A Self-Cascade Penetrating Brain Tumor Immunotherapy Mediated by Near-Infrared II Cell Membrane-Disrupting Nanoflakes via Detained Dendritic Cells.

Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell-cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG-b-C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm2), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.

ENCAP: Computational prediction of tumor T cell antigens with ensemble classifiers and diverse sequence features.

Cancer immunotherapy enhances the body's natural immune system to combat cancer, offering the advantage of lowered side effects compared to traditional treatments because of its high selectivity and efficacy. Utilizing computational methods to identify tumor T cell antigens (TTCAs) is valuable in unraveling the biological mechanisms and enhancing the effectiveness of immunotherapy. In this study, we present ENCAP, a predictor for TTCA based on ensemble classifiers and diverse sequence features. Sequences were encoded as a feature vector of 4349 entries based on 57 different feature types, followed by feature engineering and hyperparameter optimization for machine learning models, respectively. The selected feature subsets of ENCAP are primarily composed of physicochemical properties, with several features specifically related to hydrophobicity and amphiphilicity. Two publicly available datasets were used for performance evaluation. ENCAP yields an AUC (Area Under the ROC Curve) of 0.768 and an MCC (Matthew's Correlation Coefficient) of 0.522 on the first independent test set. On the second test set, it achieves an AUC of 0.960 and an MCC of 0.789. Performance evaluations show that ENCAP generates 4.8% and 13.5% improvements in MCC over the state-of-the-art methods on two popular TTCA datasets, respectively. For the third test dataset of 71 experimentally validated TTCAs from the literature, ENCAP yields prediction accuracy of 0.873, achieving improvements ranging from 12% to 25.7% compared to three state-of-the-art methods. In general, the prediction accuracy is higher for sequences of fewer hydrophobic residues, and more hydrophilic and charged residues. The source code of ENCAP is freely available at https://github.com/YnnJ456/ENCAP.

Potential Overtreatment of DCIS in Patients with Limited Life Expectancy.

INTRODUCTION: As the benefits of intensive locoregional therapy for ductal carcinoma in situ (DCIS) are realized over time in older adults, life expectancy may help to guide treatment decisions. We examined whether life expectancy was associated with extent of locoregional therapy in this population. PATIENTS AND METHODS: Women ≥ 70 years old with < 5 cm of DCIS diagnosed 2010-2015 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset and categorized by a life expectancy ≤ 5 or > 5 years, defined by a validated claims-based measure. Differences in locoregional therapy (mastectomy + axillary surgery, mastectomy-only, lumpectomy + radiation therapy (RT) + axillary surgery, lumpectomy + RT, lumpectomy-only, and no treatment) by life expectancy were assessed using Pearson chi-squared tests. Generalized linear mixed models were used to identify factors associated with receipt of lumpectomy-only. RESULTS: Of 5346 women (median age of 75 years, range 70-97 years), 927 (17.3%) had a life expectancy ≤ 5 years. Of the 4041 patients who underwent lumpectomy, 710 (13.3%) underwent axillary surgery. More patients with life expectancy ≤ 5 years underwent lumpectomy-only (39.4% versus 27%), mastectomy-only (8.1% versus 5.3%), or no treatment (5.8% versus 3.2%; p < 0.001). On multivariable analysis, women with life expectancy ≤ 5 years had a significantly greater likelihood of undergoing lumpectomy-only [OR 1.90, 95% CI (1.63-2.22)]. CONCLUSIONS: Life expectancy is associated with lower-intensity locoregional therapy for older women with DCIS, yet a large proportion of patients with a life expectancy ≤ 5 years received RT and axillary surgery, highlighting potential overtreatment and opportunities to de-escalate locoregional therapy in older adults.

Variant Impact Predictor database (VIPdb), version 2: Trends from 25 years of genetic variant impact predictors.

Background: Variant interpretation is essential for identifying patients' disease-causing genetic variants amongst the millions detected in their genomes. Hundreds of Variant Impact Predictors (VIPs), also known as Variant Effect Predictors (VEPs), have been developed for this purpose, with a variety of methodologies and goals. To facilitate the exploration of available VIP options, we have created the Variant Impact Predictor database (VIPdb). Results: The Variant Impact Predictor database (VIPdb) version 2 presents a collection of VIPs developed over the past 25 years, summarizing their characteristics, ClinGen calibrated scores, CAGI assessment results, publication details, access information, and citation patterns. We previously summarized 217 VIPs and their features in VIPdb in 2019. Building upon this foundation, we identified and categorized an additional 186 VIPs, resulting in a total of 403 VIPs in VIPdb version 2. The majority of the VIPs have the capacity to predict the impacts of single nucleotide variants and nonsynonymous variants. More VIPs tailored to predict the impacts of insertions and deletions have been developed since the 2010s. In contrast, relatively few VIPs are dedicated to the prediction of splicing, structural, synonymous, and regulatory variants. The increasing rate of citations to VIPs reflects the ongoing growth in their use, and the evolving trends in citations reveal development in the field and individual methods. Conclusions: VIPdb version 2 summarizes 403 VIPs and their features, potentially facilitating VIP exploration for various variant interpretation applications. Availability: VIPdb version 2 is available at https://genomeinterpretation.org/vipdb.

Prostate magnetic resonance imaging utilization and its relationship with advanced prostate cancer detection.

BACKGROUND: The rise in advanced prostate cancer has coincided with increased use of Magnetic Resonance Imaging (MRI), leading to the hypothesis that this increase in surveillance registries is an artifact of more sensitive imaging tools. We assessed the association between regional variation in prostate MRI and advanced prostate cancer diagnoses. METHODS: We utilized SEER-Medicare data (2004-2015), including men > 65 diagnosed with localized prostate cancer. The predictor variable was the utilization of prostate MRI in each hospital referral region (HRR, representing regional healthcare markets). We compared the proportion of disease recorded as locally advanced or of regional risk group (cT3, cT4, and cN1) which would plausibly have been detected by prostate MRI. We conducted adjusted multivariable analysis and performed correlation analysis with Spearman rank coefficient at the level of the HRR. Sensitivity analysis for years 2011 to 2015 was conducted. RESULTS: Of 98,921 men diagnosed, 4.01% had locally advanced or regional disease. The median prostate MRI utilization rate was 4.58% (IQR [3.03%, 8.12%]). Adjusted multivariable analysis revealed no statistically significant correlation between MRI utilization and proportion of advanced prostate cancer (aOR = 1.01, 95% CI, [0.99,1.03]) in each region. The correlation between MRI usage and advanced diagnosis was not significant (Spearman Ρ = 0.09, P = 0.4). Sensitivity analysis conducted between 2011 and 2015 showed similar results (aOR = 1.008, 95% CI, [0.989, 1.027]; Spearman Ρ = 0.16, P = 0.1). CONCLUSIONS: During our study period, HRR-level utilization of MRI was not associated with higher incidences of advanced prostate cancer. This suggests the rising advanced prostate cancer diagnoses observed in this period are unlikely an artifact of greater sensitivity of modern imaging tests, but potentially due to other factors such as changes in screening or risk factors. With increased utilization and evolving techniques in recent years, the association between MRI and advanced prostate cancer detection warrants continued monitoring.

Effectiveness of fentanyl buccal soluble film in cancer patients with inadequate breakthrough pain control.

BACKGROUND: Clinical evidence for the rapidity and effectiveness of fentanyl buccal soluble film (FBSF) in reducing pain intensity of breakthrough cancer pain (BTcP) remains inadequate. This study aimed to evaluate the efficacy of FBSF proportional to the around-the-clock (ATC) opioid regimens in rapidly relieving the intensity of BTcP episodes by determining the percentage of patients requiring further dose titration. METHODS: The study procedure included a dose-finding period followed by a 14-day observation period. Pain intensity was recorded with a Numeric Rating Scale (NRS) at onset and 5, 10, 15, and 30 min after FBSF self-administration. Meaningful pain relief was defined as the final NRS score ≤ 3. Satisfaction survey was conducted for each patient after treatment using the Global Satisfaction Scale. RESULTS: A total of 63 BTcP episodes occurred in 30 cancer patients. Only one patient required rescue medication at first BTcP episode and then achieved meaningful pain relief after titrating FBSF by 200 µg. Most BTcP episodes relieved within 10 min. Of 63 BTcP episodes, 30 (47.6%), 46 (73.0%), and 53 (84.1%) relieved within 5, 10, and 15 min after FBSF administration. Only grade 1/2 adverse events were reported, including somnolence, malaise, and dizziness. Of the 63 BTcP episodes, 82.6% were rated as excellent/good satisfaction with FBSF. CONCLUSION: FBSF can be administrated "on demand" by cancer patients at the onset of BTcP, providing rapid analgesia by achieving meaningful pain relief within 10 min. TRIAL REGISTRATION: This study was retrospectively registered 24 December, 2021 at Clinicaltrial.gov (NCT05209906): https://clinicaltrials.gov/study/NCT05209906 .

Complementary acupuncture treatment and reduced risk of sudden sensorineural hearing loss in nasopharyngeal carcinoma patients: a retrospective, nested case-control study.

PURPOSE: Hearing loss is a frequently observed comorbidity in patients with nasopharyngeal carcinoma (NPC). Accumulating evidence demonstrated that acupuncture can safely manage cancer and its treatment-related symptoms, but its effect in minimizing the likelihood of experiencing sudden sensorineural hearing loss (SSHL) has not been established. So this work aimed to determine the risk of SSHL among NPC persons with or without acupuncture use. METHODS: One population-level, nested case-control design within a cohort study is employed. Relevant information on persons aged 20-80 years who were afflicted with NPC between 2000 and 2010 was extracted from a nationwide health claims database. From them, we identified the cases who had the first SSHL diagnosis occurring after NPC, and all of them were randomly matched to two controls without SSHL. Conditional logistic regression was employed to calculate odds ratios (OR) and its respective 95% confidence intervals (CI) for incident SSHL in relation to acupuncture treatment. RESULTS: Eight hundred eleven SSHL cases were randomly matched to 1452 controls. Those receiving conventional care plus acupuncture use had a reduced adjusted OR of 0.39 (95% CI, 0.25-0.60) for SSHL. We further discovered that the longer usage of acupuncture remarkably correlated with reduction of SSHL risk in a dose-dependent manner. CONCLUSIONS: Delineation of the benefit from integration of acupuncture into conventional care may be a reference in instituting more appropriate care for NPC subjects. IMPLICATIONS FOR CANCER SURVIVORS: Patients living with NPC may benefit from a timely integration of acupuncture into routine care to lessen SSHL risk.

Comparison of laparoscopic and open surgery for colorectal malignancy in obese patients: a propensity score-weighted cohort study.

BACKGROUND: Insufficient evidence exists to ascertain the long-term prognosis in patients with obesity undergoing laparoscopic surgery versus open surgery for colorectal cancer. METHODS: Employing an institutional database from 2009 to 2019, we assessed individuals with a body mass index of ≥30 kg/m2 who underwent surgery for primary stage I-III colorectal adenocarcinoma. We used propensity score-weighted analysis to compare short-term and oncologic outcomes between laparoscopic and open surgical approaches. RESULTS: This study enrolled 473 patients (open vs. laparoscopic surgery: 220 vs. 253; median follow-up period, 60 mo). The laparoscopy group showed a significantly longer operative time (252 vs. 212 min), a higher anastomotic-leakage rate (5.14% vs. 0.91%), and a greater proportion of Clavien-Dindo class > III complications (5.93% vs. 1.82%). The open group showed a higher wound infection rate (7.27% vs. 3.16%) and a higher readmission rate (6.36% vs. 2.37%). After propensity-score weighting, laparoscopy was inferior to open surgery in terms of long-term overall survival (hazard ratio: 1.43), disease-free survival (1.39), and recurrence rate (21.1% vs. 14.5%). In the subgroup analysis, female patients, older individuals, stage III patients, patients with rectal cancer, and those who underwent surgery after 2014 showed inferior long-term outcomes after laparoscopy. CONCLUSIONS: Laparoscopic colorectal cancer surgery for patients with obesity requires significant caution. Despite good short-term outcomes, this procedure is associated with hidden risks and poor long-term prognoses. In female patients, older individuals, stage III patients, patients with rectal cancer, and those treated in the late surgery era subgroups, caution is advised when performing laparoscopic surgery.

Biofunctionalized hydrogel composed of genipin-crosslinked gelatin/hyaluronic acid incorporated with lyophilized platelet-rich fibrin for segmental bone defect repair.

Segmental bone defects can arise from trauma, infection, metabolic bone disorders, or tumor removal. Hydrogels have gained attention in the field of bone regeneration due to their unique hydrophilic properties and the ability to customize their physical and chemical characteristics to serve as scaffolds and carriers for growth factors. However, the limited mechanical strength of hydrogels and the rapid release of active substances have hindered their clinical utility and therapeutic effectiveness. With ongoing advancements in material science, the development of injectable and biofunctionalized hydrogels holds great promise for addressing the challenges associated with segmental bone defects. In this study, we incorporated lyophilized platelet-rich fibrin (LPRF), which contains a multitude of growth factors, into a genipin-crosslinked gelatin/hyaluronic acid (GLT/HA-0.5 % GP) hydrogel to create an injectable and biofunctionalized composite material. Our findings demonstrate that this biofunctionalized hydrogel possesses optimal attributes for bone tissue engineering. Furthermore, results obtained from rabbit model with segmental tibial bone defects, indicate that the treatment with this biofunctionalized hydrogel resulted in increased new bone formation, as confirmed by imaging and histological analysis. From a translational perspective, this biofunctionalized hydrogel provides innovative and bioinspired capabilities that have the potential to enhance bone repair and regeneration in future clinical applications.

[Corrigendum] Next­generation sequencing analysis reveals that MTH­3, a novel curcuminoid derivative, suppresses the invasion of MDA­MB­231 triple­negative breast adenocarcinoma cells.

Subsequently to the publication of the article, an interested reader drew to the authors' attention that, in Fig. 2A on p. 5, the 'Control  (24 h)' and 'MTH­3 (1 µM; 24 h)' data panels contained partially overlapping data, such that they appeared to have been derived from the same original source. The authors have examined their original data, and realized that this error arose inadvertently as a consequence of having compiled this figure incorrectly. The revised version of Fig. 2, featuring the data from one of the repeated experiments in Fig. 2A, is shown below. The revised data shown for this figure do not affect the overall conclusions reported in the paper. The authors apologize to the Editor of Oncology Reports and to the readership for any inconvenience caused. [Oncology Reports 46: 133, 2021; DOI: 10.3892/or.2021.8084].

Development of an Ex Vivo Porcine Eye Model for Exploring the Pathogenicity of Acanthamoeba.

Acanthamoeba, a widely distributed free-living amoeba found in various environments, is an opportunistic pathogen responsible for causing Acanthamoeba keratitis, a condition that may lead to blindness. However, identifying the pathogenicity of Acanthamoeba is challenging due to its complex life cycle, ability to adapt to different environments, variable virulence factors, and intricate interactions with the host immune system. Additionally, the development of an effective model for studying Acanthamoeba pathogenicity is limited, hindering a comprehensive understanding of the mechanisms underlying its virulence and host interactions. The aim of this study was to develop an ex vivo model for Acanthamoeba infection using porcine eyeballs and to evaluate the pathogenicity of the Acanthamoeba isolates. Based on slit lamp and biopsy analysis, the developed ex vivo model is capable of successfully infecting Acanthamoeba within 3 days. Histopathological staining revealed that clinical isolates of Acanthamoeba exhibited greater corneal stroma destruction and invasion in this model than environmental isolates. Our results highlight the importance of an ex vivo porcine eye model in elucidating the pathogenesis of Acanthamoeba infection and its potential implications for understanding and managing Acanthamoeba-related ocular diseases.

Site-specific thrombus formation: advancements in photothrombosis-on-a-chip technology.

Thrombosis, characterized by blood clot formation within vessels, poses a significant medical challenge. Despite extensive research, the development of effective thrombosis therapies is hindered by substantial costs, lengthy development times, and high failure rates in medication commercialization. Conventional pre-clinical models often oversimplify cardiovascular disease, leading to a disparity between experimental results and human physiological responses. In response, we have engineered a photothrombosis-on-a-chip system. This microfluidic model integrates human endothelium, human whole blood, and blood flow dynamics and employs the photothrombotic method. It enables precise, site-specific thrombus induction through controlled laser irradiation, effectively mimicking both normal and thrombotic physiological conditions on a single chip. Additionally, the system allows for the fine-tuning of thrombus occlusion levels via laser parameter adjustments, offering a flexible thrombus model with varying degrees of obstruction. Additionally, the formation and progression of thrombosis noted on the chip closely resemble the thrombotic conditions observed in mice in previous studies. In the experiments, we perfused recalcified whole blood with Rose Bengal into an endothelialized microchannel and initiated photothrombosis using green laser irradiation. Various imaging methods verified the model's ability to precisely control thrombus formation and occlusion levels. The effectiveness of clinical drugs, including heparin and rt-PA, was assessed, confirming the chip's potential in drug screening applications. In summary, the photothrombosis-on-a-chip system significantly advances human thrombosis modeling. Its precise control over thrombus formation, flexibility in the thrombus severity levels, and capability to simulate dual physiological states on a single platform make it an invaluable tool for targeted drug testing, furthering the development of organ-on-a-chip drug screening techniques.

Improved prediction of anti-angiogenic peptides based on machine learning models and comprehensive features from peptide sequences.

Angiogenesis is a key process for the proliferation and metastatic spread of cancer cells. Anti-angiogenic peptides (AAPs), with the capability of inhibiting angiogenesis, are promising candidates in cancer treatment. We propose AAPL, a sequence-based predictor to identify AAPs with machine learning models of improved prediction accuracy. Each peptide sequence was transformed to a vector of 4335 numeric values according to 58 different feature types, followed by a heuristic algorithm for feature selection. Next, the hyperparameters of six machine learning models were optimized with respect to the feature subset. We considered two datasets, one with entire peptide sequences and the other with 15 amino acids from peptide N-termini. AAPL achieved Matthew's correlation coefficients of 0.671 and 0.756 for independent tests based on the two datasets, respectively, outperforming existing predictors by a range of 5.3% to 24.6%. Further analyses show that AAPL yields higher prediction accuracy for peptides with more hydrophobic residues, and fewer hydrophilic and charged residues. The source code of AAPL is available at https://github.com/yunzheng2002/Anti-angiogenic .

A Randomized Crossover Trial Evaluating the Impact of Cultural Dexterity Training on Surgical Residents' Knowledge, Cross-Cultural Care, Skills, and Beliefs: The Provider Awareness and Cultural dexterity Training for Surgeons (PACTS) Trial.

OBJECTIVES: This trial examines the impact of the Provider Awareness and Cultural dexterity Toolkit for Surgeons (PACTS) curriculum on surgical residents' knowledge, cross-cultural care, skills, and beliefs. SUMMARY BACKGROUND DATA: Cross-cultural training of providers may reduce healthcare outcome disparities, but its effectiveness in surgical trainees is unknown. METHODS: PACTS focuses on developing skills needed for building trust, working with patients with limited English proficiency, optimizing informed consent, and managing pain. The PACTS trial was a randomized crossover trial of 8 academic general surgery programs in the United States: The Early group ("Early") received PACTS between Periods 1 and 2, while the Delayed group ("Delayed") received PACTS between Periods 2 and 3. Residents were assessed pre- and post-intervention on Knowledge, Cross-Cultural Care, Self-Assessed Skills, and Beliefs. Chi-square and Fisher's exact tests were conducted to evaluate within- and between-intervention group differences. RESULTS: Of 406 residents enrolled, 315 were exposed to the complete PACTS curriculum. Early residents' Cross-Cultural Care (79.6% to 88.2%, P<0.0001), Self-Assessed Skills (74.5% to 85.0%, P<0.0001), and Beliefs (89.6% to 92.4%, P=0.0028) improved after PACTS; Knowledge scores (71.3% to 74.3%, P=0.0661) were unchanged. Delayed resident scores pre- to post-PACTS showed minimal improvements in all domains. When comparing the two groups at Period 2, Early residents had modest improvement in all 4 assessment areas, with statistically significant increase in Beliefs (92.4% vs 89.9%, P=0.0199). CONCLUSION: The PACTS curriculum is a comprehensive tool that improved surgical residents' knowledge, preparedness, skills, and beliefs, which will help with caring for diverse patient populations.

Impact of glucose-containing fluid on acute pancreatitis outcomes: A multicenter retrospective analysis.

INTRODUCTION: Fluid resuscitation reduces mortality and morbidity in acute pancreatitis (AP); however, whether glucose-containing fluids negatively impact AP remains uncertain. We aimed to examine the association between glucose-containing fluids and AP outcomes. METHODS: This multicenter retrospective cohort study included patients diagnosed with AP between January 2015 and December 2018. Glucose density was defined as total glucose content divided by total fluid volume (g/dl) on day 1, and was considered high if the level exceeded the median. Endpoints were early organ failure (OF), including cardiovascular, renal, or respiratory system failure within 7 days; 30-day OF; ICU admission; and AP-related 90-day mortality. Logistic regression models, restricted cubic spline curves, and Cox proportional hazards models were used for statistical analysis. RESULTS: From the database, 1,146 patients with AP were included. Early OF occurred in 8.8% of patients within 7 days. The high glucose-density group (>5 g/dl) had increased risk of early OF (9.7% vs. 8.2%; adjusted odds ratio [aOR], 1.69; 95% confidence interval [CI], 1.03-2.80; P = 0.039), respiratory failure (8.0% vs. 6.2%; aOR, 1.88; 95% CI, 1.09-3.24; P = 0.024), cardiovascular failure (3.4% vs. 2.4%; aOR, 3.59; 95% CI, 1.28-10.0; P = 0.015), and ICU admission (6.8% vs. 5.8%; aOR, 2.06; 95% CI, 1.08-3.94; P = 0.029), with a dose-response effect observed for cardiovascular failure and ICU admission. A significant increase 30-day OF risk (adjusted hazard ratio [aHR], 1.70; 95% CI, 1.19-2.45) was also noted. CONCLUSION: Excess glucose-containing fluid was associated with increased risks of overall, respiratory, and cardiovascular OF and ICU admission in AP.

SpliceAPP: an interactive web server to predict splicing errors arising from human mutations.

BACKGROUND: Splicing variants are a major class of pathogenic mutations, with their severity equivalent to nonsense mutations. However, redundant and degenerate splicing signals hinder functional assessments of sequence variations within introns, particularly at branch sites. We have established a massively parallel splicing assay to assess the impact on splicing of 11,191 disease-relevant variants. Based on the experimental results, we then applied regression-based methods to identify factors determining splicing decisions and their respective weights. RESULTS: Our statistical modeling is highly sensitive, accurately annotating the splicing defects of near-exon intronic variants, outperforming state-of-the-art predictive tools. We have incorporated the algorithm and branchpoint information into a web-based tool, SpliceAPP, to provide an interactive application. This user-friendly website allows users to upload any genetic variants with genome coordinates (e.g., chr15 74,687,208 A G), and the tool will output predictions for splicing error scores and evaluate the impact on nearby splice sites. Additionally, users can query branch site information within the region of interest. CONCLUSIONS: In summary, SpliceAPP represents a pioneering approach to screening pathogenic intronic variants, contributing to the development of precision medicine. It also facilitates the annotation of splicing motifs. SpliceAPP is freely accessible using the link https://bc.imb.sinica.edu.tw/SpliceAPP . Source code can be downloaded at https://github.com/hsinnan75/SpliceAPP .

Discovery of Novel Spike Inhibitors against SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current coronavirus disease pandemic. With the rapid evolution of variant strains, finding effective spike protein inhibitors is a logical and critical priority. Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2 viral entry, and thus related therapeutic approaches associated with the spike protein-ACE2 interaction show a high degree of feasibility for inhibiting viral infection. Our computer-aided drug design (CADD) method meticulously analyzed more than 260,000 compound records from the United States National Cancer Institute (NCI) database, to identify potential spike inhibitors. The spike protein receptor-binding domain (RBD) was chosen as the target protein for our virtual screening process. In cell-based validation, SARS-CoV-2 pseudovirus carrying a reporter gene was utilized to screen for effective compounds. Ultimately, compounds C2, C8, and C10 demonstrated significant antiviral activity against SARS-CoV-2, with estimated EC50 values of 8.8 µM, 6.7 µM, and 7.6 µM, respectively. Using the above compounds as templates, ten derivatives were generated and robust bioassay results revealed that C8.2 (EC50 = 5.9 µM) exhibited the strongest antiviral efficacy. Compounds C8.2 also displayed inhibitory activity against the Omicron variant, with an EC50 of 9.3 µM. Thus, the CADD method successfully discovered lead compounds binding to the spike protein RBD that are capable of inhibiting viral infection.

A 35-gene mutation profile predicts the therapeutic outcome of patients with esophageal squamous cell carcinoma receiving neo-adjuvant chemoradiation.

Esophageal cancer is a common malignancy worldwide with a poor prognosis without radical resection. Neoadjuvant concurrent chemoradiotherapy (NACRT) followed by esophagectomy is widely used for treating locally advanced esophageal cancer in the thorax. The study aimed to assess mutation profiles and their correlation with therapeutic outcomes in patients diagnosed with locally advanced thoracic esophageal squamous cell carcinoma (ESCC). A retrospective analysis was conducted on 62 patients with ESCC who underwent NACRT. All patients received concurrent chemoradiotherapy (CCRT) utilizing intensity-modulated radiation therapy alongside concurrent chemotherapy with a cisplatin-based regimen. A 35-gene next-generation sequencing (NGS) panel detecting 402 genetic variants was used, which has been proven predictive in ESCC patients who received definitive chemoradiation. The 35-gene mutation profiles were analyzed in pre-treatment biopsies. The results reveled there were variants correlated with pathological complete remission or partial response, overall survival, and progression-free survival. A combination of p.Pro1319Ser and p.Arg2159Gly mutations in the MUC17 gene demonstrated an adverse impact on pathological response (OR [95% CI] = 7.00 (3.07-15.94), P < 0.001). Additionally, the variants located in the MUC17, MUC4, and MYH4 genes exhibited notably effects on tumor recurrence or mortality. Patients harboring either the MUC17 p.Thr2702Val or MUC4 p.Thr3355Ser mutation displayed a more than four-fold increased risk for disease recurrence or mortality. We concluded that specific mutations correlated to the pathological complete response in ESCC receiving neoadjuvant chemoradiation can be identified through the utilization of 35-gene expression profiles. Further investigation into the pathophysiological roles of MUC17 and MUC4 mutations in ESCC is warranted.

Genome­wide association study and polygenic risk scores predict psoriasis and its shared phenotypes in Taiwan.

Psoriasis is a chronic inflammatory dermatological disease, and there is a lack of understanding of the genetic factors involved in psoriasis in Taiwan. To establish associations between genetic variations and psoriasis, a genome­wide association study was performed in a cohort of 2,248 individuals with psoriasis and 67,440 individuals without psoriasis. Using the ingenuity pathway analysis software, biological networks were constructed. Human leukocyte antigen (HLA) diplotypes and haplotypes were analyzed using Attribute Bagging (HIBAG)­R software and chi­square analysis. The present study aimed to assess the potential risks associated with psoriasis using a polygenic risk score (PRS) analysis. The genetic association between single nucleotide polymorphisms (SNPs) in psoriasis and various human diseases was assessed by phenome­wide association study. METAL software was used to analyze datasets from China Medical University Hospital (CMUH) and BioBank Japan (BBJ). The results of the present study revealed 8,585 SNPs with a significance threshold of P<5x10­8, located within 153 genes strongly associated with the psoriasis phenotype, particularly on chromosomes 5 and 6. This specific genomic region has been identified by analyzing the biological networks associated with numerous pathways, including immune responses and inflammatory signaling. HLA genotype analysis indicated a strong association between HLA­A*02:07 and HLA­C*06:02 in a Taiwanese population. Based on our PRS analysis, the risk of psoriasis associated with the SNPs identified in the present study was quantified. These SNPs are associated with various dermatological, circulatory, endocrine, metabolic, musculoskeletal, hematopoietic and infectious diseases. The meta­analysis results indicated successful replication of a study conducted on psoriasis in the BBJ. Several genetic loci are significantly associated with susceptibility to psoriasis in Taiwanese individuals. The present study contributes to our understanding of the genetic determinants that play a role in susceptibility to psoriasis. Furthermore, it provides valuable insights into the underlying etiology of psoriasis in the Taiwanese community.