly synthesized quinoline-derived compound, NSC772864, against panels of the National Cancer Institute's human CRC cell lines. The compound exhibited cytotoxic activities against various CRC cell lines. Using target prediction tools, we found that c-Met/GSK3ß/MYC/CCND1 were target genes for the NSC772864 compound. Subsequently, we performed in silico molecular docking to investigate protein-ligand interactions and discovered that NSC772864 exhibited higher binding affinities with these oncogenes compared to FDA-approved drugs. These findings strongly suggest that NSC772864 is a novel and potential antiCRC agent.

Effect of speech therapy on quality of life in patients with spinocerebelar ataxia type 3.

BACKGROUND: Individuals with spinocerebellar ataxia type 3 (SCA3) present communication and swallowing disorders, and consequent deterioration in quality of life (QOL). OBJECTIVE: To evaluate the impact of a speech therapy rehabilitation program on the QOL of patients with SCA3. METHODS: All participants were randomly assigned to two groups, an intervention group receiving speech therapy (STG) and a control group (CG). The International Cooperative Ataxia Rating Scale scores were 32.4 ± 20.2, and the Scale for the Assessment and Rating of Ataxia scores were 11.8 ± 8.0. The intervention consisted of a 12-session speech therapy rehabilitation program with oral, pharyngeal, and laryngeal strengthening exercises-the so-called ATAXIA-Myofunctional Orofacial and Vocal Therapy (A-MOVT). They all were submitted to pre- and postintervention evaluations using the World Health Organization's Quality of Life (WHOQOL-BREF) assessment, as well as the Living with Dysarthria (LwD), Quality of Life in Swallowing Disorders (SWAL-QOL), and Food Assessment Tool (EAT-10). RESULTS: The study sample consisted of 48 patients with SCA3 (STG = 25; CG = 23), mean age was 47.1 ± 11.4 years; mean age at symptom onset was 36.9 ± 11.3 years; disease duration was 11.9 ± 13.3 years. After the 3-month intervention, there were significant changes in the QOL in the STG compared with the CG, when assessed by the LwD (179.12 ± 62.55 vs. 129.88 ± 51.42, p < 0.001), SWAL-QOL (869.43 ± 153.63 vs. 911.60 ± 130.90, p = 0.010), and EAT-10 (5.16 ± 7.55 vs. 2.08 ± 3.85, p = 0.018). CONCLUSIONS: Patients with SCA3 should receive continuous speech therapy as part of the A-MOVT program, because therapy helps to improve difficulty swallowing and dysarthria.

ANTECEDENTES: Indivíduos com ataxia espinocerebelar tipo 3 (AEC3) apresentam distúrbios da comunicação e deterioração da deglutição e, consequentemente, na qualidade de vida (QV). OBJETIVO: Avaliar o impacto de um programa de reabilitação fonoaudiológica na QV em pacientes com AEC3. MéTODOS: Todos os participantes foram alocados aleatoriamente em dois grupos, um grupo intervenção que recebeu terapia fonoaudiológica (GTF) e um grupo controle (GC). As pontuações das escalas: International Cooperative Ataxia Rating Scale (ICARS) foram 32,4 ± 20,2 e da Scale for the Assessment and Rating of Ataxia (SARA) foram 11,8 ± 8,0. A intervenção consistiu em um programa de reabilitação fonoaudiológica de 12 sessões composto por exercícios de fortalecimento oral, faríngeo e laríngeo - denominados ATAXIA - Terapia Miofuncional Orofacial e Vocal (A-TMOV). Todos foram submetidos a avaliações pré e pós-intervenção por meio dos protocolos World Health Organization's Quality of Life (WHOQOL-BREF), Vivendo com Disartria (VcD), Quality of Life in Swallowing Disorders (SWAL-QOL) e Food Assessment Tool (EAT-10). RESULTADOS: A amostra foi composta por 48 pacientes com AEC3 (25 no GTF e 23 no GC), média de idade 47,1 ± 11,4anos; média de idade de início dos sintomas 36,9 ± 11,3anos; duração da doença 11,9 ± 13,3anos. Após intervenção de três meses, houve mudanças significativas na QV no GTF em comparação com o GC quando avaliado pelo VcD (179,12 ± 62,55 versus129,88 ± 51,42, p < 0,001), SWAL-QOL (869,43 ± 153,63 versus 911,60 ± 130,90, p = 0,010), EAT-10 (5,16 ± 7,55 versus 2,08 ± 3,85, p = 0,018). CONCLUSõES: Pacientes com AEC3 devem receber terapia fonoaudiológica contínua como parte do programa A-TMOV, pois a terapia ajuda a melhorar a dificuldade de deglutição e a disartria.