Clinical application of digital technology in the use of anterolateral thigh lobulated perforator flaps to repair complex soft tissue defects of the limbs.

Background: It is challenging to repair wide or irregular defects with traditional skin flaps, and anterolateral thigh (ALT) lobulated perforator flaps are an ideal choice for such defects. However, there are many variations in perforators, so good preoperative planning is very important. This study attempted to explore the feasibility and clinical effect of digital technology in the use of ALT lobulated perforator flaps for repairing complex soft tissue defects in limbs. Methods: Computed tomography angiography (CTA) was performed on 28 patients with complex soft tissue defects of the limbs, and the CTA data were imported into Mimics 20.0 software in DICOM format. According to the perforation condition of the lateral circumflex femoral artery and the size of the limb defect, one thigh that had two or more perforators from the same source vessel was selected for 3D reconstruction of the ALT lobulated perforator flap model. Mimics 20.0 software was used to visualize the vascular anatomy, virtual design and harvest of the flap before surgery. The intraoperative design and excision of the ALT lobulated perforator flap were guided by the preoperative digital design, and the actual anatomical observations and measurements were recorded. Results: Digital reconstruction was successfully performed in all patients before surgery; this reconstruction dynamically displayed the anatomical structure of the flap vasculature and accurately guided the design and harvest of the flap during surgery. The parameters of the harvested flaps were consistent with the preoperative parameters. Postoperative complications occurred in 7 patients, but all flaps survived uneventfully. All of the donor sites were closed directly. All patients were followed up for 13-27 months (mean, 19.75 months). The color and texture of each flap were satisfactory and each donor site exhibited a linear scar. Conclusions: Digital technology can effectively and precisely assist in the design and harvest of ALT lobulated perforator flaps, provide an effective approach for individualized evaluation and flap design and reduce the risk and difficulty of surgery.

Species selection as a key factor in the afforestation of coastal salt-affected lands: Insights from pot and field experiments.

Soil salinization is a significant global issue that leads to land degradation and loss of ecological function. In coastal areas, salinization hampers vegetation growth, and forestation efforts can accelerate the recovery of ecological functions and enhance resilience to extreme climates. However, the salinity tolerance of tree species varies due to complex biological factors, and results between lab/greenhouse and field studies are often inconsistent. Moreover, in salinized areas affected by extreme climatic and human impacts, afforestation with indigenous species may face adaptability challenges. Therefore, it is crucial to select appropriate cross-species salinity tolerance indicators that have been validated in the field to enhance the success of afforestation and reforestation efforts. This study focuses on five native coastal tree species in Taiwan, conducting afforestation experiments on salt-affected soils mixed with construction and demolition waste. It integrates short-term controlled experiments with potted seedlings and long-term field observations to establish growth performance and physiological and biochemical parameters indicative of salinity tolerance. Results showed that Heritiera littoralis Dryand. exhibited the highest salinity tolerance, accumulating significant leaf proline under increased salinity. Conversely, Melia azedarach Linn. had the lowest tolerance, evidenced by complete defoliation and reduced biomass under salt stress. Generally, the field growth performance of these species aligns with the results of short-term pot experiments. Leaf malondialdehyde content from pot experiments proved to be a reliable cross-species salinity tolerance indicator, correlating negatively with field relative height growth and survival rates. Additionally, parameters related to the photosynthetic system or water status, measured using portable devices, also moderately indicated field survival, aiding in identifying potential salt-tolerant tree species. This study underscores the pivotal role of species selection in afforestation success, demonstrating that small-scale, short-term salinity control experiments coupled with appropriate assessment tools can effectively identify species suitable for highly saline and degraded environments. This approach not only increases the success of afforestation but also conserves resources needed for field replanting and maintenance, supporting sustainable development goals.

Pure separation of acetylene based on a sulfonic acid and amino group functionalized Zn-MOF.

The dual-ligand strategy was employed to synthesize a new microporous material, [Zn3(SNDC)(AmTAZ)3(H2O)]·H2O·CH3CN (1), incorporating sulfonic acid and amino groups for enhancing gas adsorption and separation. The activated 1 (named 1a) exhibited selective adsorption of acetylene over carbon dioxide and methane. Hence, the dual-ligand strategy optimized the pore environment and provided an effective approach for pure separation of gases.

Effects of electroacupuncture of different intensities and durations on PERK/ATF4/CHOP signaling pathway in liver of non-alcoholic fatty liver disease rats. / ä¸åŒå¼ºåº¦åŠæ—¶ç¨‹ç”µé’ˆå¹²é¢„å¯¹éžé ’ç²¾æ€§è„‚è‚ªè‚ç— å¤§é¼ è‚è„PERK/ATF4/CHOP通路的影响.

OBJECTIVES: To analyze the effects of electroacupuncture (EA) at "Fenglong" (ST40) and "Zusanli" (ST36) of different intensities and durations on rats with non-alcoholic fatty liver disease (NAFLD) based on the protein kinase R-like endoplasmic reticulum kinase (PERK)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) signaling pathway, so as to explore its mechanism underlying improvement of NAFLD. METHODS: SD rats were randomly divided into normal diet group, high-fat model group, sham EA group, strong stimulation EA (SEA) group, and weak stimulation EA (WEA) group, with 15 rats in each group. Each group was further divided into 2, 3, and 4-week subgroups. NAFLD rat model was established by feeding a high-fat diet. After successful modeling, rats in the SEA and WEA groups received EA at bilateral ST40 and ST36 with dense and sparse waves (4 Hz/20 Hz) at current intensities of 4 mA (SEA group) and 2 mA (WEA group), lasting for 20 minutes, once a day, 5 days a week with 2 days of rest. The sham EA group only had the EA apparatus connected without electricity. Different duration subgroups were intervened for 2, 3, and 4 weeks. After the intervention, the contents of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rats were detected by an automatic biochemical analyzer；liver morphological changes were observed by Oil Red O staining；real-time fluorescence quantitative PCR and Western blot were used to detect the expression of PERK, ATF4, and CHOP mRNAs and proteins in the rat liver tissue. RESULTS: In the high-fat model group, there was a significant accumulation of red lipid droplets in the liver cells, which was reduced significantly in the SEA group at the 4th week. Compared with the normal diet group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated (P<0.01) in the high-fat model group . Compared with the high-fat model group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, CHOP mRNAs and proteins in the liver tissue were decreased (P<0.01, P<0.05) in the SEA and WEA groups. Compared with the sham EA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were decreased (P<0.01, P<0.05) in the SEA and WEA groups, the expression of PERK, ATF4, and CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA group at the 2nd, 3rd, and 4th week, the expression of PERK and CHOP proteins at the 2nd, 3rd, 4th week and ATF4 protein at 2nd week in the liver tissue were decreased (P<0.01, P<0.05) in the WEA group. Compared with the SEA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated (P<0.05, P<0.01) in the WEA group. Compared with the 2-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and PERK proteins in the liver tissue were decreased (P<0.01, P<0.05) in the SEA and WEA groups at 3rd and 4th week, the expression of ATF4 proteins in the liver tissue was decreased (P<0.01) in the SEA group at 3rd and 4th week, and the expression of CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA group at 4th week and in the WEA group at 3rd and 4th week. Compared with the 3-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were significantly decreased (P<0.05, P<0.01) in the SEA and WEA groups at 4th week, the expression of PERK and CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA and WEA groups at 4th week, and the expression of ATF4 protein in the liver tissue was decreased (P<0.05) in the SEA group at 4th week. CONCLUSIONS: EA at ST40 and ST36 can significantly improve liver function in NAFLD rats, and its mechanism of action may involve inhibiting PERK expression thereby targeting the downstream ATF4/CHOP signaling pathway to suppress endoplasmic reticulum stress, exerting a liver protective effect；the optimal effect was observed with EA intensity of 4 mA for 4 weeks.

Unveiling IL6R and MYC as Targeting Biomarkers in Imatinib-Resistant Chronic Myeloid Leukemia through Advanced Non-Invasive Apoptosis Detection Sensor Version 2 Detection.

The management of chronic myelogenous leukemia (CML) has seen significant progress with the introduction of tyrosine kinase inhibitors (TKIs), particularly Imatinib. However, a notable proportion of CML patients develop resistance to Imatinib, often due to the persistence of leukemia stem cells and resistance mechanisms independent of BCR::ABL1 This study investigates the roles of IL6R, IL7R, and MYC in Imatinib resistance by employing CRISPR/Cas9 for gene editing and the Non-Invasive Apoptosis Detection Sensor version 2 (NIADS v2) for apoptosis assessment. The results indicate that Imatinib-resistant K562 cells (K562-IR) predominantly express IL6R, IL7R, and MYC, with IL6R and MYC playing crucial roles in cell survival and sensitivity to Imatinib. Conversely, IL7R does not significantly impact cytotoxicity, either alone or in combination with Imatinib. Further genetic editing experiments confirm the protective functions of IL6R and MYC in K562-IR cells, suggesting their potential as therapeutic targets for overcoming Imatinib resistance in CML. This study contributes to understanding the mechanisms of Imatinib resistance in CML, proposing IL6R and MYC as pivotal targets for therapeutic strategies. Moreover, the utilization of NIADS v2 enhances our capability to analyze apoptosis and drug responses, contributing to a deeper understanding of CML pathogenesis and treatment options.

Impact of resection margin on outcome in soft-tissue sarcomas of the extremities treated with limb-sparing surgery and postoperative radiotherapy.

BACKGROUND: The standard curative treatments for extremity soft tissue sarcoma (ESTS) include surgical resection with negative margins and perioperative radiotherapy. However, the optimal resection margin remains controversial. This study aimed to evaluate the outcomes in ESTS between microscopically positive margin (R1) and microscopically negative margin (R0) according to the Union for International Cancer Control (UICC) (R + 1 mm) classification. METHODS: Medical records of patients with localized ESTS who underwent primary limb-sparing surgery and postoperative radiotherapy between 2004 and 2015 were retrospectively reviewed. Patients were followed for at least 5 years or till local or distant recurrence was diagnosed during follow-up. Outcomes were local and distal recurrences and survival. RESULTS: A total of 52 patients were included in this study, in which 17 underwent R0 resection and 35 underwent R1 resection. No significant differences were observed in rates of local recurrence (11.4% vs. 35.3%, p = 0.062) or distant recurrence (40.0% vs. 41.18%, p = 0.935) between R0 and R1 groups. Multivariate analysis showed that distant recurrences was associated with a Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade (Grade III vs. I, adjusted hazard ratio (aHR): 12.53, 95% confidence interval (CI): 2.67-58.88, p = 0.001) and tumor location (lower vs. upper extremity, aHR: 0.23, 95% CI: 0.07-0.7, p = 0.01). Kaplan-Meier plots showed no significant differences in local (p = 0.444) or distant recurrent-free survival (p = 0.161) between R0 and R1 groups. CONCLUSIONS: R1 margins, when complemented by radiotherapy, did not significantly alter outcomes of ESTS as R0 margins. Further studies with more histopathological types and larger cohorts are necessary to highlight the path forward.

Transition-Metal Porphyrin-Based MOFs In Situ-Derived Hybrid Catalysts for Electrocatalytic CO2 Reduction.

Excellent electrocatalytic CO2 reduction reaction activity has been demonstrated by transition metals and nitrogen-codoped carbon (M-N-C) catalysts, especially for transition-metal porphyrin (MTPP)-based catalysts. In this work, we propose to use one-step low-temperature pyrolysis of the isostructural MTPP-based metal-organic frameworks (MOFs) and electrochemical in situ reduction strategies to obtain a series of hybrid catalysts of Co nanoparticles (Co NPs) and MTPP, named Co NPs/MTPP (M = Fe, Co, and Ni). The in situ introduction of Co NPs can efficiently enhance the electrocatalytic ability of MTPP (M = Fe, Co, and Ni) to convert CO2 to CO, particularly for FeTPP. Co NPs/FeTPP endowed a high CO faradaic efficiency (FECOmax = 95.5%) in the H cell, and the FECO > 90.0% is in the broad potential range of -0.72 to -1.22 VRHE. In addition, the Co NPs/FeTPP achieved 145.4 mA cm-2 at a lower potential of -0.70 VRHE with an FECO of 94.7%, and the CO partial currents increased quickly to reach 202.2 mA cm-2 at -0.80 VRHE with an FECO of 91.6% in the flow cell. It is confirmed that Co NPs are necessary for hybrid catalysts to get superior electrocatalytic activity; Co NPs also can accelerate H2O dissociation and boost the proton supply capacity to hasten the proton-coupled electron-transfer process, effectively adjusting the adsorption strength of the reaction intermediates.

Multifunctional bimetallic MOF with oxygen vacancy synthesized by microplasma for rapid total antioxidant capacity assessment in agricultural products.

The assessment of total antioxidant capacity (TAC) is crucial for evaluating overall antioxidant potential, predicting the risk of chronic diseases, guiding dietary and nutritional interventions, and studying the effectiveness of antioxidants. However, achieving rapid TAC assessment with high sensitivity and stability remains a challenge. In this study, Ce/Fe-MOF with abundant oxygen vacancies was synthesized using microplasma for TAC determination. The microplasma synthesis method was rapid (30 min) and cost-effective. The presence of oxygen vacancies and the collaboration between iron and cerium in Ce/Fe-MOF not only enhanced the catalyst's efficiency but also conferred multiple enzyme-like properties: peroxidase-like, oxidase-like, and superoxide dismutase mimetic activities. Consequently, a simple colorimetric assay was established for TAC determination in vegetables and fruits, featuring a short analysis time of 15 min, a good linear range of 5-60 µM, a low detection limit of 1.3 µM and a good recovery of 91 %-107 %. This method holds promise for rapid TAC assessment in agricultural products.

Ten-year epidemiology and risk factors of cytomegalovirus infection in hematopoietic stem cell transplantation patients in Taiwan.

BACKGROUND: Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for CMV infection and disease among HSCT recipients in Taiwan. METHODS: This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease. RESULTS: There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors. CONCLUSION: The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.

Designing Different Heterometallic Organic Frameworks by Heteroatom and Second Metal Doping Strategies for the Electrocatalytic Oxygen Evolution Reaction.

Metal-organic frameworks (MOFs) are considered one of the most significant electrocatalysts for the sluggish oxygen evolution reaction (OER). Hence, a series of novel N,S-codoped Ni-based heterometallic organic framework (HMOF) (NiM-bptz-HMOF, M = Co, Zn, and Mn; bptz = 2,5-bis((3-pyridyl)methylthio)thiadiazole) precatalysts are constructed by the heteroatom and second metal doping strategies. The effective combination of the two strategies promotes electronic conductivity and optimizes the electronic structure of the metal. By regulation of the type and proportion of metal ions, the electrochemical performance of the OER can be improved. Among them, the optimized Ni6Zn1-bptz-HMOF precatalyst exhibits the best performance with an overpotential of 268 mV at 10 mA cm-2 and a small Tafel slope of 72.5 mV dec-1. This work presents a novel strategy for the design of modest heteroatom-doped OER catalysts.

Metabolomic Analysis Reveals Association between Decreased Ovarian Reserve and In Vitro Fertilization Outcomes.

In vitro fertilization (IVF) is a highly effective treatment for infertility; however, it poses challenges for women with decreased ovarian reserve (DOR). Despite the importance of understanding the impact of DOR on IVF outcomes, limited research has explored this relationship, particularly using omics approaches. Hence, we conducted a study to investigate the association between DOR and IVF outcomes, employing a metabolomic approach. We analyzed serum samples from 207 women undergoing IVF treatment, including 89 with DOR and 118 with normal ovarian reserve (NOR). Our findings revealed that DOR was significantly associated with unfavorable IVF outcomes, characterized by a reduced oocyte count, lower embryo quality, and decreased rates of pregnancy and live births. Furthermore, we identified 82 metabolites that displayed significant alterations in DOR patients, impacting diverse metabolic pathways. Notably, a distinct panel of metabolites, including palmitic acid, stearic acid, LysoPC(9:0(CHO)/0:0), PC(18:0/9:0(CHO)), and PC(16:0/9:0(CHO)), exhibited discriminatory power between the DOR and NOR groups, showcasing a strong correlation with IVF outcomes. These findings emphasize the crucial role of metabolomic disruptions in influencing IVF outcomes among women with DOR.

Evaluation of the prognostic and therapeutic potential of inhibin beta B for oral squamous cell carcinoma.

Background/purpose: Oral squamous cell carcinoma (OSCC) is a common cancer worldwide, and its metastasis is difficult to predict and prevent. Inhibin beta B (INHBB) protein has been linked to cancer prognosis and epithelial-mesenchymal transition (EMT). However, previous study about INHBB expression focused on patients in a single region while the risk factors vary among regions. This study aimed to provide a broader perspective on INHBB expression in OSCC. Materials and methods: Tissue micro-arrays comprising 118 specimens were subjected to immunohistochemistry, and all slides were quantified using StrataQuest software. Results: The ratio of INHBB-positive cells to total cells was significantly higher in OSCC samples than in normal samples, and the intensity of INHBB expression was significantly greater in the late-stage OSCC. After classifying specimens into high and low INHBB expression groups, a significant association with clinical staging was found. Though a previous study suggested that menin regulates INHBB, menin expression was not detected in specimens. Conclusion: The ratio of INHBB-positive cells in OSCC may be druggable for targeting tumor cells or assisting in diagnosis, and the intensity of INHBB expression may provide prognostic information for predicting potential metastasis. Moreover, the regulatory mechanism of INHBB in OSCC remains unclear and requires further investigation.

[Alignment method for metabolite chromatographic peaks using an N-acyl glycine retention index system].

Peak alignment is a crucial data-processing step in untargeted metabolomics analysis that aims to integrate metabolite data from multiple liquid chromatography-mass spectrometry (LC-MS) batches for enhanced comparability and reliability. However, slight variations in the chromatographic separation conditions can result in retention time (RT) shifts between consecutive analyses, adversely affecting peak alignment accuracy. In this study, we present a retention index (RI)-based chromatographic peak-shift correction (CPSC) strategy to address RT shifts and align chromatographic peaks for metabolomics studies. A series of N-acyl glycine homologues (C2-C23) was synthesized as calibrants, and an LC RI system was established. This system effectively corrected RT shifts arising from variations in flow rate, gradient elution, instrument systems, and chromatographic columns. Leveraging the RI system, we successfully adjusted the RT of raw data to mitigate RT shifts and then implemented the Joint Aligner algorithm for peak alignment. We assessed the accuracy of the RI-based CPSC strategy using pooled human fecal samples as a test model. Notably, the application of the RI-based CPSC strategy to a long-term dataset spanning 157 d as an illustration revealed a significant enhancement in peak alignment accuracy from 15.5% to 80.9%, indicating its ability to substantially improve peak-alignment precision in multibatch LC-MS analyses.

Mirror QCD phase transition as the origin of the nanohertz Stochastic Gravitational-Wave Background.

Several Pulsar Timing Array (PTA) Collaborations have recently provided strong evidence for a nHz Stochastic Gravitational-Wave Background (SGWB). Here we investigate the implications of a first-order phase transition occurring within the early Universe's dark quantum chromodynamics epoch, specifically within the framework of the mirror twin Higgs dark sector model. Our analysis indicates a distinguishable SGWB signal originating from this phase transition, which can explain the measurements obtained by PTAs. Remarkably, a significant portion of the parameter space for the SGWB signal also effectively resolves the existing tensions in both the H0 and S8 measurements in Cosmology. This intriguing correlation suggests a possible common origin of these three phenomena for 0.2<ΔNeff<0.5, where the mirror dark matter component constitutes less than 30% of the total dark matter abundance. Next-generation CMB experiments such as CMB-S4 can test this parameter region.

Scalable Synthesis of Robust MOF for Challenging Ethylene Purification and Propylene Recovery with Record Productivity.

Ethylene (C2H4) purification and propylene (C3H6) recovery are highly relevant in polymer synthesis, yet developing physisorbents for these industrial separation faces the challenges of merging easy scalability, economic feasibility, high moisture stability with great separation efficiency. Herein, we reported a robust and scalable MOF (MAC-4) for simultaneous recovery of C3H6 and C2H4. Through creating nonpolar pores decorated by accessible N/O sites, MAC-4 displays top-tier uptakes and selectivities for C2H6 and C3H6 over C2H4 at ambient conditions. Molecular modelling combined with infrared spectroscopy revealed that C2H6 and C3H6 molecules were trapped in the framework with stronger contacts relative to C2H4. Breakthrough experiments demonstrated exceptional separation performance for binary C2H6/C2H4 and C3H6/C2H4 as well as ternary C3H6/C2H6/C2H4 mixtures, simultaneously affording record productivities of 27.4 and 36.2 L kg-1 for high-purity C2H4 (≥99.9 %) and C3H6 (≥99.5 %). MAC-4 was facilely prepared at deckgram-scale under reflux condition within 3 hours, making it as a smart MOF to address challenging gas separations.

Effect of remimazolam on electroencephalogram burst suppression in elderly patients undergoing cardiac surgery: Protocol for a randomized controlled noninferiority trial.

Background: Postoperative delirium (POD) is a common complication following cardiac surgery and increases postoperative morbidity and mortality. Intraoperative electroencephalogram (EEG) burst suppression suggests excessively deep anesthesia and predicts POD. Use of remimazolam provides a stable hemodynamic status and an appropriate depth of anesthesia. We aim to assess remimazolam administered for anesthesia and sedation in elderly patients having cardiac surgery. Methods: This is a randomized controlled clinical trial with noninferiority design. A total of 260 elderly patients aged equal to or greater than 60 years undergoing cardiac surgery will be randomly allocated to receive remimazolam or propofol (1:1) for general anesthesia and postoperative sedation until extubation. The primary outcome is the cumulative time with EEG burst suppression which is obtained from the SedLine system. The noninferiority margin is 2.0 min. The secondary outcomes include the POD occurrence within the first 5 days postoperatively and the duration of perioperative hypotension. Discussion: This noninferiority trial is the first to evaluate the effect of perioperative remimazolam administration on EEG burst suppression, POD occurrence, and duration of hypotension in elderly patients who undergo cardiac surgery. Trial registration: Chinese Clinical Trial Registry (ChiCTR2200056353).

Dose-Escalated Radiation Therapy as Primary Treatment for Residual Bladder Cancer After Transurethral Resection.

Purpose: The aim of this study was to determine whether escalating the local radiation dose can improve the outcome of residual bladder cancer after transurethral resection of bladder tumor without increasing treatment-related toxicity. Methods and Materials: The treatment plans and medical records of patients with bladder cancer treated with curative-intent radiation therapy between 2008 and 2020 were reviewed. Those who had residual tumors in the computed tomography simulation images were included. A cumulative radiation dose higher than 6600 cGy was defined as dose escalation. The effect of dose escalation on 3-year locoregional control, progression-free survival, and overall survival was evaluated. Results: A total of 149 patients with residual tumors were identified. The median follow-up period was 27.5 months. Among them, 51 patients received an escalated radiation dose, and 98 received a standard dose in the residual tumor area. Patients in the dose-escalation group had higher 3-year locoregional control (65.6% vs 27.8%; P < .001) and progression-free survival (42.6% vs 18.2%; P < .001) than the standard-dose group. Overall survival also showed a trend favoring the dose-escalation group (54.9% vs 36.2%; P = .059). In the multivariate analyses, the differences between the dose-escalation and standard-dose groups were significant in terms of locoregional control (hazard ratio, 0.32; CI, 0.18-0.59; P = <.001) and progression-free survival (hazard ratio, 0.51; CI, 0.32-0.82; P = .005). There was no statistical difference in acute and chronic treatment-related toxicities between the 2 groups. Conclusions: The outcome of residual bladder cancer after transurethral resection of bladder tumor could be improved by dose-escalated radiation therapy.

Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity.

The circadian clock regulator Bmal1 modulates tumorigenesis, but its reported effects are inconsistent. Here, we show that Bmal1 has a context-dependent role in mouse melanoma tumor growth. Loss of Bmal1 in YUMM2.1 or B16-F10 melanoma cells eliminates clock function and diminishes hypoxic gene expression and tumorigenesis, which could be rescued by ectopic expression of HIF1α in YUMM2.1 cells. By contrast, over-expressed wild-type or a transcriptionally inactive mutant Bmal1 non-canonically sequester myosin heavy chain 9 (Myh9) to increase MRTF-SRF activity and AP-1 transcriptional signature, and shift YUMM2.1 cells from a Sox10high to a Sox9high immune resistant, mesenchymal cell state that is found in human melanomas. Our work describes a link between Bmal1, Myh9, mouse melanoma cell plasticity, and tumor immunity. This connection may underlie cancer therapeutic resistance and underpin the link between the circadian clock, MRTF-SRF and the cytoskeleton.

Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance.

Microtubule-targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule-targeting agents without such limitations are urgently needed. By employing a gene expression-based drug repositioning strategy, this study identifies VU-0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules. VU-0365114 exhibits a broad-spectrum in vitro anticancer activity, especially in colorectal cancer cells. A tumor xenograft study in nude mice shows that VU-0365114 slowed the in vivo colorectal tumor growth. The anticancer activity of VU-0365114 is not related to its original target, M5 mAChR. In addition, VU-0365114 does not serve as a substrate of multidrug resistance (MDR) proteins, and thus, it can overcome MDR. Furthermore, a kinome analysis shows that VU-0365114 did not exhibit other significant off-target effects. Taken together, our study suggests that VU-0365114 primarily targets microtubules, offering potential for repurposing in cancer treatment, although more studies are needed before further drug development.

Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.