Paradoxical action of PP2A inhibition and its potential for therapeutic sensitization.

The protein phosphatase 2A (PP2A), a serine/threonine phosphatase, is recognized as a tumor suppressor involved in diverse cellular processes and essential for maintaining cell viability in vivo. However, endogenous inhibitors of PP2A such as cancerous inhibitor of PP2A (CIP2A) and endogenous nuclear protein inhibitor 2 of PP2A (SET) counteract the anticancer function of PP2A, promoting tumorigenesis, development, and drug resistance in tumors. Surprisingly though, contrary to conventional understanding, inhibition of the tumor suppressor gene PP2A with exogenous small molecule compounds can enhance the efficacy of cancer treatment and achieve superior tumor inhibition. Moreover, exogenous PP2A inhibitors resensitize cancers to treatment and provide novel therapeutic strategies for drug-resistant tumors, which warrant further investigation.

Potassium voltage-gated channel subfamily H member 2 (KCNH2) is a promising target for incretin secretagogue therapies.

Derived from enteroendocrine cells (EECs), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are pivotal incretin hormones crucial for blood glucose regulation. Medications of GLP-1 analogs and GLP-1 receptor activators are extensively used in the treatment of type 2 diabetes (T2D) and obesity. However, there are currently no agents to stimulate endogenous incretin secretion. Here, we find the pivotal role of KCNH2 potassium channels in the regulation of incretin secretion. Co-localization of KCNH2 with incretin-secreting EECs in the intestinal epithelium of rodents highlights its significance. Gut epithelial cell-specific KCNH2 knockout in mice improves glucose tolerance and increases oral glucose-triggered GLP-1 and GIP secretion, particularly GIP. Furthermore, KCNH2-deficient primary intestinal epithelial cells exhibit heightened incretin, especially GIP secretion upon nutrient stimulation. Mechanistically, KCNH2 knockdown in EECs leads to reduced K+ currents, prolonged action potential duration, and elevated intracellular calcium levels. Finally, we found that dofetilide, a KCNH2-specific inhibitor, could promote incretin secretion in enteroendocrine STC-1 cells in vitro and in hyperglycemic mice in vivo. These findings elucidate, for the first time, the mechanism and application of KCNH2 in regulating incretin secretion by EECs. Given the therapeutic promise of GLP-1 and GIP in diabetes and obesity management, this study advances our understanding of incretin regulation, paving the way for potential incretin secretagogue therapies in the treatment of diabetes and obesity.

Efficacy and safety of KRAS G12C inhibitor IBI351 monotherapy in patients with advanced non-small cell lung cancer: results from a phase 2 pivotal study.

INTRODUCTION: KRAS G12C mutation is a well-recognized and increasingly promising therapeutic target with significant unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. METHODS: Eligible NSCLC patients with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. Primary endpoint was confirmed objective response rate (ORR) assessed by independent radiological review committee (IRRC) as per RECIST v1.1. Other endpoints were safety, IRRC-confirmed disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS). RESULTS: As of December 13, 2023, 116 pts were enrolled (ECOG PS 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1/PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per IRRC assessment, confirmed ORR was 49.1% (95% CI: 39.7-58.6), and DCR was 90.5% (95% CI: 83.7-95.2). The median DoR was not reached while disease progression or death events occurred in 22 (38.6%) pts, and the median PFS was 9.7 months (95% CI: 5.6-11.0). OS data was immature. Treatment-related adverse events (TRAEs) occurred in 107 (92.2%) pts while 48 (41.4%) pts had grade≥3 TRAEs. Common TRAEs were anemia (44.8%), alanine aminotransferase increased (28.4%), aspartate aminotransferase increased (27.6%), asthenia (26.7%) and protein urine present (25.0%). TRAEs leading to treatment discontinuation occurred in 9 (7.8%) pts. In biomarker evaluable pts (n=95), all pts had positive KRAS G12C in tissue while 72 pts were blood positive and 23 pts were blood negative for KRAS G12C. Pts with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p <0.05) and worse PFS (p <0.05). Tumor mutation profiling identified TP53 (45.3%), STK11 (30.5%) and KEAP1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency ≥5%, mutations of 6 genes (STK11, KEAP1, PIK3CG, POLE, SMAD4, and BRINP3) were significantly associated with worse PFS (p <0.05). Mutation in STK11 also showed significant association with higher tumor burden at baseline and lower response rate (p <0.05). CONCLUSIONS: IBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.

Joint computation offloading and resource allocation for end-edge collaboration in internet of vehicles via multi-agent reinforcement learning.

Vehicular edge computing (VEC), a promising paradigm for the development of emerging intelligent transportation systems, can provide lower service latency for vehicular applications. However, it is still a challenge to fulfill the requirements of such applications with stringent latency requirements in the VEC system with limited resources. In addition, existing methods focus on handling the offloading task in a certain time slot with statically allocated resources, but ignore the heterogeneous tasks' different resource requirements, resulting in resource wastage. To solve the real-time task offloading and heterogeneous resource allocation problem in VEC system, we propose a decentralized solution based on the attention mechanism and recurrent neural networks (RNN) with a multi-agent distributed deep deterministic policy gradient (AR-MAD4PG). First, to address the partial observability of agents, we construct a shared agent graph and propose a periodic communication mechanism that enables edge nodes to aggregate information from other edge nodes. Second, to help agents better understand the current system state, we design an RNN-based feature extraction network to capture the historical state and resource allocation information of the VEC system. Thirdly, to tackle the challenges of excessive joint observation-action space and ineffective information interference, we adopt the multi-head attention mechanism to compress the dimension of the observation-action space of agents. Finally, we build a simulation model based on the actual vehicle trajectories, and the experimental results show that our proposed method outperforms the existing approaches.

Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial.

BACKGROUND: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood. METHODS: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples. FINDINGS: Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-ß, and ß-catenin signaling. CONCLUSIONS: Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker. FUNDING: This investigator-initiated trial was funded by Merck.

Toll-like receptor 4 deficiency in Purkinje neurons drives cerebellar ataxia by impairing the BK channel-mediated after-hyperpolarization and cytosolic calcium homeostasis.

Toll-like receptor (TLR) 4 contributes to be the induction of neuroinflammation by recognizing pathology-associated ligands and activating microglia. In addition, numerous physiological signaling factors act as agonists or antagonists of TLR4 expressed by non-immune cells. Recently, TLR4 was found to be highly expressed in cerebellar Purkinje neurons (PNs) and involved in the maintenance of motor coordination through non-immune pathways, but the precise mechanisms remain unclear. Here we report that mice with PN specific TLR4 deletion (TLR4PKO mice) exhibited motor impairments consistent with cerebellar ataxia, reduced PN dendritic arborization and spine density, fewer parallel fiber (PF) - PN and climbing fiber (CF) - PN synapses, reduced BK channel expression, and impaired BK-mediated after-hyperpolarization, collectively leading to abnormal PN firing. Moreover, the impaired PN firing in TLR4PKO mice could be rescued with BK channel opener. The PNs of TLR4PKO mice also exhibited abnormal mitochondrial structure, disrupted mitochondrial endoplasmic reticulum tethering, and reduced cytosolic calcium, changes that may underly abnormal PN firing and ultimately drive ataxia. These results identify a previously unknown role for TLR4 in regulating PN firing and maintaining cerebellar function.

A randomized non-inferiority study comparing imipenem/cilastatin/relebactam with standard-of-care Gram-negative coverage in cancer patients with febrile neutropenia.

BACKGROUND: Antibiotic overuse leads to the emergence of antibiotic resistance that threatens immunocompromised cancer patients. Infections caused by MDR Gram-negative pathogens are difficult to treat and associated with high mortality. Hence, empirical therapy with standard-of-care (SOC) antibiotics could be suboptimal in these vulnerable patients. New antibiotics covering potential resistant pathogens may be considered. METHODS: We conducted a randomized non-inferiority study comparing safety and efficacy of imipenem/cilastatin/relebactam (IPM/REL), a ß-lactam/ß-lactamase inhibitor combination, with SOC antibiotics (cefepime, piperacillin/tazobactam or meropenem) in cancer patients with febrile neutropenia. Patients received at least 48 h of IV antibiotics and were assessed at end-of-IV (EOIV) therapy, test of cure (TOC; Days 21-28), and late follow-up (LFU; Days 35-42). RESULTS: A total of 100 patients were enrolled (49 IPM/REL and 50 SOC). Demographics and rates of documented microbiological infections were similar in both groups. In the SOC arm, 86% of antibiotics consisted of cefepime. Patients on IPM/REL had a higher favourable clinical response at EOIV than those on SOC (90% versus 74%; P = 0.042); however, responses were similar at TOC and LFU. Microbiological eradication was comparable at all three timepoints. Study drug-related adverse events and adverse events leading to drug discontinuation were similar in both groups, with no study drug-related mortality. CONCLUSIONS: Our results suggest that compared with SOC antibiotics, predominantly cefepime, IPM/REL for empirical coverage of febrile neutropenia in cancer patients is generally safe and could be associated with a better clinical outcome at EOIV. The current SOC consisting mainly of agents that do not cover for ESBL-producing and carbapenem-resistant Enterobacterales bacteria should be reconsidered.

Prenatal ultrasound diagnosis of complete cryptophthalmos, congenital aphakia, and corneal vascularization in a fetus: A case report and literature review.

BACKGROUND: Complete cryptophthalmos, congenital aphakia, and corneal vascularization are relatively uncommon congenital eye malformations during the fetal period. Herein, we report a case of a fetus with complete cryptophthalmos, congenital aphakia, and corneal vascularization in both eyes and review previous prenatal reports of related cases. CASE PRESENTATION: The patient was a 27-year-old pregnant woman, gravida 2, para 1, who was referred to our hospital for consultation at 23 weeks of gestation due to a diagnosis of fetal right renal agenesis at an external hospital. The ultrasound system of our hospital diagnosed the fetus with complete cryptophthalmos, congenital aphakia, and corneal vascularization, which was verified under the postnatal water basin test, anatomical and pathological sections. CONCLUSIONS: Fetal ocular malformations are often associated with malformations of other organs, and if ultrasound findings are associated with such malformations, attention should be paid to the ocular examination to avoid missing the diagnosis.

Proportional Hazards Violations in Phase 3 Cancer Clinical Trials: A Potential Source of Trial Misinterpretation.

BACKGROUND: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHVs) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase 3 oncology trials and assess the utility of restricted mean survival time (RMST) and MaxCombo as additional analyses. METHODS: Clinicaltrials.gov and PubMed were searched to identify 2-arm, randomized, phase 3 superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. RESULTS: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 (23.8%; 95%CI 19.7%, 28.5%) comparisons. In multivariable analysis, non-OS endpoints (odds ratio [OR] 2.16 [95%CI 1.21, 3.87]; P=.009) were associated with higher odds of PHVs, and immunotherapy comparisons (OR 1.94 [95%CI 0.98, 3.86]; P=.058) were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) pre-specified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with RMST or MaxCombo, of which ten (71%) reported negative results. CONCLUSION: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting non-proportional hazards to be misinterpreted.

A Feasibility Study of AI-Assisted Compressed Sensing in Prostate T2-Weighted Imaging.

RATIONALE AND OBJECTIVES: To evaluate the image quality and PI-RADS scoring performance of prostate T2-weighted imaging (T2WI) based on AI-assisted compressed sensing (ACS). MATERIALS AND METHODS: In this prospective study, adult male urological outpatients or inpatients underwent prostate MRI, including T2WI, diffusion-weighted imaging and apparent diffusion coefficient maps. Three accelerated scanning protocols using parallel imaging (PI) and ACS: T2WIPI, T2WIACS1 and T2WIACS2 were evaluated through comparative analysis. Quantitative analysis included signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), slope profile, and edge rise distance (ERD). Image quality was qualitatively assessed using a five-point Likert scale (ranging from 1 = non-diagnostic to 5 = excellent). PI-RADS scores were determined for the largest or most suspicious lesions in each patient. The Friedman test and one-way ANOVA with post hoc tests were utilized for group comparisons, with statistical significance set at P < 0.05. RESULTS: This study included 40 participants. Compared to PI, ACS reduced acquisition time by over 50%, significantly enhancing the CNR of sagittal and axial T2WI (P < 0.05), significantly improving the image quality of sagittal and axial T2WI (P < 0.05). No significant differences were observed in slope profile, ERD, and PI-RADS scores between groups (P > 0.05). CONCLUSION: ACS reduced prostate T2WI acquisition time by half while improving image quality without affecting PI-RADS scores.

Considerations on Design and Analysis of External Control in Pediatric Oncology.

Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.

Comparing the efficacy of dexamethasone implant and anti-VEGF for the treatment of macular edema: A systematic review and meta-analysis.

OBJECTIVES: To evaluate the clinical efficacy of dexamethasone (DEX) implant, for the treatment of macular edema (ME) caused by retinal vein occlusion (RVO) and diabetic retinopathy (DR) through a systematic review and meta-analysis. METHODS: The PubMed, Embase and Cochrane Library databases were comprehensively searched from inception to November 21, 2022, for studies evaluating the clinical efficacy of DEX implant for patients with retinal vein occlusion macular edema (RVO-ME) or diabetic macular edema (DME). Randomized controlled trials (RCTs) published in English were considered eligible. The Cochrane Collaboration tool was applied to assess the risk of bias in each study. Effect estimates with 95% confidence intervals (CIs) were pooled using the random effects model. We also conducted subgroup analyses to explore the sources of heterogeneity and the stability of the results. RESULTS: This meta-analysis included 8 RCTs (RVO-ME [n = 2] and DME [n = 6]) assessing a total of 336 eyes. Compared with anti-VEGF therapy, DEX implant treatment achieved superior outcomes in terms of best corrected visual acuity (BCVA) (mean difference [MD] = -3.68 ([95% CI, -6.11 to -1.25], P = 0.003), and no heterogeneity was observed (P = 0.43, I2 = 0%). DEX implant treatment also significantly reduced central macular thickness (CMT) compared with anti-VEGF treatment (MD = -31.32 [95% CI, -57.92 to -4.72], P = 0.02), and there was a high level of heterogeneity between trials (P = 0.04, I2 = 54%). In terms of severe adverse events, DEX implant treatment had a higher risk of elevated intraocular pressure than anti-VEGF therapy (RR = 6.98; 95% CI: 2.16 to 22.50; P = 0.001), and there was no significant difference in cataract progression between the two groups (RR = 1.83; 95% CI: 0.63 to 5.27, P = 0.31). CONCLUSIONS: Compared with anti-VEGF therapy, DEX implant treatment is more effective in improving BCVA and reducing ME. Additionally, DEX implant treatment has a higher risk of elevated intraocular pressure. Due to the small number of studies and the short follow-up period, the results should be interpreted with caution. The long-term effects of the two treatments need to be further determined. TRIAL REGISTRATION: Prospero Registration Number CRD42021243185.

Discovery, identification and mechanism of chemosensitivity-relate biomarker inter-α-trypsin inhibitor heavy chain 4 in metastatic colorectal cancer.

Predictive biomarkers of response to chemotherapy in patients with metastatic colorectal cancer (mCRC) are needed to better characterize tumors and enable more tailored therapies. Here we used serum proteomics to screen for chemotherapy predictive markers. We found that higher baseline serum inter-α-trypsin inhibitor Heavy Chain 4 (ITIH4) expression in newly diagnosed mCRC patients was associated with poorer response to standard first-line chemotherapy. In addition, the higher expression of ITIH4 in CRC tissue also suggested poorer prognosis mCRC patients. Moreover, the overexpression of ITIH4 could promote the proliferation of CRC cells and reduce the sensitivity of CRC cells to 5-fluorouracil (5-FU) by inhibiting apoptosis in vivo and vitro. Through RNA-seq combined with bioinformatics analysis, we speculated that ITIH4 may activate phosphatidyl 3-kinase-protein kinase B (PI3K-AKT) pathway to inhibit apoptosis, thereby reducing the sensitivity of CRC cells to 5-FU. In conclusion, our findings unveil that ITIH4 is associated with CRC resistance to 5-FU, and may serve as a potential predictive biomarker for the sensitivity of advanced CRC patients to standard first-line chemotherapy regimens, and also provide a potential therapeutic target to render 5-FU resistance in CRC patients.

In Silico drug repurposing pipeline using deep learning and structure based approaches in epilepsy.

Due to considerable global prevalence and high recurrence rate, the pursuit of effective new medication for epilepsy treatment remains an urgent and significant challenge. Drug repurposing emerges as a cost-effective and efficient strategy to combat this disorder. This study leverages the transformer-based deep learning methods coupled with molecular binding affinity calculation to develop a novel in-silico drug repurposing pipeline for epilepsy. The number of candidate inhibitors against 24 target proteins encoded by gain-of-function genes implicated in epileptogenesis ranged from zero to several hundreds. Our pipeline has repurposed the medications with most anti-epileptic drugs and nearly half psychiatric medications, highlighting the effectiveness of our pipeline. Furthermore, Lomitapide, a cholesterol-lowering drug, first emerged as particularly noteworthy, exhibiting high binding affinity for 10 targets and verified by molecular dynamics simulation and mechanism analysis. These findings provided a novel perspective on therapeutic strategies for other central nervous system disease.

Loss-of-function mutation of REV1 (p.R704Q) mediates cetuximab primary resistance by activating autophagy in RAS-wild type metastatic colorectal cancer.

Cetuximab in combination with FOLFIRI/FOLFOX is the standard first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, some patients experience rapid tumor progression after treatment with cetuximab (primary resistance). Our previous research identified a gene mutation, REV1 p.R704Q, which may be a key biomarker for primary cetuximab resistance. This study aimed to study the mechanism of cetuximab resistance caused by REV1 p.R704Q mutation and reveal a novel mechanism to induce cetuximab resistance. Sanger sequencing and multivariate clinical prognostic analysis of 208 patients with mCRC showed that REV1 p.R704Q mutation is an independent risk factor for tumor progression after treatment with cetuximab in patients with RAS wild-type mCRC (Hazard ratio = 2.481, 95 % Confidence interval: 1.389-4.431, P = 0.002). The sensitivity of REV1 p.R704Q mutant cell lines to cetuximab decreased in vitro Cell Counting Kit-8 assay and in vivo subcutaneous tumor model. In vitro, we observed that decreased stability and accelerated degradation of REV1 mutant protein results in REV1 dysfunction, which activated autophagy and mediated cetuximab resistance. These findings suggested that REV1 p.R704Q mutation could predict cetuximab primary resistance in mCRC. REV1 p.R704Q mutation caused decreased stability and degradation of REV1 protein, as well as dysfunction of p.R704Q protein. REV1 p.R704Q mutation activates autophagy and mediates cetuximab resistance; further, inhibition of autophagy could reverse cetuximab resistance.

Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

Objective: The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Methods: Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Results: Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Conclusions: Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Application value research of swallowing treatment device combined with swallowing rehabilitation training in the treatment of swallowing disorders after stroke.

BACKGROUND: Stroke is a common disabling disease, whether it is ischemic stroke or hemorrhagic stroke, both can result in neuronal damage, leading to various manifestations of neurological dysfunction. AIM: To explore of the application value of swallowing treatment device combined with swallowing rehabilitation training in the treatment of swallowing disorders after stroke. METHODS: This study selected 86 patients with swallowing disorders after stroke admitted to our rehabilitation department from February 2022 to December 2023 as research subjects. They were divided into a control group (n = 43) and an observation group (n = 43) according to the treatment. The control group received swallowing rehabilitation training, while the observation group received swallowing treatment device in addition to the training. Both groups underwent continuous intervention for two courses of treatment. RESULTS: The total effective rate in the observation group (93.02%) was higher than that in the control group (76.74%) (P = 0.035). After intervention, the oral transit time, swallowing response time, pharyngeal transit time, and laryngeal closure time decreased in both groups compared to before intervention. In the observation group, the oral transit time, swallowing response time, and pharyngeal transit time were shorter than those in the control group after intervention. However, the laryngeal closure time after intervention in the observation group was compared with that in the control group (P = 0.142). After intervention, average amplitude value and duration of the genioglossus muscle group during empty swallowing and swallowing 5 mL of water are reduced compared to before intervention in both groups. After intervention, the scores of the chin-tuck swallowing exercise and the Standardized Swallowing Assessment are both reduced compared to pre-intervention levels in both groups. However, the observation group scores lower than the control group after intervention. Additionally, the Functional Oral Intake Scale scores of both groups are increased after intervention compared to pre-intervention levels, with the observation group scoring higher than the control group after intervention (P < 0.001). The cumulative incidence of complications in the observation group is 9.30%, which is lower than the 27.91% in the control group (P = 0.027). CONCLUSION: The combination of swallowing therapy equipment with swallowing rehabilitation training can improve the muscle movement level of the genioglossus muscle group, enhance swallowing function, and prevent the occurrence of swallowing-related complications after stroke.

A 3D self-floating solar vapor generator based on a novel self-healing aero-hydrogel containing peach gum polysaccharide with durability and continuous operation.

Solar energy interfacial evaporation represents a promising and sustainable approach with considerable potential for seawater desalination and wastewater treatment. Nonetheless, creating durable evaporators for continuous operation presents a challenge. Motivated by natural self-healing mechanisms, this study developed a novel 3D hybrid aero-hydrogel, which exhibited a self-healing efficiency of 89.4 % and an elongation at break post-healing of 637.7 %, featuring self-healing capabilities and continuous operation potential. Especially, the incorporation of hyperbranched water-soluble polymers (peach gum polysaccharide) endow the final solar water evaporators with a lower evaporation enthalpy of water, resulting in that the refined SVG3, with a notable water surface architecture and an expanded evaporation area, achieved a steam generation rate of 2.13 kg m-2 h-1 under 1 Sun. Notably, SVG2 achieved a high evaporation rate of 2.43 kg m-2 h-1 with the combined energy input of 1 Sun and 6 V, significantly surpassing the rate of 1.96 kg m-2 h-1 without voltage input. The results indicate that electrical energy significantly enhances and synergizes with SVG, facilitating continuous operation both day and night through the combined use of solar energy and electrical input. This study offers insightful perspectives for the strategic design of multifunctional hydrogels for solar water evaporation.