Acupuncture combined with repetitive transcranial magnetic stimulation for the treatment of post-stroke depression: a systematic evaluation and meta-analysis based on a randomised controlled trial.

Objective: This study aimed to systematically assess the efficacy of combining acupuncture with repetitive transcranial magnetic stimulation (rTMS) in treating post-stroke depression (PSD). Methods: We conducted a comprehensive search of eight major domestic and international databases, including the China Knowledge Network, from inception until December 2023. Included were randomized controlled trials that investigated acupuncture combined with rTMS for PSD. The screening process adhered to predetermined inclusion and exclusion criteria, and study quality was assessed using Cochrane Handbook 5.1 guidelines. Meta-analysis was conducted using RevMan 5.4 software. Results: Twelve studies involving 800 patients were included in the analysis. The meta-analysis showed that acupuncture combined with rTMS significantly improved the clinical effectiveness rate (RR = 1.19, 95% CI: 1.12 to 1.27, p < 0.00001) and reduced scores on several scales: Hamilton Depression Scale (HAMD) (MD = -3.35, 95% CI: -3.79 to -2.90, p < 0.00001), Self-Depression Scale (SDS) (MD = -9.57, 95% CI: -12.26 to -6.89, p < 0.00001), Chinese Medicine Symptom Score (MD = -3.34, 95% CI: -3.76 to -2.91, p < 0.00001), Pittsburgh Sleep Quality Scale (MD = -3.91, 95% CI: -4.58 to -3.25, p < 0.00001), and National Institutes of Health Stroke Scale (NIHSS) (MD = -2.77, 95% CI: -3.21 to -2.32, p < 0.00001). Furthermore, acupuncture combined with rTMS treatment improved cognitive functioning (MMSE, MoCA scores) (p < 0.00001) and ability to perform activities of daily living scores (MD = 10.40, 95% CI: 9.53 to 11.28, p < 0.00001). Additionally, it was found to reduce interleukin 6, tumor necrosis factor alpha, interleukin 1ß, and increase 5-hydroxytryptamine and brain-derived neurotrophic factor levels (p < 0.001). Conclusion: Acupuncture combined with rTMS therapy is recommended for treating PSD, as it effectively improves clinical outcomes, alleviates depressive symptoms, enhances cognitive function, and daily living capabilities, and modulates inflammatory responses and neurotransmitter levels. However, it is important to note that the limitations of the sample size and quality of the included studies warrant the need for more high-quality research to validate these conclusions. Systematic review registration: INPLASY, Identifier INPLASY202430085.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor + chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers.

BACKGROUND: The combination of programmed cell death protein-1 (PD-1) inhibitor and chemotherapy is approved as a standard first- or second-line treatment in patients with advanced oesophageal or gastric cancer. However, it is unclear whether this combination is superior to chemotherapy alone. AIM: To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or oesophageal carcinoma. METHODS: We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer. We employed either random or fixed models to analyze the outcomes of each clinical trial, encompassing data on overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events (AEs). RESULTS: Nine phase 3 clinical trials (7016 advanced oesophageal and gastric cancer patients) met the inclusion criteria. Our meta-analysis demonstrated that the pooled PD-1 inhibitor + chemotherapy group had a significantly longer OS than the chemotherapy-alone group [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.71-0.81]; the pooled PFS result was consistent with that of OS (HR = 0.67, 95%CI: 0.61-0.74). The count of patients achieving an objective response in the PD-1 inhibitor + chemotherapy group surpassed that of the chemotherapy-alone group [odds ratio (OR) = 1.86, 95%CI: 1.59-2.18]. AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group, regardless of whether ≥ grade 3 only (OR = 1.30, 95%CI: 1.07-1.57) or all AE grades (OR = 1.88, 95%CI: 1.39-2.54) were examined. We performed a subgroup analysis based on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) and noted extended OS and PFS durations within the CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 subgroups of the PD-1 inhibitor + chemotherapy group. CONCLUSION: In contrast to chemotherapy alone, the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer, GEJ tumor, or oesophageal cancer. This holds true particularly for individuals with PD-L1 CPS scores of ≥ 5 and ≥ 10.

Velocity field and turbulence structure of the meandering flow produced by alternating deflectors.

Meandering flow can be formed during the advance of natural rivers by the scouring of river banks. However, this phenomenon is not common in artificial cement channels. This study used experimental scouring terrain data for a numerical simulation to study the meandering flow pattern formed between double alternating deflectors in a straight channel. The numerical results showed that the path of the accelerated flow generated by the upstream deflector was changed by installing a downstream deflector while the flow rate remained unchanged. Thus, a meandering flow formed, and a stable, narrow, high-speed zone formed in the downstream area. The accelerated flow between the two deflectors hit the channel bank soon after its direction changed. Then, a strong downward flow formed in this area, which may have produced an elliptical scour hole. A large-scale vortex structure was formed in the elliptical scour hole, which was influenced by the horseshoe vortex system before the downstream deflector.

Application of surface-modified functional packaging in food storage: A comprehensive review.

Innovations in food packaging systems could meet the evolving needs of the market; emerging concepts of non-migrating technologies reduce the negative migration of preservatives from packaging materials, extend shelf life, and improve food quality and safety. Non-migratory packaging activates the surface of inert materials through pretreatment to generate different active groups. The preservative is covalently grafted with the resin of the pretreated packaging substrate through the graft polymerization of the monomer and the coupling reaction of the polymer chain. The covalent link not only provides the required surface properties of the material for a long time but also retains the inherent properties of the polymer. This technique is applied to the processing for durable, stable, and easily controllable packaging widely. This article reviews the principles of various techniques for packaging materials, surface graft modification, and performance characterization of materials after grafting modification. Potential applications in the food industry and future research trends are also discussed.

Long-Term Outcomes in Older Patients with Sepsis in the ICU: A Retrospective Study.

Objective: The primary objectives of this study were to compare the characteristics of older and younger patients with sepsis and to analyze risk factors associated with 28-day and 90-day mortality in critically ill patients. Our study aimed to explore whether there are significant differences between sepsis patients in different age groups and whether these differences are related to the association between disease severity and mortality. Methods: We conducted a single-center, retrospective study of 5783 critically ill patients over 18 years of age from the Medical Information Mart for Intensive Care III database diagnosed with sepsis and admitted to the intensive care unit between 2008 and 2012. We performed a retrospective analysis, selected the Critical Care Medicine Information Mart III database, and collected data on patients with sepsis. We then collated and analyzed these data to compare differences in characteristics between older and younger patients and identify associated risk factors, which can help understand patient mortality. This approach leverages existing clinical data and avoids new experiments or data collection. Kaplan-Meier survival curve was used to assess 28-day and 90-day mortality, and a Cox proportional hazards regression model was used to evaluate the associated risk factors with 28-day and 90-day mortality. Results: Our study identified significant differences in mortality between older and younger patients with sepsis, finding that older patients had significantly higher mortality than younger patients. Furthermore, we successfully identified risk factors associated with mortality, results that have important implications for optimizing patient care and making clinical decisions. Of 5783 patients with sepsis, 2044 (35.3%) were younger than 60 years, and 3739 (64.7%) were aged 60 years or older. The 28-day mortality rate was 11.8% and 21.2% in the younger and older cohorts, respectively (P < .01). In the age-stratified analysis, the 28-day mortality was the highest in patients aged over 80 years (14.6% vs. 21.2% vs. 26.8%, P < .001). Factors associated with 28-day and 90-day mortality in patients with sepsis included age, weight, the need for mechanical ventilation, congestive heart failure, chronic pulmonary disease, malignancy, and Sequential Organ Failure Assessment score. Higher mortality in older patients with sepsis suggests the need for more aggressive treatment and monitoring. We also identified risk factors associated with mortality, helping to develop individualized treatment strategies. In addition, the different clinical characteristics of patients in different age groups emphasize the need for refined care pathways to meet their special needs. These results will help improve the treatment effect and quality of life of patients with sepsis. Conclusions: Our study fills the knowledge gap on the manifestations of sepsis patients in different age groups and helps medical staff better predict and manage disease progression in these two groups and provide personalized treatment. This lays the foundation for future in-depth research on age-related sepsis factors and is expected to improve patient survival and recovery rates. Older patients with sepsis had higher mortality rates and adverse outcomes. The mortality rate in patients with sepsis gradually increased with age. The importance of these findings is that they can help guide patient care and clinical decision-making, particularly when dealing with older and younger patients with sepsis, to improve treatment outcomes and reduce mortality. We would like to acknowledge that there are several limitations to the study, including the selectivity of the database and the retrospective nature, which preclude inference of causal relationships. In addition, some unconsidered variables may affect the results, and missing information in the data may also have an impact on the study. Future research could further explore these issues.This study highlights the critical role of age in sepsis patient outcomes and provides a strong basis for more sophisticated care and treatment. Our findings will help save more lives and improve patients' chances of recovery, which has profound implications for future research and clinical practice in the field of sepsis.

[Clinical Study of Blinatumomab in the Treatment of Adult Relapsed/Refractory Ph-Negative Acute B-Lymphoblastic Leukemia].

OBJECTIVE: To investigate the efficacy and safety of CD19/CD3 bisecific monoclonalantibody (Blinatumomab) in the treatment of adult patients with relapsed / refractory Ph-negative acute B-lymphoblastic leukemia (R/R-B-ALL). METHODS: Ten adult R/R B-ALL patients were all treated with Blinatumomab. Each treatment cycle was administered for 28 days and stopped for 14 days. The dose was 9 µg/day for the first 7 days of cycle 1, and 28 µg/day for days 8-28 if there were no adverse reactions. From the second cycle onwards, the daily dose was 28 µg. The remission, survival time (EFS and OS) and adverse reactions were observed after treatment. RESULTS: Nine patients with curative effect could be evaluated. Four patients achieved CR after one course, and one patient achieved CR after two courses, the overall remission rate was 55.6%(5/9). The median EFS was 4 months (1-12 months), and the median OS was 6 months (2-44 months). Nine of the 10 patients had fever of different degrees. Serum levels of cytokines such as IL-6, IL-10, IL-17 and IFN-γ increased. Two patients resumed medication after 1 week of treatment interruption due to neurotoxicity and CRS, respectively. One patient was discontinued due to grade 3 CRS and died of tropical candidiaemia. CONCLUSION: Blinatumomab has a good response rate in the treatment of relapsed/refractory B-ALL patients, but the duration of remission is shorter. Drug-related adverse reactions are mainly CRS and neurotoxicity. Inflammatory factors IL-6, IL-10, IL-17 and IFN-γ can be used as indicators to monitor CRS. The bisspecificity MAbs provide an opportunity for subsequent allogeneic hematopoietic stem cell transplantation in R/R-B-ALL patients.

[High-Throughput Sequencing Technology for Detection of Gene Mutations in Myeloid Malignancies and Its Clinical Prognostic Significance].

OBJECTIVE: To detect the gene mutations in patients with myeloid malignancies by high-throughput sequencing and explore the correlation between gene mutations and prognosis. METHODS: A retrospective analysis was performed on 56 patients with myeloid malignancies who were hospitalized in the department of hematology, Peking University International Hospital from January 2020 to May 2021. The genetic mutations of the patients were detected by next-generation sequencing technology, and the correlation between the genetic mutations and prognosis of myeloid malignancies was analyzed. RESULTS: In 56 patients, the number of mutated genes detected in a single patient is 0-9, with a median of 3. Sequencing results showed that the most common mutated genes were RUNX1(21.4%), TET2(17.9%), DNMT3A(17.9%), TP53(14.3%) and ASXL1(14.3%), among which the most common mutations occurred in the signaling pathway-related genes (23.3%) and the transcription factor genes (18.3%). 84% of the patients carried multiple mutated genes (≥2), and correlation analysis showed there were obvious co-occurring mutations between WT1 and FLT3, NPM1 and FLT3-ITD, and MYC and FLT3. TP53 mutation was more common in MDS patients.The overall survival time of patients with NRAS mutation was significantly shortened (P =0.049). The prognosis of patients with TP53 mutation was poor compared with those without TP53 mutation, but the difference wasn't statistically significant (P =0.08). CONCLUSION: The application of next-generation sequencing technology is of great significance in myeloid malignancies, which is helpful to better understand the pathogenesis of the disease, to judge the prognosis and to find possible therapeutic targets.

OCRFinder: a noise-tolerance machine learning method for accurately estimating open chromatin regions.

Open chromatin regions are the genomic regions associated with basic cellular physiological activities, while chromatin accessibility is reported to affect gene expressions and functions. A basic computational problem is to efficiently estimate open chromatin regions, which could facilitate both genomic and epigenetic studies. Currently, ATAC-seq and cfDNA-seq (plasma cell-free DNA sequencing) are two popular strategies to detect OCRs. As cfDNA-seq can obtain more biomarkers in one round of sequencing, it is considered more effective and convenient. However, in processing cfDNA-seq data, due to the dynamically variable chromatin accessibility, it is quite difficult to obtain the training data with pure OCRs or non-OCRs, and leads to a noise problem for either feature-based approaches or learning-based approaches. In this paper, we propose a learning-based OCR estimation approach with a noise-tolerance design. The proposed approach, named OCRFinder, incorporates the ideas of ensemble learning framework and semi-supervised strategy to avoid potential overfitting of noisy labels, which are the false positives on OCRs and non-OCRs. Compared to different noise control strategies and state-of-the-art approaches, OCRFinder achieved higher accuracies and sensitivities in the experiments. In addition, OCRFinder also has an excellent performance in ATAC-seq or DNase-seq comparison experiments.

Effect of Transcranial Direct Current Stimulation Combined with Donepezil on stroke patients with memory impairment.

Objective: To investigate the therapeutic effect of transcranial direct current stimulation (TDCS) combined with donepezil on stroke patients with memory impairment. Methods: The subjects of the study were 120 stroke patients with memory impairment admitted to the Rehabilitation Department of Tianjin Medical University General Hospital from July 2017 to March 2020. Enrolled patients were divided into Group-A (58 cases) and Group-B (62 cases) according to different treatment intervention methods. Patients in Group-A were treated with TDCS and those in Group-B received donepezil on the basis of TDCS. The changes in Montreal Cognitive Assessment (MoCA) memory index score, Barthel Index (MBI) score, cognitive function and cognitive potential were observed and compared between the two groups before and after treatment. Results: The improvement of total MoCA score, a single score of memory, MBI score, cognitive function and P300 potential index in Group-B was significantly better than that in Group-A (p<0.05). Conclusion: TDCS combined with donepezil can reduce or delay the cognitive impairment of stroke patients, improve their delayed memory ability, increase the neurotransmitter acetylcholine in the cerebral cortex, and further enhance their neural function. Findings in our study support that the proposed therapeutic method is worthy of clinical application.

Antioxidant mechanism of a continuous microenvironment regulation system for prolonging the shelf-life of red grapes.

Red grapes (Vitis vinifera L.) have a high sugar content, thin skins, and relatively short shelf-life after harvesting. We developed polylactic acid/polybutylene succinate film, prepared by extrusion of polylactic acid and polybutylene succinate, that significantly prolonged the shelf-life of red grapes from 8 to 12 days by delaying the loss of weight, loss of hardness, and reduction in soluble solid content after harvesting. Further mechanistic study showed that this modified atmosphere film delayed the senescence of harvested red grape, the phenomenon that was highly related to the lower active oxygen species production and higher antioxidant enzyme activity compared to the non-packaged grape. The proposed continuous and dynamic microenvironment regulation system is a promising method to study the mechanisms of respiratory metabolism in fruit and extends food shelf-life while reducing food waste. PRACTICAL APPLICATION: In this study, we designed a means to microenvironmental regulatory packaging that directly creates a continuous, dynamic, and monitorable microenvironment. To ensure that the fruit inside the package underwent coordinated aerobic and anaerobic respiration, we melt-extruded polylactic acid (PLA) and polybutylene succinate (PBS) to form a homogeneous biodegradable film. We demonstrated that the best preservation results were achieved with a film comprising an 80/20 PLA-to-PBS ratio. This film can prolong the shelf-life of fruits by regulating respiratory metabolism.

Intraoperative microelectrode recording under general anesthesia guided subthalamic nucleus deep brain stimulation for Parkinson's disease: One institution's experience.

Objective: Microelectrode recording (MER) guided subthalamic nucleus deep brain stimulation (STN-DBS) under local anesthesia (LA) is widely applied in the management of advanced Parkinson's disease (PD). Whereas, awake DBS under LA is painful and burdensome for PD patients. We analyzed the influence of general anesthesia (GA) on intraoperative MER, to assess the feasibility and effectiveness of GA in MER guided STN-DBS. Methods: Retrospective analysis was performed on the PD patients, who underwent bilateral MER guided STN-DBS in Wuhan Union Hospital from July 2019 to December 2021. The patients were assigned to LA or GA group according to the anesthetic methods implemented. Multidimensional parameters, including MER signals, electrode implantation accuracy, clinical outcome and adverse events, were analyzed. Results: A total of 40 PD patients were enrolled in this study, including 18 in LA group and 22 in GA group. There were no statistically significant differences in patient demographics and baseline characteristics between two groups. Although, the parameters of MER signal, including frequency, inter-spike interval (ISI) and amplitude, were obviously interfered under GA, the waveforms of MER signals were recognizable and shared similar characteristics with LA group. Both LA and GA could achieve effective electrode implantation accuracy and clinical outcome. They also shared similar adverse events postoperatively. Conclusion: GA is viable and comparable to LA in MER guided STN-DBS for PD, regarding electrode implantation accuracy, clinical outcome and adverse events. Notably, GA is more friendly and acceptable to the patients who are incapable of enduring intraoperative MER under LA.

Prognostic Value of Inflammatory and Nutritional Markers for Patients With Early-Stage Poorly-to Moderately-Differentiated Cervical Squamous Cell Carcinoma.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammatory index (SII), systemic inflammation response index (SIRI), and Onodera's prognostic nutritional index (OPNI) have been reported as prognostic markers for various cancers. We evaluated the prognostic value of the NLR, PLR, MLR, SII, SIRI, and OPNI for poorly-to moderately-differentiated cervical squamous cell carcinoma (CSCC). PATIENTS AND METHODS: We retrospectively analyzed the cases of 109 patients with early-stage poorly-to moderately-differentiated CSCC who underwent radical surgery at our institution in 2014-2017. The optimal cutoff points for the NLR, PLR, MLR, SII, SIRI, and OPNI were determined by receiver operating characteristic curves. Overall survival was analyzed by the Kaplan-Meier method. We performed a multivariate analysis using the Cox proportional hazard regression model to determine the independent prognostic indicators for early-stage poorly-to moderately-differentiated CSCC. RESULTS: The appropriate cutoff points were: NLR, 1.72; PLR, 111.96; MLR, .24; SII, 566.23; SIRI, 1.38; and OPNI, 52.68. The OS of the patients with a high OPNI (P = .04), low SII (P = .03), or low SIRI (P = .01) was significantly better. The uni- and multivariate analyses identified only the OPNI as an independent prognostic marker for early-stage poorly-to moderately-differentiated CSCC (P = .04 and P = .02). CONCLUSION: The OPNI is an independent prognostic marker for early-stage poorly-to moderately-differentiated CSCC; the NLR, PLR, MLR, SII, and SIRI are not.

[Plasma components of Danzhi Xiaoyao Formula and its mechanism of action in treating perimenopausal depression based on UPLC-Q-TOF-MS~E integrated with network pharmacology].

In this study, ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS~E) was used to analyze the plasma components of Danzhi Xiaoyao Formula after oral administration. Forty-nine plasma components were found in the serum of rats by comparing the compound extract, drug-containing serum, and blank serum. Components, such as 6-hydroxycoumarin, poricoic acid F, deoxoglabrolide, 30-norhederagenin, kanzonol R, 3',6'-di-O-galloylpaeoniflorin, 16α-hydroxytrametenolic acid, 16-deoxyporicoic acid B, 3-O-acetyl-16α-hydroxytrametenolic acid, and 16α,25-dihydroxydehydroeburiconic acid, were first found in rat serum. Behavioral tests, including the tail suspension test, novel object recognition test, and novelty-suppressed feeding test, were conducted for behavioral analysis. It was confirmed that this formula had therapeutic effects on perimenopausal depression. Furthermore, in combination with the network pharmacology method, 53 core targets including MAPK1, HRAS, AKT1, EGFR, and ESR1 were screened, and these targets participated in 165 signaling pathways, including PI3K-AKT, AMPK, VEGFA, MAPK, and HIF-1. In summary, the potential effects of Danzhi Xiaoyao Formula in treating perimenopausal depression are associated with mechanisms in accelerating inflammation repair, improving neuroplasticity, affecting neurotransmitters, regulating estrogen levels, and promoting new blood vessel formation.

CIMP-positive glioma is associated with better prognosis: A systematic analysis.

BACKGROUND: CpG island methylator phenotype (CIMP) was closely related to the degree of pathological differentiation of tumors, and it's an important determinant of glioma pathogenicity. However, the molecular and pathological features of CIMP-positive glioma have not been fully elucidated. In addition, CIMP have been reported to be a useful prognostic marker in several human cancers, yet its prognostic value in gliomas is still controversial. Therefore, we aimed to evaluate gene mutations and pathological features of CIMP-positive glioma and explore the prognostic value of CIMP in gliomas. METHODS: We comprehensively searched PubMed, Embase, and MEDLINE for studies describing gene mutations, pathological features and overall survival of gliomas stratified by CIMP status. Odds ratios (OR), hazard ratios (HR), and their 95% confidence intervals (CI) were used to estimate the correlation between CIMP and the outcome parameters. RESULTS: Twelve studies with 2386 gliomas (1051 CIMP-positive and 1335 CIMP-negative) were included. Our results showed that CIMP was more frequent in isocitrate dehydrogenase 1 (IDH1)-mutated gliomas (OR 229.07; 95% CI 138.72-378.26) and 1p19q loss of heterozygosis (LOH) gliomas (OR 5.65; 95% CI 2.66-12.01). Pathological analysis showed that CIMP was common in low-malignant oligodendroglioma (OR 5.51; 95% CI 3.95-7.70) with molecular features including IDH1 mutations and 1p19q LOH, but rare in glioblastoma (OR 0.14; 95% CI 0.10-0.19). However, CIMP showed no obvious correlation with anaplastic oligoastrocytomas (OR 1.57; 95% CI 1.24-2.00) or oligoastrocytomas (OR 0.79; 95% CI 0.35-1.76). Concerning the prognosis, we found that CIMP-positive gliomas had longer overall survival (HR 0.57; 95% CI 0.97-0.16) than CIMP-negative gliomas. CONCLUSIONS: CIMP could be used as a potential independent prognostic indicator for glioma.

PD-1 inhibitor treatment in a penile cancer patient with MMR/MSI status heterogeneity: A case report.

Penile cancer is a rare malignant disease. Paclitaxel combined with platinum is often used as a first-line chemotherapeutic regimen for late-stage penile cancer, and there is no standard second-line treatment. Clinical trials of immunotherapy for penile cancer are ongoing. There are no reports on PD1 inhibitor treatment in metastatic penile carcinoma patients with MMR/MSI status heterogeneity. A 68-year-old patient was hospitalized with bilateral inguinal lymph node metastasis and local penile recurrence after penile cancer surgery. The lesion of the right inguinal lymph node showed a mismatch-repair-deficient (dMMR)/microsatellite instability-low (MSI-L) status. After 3 cycles of sintilimab (a PD1 inhibitor) combined with paclitaxel and cisplatin, the partial response of the tumor was evaluated. Subsequently, sintilimab monotherapy was used as maintenance treatment for 2 months. However, The lesion of local penile recurrence showed mismatch repair proficient (pMMR)/microsatellite stability (MSS) status by secondary biopsy when progressed rapidly. Interestingly, after continued treatment with sintilimab combined with gemcitabine, the patient achieved a partial response again. We should be aware of the importance of secondary biopsy for different lesions to confirm the heterogeneity of MMR/MSI status. For penile cancer patients with MMR/MSI status heterogeneity, PD1 inhibitors combined with chemotherapy are safe and effective. Due to oligometastatic lesion progression caused only by the heterogeneity of MMR/MSI status, PD1 inhibitor cross-line therapy can also be considered an appropriate treatment.

Long-term survival after immunotherapy and targeted therapy without chemotherapy in an elderly patient with HER2-positive gastroesophageal junction cancer: A case report.

A 74-yr-old man underwent thoracic laparoscopy combined with radical gastrectomy, and the postoperative pathological diagnosis was esophageal and gastric cardia cancer pT3N1M0, pStage IIB. Immunohistochemical staining for HER2 (3+) and PD-L1 (<5%) was positive. Adjuvant chemotherapy was not performed because the patient developed severe thrombocytopenia (platelet counts <30 × 109/L), which was never cured throughout the reporting period. At 10.7 months post-surgery, he suffered metastases in multiple organs, including the peritoneum, liver, lung, and bone. Following two cycles of first-line trastuzumab and pembrolizumab (200 mg), he developed immune-related myositis (G2), myocarditis (G2), and hepatitis (G1). Therefore, pembrolizumab was discontinued. Trastuzumab was administered as a monotherapy; meanwhile, adoptive cytokine-induced killer (CIK) cell infusions were initiated. Eight months after the initial immunotherapy, a solitary brain metastasis was detected, and the patient underwent CyberKnife radiosurgery. For second-line therapy, adoptive CIK cell immunotherapy plus trastuzumab was still used. At the time of reporting, the patient had achieved a complete response (CR) in the brain and liver and a partial response (PR) in the ilium, and he had been followed-up for 36.6 months, much longer than the median survival time for patients with advanced GEJ cancer. We suggest that HER2-targeted therapy and immunotherapy with pembrolizumab or CIK adoptive cell infusions prolonged the overall survival of an elderly patient with HER2-positive GEJ cancer with multiple metastases.

HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives.

Recently, the global incidence of gastric/gastroesophageal junction (G/GEJ) cancer has remained high. China is also a large country with a high gastric cancer (GC) incidence rate, where the cases of GC account for 40% of all cases worldwide. More than 90% of GEJ cancers are the adenocarcinoma pathological type. Patients with early-stage G/GEJ adenocarcinoma may have a better prognosis after surgery. In contrast, patients with advanced metastatic G/GEJ adenocarcinoma usually choose comprehensive treatment based on systemic pharmacotherapy, but the subsequent long-term survival is not optimistic. The discovery of various biomarkers, especially microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutational burden (TMB) and Epstein-Barr virus (EBV), has led to the identification of an increasing number of targeted populations and has greatly improved the clinical efficacy of treatments for G/GEJ adenocarcinoma. The ToGA trial added trastuzumab to standard chemotherapy, showed improved survival of patients with HER2-positive advanced G/GEJ adenocarcinoma and brought these patients into a new era of HER2-targeted therapy. Moreover, many HER2-targeted agents have been developed and studied in patients with advanced HER2-positive G/GEJ adenocarcinoma who have demonstrated excellent clinical outcomes. However, many patients experience disease progression with HER2-targeted therapy; hence, new anti-HER2 drugs keep being developed, significantly reducing HER2 resistance. This paper reviews HER2-targeted drugs for advanced metastatic G/GEJ adenocarcinoma, potential resistance mechanisms and future directions.

NICD3 regulates the expression of MUC5AC and MUC2 by recruiting SMARCA4 and is involved in the differentiation of mucinous colorectal adenocarcinoma.

Adenocarcinoma is the most prevalent histological subtype of colorectal cancer (CRC), with mucinous colorectal adenocarcinoma (MCA) being a unique form. Although the mucinous subtype is known to elicit a worse response to chemotherapy and immunotherapy than the nonmucinous subtype, its pathogenesis remains poorly understood. Neurogenic locus notch homolog protein 3 (NOTCH3), a member of the NOTCH subfamilies, is highly expressed in CRC. In the past three decades, many studies have been performed evaluating the biological role of NOTCH3 in CRC. However, the precise activities of NOTCH3 in MCA, as well as the mechanisms involved in its transcriptional control, are yet to be elucidated. Our finding showed that the critical transcriptional regulatory factor transcription activator BRG1 (SMARCA4) directly binds to the intracellular domain of NOTCH3 to control transcriptional regulation. Moreover, RNA-sequencing results indicated a common targeting effect on the transcriptional activity of mucin-5AC (MUC5AC) and mucin-2 (MUC2) in CRC cells by NOTCH3 and SMARCA4. Furthermore, NOTCH3 was found to control the expressions of MUC5AC and MUC2 in a SMARCA4-dependent manner. MUC5AC and MUC2, which encode two secreted mucins, are located on chromosome 11p15.5, and are linked to the development of MCA. This finding suggests that the interaction between NOTCH3 and SMARCA4 may be involved in MCA differentiation by jointly targeting MUC5AC and MUC2. Patients with MCA are often treated in accordance with CRC guidelines. Determining the relationship between NOTCH3 and SMARCA4 by demonstrating their interactions in the pathophysiology of MCA could provide novel therapeutic targets and help identify potential prognostic markers for MCA.

Effect of Different Vitamin D Levels on Cognitive Function in Aged Mice After Sevoflurane Anesthesia.

Although the biological relationship between vitamin D (VD) deficiency and cognitive function has been recognized by many scholars, the theoretical mechanisms involved are still not well-understood. In this study, we demonstrated the role of VD in alleviating the cognitive dysfunction in aged mice caused by sevoflurane anesthesia. Forty female C57BL/6 mice aged 12 months were selected for the experiment. VD (-) and VD (+) mouse models and sevoflurane anesthesia models were established. Mice were randomly divided into normal elderly group (NC group), normal aged mice + sevoflurane anesthesia treatment group (NS group), aged VD (-) mice + sevoflurane anesthesia treatment group [VD (-) group], and aged VD (+) + sevoflurane anesthesia treatment group [VD (+) group]. To compare the emergence time after sevoflurane anesthesia in aged mice with different levels of VD and to test the cognitive function of four groups through the water maze. Inflammatory factor expression and cholinergic activity in hippocampus tissue of all mice were measured at the end of behavioral tests. These data show that, low levels of VD aggravated the delayed emergence and cognitive dysfunction in aged mice caused by sevoflurane anesthesia, while higher levels of VD mitigated this impairment by enhancing cholinergic activity and reducing inflammatory factor expression in the hippocampus.

The clinical application value of phase angle of six parts in nutritional evaluation of tumor patients.

OBJECTIVES: The purpose of this study was to explore the clinical application value of phase angle (PA) of six parts in the nutritional evaluation and construct a prediction model for diagnosing malnutrition of tumor patients. METHODS: A total of 1129 patients with malignant tumors were analyzed retrospectively. The age, sex, tumor location and body mass index (BMI) of the patients were collected, and PA of six parts was measured. The Patient Subjective Global Assessment (PG-SGA) was used to evaluate the nutritional status of each patient. RESULTS: According to the PG-SGA, 66.5% (n = 750) of the patients were evaluated as malnourished. Patients under the age of 65 had higher PA values. The PA value of men was higher than that of women (except PA-RL). In different disease groups, the PA-RA and PA-TR values were significantly different. In our study, PA value increases with BMI and decreases with PG-SGA (except PG-SGA 0-1 group). Multivariate regression analysis indicates that the age (HR = 1.051, 95% CI 1.037-1.066, P < 0.001), BMI (HR = 0.885, 95% CI 0.849-0.924, P < 0.001), and PA-WB (HR = 0.615, 95% CI 0.546-0.692, P < 0.001) were independent significant predictors associated with malnutrition. The AUC of the prediction model is 0.7631 (p < 0.001), indicating that the model including age, BMI, and PA-WB has certain diagnostic value for the diagnosis of malnutrition. CONCLUSION: The PA-WB is an independent prognostic factor of malnutrition. The prediction model constructed by age, BMI, and PA-WB can be used as a useful tool for nutritional evaluation of tumor patients. TRIAL REGISTRATION: Clinical Trial No.: ChiCTR2100047858.