Genotype-phenotype correlation and founder effect analysis in southeast Chinese patients with sialidosis type I.

BACKGROUND: Sialidosis type 1 (ST-1) is a rare autosomal recessive disorder caused by mutation in the NEU1 gene. However, limited reports on ST-1 patients in the Chinese mainland are available. METHODS: This study reported the genetic and clinical characteristics of 10 ST-1 patients from southeastern China. A haplotype analysis was performed using 21 single nucleotide polymorphism (SNP) markers of 500 kb flanking the recurrent c.544 A > G in 8 families harboring the mutation. Furthermore, this study summarized and compared previously reported ST-1 patients from Taiwan and mainland China. RESULTS: Five mutations within NEU1 were found, including two novel ones c.557 A > G and c.799 C > T. The c.544 A > G mutation was most frequent and identified in 9 patients, 6 patients were homozygous for c.544 A > G. Haplotype analysis revealed a shared haplotype surrounding c.544 A > G was identified, suggesting a founder effect presenting in southeast Chinese population. Through detailed assessment, 52 ST-1 patients from 45 families from Taiwan and mainland China were included. Homozygous c.544 A > G was the most common genotype and found in 42.2% of the families, followed by the c.544 A > G/c.239 C > T compound genotype, which was observed in 22.2% of the families. ST-1 patients with the homozygous c.544 A > G mutation developed the disease at a later age and had a lower incidence of cherry-red spots significantly. CONCLUSION: The results contribute to gaps in the clinical and genetic features of ST-1 patients in southeastern mainland China and provide a deeper understanding of this disease to reduce misdiagnosis.

Propofol attenuates prostate cancer progression by upregulating TRHDE-AS1 expression, and METTL14 could mediate its m6A modification.

Propofol has become a microtubule-stabilizing drug for prostate cancer (PC) therapy, but propofol resistance impairs the therapeutic effect. This study aimed to explore the regulatory mechanism of propofol in the pathogenesis of PC through mechanisms involving N6-methyladenosine (m6A) modification. The changes in PC cell malignancy were evaluated by means of transwell, cell counting kit 8 (CCK-8), western blotting and tumour xenograft model assays. Long noncoding RNA TRHDE-AS1 and m6A methyltransferase METTL14 expression levels were determined via reverse transcription quantitative polymerase chain reaction (RT-qPCR). The m6A modification of TRHDE-AS1 which was mediated by METTL14 was confirmed by conducting methylated RNA immunoprecipitation (MeRIP) assay. We observed that propofol (200 µM) inhibited PC cell malignancy in vivo and in vitro, elucidating that it impaired cell proliferation, migration and tumour growth but induced apoptosis. TRHDE-AS1 expression was observed to be lower in PC cells and tissues, and propofol induced TRHDE-AS1 upregulation in PC cells. Propofol was capable of reversing the tumour-promoting effect of TRHDE-AS1 knockdown in PC cells. Additionally, METTL14 was upstream of TRHDE-AS1 to induce m6A modification of TRHDE-AS1 in PC cells. Collectively, our results show that propofol prevents PC progression by upregulating TRHDE-AS1 expression and METTL14 is involved in the m6A modification of TRHDE-AS1. These findings suggest that TRHDE-AS1 may be a potential therapeutic target for the improvement of propofol's therapeutic effect.

High-dose hyperfractionated simultaneous integrated boost radiotherapy versus standard-dose radiotherapy for limited-stage small-cell lung cancer in China: a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: For the past 20 years, twice-daily thoracic radiotherapy with concurrent chemotherapy has been the treatment of choice for limited-stage small-cell lung cancer (LS-SCLC), which has a poor prognosis. We aimed to assess the efficacy and safety of high-dose, accelerated, hyperfractionated, twice-daily thoracic radiotherapy (54 Gy in 30 fractions) versus standard-dose radiotherapy (45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. METHODS: This open-label, randomised, phase 3 trial was performed at 16 public hospitals in China. The key inclusion criteria were patients aged 18-70 years, with histologically or cytologically confirmed LS-SCLC, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and who were previously untreated or had received one course of cisplatin or carboplatin and etoposide. Eligible patients were randomly assigned (1:1) to receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions to the gross tumour volume or VMAT with a simultaneous integrated boost of 54 Gy in 30 fractions to the gross tumour volume starting 0-42 days after the first chemotherapy course. Both groups received 10 fractions of twice-daily thoracic radiotherapy per week. The planning target volume was 45 Gy in 30 fractions in both groups. Patients with responsive disease received prophylactic cranial radiotherapy (25 Gy in 10 fractions). Randomisation was performed using a centralised interactive web response system, stratified by ECOG performance status, disease stage, previous chemotherapy course, and chemotherapy choice. The primary outcome was overall survival in the intention-to-treat population. Safety was analysed in the as-treated population. This study was registered at ClinicalTrials.gov, NCT03214003. FINDINGS: From June 30, 2017, to April 6, 2021, 224 patients (102 [46%] females and 122 [54%] males; median age 64 years [IQR 58-68]) were enrolled and randomly assigned to the 54 Gy group (n=108) or 45 Gy (n=116) group. The median follow-up was 46 months (IQR 33-56). The median overall survival was significantly longer in the 54 Gy group (60·7 months [95% CI 49·2-62·0]) than in the 45 Gy group (39·5 months [27·5-51·4]; hazard ratio 0·55 [95% CI 0·37-0·72]; p=0·003). Treatment was tolerable, and the chemotherapy-related and radiotherapy-related toxicities were similar between the groups. The grade 3-4 radiotherapy toxicities were oesophagitis (14 [13%] of 108 patients in the 54 Gy group vs 14 [12%] of 116 patients in the 45 Gy group; p=0·84) and pneumonitis (five [5%] of 108 patients vs seven [6%] of 116 patients; p=0·663). Only one treatment-related death occurred in the 54 Gy group (myocardial infarction). The study was prematurely terminated by an independent data safety monitoring board on April 30, 2021, based on evidence of sufficient clinical benefit. INTERPRETATION: Compared with standard-dose thoracic radiotherapy (45 Gy), high-dose radiotherapy (54 Gy) improved overall survival without increasing toxicity in a cohort of patients aged 18-70 years with LS-SCLC. Our results support the use of twice-daily accelerated thoracic radiotherapy (54 Gy) with concurrent chemotherapy as an alternative first-line LS-SCLC treatment option. FUNDING: Chinese Society of Clinical Oncology-Linghang Cancer Research, the Wu Jieping Medical Foundation, and Clinical Research Fund For Distinguished Young Scholars of Peking University Cancer Hospital and Beijing Municipal Administration of Hospitals Incubating Program.

Dexmedetomidine facilitates autophagic flux to promote liver regeneration by suppressing GSK3ß activity in mouse partial hepatectomy.

INTRODUCTION: Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is widely used for sedation and anesthesia in patients undergoing hepatectomy. However, the effect of DEX on autophagic flux and liver regeneration remains unclear. OBJECTIVES: This study aimed to determine the role of DEX in hepatocyte autophagic flux and liver regeneration after PHx. METHODS: In mice, DEX was intraperitoneally injected 5 min before and 6 h after PHx. In vitro, DEX was co-incubated with culture medium for 24 h. Autophagic flux was detected by LC3-II and SQSTM1 expression levels in primary mouse hepatocytes and the proportion of red puncta in AML-12 cells transfected with FUGW-PK-hLC3 plasmid. Liver regeneration was assessed by cyclinD1 expression, Edu incorporation, H&E staining, ki67 immunostaining and liver/body ratios. Bafilomycin A1, si-GSK3ß and Flag-tagged GSK3ß, α2-ADR antagonist, GSK3ß inhibitor, AKT inhibitor were used to identify the role of GSK3ß in DEX-mediated autophagic flux and hepatocyte proliferation. RESULTS: Pre- and post-operative DEX treatment promoted liver regeneration after PHx, showing 12 h earlier than in DEX-untreated mice, accompanied by facilitated autophagic flux, which was completely abolished by bafilomycin A1 or α2-ADR antagonist. The suppression of GSK3ß activity by SB216763 and si-GSK3ß enhanced the effect of DEX on autophagic flux and liver regeneration, which was abolished by AKT inhibitor. CONCLUSION: Pre- and post-operative administration of DEX facilitates autophagic flux, leading to enhanced liver regeneration after partial hepatectomy through suppression of GSK3ß activity in an α2-ADR-dependent manner.

Clinical association between plan complexity and the local-recurrence-free-survival of non-small-cell lung cancer patients receiving stereotactic body radiation therapy.

PURPOSE: To investigate the clinical impact of plan complexity on the local recurrence-free survival (LRFS) of non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). METHODS: Data from 123 treatment plans for 113 NSCLC patients were analyzed. Plan-averaged beam modulation (PM), plan beam irregularity (PI), monitor unit/Gy (MU/Gy) and spherical disproportion (SD) were calculated. The γ passing rates (GPR) were measured using ArcCHECK 3D phantom with 2 %/2mm criteria. High complexity (HC) and low complexity (LC) groups were statistically stratified based on the aforementioned metrics, using cutoffs determined by their significance in correlation with survival time, as calculated using the R-3.6.1 packages. Kaplan-Meier analysis, Cox regression, and Random Survival Forest (RSF) models were employed for the analysis of local recurrence-free survival (LRFS). Propensity-score-matched pairs were generated to minimize bias in the analysis. RESULTS: The median follow-up time for all patients was 25.5 months (interquartile range 13.4-41.2). The prognostic capacity of PM was suggested using RSF, based on Variable Importance and Minimal Depth methods. The 1-, 2-, and 3-year LRFS rates in the HC group were significantly lower than those in the LC group (p = 0.023), when plan complexity was defined by PM. However, no significant difference was observed between the HC and LC groups when defined by other metrics (p > 0.05). All γ passing rates exceeded 90.5 %. CONCLUSIONS: This study revealed a significant association between higher PM and worse LRFS in NSCLC patients treated with SBRT. This finding offers additional clinical evidence supporting the potential optimization of pre-treatment quality assurance protocols.

P4HA2 hydroxylates SUFU to regulate the paracrine Hedgehog signaling and promote B-cell lymphoma progression.

Aberrations in the Hedgehog (Hh) signaling pathway are significantly prevailed in various cancers, including B-cell lymphoma. A critical facet of Hh signal transduction involves the dynamic regulation of the suppressor of fused homolog (SUFU)-glioma-associated oncogene homolog (GLI) complex within the kinesin family member 7 (KIF7)-supported ciliary tip compartment. However, the specific post-translational modifications of SUFU-GLI complex within this context have remained largely unexplored. Our study reveals a novel regulatory mechanism involving prolyl 4-hydroxylase 2 (P4HA2), which forms a complex with KIF7 and is essential for signal transduction of Hh pathway. We demonstrate that, upon Hh pathway activation, P4HA2 relocates alongside KIF7 to the ciliary tip. Here, it hydroxylates SUFU to inhibit its function, thus amplifying the Hh signaling. Moreover, the absence of P4HA2 significantly impedes B lymphoma progression. This effect can be attributed to the suppression of Hh signaling in stromal fibroblasts, resulting in decreased growth factors essential for malignant proliferation of B lymphoma cells. Our findings highlight the role of P4HA2-mediated hydroxylation in modulating Hh signaling and propose a novel stromal-targeted therapeutic strategy for B-cell lymphoma.

Melatonin alleviates septic ARDS by inhibiting NCOA4-mediated ferritinophagy in alveolar macrophages.

Ferroptosis is a novel form of programmed cell death which can exacerbate lung injury in septic acute respiratory distress syndrome (ARDS). Alveolar macrophages, crucial innate immune cells, play a pivotal role in the pathogenesis of ARDS. Ferritinophagy is a process of ferritin degradation mediated by nuclear receptor coactivator 4 (NCOA4) which releases large amounts of iron ions thus promoting ferroptosis. Recent evidence revealed that inhibiting macrophage ferroptosis can effectively attenuate pulmonary inflammatory injury. Melatonin (MT), an endogenous neurohormone, has antioxidant and anti-inflammatory effects and can reduce septic ARDS. However, it is not clear whether MT's pulmonary protective effect is related to the inhibition of macrophage ferritinophagy. Our in vitro experiments demonstrated that MT decreased intracellular malondialdehyde (MDA), Fe2+, and lipid peroxidation levels, increased glutathione (GSH) levels and cell proliferation, and upregulated glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) protein levels in LPS-treated macrophages. Mechanistically, the antiferroptotic effect of MT on LPS-treated macrophages was significantly compromised by the overexpression of NCOA4. Our in vivo experiments revealed that MT alleviated the protein expression of NCOA4 and FTH1 in the alveolar macrophages of septic mice. Furthermore, MT improved lipid peroxidation and mitigated damage in alveolar macrophages and lung tissue, ultimately increasing the survival rates of septic mice. These findings indicate that MT can inhibit ferroptosis in an NCOA4-mediated ferritinophagy manner, thereby ameliorating septic ARDS.

Dynamic changes in body composition during XELOX/SOX chemotherapy in patients with gastric cancer.

Objectives: In this study, we compared the dynamic changes in body composition during XELOX/SOX chemotherapy in patients with gastric cancer. Furthermore, we investigated the potential impact of these changes on the occurrence of toxic side effects. Methods: Patients with gastric cancer who received adjuvant or first-line XELOX/SOX chemotherapy between January 2020 and June 2023 were enrolled. The Brief Conghua Scale was used to assess energy intake, and nutritional management was carried out with reference to the Chinese Guidelines for Nutritional Therapy of Cancer 2020. The NRS 2002 Nutritional Risk Screening Scale, PG-SGA scale, bioelectrical impedance analysis, and dynamic changes in lumbar 3 vertebral skeletal muscle index were compared between baseline and post-chemotherapy in the study. The neutropenia was evaluated using the Common Terminology Criteria for Adverse Events V.5.0, developed by the National Institutes of Health. Results: Dynamic follow-up was completed in 39 cases, with a mean follow-up time of 117.62 ± 43.38 days. The incidence of sarcopenia increased significantly after chemotherapy, escalating from 46.2% to 51.3%. After chemotherapy, the mean L3SMI decreased from 36.00 cm2/m2 to 34.99 cm2/m2. Furthermore, when compared to pre-chemotherapy values, the body composition indexes body mass index (BMI), SL3, fat mass free index (FFMI), lean body mass (LBM), and body surface area (BSA) were significantly reduced after chemotherapy. Regardless of baseline or post-chemotherapy status, the incidence of grade ≥ 3 neutropenia was significantly higher in the sarcopenia group than in the non-sarcopenia group. Furthermore, when the skeletal muscle index decreased during chemotherapy, the incidence of grade ≥ 3 neutropenia was significantly higher in both the sarcopenia and non-sarcopenia groups compared to baseline. When the incidence of grade ≥ 3 neutropenia in the post-chemotherapy sarcopenia group was compared to baseline status, the increase was significantly higher in the sarcopenia group than in the maintenance/increase group. Conclusions: Skeletal muscle mass decreased progressively during XELOX/SOX chemotherapy in gastric cancer patients, followed by a higher incidence of grade ≥ 3 neutropenia.

A prospective randomized controlled clinical trial investigating the efficacy of low-dose olanzapine in preventing nausea and vomiting associated with oxaliplatin-based and irinotecan-based chemotherapy.

OBJECTIVE: The aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) among female patients diagnosed with gastrointestinal tract tumors. METHODS: Patients undergoing the oxaliplatin/irinotecan chemotherapy regimen were enrolled in this prospective controlled study. The olanzapine group received a 5 mg dosage of olanzapine along with palonosetron and dexamethasone, while the control group received a standard two-combination regimen consisting of dexamethasone and palonosetron. The primary endpoints included the total protection (TP) rates for the entire age group and the subgroup aged 60 years and above. Secondary endpoints encompassed the total protection rates during the acute and delayed phases within the two age brackets, as well as the total control (TC) rates and complete remission (CR) rates across all three phases (total, acute, and delayed). Additionally, the study involved the assessment of quality of life and the collection of adverse events associated with the interventions. RESULTS: 1) Regarding the primary endpoint, the total phase TP rates within both the entire age group and the age group exceeding 60 years demonstrated superiority in the olanzapine group when compared to the control group (66.7% vs 37.25%, P = 0.003; 68.8% vs 44.4%, P = 0.044). 2) In terms of secondary endpoints, the olanzapine group exhibited superior acute phase TP rates in both age brackets when compared to the control group (P < 0.05). The olanzapine group also demonstrated higher delayed-phase TP rates, TC rates across all three phases, and CR rates within the two age brackets, although the differences were not statistically significant (P > 0.05). Furthermore, the quality of life in the olanzapine group surpassed that of the control group for both age brackets (P < 0.05), characterized by enhanced appetite and a higher incidence of drowsiness in the patients treated with olanzapine when compared to those in the control group (P < 0.05). CONCLUSION: Olanzapine can enhance CINV induced by MEC regimen in female patients across all age groups, including the elderly, and therefore improve the quality of life for these patients. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/index.html , identifier: ChiCTR20000368269, 25/08/2020.

A randomized trial evaluating the association between related gene polymorphism and nausea and vomiting induced by cisplatin multi-day chemotherapy.

PURPOSE: We aim to investigate the correlation between gene polymorphisms and cisplatin chemotherapy-induced nausea and vomiting (CINV), which was prevented by olanzapine or aprepitant triple antiemetic regimen. METHODS: Before chemotherapy, the blood samples of 89 malignant tumor patients who received multi-day chemotherapy with cisplatin were collected for sequencing and typing. As there were duplicate patients enrolled in different chemotherapy cycles, there were a total of 190 cases. The patients were divided into two groups randomly, who received the triple antiemetic regimen of olanzapine or aprepitant combined with 5-HT3RA and dexamethasone. The main evaluation indicators were the total protection (TP) rate in the acute phase (0-24 h), the delayed phase (25-120 h) and the overall phase (0-120 h). RESULTS: Univariate analysis was performed on genetic loci that reached H-W balance with TP. In the olanzapine group, increased TP in the acute phase was associated with HTR3A rs1176719 non-GG (P < 0.05) genotype etc. Increased TP in the delayed phase was associated with HTR3A rs1176719 non-GG (P < 0.05) genotype etc. In the aprepitant group, increased TP in the acute phase was associated with the MTHFR rs1801131 TT (P < 0.05) genotype etc. Increased TP in the delayed phase was associated with HTR3A rs1062613 CC (P < 0.05) genetype ect. Multivariate Logistic regression analysis showed that HTR3B rs7943062GG (P < 0.05) genotype etc. were correlated with increased TP in the delayed phase. MTHFR rs1801131TT genotype was associated with increased TP in the acute phase (P < 0.05) and delayed phase (P < 0.05). CONCLUSION: This study found that gene polymorphisms, including HTR3B (rs1062613, rs1176719, rs2276303), HTR3B (rs45460698, rs7943062), HTR3C (rs6766410), ERCC1 (rs3212986), ERCC4 (rs744154) and MTHFR(rs1801131), may be independent prognostic factors for CINV.

Melatonin Alleviates Acute Respiratory Distress Syndrome by Inhibiting Alveolar Macrophage NLRP3 Inflammasomes Through the ROS/HIF-1α/GLUT1 Pathway.

Sepsis-induced acute respiratory distress syndrome (ARDS) is a devastating clinically severe respiratory disorder, and no effective therapy is available. Melatonin (MEL), an endogenous neurohormone, has shown great promise in alleviating sepsis-induced ARDS, but the underlying molecular mechanism remains unclear. Using a lipopolysaccharide (LPS)-treated mouse alveolar macrophage cell line (MH-S) model, we found that MEL significantly inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation in LPS-treated macrophages, whereas this inhibitory effect of MEL was weakened in MH-S cells transfected with glucose transporter 1 (GLUT1) overexpressing lentivirus. Further experiments showed that MEL downregulated GLUT1 via inhibition of hypoxia-inducible factor 1 (HIF-1α). Notably, hydrogen peroxide (H2O2), a donor of reactive oxygen species (ROS), significantly increased the level of intracellular ROS and inhibited the regulatory effect of MEL on the HIF-1α/GLUT1 pathway. Interestingly, the protective effect of MEL was attenuated after the knockdown of melatonin receptor 1A (MT1) in MH-S cells. We also confirmed in vivo that MEL effectively downregulated the HIF-1α/GLUT1/NLRP3 pathway in the lung tissue of LPS-treated mice, as well as significantly ameliorated LPS-induced lung injury and improved survival in mice. Collectively, these findings revealed that MEL regulates the activation of the ROS/HIF-1α/GLUT1/NLRP3 pathway in alveolar macrophages via the MT1 receptor, further alleviating sepsis-induced ARDS.

Mitochondrial energy metabolism correlates with an immunosuppressive tumor microenvironment and poor prognosis in esophageal squamous cell carcinoma.

Background: Reprogramming of mitochondrial energy metabolism (MEM) is an important hallmark of tumorigenesis and cancer progression. Currently, there are no studies that have examined MEM in the tumor microenvironment (TME) of esophageal squamous cell carcinoma (ESCC), and relevant drug targets have not yet been identified. Methods: The ESCC single-cell transcriptome sequencing dataset, GSE145370, was analyzed, using the AUCell R package to screen for MEM-related genes in high-scoring cell populations. Monocle was used to infer cell differentiation and CellChat to analyze intercellular communication networks. Finally, transcription levels of prognostic genes were analyzed using a complementary DNA microarray from 15 patients with ESCC. Results: A total of 121 MEM-related genes were differentially expressed in seven cell populations in the TME, and four high-scoring cell populations were identified. As a result, the MEM state of T cells is significantly different from that of macrophages and epithelial cells, and signaling communication between T cells and macrophages is the strongest. These findings suggest that immunosuppression is related to metabolic reprogramming. Additionally, marker genes of high-scoring cells and the top10 receptor-ligand pairs may become new targets for rebuilding immune cell metabolism. Furthermore, the 4-MEM gene risk signature had good predictive power for overall survival and drug sensitivity. MAP1LC3A, APOE, APPL1, and NDUFA are novel potential immunotherapeutic targets for remodeling the TME. Finally, teal-time quantitative PCR was used to verify APOE and MAP1LC3A expression. Conclusion: MEM heterogeneity was observed in the immunosupressive TME of ESCC. Prognostic models based on MEM-related genes are helpful for screening early treatment patient groups and realizing personalized treatment. APOE and MAP1LC3A are potential target genes for the development of anti-ESCC drugs based on MEM-related genes.

Low Dose Olanzapine in the Prevention and Treatment of Carboplatin Induced Nausea and Vomiting: A Prospective Clinical Randomized Controlled Trial.

OBJECTIVE: This study aimed to determine the effectiveness and safety of 5 mg olanzapine (OLZ) in preventing vomiting and nausea caused by carboplatin chemotherapy. METHODS: All patients with malignant tumors (n = 113) who underwent Carboplatin (AUC ≥ 5) treatment were randomly categorized into two groups: the standard group (n = 57) and the OLZ regimen (n = 56). The major endpoints of the trial were the TC (total control) between two groups during the OP (Overall phase, 0-120 hours), DP (delayed phase, 25-120 hours), and AP (acute phase, 0-24 hours). The secondary endpoints were the CR (complete response) and TP (total protection) during AP, OP, and DP. The time of first vomiting was compared between the two groups using Kaplan-Meier curves. The impact of CINV on the quality of life was assessed by the Functional Living Index-Emesis (FLIE). OLZ-related side effects were also recorded. RESULTS: (1) The primary endpoint TC rates were more favorable in the OLZ regimen group than in the standard group during the AP 87.50% (49/56) vs. 63.15% (36/57) P = 0.003, OP 62.50% (35/56) vs. 31.57% (18/57) P = 0.001, and DP 64.28% (36/56) vs. 33.33% (19/57) P = 0.001. (2) The secondary endpoints TP were 82.14% (46/56) vs. 63.15% (36/57), P = 0.024, 83.92% (47/56) vs. 63.15% (36/57). P = 0.012 during the DP and OP. There was no statistical significance during AP between the two groups. The CR rates were not statistically different between the two groups during the three periods, P > 0.05; (3) The first vomiting time in the OLZ group was delayed compared with the standard group (P = 0.248). The effect on life quality (score ≥ 108) assessed by FLIE was 62.50% vs. 43.48% between the two groups, P < 0.05. The primary side effects of OLZ are fatigue (85%) and somnolence (75%). The primary side effects of the standard group are fatigue (77%) and loss of appetite (85%). CONCLUSION: The 5 mg OLZ-based triple antiemetic regimen is effective and safe in preventing vomiting and nausea induced by Carboplatin.

A novel immune-related prognostic signature based on Chemoradiotherapy sensitivity predicts long-term survival in patients with esophageal squamous cell carcinoma.

Background: There is a heterogenous clinical response following chemoradiotherapy (CRT) in esophageal squamous cell carcinoma (ESCC). Therefore, we aimed to study signaling pathway genes that affect CRT sensitivity and prognosis. Methods: Gene expression analyses were performed in the GEO and TCGA datasets. A immunohistochemistry (IHC) analysis was performed in pretreatment biopsies. Results: MMP13 was found to be highly expressed in the "Pathologic Complete Response (pCR)" and "Complete Remission (CR)" and "Alive" groups. Th17 cells and MMP9/13 showed a negative correlation in immune infiltration analysis. In GSEA analysis, IL-4 and IL-13 signaling pathways were highly enriched in patients exhibiting high MMP expression in pCR and CR groups. IHC results suggested higher MMP13 & IL-4 and lower IL-17A & RORC expression in the CR group compared to the 0.70, and the model could well distinguish high-risk and low-risk subgroups. Conclusion: The above results may provide guidance for developing novel treatment and prognostic strategies in ESCC patients.

A Bibliometric Analysis of Mesenchymal Stem Cell-Derived Exosomes in Acute Lung Injury/Acute Respiratory Distress Syndrome from 2013 to 2022.

Background: Mesenchymal stem cell-derived exosomes (MSC-exosomes) have been found to effectively improve the systemic inflammatory response caused by acute lung injury and acute respiratory distress syndrome (ALI/ARDS), regulate systemic immune disorders, and help injured cells repair. The purpose of this study was to take a holistic view of the current status and trends of MSC-exosomes research in ALI/ARDS. Methods: Bibliometrix, Citespace and VOSviewer software were used for bibliometric analysis of the data. We analysed the world trends, country distribution, institution contribution, most relevant journals and authors, research hotspots, and research hotspots related to Coronavirus Disease 2019 (COVID-19) based on the data collected. Results: China possessed the largest number of publications, while the USA had the highest H-index and the number of citations. Both China and the USA had a high influence in this research field. The largest number of publications in the field of MSC-exosomes and ALI/ARDS were mainly from the University of California system. Stem Cell Research & Therapy published the largest number of papers in this scope. The author with the greatest contribution was LEE JW, and ZHU YG published an article in Stem Cell with the highest local citation score. The most frequent keyword and the latest research hotspot were "NF-κB" and "Coronavirus Disease 2019". Furthermore, our bibliometric analysis results demonstrated that MSC-exosomes intervention and treatment can effectively alleviate the inflammatory response caused by ALI/ARDS. Conclusion: Our bibliometric study suggested the USA and China have a strong influence in this field. COVID-19-induced ALI/ARDS had become a hot topic of research.

Hsa_Circ_0104206 is An Oncogenic circRNA in Colon Cancer by Targeting Mir-188-3p/CCNA2 Axis.

The identification of specific biomarkers is essential to improve cancer therapy, and circular RNAs (circRNAs) have great potency to be biomarkers. We harbor the goal to unveil the role of circ_0104206 in colon cancer (CC). The relative expressions of circ_0104206, miR-188-3p and CCNA2 in different groups were studied using real-time quantitative PCR (qPCR) or western blotting. The proliferative and migratory capacity of cancer cells were monitored via CCK-8, colony formation and Transwell assays. The transplanted tumor models were generated to analyze circ_0104206's role in vivo. The putative relationship between miR-188-3p and circ_0104206 or CCNA2 by bioinformatics tools was testified through dual-luciferase or RIP assay. The abnormal elevation of circ_0104206 expression was observed in CC. Circ_0104206 silencing repressed CC cell proliferative and migratory behaviors, and also decelerated tumor development in animal models. MiR-188-3p was directly targeted by circ_0104206, and its inhibitor had the ability to reverse the anticancer effects of circ_0104206 silencing on CC cells. CCNA2 was a target downstream of circ_0104206/miR-188-3p network. Moreover, the repressive effects of CCNA2 absence on cell proliferation and migration were attenuated by miR-188-3p inhibitor. In conclusion, Circ_0104206 plays oncogenic roles in CC via the implication of miR-188-3p/CCNA2 network, which further discloses CC pathogenesis and supplies potential markers for CC.

Myelosuppression Caused by Nanoparticle Albumin-Bound Paclitaxel in the Northern Chinese Population and the Role of Body Composition.

The aim of this study was to examine the relationship between lean body mass (LBM) and the incidence and severity of neutropenia in patients with malignant tumors from Northern China who have received nanoparticle albumin-bound paclitaxel. Twenty-six patients with pathologically confirmed malignant tumors were prospectively included in this study. These 26 patients were divided into Group A (sarcopenia) and Group B (nonsarcopenia). Group A comprised 50% (13/26) of the patients, while Group B comprised the other 50% (13/26). There was no statistically significant difference between both groups in terms of body surface area (P = .052). The incidence of neutropenia in Group A was 76.9% compared to 61.5% in Group B (P = .0673). The incidence of Grade 3 and severe neutropenia was 76.9% versus 61.5% in Groups A and B, respectively (P = .645). These 26 patients were divided into Groups 1 and 2 based on the administered nab-paclitaxel dose per kilogram of LBM, with both groups receiving a body surface area dose of 260 mg/m2 . Group 1 received a nab-paclitaxel dose of 14.19 mg/kg of LBM, whereas Group 2 received 11.37 mg/kg of LBM. In Group 1, the incidence of neutropenia was 71.4%, whereas it was 66.7% in Group 2. Grade 3 or higher neutropenia incidence was 28.6% in Group 1 versus 16.7% in Group 2. Patients with sarcopenia in northern China experienced a higher incidence of severe neutropenia after receiving nab-paclitaxel than patients without sarcopenia. Higher drug dose intensity per unit of LBM may be a contributing factor.

4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway.

Acute respiratory distress syndrome (ARDS) is a high-mortality pulmonary disorder characterized by an intense inflammatory response and a cytokine storm. As of yet, there is no proven effective therapy for ARDS. Itaconate, an immunomodulatory derivative accumulated during inflammatory macrophage activation, has attracted widespread attention for its potent anti-inflammatory and anti-oxidative properties. This study pointed to explore the protective impacts of 4-octyl itaconate (4-OI) on ARDS. The results showed that lung injury was attenuated markedly after 4-OI pre-treatment, as represented by decreased pulmonary edema, inflammatory cell infiltration, and production of inflammatory factors. LPS stimulation induced NLRP3-mediated pyroptosis in vitro and in vivo, as represented by the cleavage of gasdermin D (GSDMD), IL-18 and IL-1ß release, and these changes could be prevented by 4-OI pretreatment. Mechanistically, 4-OI eliminated mitochondrial reactive oxygen species (mtROS) and mtDNA escaping to the cytosol through the opening mitochondrial permeability transition pore (mPTP) in alveolar macrophages (AMs) under oxidative stress. In addition, 4-OI pretreatment markedly downregulated cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) expression, and interferon regulatory factor 3 (IRF3) phosphorylation in vitro and in vivo. Meanwhile, inhibition of STING/IRF3 pathway alleviated NLRP3-mediated pyroptosis induced by LPS in vitro. Taken together, this study indicated that 4-OI ameliorated ARDS by rescuing mitochondrial dysfunction and inhibiting NLRP3-mediated macrophage pyroptosis in a STING/IRF3-dependent manner, which further revealed the potential mechanism of itaconate in preventing inflammatory diseases.

Pt/MXene-Based Flexible Wearable Non-Enzymatic Electrochemical Sensor for Continuous Glucose Detection in Sweat.

Wearable non-invasive sensors facilitate the continuous measurement of glucose in sweat for the treatment and management of diabetes. However, the catalysis of glucose and sweat sampling are challenges in the development of efficient wearable glucose sensors. Herein, we report a flexible wearable non-enzymatic electrochemical sensor for continuous glucose detection in sweat. We synthesized a catalyst (Pt/MXene) by the hybridization of Pt nanoparticles onto MXene (Ti3C2Tx) nanosheets with a broad linear range of glucose detection (0-8 mmol/L) under neutral conditions. Furthermore, we optimized the structure of the sensor by immobilizing Pt/MXene with a conductive hydrogel to enhance the stability of the sensor. Based on Pt/MXene and the optimized structure, we fabricated a flexible wearable glucose sensor by integrating a microfluidic patch for sweat collection onto a flexible sensor. We evaluated the utility of the sensor for the detection of glucose in sweat, and the sensor could detect the glucose change with the replenishment and consumption of energy by the body, and a similar trend was observed in the blood. An in vivo glucose test in sweat indicated that the fabricated sensor is promising for the continuous measurement of glucose, which is essential for the treatment and management of diabetes.

Marine-Derived Natural Product HDYL-GQQ-495 Targets P62 to Inhibit Autophagy.

Autophagy is widely implicated in pathophysiological processes such as tumors and metabolic and neurodegenerative disorders, making it an attractive target for drug discovery. Several chemical screening approaches have been developed to uncover autophagy-modulating compounds. However, the modulation capacity of marine compounds with significant pharmacological activities is largely unknown. We constructed an EGFPKI-LC3B cell line using the CRISPR/Cas9 knock-in strategy in which green fluorescence indicated endogenous autophagy regulation. Using this cell line, we screened a compound library of approximately 500 marine natural products and analogues to investigate molecules that altered the EGFP fluorescence. We identified eight potential candidates that enhanced EGFP fluorescence, and HDYL-GQQ-495 was the leading one. Further validation with immunoblotting demonstrated that cleaved LC3 was increased in dose- and time-dependent manners, and the autophagy adaptor P62 showed oligomerization after HDYL-GQQ-495 treatment. We also demonstrated that HDYL-GQQ-495 treatment caused autophagy substrate aggregation, which indicated that HDYL-GQQ-495 serves as an autophagy inhibitor. Furthermore, HDYL-GQQ-495 induced Gasdermin E (GSDME) cleavage and promoted pyroptosis. Moreover, HDYL-GQQ-495 directly combined with P62 to induce P62 polymerization. In P62 knockout cells, the cleavage of LC3 or GSDME was blocked after HDYL-GQQ-495 treatment. The EGFPKI-LC3B cell line was an effective tool for autophagy modulator screening. Using this tool, we found a novel marine-derived compound, HDYL-GQQ-495, targeting P62 to inhibit autophagy and promote pyroptosis.