Targeting TGFß receptor-mediated snail and twist: WSG, a polysaccharide from Ganoderma lucidum, and it-based dissolvable microneedle patch suppress melanoma cells.

Cutaneous melanoma is a lethal skin cancer variant with pronounced aggressiveness and metastatic potential. However, few targeted medications inhibit the progression of melanoma. Ganoderma lucidum, which is a type of mushroom, is widely used as a non-toxic alternative adjunct therapy for cancer patients. This study determines the effect of WSG, which is a water-soluble glucan that is derived from G. lucidum, on melanoma cells. The results show that WSG inhibits cell viability and the mobility of melanoma cells. WSG induces changes in the expression of epithelial-to-mesenchymal transition (EMT)-related markers. WSG also downregulates EMT-related transcription factors, Snail and Twist. Signal transduction assays show that WSG reduces the protein levels in transforming growth factor ß receptors (TGFßRs) and consequently inhibits the phosphorylation of intracellular signaling molecules, such as FAK, ERK1/2 and Smad2. An In vivo study shows that WSG suppresses melanoma growth in B16F10-bearing mice. To enhance transdermal drug delivery and prevent oxidation, two highly biocompatible compounds, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), are used to synthesize a dissolvable microneedle patch that is loaded with WSG (MN-WSG). A functional assay shows that MN-WSG has an effect that is comparable to that of WSG alone. These results show that WSG has significant potential as a therapeutic agent for melanoma treatment. MN-WSG may allow groundbreaking therapeutic approaches and offers a novel method for delivering this potent compound effectively.

Elucidating the Role of Let-7d-5p and OLR1 in the Progression and Prognosis of Oral Squamous Cell Carcinoma via FAK/P53 Signaling Axis.

BACKGROUND/AIM: Despite advances in oral squamous cell carcinoma (OSCC) diagnosis and treatment, the five-year survival rate remains low, underscoring the need for improved biomarkers and therapeutic strategies. This study investigated the role of let-7d-5p microRNA (miRNA) and its target gene OLR1 in OSCC, focusing on their implications in tumor progression, metastasis and potential as therapeutic targets. MATERIALS AND METHODS: Employing next-generation sequencing and bioinformatic tools, we profiled differentially expressed miRNAs in metastatic OSCC cell lines, identifying let-7d-5p as a key down-regulated miRNA and OLR1 as a novel target of let-7d-5p. We validated this interaction using luciferase reporter assays and studied the biological effects of modulating let-7d-5p and OLR1 expression on OSCC cell proliferation, migration, invasion, and stemness. Additionally, we analyzed clinical data to establish the relevance of OLR1 expression in OSCC prognosis. RESULTS: Our findings revealed let-7d-5p as a potent suppressor of OSCC metastasis, primarily by targeting and down-regulating OLR1. OLR1-silencing reduced OSCC cell invasiveness, migration, and stemness, indicating its prominent role in tumor progression. Mechanistically, let-7d-5p modulates a signaling cascade involving FAK, SRC, PAXILLIN, and p53, influencing cellular apoptosis and chemoresistance. Clinically, elevated OLR1 expression significantly correlates with advanced OSCC stages and poorer survival rates, highlighting its potential as a prognostic marker and therapeutic target. CONCLUSION: Our study uncovers the significance of the let-7d-5p-OLR1 axis in OSCC pathogenesis, offering novel insights for future therapeutic interventions.

Spatially controlled diffusion range of tumor-associated angiogenic factors to develop a tumor model using a microfluidic resistive circuit.

Developing a tumor model with vessels has been a challenge in microfluidics. This difficulty is because cancer cells can overgrow in a co-culture system. The up-regulation of anti-angiogenic factors during the initial tumor development can hinder neovascularization. The standard method is to develop a quiescent vessel network before loading a tumor construct in an adjacent chamber, which simulates the interaction between a tumor and its surrounding vessels. Here, we present a new method that allows a vessel network and a tumor to develop simultaneously in two linked chambers. The physiological environment of these two chambers is controlled by a microfluidic resistive circuit using two symmetric long microchannels. Applying the resistive circuit, a diffusion-dominated environment with a small 2-D pressure gradient is created across the two chambers with velocity <10.9 nm s-1 and Péclet number <6.3 × 10-5. This 2-D pressure gradient creates a V-shaped velocity clamp to confine the tumor-associated angiogenic factors at pores between the two chambers, and it has two functions. At the early stage, vasculogenesis is stimulated to grow a vessel network in the vessel chamber with minimal influence from the tumor that is still developed in the adjacent chamber. At the post-tumor-development stage, the induced steep concentration gradient at pores mimics vessel-tumor interactions to stimulate angiogenesis to grow vessels toward the tumor. Applying this method, we demonstrate that vasculogenic vessels can grow first, followed by stimulating angiogenesis. Angiogenic vessels can grow into stroma tissue up to 1.3 mm long, and vessels can also grow into or wrap around a 625 µm tumor spheroid or a tumor tissue developed from a cell suspension. In summary, our study suggests that the interactions between a developing vasculature and a growing tumor must be controlled differently throughout the tissue development process, including at the early stage when vessels are still forming and at the later stage when the tumor needs to interact with the vessels.

Venetoclax Plus Azacitidine as a Bridge Treatment to Allogeneic Stem Cell Transplantation in Unfit Patients with Acute Myeloid Leukemia.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely recommended for unfit patients with newly diagnosed acute myeloid leukemia (AML). Patient survival can improve with venetoclax plus azacitidine (VEN plus AZA). However, the long-term outcome of this treatment strategy is still unsatisfactory. The high response and low treatment toxicity rates of patients receiving VEN plus AZA can provide an opportunity for HSCT among unfit patients. Nevertheless, the outcomes and complications of VEN plus AZA, followed by HSCT, remain unclear. METHODS: This single-center retrospective study aimed to compare patients with newly diagnosed AML receiving VEN plus AZA as induction therapy (n = 27) to those receiving the conventional I3A7 regimen as induction therapy (n = 34). RESULT: The 1-year overall survival, relapse, and non-relapse mortality rates in the two groups were similar. The cytogenetic risks and the hematopoietic cell transplantation-specific comorbidity index are the most significant predictive factors of overall survival. CONCLUSION: In older patients unfit for intensive chemotherapy, a low-intensity regimen with VEN plus AZA is a suitable bridge therapy. Furthermore, allo-HSCT is feasible and can be a curative option.

Association Between Use of Sodium-Glucose Cotransporter-2 Inhibitors or Angiotensin Receptor-Neprilysin Inhibitor and the Risk of Atherosclerotic Cardiovascular Disease With Coexisting Diabetes and Heart Failure.

PURPOSE: This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. METHODS: This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. RESULTS: The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. CONCLUSION: The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions.

The role of vestibular function tests in nontuberculous mycobacterial otomastoiditis: A case report.

BACKGROUND: Nontuberculous mycobacteria (NTM), an extremely rare pathogen causing cervicofacial infections, may result in permanent hearing impairment or intracranial complications. Due to the lack of specific manifestations during the initial onset of NTM otomastoiditis, physicians may misdiagnose it as cholesteatoma or other common bacterial infections. PATIENT CONCERNS: A 44-year-old male who complained of left-sided aural fullness, otalgia, and dizziness for 2 months. DIAGNOSIS: The initial diagnosis was hypothesized to be cholesteatoma based on a whitish mass with mucoid discharge filling the entire outer ear canal on otoscopy and left-sided mixed hearing loss. However, NTM was identified by microbial culture at the 2-month follow-up after surgery. INTERVENTIONS: The patient underwent a left-sided exploratory tympanotomy. Because NTM otomastoiditis was diagnosed, 3 weeks of starting therapies were administered with azithromycin (500 mg/day, oral administration), cefoxitin (3 g/day, intravenous drip), and amikacin (750 mg/day, intravenous drip). The maintenance therapies were azithromycin (500 mg/day, oral administration) and doxycycline (200 mg/day, oral administration) for 7 months. OUTCOMES: The patient's clinical condition improved initially after surgery, but the otomastoiditis gradually worsened, combined with subtle meningitis, 2 months after surgery. The external auditory canal became swollen and obstructed, making it difficult to monitor the treatment efficacy through otoscopy. Thus, we used regular vestibular function tests, including static posturography, cervical vestibular evoked myogenic potentials, and video Head Impulse Test, to assess recovery outcomes. After antibiotic treatment, the infectious symptoms subsided significantly, and there was no evidence of infection recurrence 7 months after treatment. Improvements in static posturography and cervical vestibular evoked myogenic potentials were compatible with the clinical manifestations, but video Head Impulse Test showed an unremarkable correlation. LESSONS: The clinical condition of NTM otomastoiditis may be evaluated using vestibular tests if patients have symptoms of dizziness.

Nuclear translocation of Axl contributes to the malignancy of oral cancer cells.

Background/purpose: Dysregulation of receptor tyrosine kinases is implicated in cancer development. This study aimed to investigate the nuclear translocation of Axl, a membrane protein and receptor tyrosine kinase in cancer malignancy. Materials and methods: We examined Axl's entry into the cell nucleus and validated it with the nuclear export inhibitor leptomycin. Transfection experiments with mutated nuclear localization signals were conducted to assess the impact of reduced nuclear Axl levels on cancer cell malignancy. Additionally, we evaluated the effects of decreased nuclear Axl on sensitivity to radiation and cisplatin, a chemotherapeutic drug. Results: In the present study, we observed nuclear translocation of Axl in cancer cells. Reducing nuclear Axl levels led to a decrease in cancer cell malignancy. This nuclear translocation was further validated using a nuclear export inhibitor, leptomycin. Additionally, transfection experiments with mutated nuclear localization signals confirmed the functional significance of Axl's nuclear localization. Notably, decreased nuclear Axl levels also increased the sensitivity of cancer cells to radiation and cisplatin treatment. Conclusion: This study suggests that Axl's nuclear translocation plays a significant role in cancer malignancy. Targeting Axl's nuclear localization could offer a potential strategy to inhibit cancer progression and improve the efficacy of radiation and chemotherapy treatments.

MiR-34a functions as a tumor suppressor in oral cancer through the inhibition of the Axl/Akt/GSK-3ß pathway.

Background/purpose: Oral cancer is a prevalent malignancy affecting men globally. This study aimed to investigate the regulatory role of miR-34a in oral cancer cells through the Axl/Akt/glycogen synthase kinase-3ß (GSK-3ß) pathway and its impact on cellular malignancy. Materials and methods: We examined the effects of miR-34a overexpression on the malignancy of oral cancer cells. Multiple oral cancer cell lines were assessed to determine the correlation between endogenous miR-34a and Axl levels. Transfection experiments with miR-34a were conducted to analyze its influence on Axl mRNA and protein expression. Luciferase reporter assays were performed to investigate miR-34a's modulation of Axl gene transcription. Manipulation of miR-34a expression was utilized to demonstrate its regulatory effects on oral cancer cells through the Axl/Akt/GSK-3ß pathway. Results: Overexpression of miR-34a significantly suppressed the malignancy of oral cancer cells. We observed an inverse correlation between endogenous miR-34a and Axl levels across multiple oral cancer cell lines. Transfection of miR-34a resulted in decreased Axl mRNA and protein expression, and luciferase reporter assays confirmed miR-34a-mediated modulation of Axl gene transcription. The study revealed regulatory effects of miR-34a on oral cancer cells through the Axl/Akt/GSK-3ß pathway, leading to alterations in downstream target genes involved in cellular proliferation and tumorigenesis. Conclusion: Our findings highlight the significance of the miR-34a/Axl/Akt/GSK-3ß signaling axis in modulating the malignancy of oral cancer cells. Targeting miR-34a may hold therapeutic potential in oral cancer treatment, as manipulating its expression can attenuate the aggressive behavior of oral cancer cells via the Axl/Akt/GSK-3ß pathway.

AIM2 promotes irradiation resistance, migration ability and PD-L1 expression through STAT1/NF-κB activation in oral squamous cell carcinoma.

BACKGROUND: Radioresistance and lymph node metastasis are common phenotypes of refractory oral squamous cell carcinoma (OSCC). As a result, understanding the mechanism for radioresistance and metastatic progression is urgently needed for the precise management of refractory OSCC. Recently, immunotherapies, e.g. immune checkpoint inhibitors (ICIs), were employed to treat refractory OSCC; however, the lack of predictive biomarkers still limited their therapeutic effectiveness. METHODS: The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) databases and RT-PCR analysis were used to determine absent in melanoma 2 (AIM2) expression in OSCC samples. Colony-forming assay and trans-well cultivation was established for estimating AIM2 function in modulating the irradiation resistance and migration ability of OSCC cells, respectively. RT-PCR, Western blot and flow-cytometric analyses were performed to examine AIM2 effects on the expression of programmed death-ligand 1 (PD-L1) expression. Luciferase-based reporter assay and site-directed mutagenesis were employed to determine the transcriptional regulatory activity of Signal Transducer and Activator of Transcription 1 (STAT1) and NF-κB towards the AIM2-triggered PD-L1 expression. RESULTS: Here, we found that AIM2 is extensively upregulated in primary tumors compared to the normal adjacent tissues and acts as a poor prognostic marker in OSCC. AIM2 knockdown mitigated, but overexpression promoted, radioresistance, migration and PD-L1 expression via modulating the activity of STAT1/NF-κB in OSCC cell variants. AIM2 upregulation significantly predicted a favorable response in patients receiving ICI treatments. CONCLUSIONS: Our data unveil AIM2 as a critical factor for promoting radioresistance, metastasis and PD-L1 expression and as a potential biomarker for predicting ICI effectiveness on the refractory OSCC.

Re-evaluating the role of pelvic radiation in the age of modern precision medicine and systemic therapy.

The efficacy of pelvic radiation in the management of locally advanced stage rectal cancer has come under scrutiny in the context of modern precision medicine and systemic therapy as evidenced by recent clinical trials such as FOWARC (J Clin Oncol 2019; 37: 3223-3233), NCT04165772 (N Engl J Med 2022; 386: 2363-2376), and PROSPECT (N Engl J Med 2023; 389: 322-334). In this review, we comprehensively assess these pivotal trials and offer additional insights into the evolving role of pelvic radiation in contemporary oncology.

Guanylate binding protein 5 triggers NF-κB activation to foster radioresistance, metastatic progression and PD-L1 expression in oral squamous cell carcinoma.

Radioresistance and metastasis are critical issues in managing oral squamous cell carcinoma (OSCC). Although immune checkpoint inhibitors (ICIs) has been recommended to treat OSCC, lacking useful biomarkers limited their anti-cancer effectiveness. We found that guanylate binding protein 5 (GBP5) is upregulated in primary tumors and associates with radioresistance in OSCC. GBP5 expression causally associated with cellular radioresistance and migration ability in the OSCC cell variants. GBP5 upregulation was examined to be correlated with NF-κB activation and programmed cell death-ligand 1 (PD-L1) elevation in OSCC samples. GBP5 knockdown was mitigated, but overexpression enhanced, NF-κB activity and PD-L1 expression in the OSCC cells. NF-κB inhibition by SN50 dramatically suppressed the GBP5-forested irradiation resistance, cellular migration ability and PD-L1 expression in OSCC cells. Importantly, GBP5 upregulation predicted a favorable outcome in cancer patients received ICI treatment. Our findings provide GBP5 as a useful biomarker to predict the anti-OSCC effectiveness of irradiation and ICIs.

The largest genome-wide association study for breast cancer in Taiwanese Han population.

PURPOSE: Breast cancer is a molecularly heterogeneous disease, and multiple genetic variants contribute to its development and prognosis. Most of previous genome-wide association studies (GWASs) and polygenic risk scores (PRSs) analyses focused on studying breast cancers of Caucasian populations, which may not be applicable to other population. Therefore, we conducted the largest breast cancer cohort of Taiwanese population to fill in the knowledge gap. METHODS: A total of 152,534 Participants recruited by China Medical University Hospital between 2003 and 2019 were filtered by several patient selection criteria and GWAS quality control steps, resulting in the inclusion of 2496 cases and 9984 controls for this study. We then conducted GWAS for all breast cancers and PRS analyses for all breast cancers and the four breast cancer subtypes, including luminal A, luminal B, basal-like, and HER2-enriched. RESULTS: The GWAS analyses identified 113 SNPs, 50 of which were novel. The PRS models for all breast cancers and the luminal A subtype showed positively correlated trends between the PRS and the risk of developing breast cancer. The odds ratios (95% confidence intervals) for the groups with the highest PRS in all breast cancers and the luminal A subtype were 5.33 (3.79-7.66) and 3.55 (2.13-6.14), respectively. CONCLUSION: In summary, we explored the association of genetic variants with breast cancer in the largest Taiwanese cohort and developed two PRS models that can predict the risk of developing any breast cancer and the luminal A subtype in Taiwanese women.

Age-specific percentile-based prostate-specific antigen cutoff values predict the risk of prostate cancer: A single hospital observation.

Background: Testing for prostate-specific antigen (PSA) is often recommended for men with a potential risk of prostate cancer (PCa) before requiring advanced examination. However, the best PSA cutoff value remains controversial. Object: We compared the predictive performance of age-specific percentile-based PSA thresholds with a conventional cutoff of >4 ng/mL for the risk of PCa. Methods: We included men who received PSA measurements between 2003 and 2017 in a medical center in Taiwan. Logistic regression modeling was used to assess the association between age-specific percentile-based PSA thresholds and PCa risk in age subgroups. We further applied C-statistic and decision curve analysis to compare the predictive performance of age-specific percentile-based PSA with that of a conventional cutoff PSA. Results: We identified 626 patients with PCa and 40 836 patients without PCa. The slope of PSA in patients >60-year-old was almost 3 times that of those <60-year-old (0.713 vs 0.259). The risk effect sizes of the 75th percentile PSA cutoff (<60-year-old: 2.19; 60-70-year-old: 4.36; >70-year-old: 5.84 ng/mL) were comparable to those observed based on the conventional cutoff in all age groups. However, the discrimination performance of the 75th percentile PSA cutoff was better than that of the conventional cutoff among patients aged <60-year-old (C-statistic, 0.783 vs. 0.729, p < 0.05). The 75th percentile cutoffs also correctly identified an additional 2 patients with PCa for every 100 patients with PSA screening at the threshold probability of 20%. Conclusions: Our data support the use of the 75th percentile PSA cutoff to facilitate individualized risk assessment, particularly for patients aged <60-year-old.

Neoadjuvant Chemotherapy With/Without Radiotherapy for Locally Advanced Rectal Cancer: A Nationwide Retrospective Cohort Study.

BACKGROUND/AIM: The role of neoadjuvant radiotherapy in the management of patients with locally advanced rectal cancer (LARC) who have undergone neoadjuvant systemic therapy has been the subject of recent debate. PATIENTS AND METHODS: We identified eligible rectal cancer patients diagnosed between 2011 and 2020 using data from the Taiwan Cancer Registry. In our primary analysis, we applied propensity score weighting (PSW) to balance observable potential confounders. We then compared the hazard ratio (HR) of death the neoadjuvant concurrent chemoradiotherapy (nCCRT) group and the neoadjuvant chemotherapy without radiotherapy (nCT) group. Additionally, we conducted a comprehensive assessment of other outcomes and performed various supplementary analyses. RESULTS: The primary analysis included 2,298 patients. The overall survival did not exhibit statistically significant differences, with a PSW-adjusted HR of 0.72 (95% confidence interval=0.33-1.56, p=0.40) when comparing the nCCRT group to the nCT group. These findings were consistent with those of other long-term outcomes and supplementary analyses. CONCLUSION: In patients with LARC who have undergone neoadjuvant systemic therapy, the addition of radiotherapy did not yield statistically significant differences in long-term clinical outcomes.

Different Gabapentin and Pregabalin Dosages for Perioperative Pain Control in Patients Undergoing Spine Surgery: A Systematic Review and Network Meta-Analysis.

IMPORTANCE: Patients undergoing spine surgery often experience severe pain. The optimal dosage of pregabalin and gabapentin for pain control and safety in these patients has not been well established. OBJECTIVE: To evaluate the associations of pain, opioid consumption, and adverse events with different dosages of pregabalin and gabapentin in patients undergoing spine surgery. DATA SOURCES: PubMed/MEDLINE, Embase, Web of Science, Cochrane library, and Scopus databases were searched for articles until August 7, 2021. STUDY SELECTION: Randomized clinical trials conducted among patients who received pregabalin or gabapentin while undergoing spine surgery were included. DATA EXTRACTION AND SYNTHESIS: Two investigators independently performed data extraction following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) reporting guideline. The network meta-analysis was conducted from August 2022 to February 2023 using a random-effects model. MAIN OUTCOMES AND MEASURES: The primary outcome was pain intensity measured using the Visual Analog Scale (VAS), and secondary outcomes included opioid consumption and adverse events. RESULTS: Twenty-seven randomized clinical trials with 1861 patients (median age, 45.99 years [range, 20.00-70.00 years]; 759 women [40.8%]) were included in the systematic review and network meta-analysis. Compared with placebo, the VAS pain score was lowest with gabapentin 900 mg per day, followed by gabapentin 1200 mg per day, gabapentin 600 mg per day, gabapentin 300 mg per day, pregabalin 300 mg per day, pregabalin 150 mg per day, and pregabalin 75 mg per day. Additionally, gabapentin 900 mg per day was found to be associated with the lowest opioid consumption among all dosages of gabapentin and pregabalin, with a mean difference of -22.07% (95% CI, -33.22% to -10.92%) for the surface under the cumulative ranking curve compared with placebo. There was no statistically significant difference in adverse events (nausea, vomiting, and dizziness) among all treatments. No substantial inconsistency between direct and indirect evidence was detected for all outcomes. CONCLUSIONS AND RELEVANCE: These findings suggest that gabapentin 900 mg per day before spine surgery is associated with the lowest VAS pain score among all dosages. In addition, no differences in adverse events were noted among all treatments.

Enzalutamide Prior to Radium-223 Is Associated with Better Overall Survival in Metastatic Castration-Resistant Prostate Cancer Patients Compared to Abiraterone-A Retrospective Study.

Metastatic castration-resistant prostate cancer (mCRPC) is a progressive stage of prostate cancer that often spreads to the bone. Radium-223, a bone-targeting radiopharmaceutical, has been shown to improve the overall survival in mCRPC in patients without visceral metastasis. However, the impact of prior systemic therapy on the treatment outcome of mCRPC patients receiving radium-223 remains unclear. This study aimed to investigate the optimal choice of systemic therapy before radium-223 in mCRPC patients. The study included 41 mCRPC patients who received radium-223 therapy, with 22 receiving prior enzalutamide and 19 receiving prior abiraterone. The results showed that the median overall survival was significantly longer in the enzalutamide group than in the abiraterone group (25.1 months vs. 14.8 months, p = 0.049). Moreover, the number of patients requiring blood transfusion was higher in the abiraterone group than in the enzalutamide group (9.1% vs. 26.3%, p = 0.16). The study also found that the number of doses of Radium-223 received was significantly associated with overall survival (≥5 vs. <5, HR 0.028, 95%CI 0.003-0.231, p = 0.001). Our study provides insights into the optimal treatment choice for mCRPC prior to radium-223, indicating that enzalutamide prior to radium-223 administration may have better outcomes compared to abiraterone in mCRPC patients without visceral metastasis.

A Biomimicking and Multiarm Self-Indicating Nanoassembly for Site-Specific Photothermal-Potentiated Thrombolysis Assessed in Microfluidic and In Vivo Models.

Thrombolytic and antithrombotic therapies are limited by short circulation time and the risk of off-target hemorrhage. Integrating a thrombus-homing strategy with photothermal therapy are proposed to address these limitations. Using glycol chitosan, polypyrrole, iron oxide and heparin, biomimicking GCPIH nanoparticles are developed for targeted thrombus delivery and thrombolysis. The nanoassembly achieves precise delivery of polypyrrole, exhibiting biocompatibility, selective accumulation at multiple thrombus sites, and enhanced thrombolysis through photothermal activation. To simulate targeted thrombolysis, a microfluidic model predicting thrombolysis dynamics in realistic pathological scenarios is designed. Human blood assessments validate the precise homing of GCPIH nanoparticles to activated thrombus microenvironments. Efficient near-infrared phototherapeutic effects are demonstrated at thrombus lesions under physiological flow conditions ex vivo. The combined investigations provide compelling evidence supporting the potential of GCPIH nanoparticles for effective thrombus therapy. The microfluidic model also offers a platform for advanced thrombolytic nanomedicine development.

First report of Robbsia andropogonis causing bacterial leaf spot of bougainvilleas in Taiwan.

Bougainvilleas (Bougainvillea spp.) are popular ornamentals commonly grown as bushes, vines, or trees worldwide (Kobayashi et al. 2007). Leaf spot symptoms were observed on a bougainvillea hedge located in North District, Taichung, Taiwan during August of 2022. The lesions were brown, necrotic and had yellow halos (Fig. S1). All the plants at the location showed similar symptoms. Leaf samples were collected from five plants and symptomatic tissues were minced in 10 mM MgCl2. The samples were streaked onto nutrient agar (NA) and after culturing at 28°C for 2 days, small, round, creamy white colonies were consistently isolated from all the samples. A total of five strains (BA1 to BA5) were obtained; each of them was isolated from a different plant. All five strains induced hypersensitive response in tobacco leaves. Amplification and sequencing of the isolated strains' 16S rDNA using primers 27F and 1492R (Lane 1991) revealed that all five strains shared identical sequences (GenBank accession no. OQ053015) with Robbsia andropogonis LMG 2129T (formerly Burkholderia andropogonis and Pseudomonas andropogonis; GenBank accession no. NR104960; 1,393/1,393 bp). Further testing of BA1 to BA5's DNA samples using the pathogen's species-specific primers Pf (5'-AAGTCGAACGGTAACAGGGA-3') and Pr (5'-AAAGGATATTAGCCCTCGCC-3'; Bagsic et al. 1995) successfully amplified the expected 410-bp amplicon in all five samples; the sequences of the PCR products completely matched to those of BA1 to BA5's 16S rDNA. Strains BA1 to BA5 also tested negative for arginine dihydrolase and oxidase activity, and failed to grow at 40°C, all of which are consistent with descriptions of R. andropogonis (Schaad et al. 2001). Pathogenicity of the isolated bacteria was confirmed by spray inoculation. Three representative strains, BA1 to BA3, were used for the assay. Bacterial colonies were scraped from NA plates and suspended in 10 mM MgCl2 added with 0.02% Silwet L-77. The concentrations of the suspensions were adjusted to 4.4-5.8 x 108 cfu/ml. The suspensions were sprayed onto three-month-old, cutting-propagated bougainvillea plants (to runoff). Controls were treated with bacteria-free solutions. Three plants were used for each treatment group (and the controls). The plants were placed in a growth chamber (27/25°C, day/night; 14-hour photoperiod) and bagged for three days. Within 20 days post inoculation, brown, necrotic lesions resembling those observed in the sampling site were observed on all inoculated plants, but not on the controls. One strain was re-isolated for each treatment group and the re-isolated strains all shared the same colony morphology and 16S rDNA sequence with BA1 to BA5. Additional PCR testing of these re-isolated strains using Pf and Pr also produced the expected amplicon. This is the first formal report of R. andropogonis affecting bougainvilleas in Taiwan. The pathogen has been reported causing diseases of betel palm (Areca catechu), corn and sorghum in Taiwan (Hseu et al. 2007; Hsu et al. 1991), some of which are economically important (Lisowicz 2000; Navi et al. 2002). As such, infected bougainvilleas could potentially serve as an inoculum source for these diseases.

Endoscopic and Image Analysis of the Airway in Patients with Mucopolysaccharidosis Type IVA.

Mucopolysaccharidosis (MPS) is a hereditary disorder arising from lysosomal enzymes deficiency, with glycosaminoglycans (GAGs) storage in connective tissues and bones, which may compromise the airway. This retrospective study evaluated patients with MPS type IVA with airway obstruction detected via endoscopy and imaging modalities and the effects of surgical interventions based on symptoms. The data of 15 MPS type IVA patients (10 males, 5 females, mean age 17.8 years) were reviewed in detail. Fiberoptic bronchoscopy (FB) was used to distinguish adenotonsillar hypertrophy, prolapsed soft palate, secondary laryngomalacia, vocal cord granulation, cricoid thickness, tracheal stenosis, shape of tracheal lumen, nodular deposition, tracheal kinking, tracheomalacia with rigid tracheal wall, and bronchial collapse. Computed tomography (CT) helped to measure the deformed sternal angle, the cross-sectional area of the trachea, and its narrowest/widest ratio (NW ratio), while angiography with 3D reconstruction delineated tracheal torsion, kinking, or framework damage and external vascular compression of the trachea. The NW ratio correlated negatively with age (p < 0.01), showing that airway obstruction progressed gradually. Various types of airway surgery were performed to correct the respiratory dysfunction. MPS type IVA challenges the management of multifactorial airway obstruction. Preoperative airway evaluation with both FB and CT is strongly suggested to assess both intraluminal and extraluminal factors causing airway obstruction.

Pelvic Neoadjuvant Radiotherapy for Stage M1a Rectal Adenocarcinoma Patients Treated With Systemic Therapy Followed by Proctectomy and Metastasectomy: A Nationwide Retrospective Cohort Study.

BACKGROUND/AIM: The effect of pelvic neoadjuvant radiotherapy (nRT) for stage M1a rectal adenocarcinoma patients treated with systemic therapy followed by proctectomy and metastasectomy was scarcely investigated in the literatures. PATIENTS AND METHODS: The eligible rectal cancer patients diagnosed between 2011-2019 were identified via the Taiwan Cancer Registry. In the primary analysis, we used propensity score weighting to balance observable potential confounders and compared the hazard ratio (HR) of death for the nRT group vs. without RT group. We also compared the incidence of rectal cancer mortality (IRCM) and performed various supplementary analyses. RESULTS: Our primary analyses included 145 patients. nRT was associated with improved OS (HR=0.51, p=0.01). The numerical trends remained similar for IRCM and in supplementary analyses. CONCLUSION: nRT was associated with improved OS in our study population.