MicroRNA-126 (MiR-126): key roles in related diseases.

In eukaryotes such as humans, some non-coding single-stranded RNAs (ncRNAs) help to regulate the pre- and post-transcriptional expression of certain genes, which in turn control many important physiological processes, such as cell proliferation, distinctions, invasion, angiogenesis, and embryonic development. microRNA-126 is an important member of these miRNAs that can be directly or indirectly involved in the control of angiogenesis. Recently, numerous studies have expounded that microRNA-126 can inhibit or promote angiogenesis as well as attenuate inflammatory responses through complex molecular mechanisms. As such, it serves as a biomarker or potential therapeutic target for the prediction, diagnosis, and treatment of relevant diseases. In this review, we present the advancements in research regarding microRNA-126's role in the diagnosis and treatment of related diseases, aiming to provide innovative therapeutic options for the diagnosis and treatment of clinically relevant diseases.

Perioperative Treatment with Rivaroxaban and Dabigatran on Changes of Coagulation and Platelet Activation Biomarkers following Left Atrial Appendage Closure.

Insufficient data exist regarding the investigation of the impact of novel oral anticoagulants (NOACs) on coagulation activation biomarkers in the context of left atrial appendage closure (LAAC) and device-related thrombosis (DRT). The study was designed to investigate the changes and presence of coagulation activation biomarkers between different antithrombotic strategies following LAAC. A total of 120 nonvalvular atrial fibrillation patients intolerant of long-term anticoagulants, who underwent successful WATCHMAN closure implantation, were enrolled (rivaroxaban, n = 82; dabigatran, n = 38). Blood samples were obtained from left atrium (LA) and left atrial appendage (LAA) during the operation and fasting blood samples on the same day of LAAC and 45 days after discharge. The biochemical indicators, thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), von Willebrand factor (vWF), and CD40 ligand (CD40L), were measured by enzyme-linked immunosorbent assay. The primary endpoints of this study were the efficacy and safety characteristics of different antithrombotic strategies, including DRT incidence, stroke or transient ischemic attack, systemic embolism, and clinical major and nonmajor bleeding complications during the follow-up of 180 days. The results revealed that TAT, vWF, sP-selectin, and CD40L levels in vein were significantly reduced by 2.4% (p = 0.043), 5.0% (p < 0.001), 8.7% (p < 0.001), and 2.5% (p = 0.043) from their baseline levels after rivaroxaban treatment. Conversely, no significant changes were detected in the dabigatran group. Furthermore, the plasma levels of platelet activation biomarkers (CD40L and sP-selectin) in both LA and LAA groups were significantly lower after anticoagulation with rivaroxaban, as compared to dabigatran treatment (CD40L: 554.62 ± 155.54 vs. 445.02 ± 130.04 for LA p = 0.0013, 578.51 ± 156.28 vs. 480.13 ± 164.37 for LAA p = 0.0052; sP-selectin: 2849.07 ± 846.69 vs. 2225.54 ± 799.96 for LA p = 0.0105, 2915.52 ± 1402.40 vs. 2203.41 ± 1061.67 for LAA p = 0.0022). Notably, the present study suggests that rivaroxaban may be more effective in the prevention of DRT for patients undergoing LAAC.

Surgical procedure and recurrence of upper urinary tract stone: a national-wide study based on hospitalized patients.

PURPOSE: This study aimed to investigate the influence of surgical intervention on recurrence risk of upper urinary tract stone and compare the medical burden of various surgical procedures. METHODS: This study analyzed data from patients with upper urinary tract stone extracted from a national database of hospitalized patients in China, from January 2013 to December 2018. Surgical recurrence was defined as patients experience surgical procedures for upper urinary tract stone again with a time interval over 90 days. Associations of surgical procedures with surgical recurrence were evaluated by Cox regression. RESULTS: In total, 556,217 patients with upper urinary tract stone were included in the present analysis. The mean age of the population was 49.9 ± 13.1 years and 64.1% were men. During a median follow-up of 2.7 years (IQR 1.5-4.0 years), 23,012 patients (4.1%) had surgical recurrence with an incidence rate of 14.9 per 1000 person-years. Compared to patients receiving open surgery, ESWL (HR, 1.59; 95% CI 1.49-1.70), URS (HR, 1.38; 95% CI 1.31-1.45), and PCNL (HR, 1.11; 95% CI 1.06-1.18) showed a greater risk for surgical recurrence. Patients receiving ESWL had the shortest hospital stay length and the lowest cost among the 4 procedures. CONCLUSIONS: Compared with open surgery, ESWL, URS, and PCNL are associated with higher risks of surgical recurrence for upper urinary tract stone, while ESWL showed the least medical burden including both expenditure and hospital stay length. How to keep balance of intervention efficacy and medical expenditure is an important issue to be weighed cautiously in clinic practice and studied more in the future.

Effects of Traditional Chinese Medicine "Fuzheng Qingdu Decoction" on Autonomic Function and Cancer-Related Symptoms in Patients with Advanced Gastric Cancer undergoing Chemotherapy: A Controlled Trial.

OBJECTIVE: To evaluate the effects of Fuzheng Qingdu Decoction (FZQDD) on the autonomic function and cancer-related symptoms of patients with advanced gastric cancer undergoing chemotherapy to verify its clinical efficacy. METHODS: Sixty-two patients with stage III or IV gastric cancer were included in this study. The patients were divided into 2 groups: the chemotherapy (33 patients) and chemotherapy with FZQDD (29 patients) groups. The primary outcome was the autonomic function of the patients before and after the interventions. The parameters that were used to assess autonomic function were deceleration capacity (DC) and acceleration capacity (AC) of heart rate and heart rate variability (HRV), which comprised standard deviation of the normal-normal interval (SDNN), root mean square of successive interval differences (RMSSD), low-frequency power (LF), high-frequency power (HF), total power (TP), and LF-HF ratio. The secondary outcomes were cancer-related symptoms and the quality of life. RESULTS: DC and HRV parameters (ie, SDNN, RMSSD, LF, HF, and TP) were significantly decreased in the chemotherapy group; however, AC significantly increased after the interventions. No significant differences were observed in the DC, AC, and HRV parameters before and after the interventions in the chemotherapy with FZQDD group. Nevertheless, the changes in DC, AC, and HRV parameters (SDNN, RMSSD, HF, and TP) before and after the interventions were statistically significant between both the groups. FZQDD significantly improved the cancer-related symptoms and the quality of life of the patients. CONCLUSIONS: Oxaliplatin combined with S-1 (tegafur, gimeracil, and oteracil potassium) can impair autonomic modulation in patients with advanced gastric cancer. FZQDD can alleviate autonomic dysfunction by increasing the parasympathetic activity and decreasing the sympathetic tone, helping patients restore the dynamic sympathovagal balance, and significantly improving the cancer-related symptoms and the quality of life of patients.

Proansamycin B derivatives from the post-PKS modification gene deletion mutant of Amycolatopsis mediterranei S699.

Ten new proansamycin B congeners (1-10) together with one known (11) were isolated and characterized on the basis of 1D and 2D NMR spectroscopic and HRESIMS data from the Amycolatopsis mediterranei S699 ΔPM::rifR+rif-orf19 mutant. Compounds 8 and 9 featured with six-membered ring and five-membered ring hemiketal, respectively. Compounds 1, 2, and 9 displayed antibacterial activity against MRSA (methicillin-resistant Staphylococcus aureus), with the MIC (minimal inhibitory concentration) values of 64, 8, and 128 µg/mL, respectively. Compound 1 showed significant cytotoxicity against MDA-MB-231, HepG2 and Panc-1 cell lines with IC50 (half maximal inhibitory concentration) values of 2.3 ± 0.2, 2.5 ± 0.3 and 3.8 ± 0.5 µM, respectively.

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial.

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.

Role of YES1 signaling in tumor therapy resistance.

YES proto-oncogene 1 (YES1) is an SRC family kinase (SFK) that plays a key role in cancer cell proliferation, adhesion, invasion, survival, and angiogenesis during tumorigenesis and tumor development. Reports suggest that YES1 amplification is associated with resistance to chemotherapeutic drugs and tyrosine kinase inhibitors (TKIs) in human malignancies. However, the mechanisms of drug resistance have not been fully elucidated. In this article, we review the literature on YES1 and discuss the implications of YES1 signaling for targeted therapy and chemotherapy resistance in malignancies. Moreover, recent advances in targeted therapy for YES1-amplified malignancies are summarized. Finally, we conclude that targeting YES1 may reverse drug resistance and serve as a valuable tumor treatment strategy.

Promoting the application of pediatric radiomics via an integrated medical engineering approach.

Radiomics is widely used in adult tumors but has been rarely applied to the field of pediatrics. Promoting the application of radiomics in pediatric diseases, especially in the early diagnosis and stratified treatment of tumors, is of great value to the realization of the WHO 2030 "Global Initiative for Childhood Cancer." This paper discusses the general characteristics of radiomics, the particularity of its application to pediatric diseases, and the current status and prospects of pediatric radiomics. Radiomics is a data-driven science, and the combination of medicine and engineering plays a decisive role in improving data quality, data diversity, and sample size. Compared with adult radiomics, pediatric radiomics is significantly different in data type, disease spectrum, disease staging, and progression. Some progress has been made in the identification, classification, stratification, survival prediction, and prognosis of tumor diseases. In the future, big data applications from multiple centers and cross-talent training should be strengthened to improve the benefits for clinical workers and children.

Prognostic role of short-term heart rate variability and deceleration/acceleration capacities of heart rate in extensive-stage small cell lung cancer.

Background: Prior research suggests that autonomic modulation investigated by heart rate variability (HRV) might act as a novel predictive biomarker for cancer prognosis, such as in breast cancer and pancreatic cancer. It is not clear whether there is a correlation between autonomic modulation and prognosis in patients with extensive-stage small cell lung cancer (ES-SCLC). Therefore, the purpose of the study was to examine the association between short-term HRV, deceleration capacity (DC) and acceleration capacity (AC) of heart rate and overall survival in patients with ES-SCLC. Methods: We recruited 40 patients with ES-SCLC, and 39 were included in the final analysis. A 5-min resting electrocardiogram of patients with ES-SCLC was collected using a microelectrocardiogram recorder to analyse short-term HRV, DC and AC. The following HRV parameters were used: standard deviation of the normal-normal intervals (SDNN) and root mean square of successive interval differences (RMSSD). Overall survival of patients with ES-SCLC was defined as time from the date of electrocardiogram measurement to the date of death or the last follow-up. Follow-up was last performed on 07 June 2023. There was a median follow-up time of 42.2 months. Results: Univariate analysis revealed that the HRV parameter SDNN, as well as DC significantly predicted the overall survival of ES-SCLC patients (all p < 0.05). Multivariate analysis showed that the HRV parameters SDNN (hazard ratio = 5.254, 95% CI: 1.817-15.189, p = 0.002), RMSSD (hazard ratio = 3.024, 95% CI: 1.093-8.372, p = 0.033), as well as DC (hazard ratio = 3.909, 95% CI: 1.353-11.293, p = 0.012) were independent prognostic factors in ES-SCLC patients. Conclusion: Decreased HRV parameters (SDNN, RMSSD) and DC are independently associated with shorter overall survival in ES-SCLC patients. Autonomic nervous system function (assessed based on HRV and DC) may be a new biomarker for evaluating the prognosis of patients with ES-SCLC.

Changes in T lymphocyte subsets predict the efficacy of atezolizumab in advanced non-small cell lung cancer: a retrospective study.

Background: It has remained unclear how programmed cell death ligand 1 (PD-L1) inhibitors affect peripheral blood lymphocyte (PBL) subsets in patients with advanced non-small cell lung cancer (NSCLC). This study assessed the predictive and prognostic value of PBL subsets in patients with advanced NSCLC who were treated with atezolizumab. Methods: A total of 30 patients with advanced NSCLC treated with atezolizumab were selected as the observation group, and 30 healthy individuals were chosen as the control group during same period. Flow cytometry was used to detect lymphocyte subsets before and after treatment. The relationship between the changes of lymphocyte subsets and atezolizumab in the treatment of NSCLC was analyzed and calculated. Results: Before treatment, compared with the control group, the number of CD3+, CD4+ T, and CD4+/CD8+ indexes in the observation group were significantly decreased, whereas the level of CD8+ was significantly increased. The number of CD3+, CD4+ T, and CD4+/CD8+ indexes gradually increased with the process of atezolizumab treatment, whereas the number of CD8+ T gradually decreased. After the 4 cycles, the number of CD3+, CD4+ T, and CD4+/CD8+ indexes were significantly increased, and the number of CD8+ was significantly decreased. In the observation group, 22 patients achieved partial response (PR)/stable disease (SD) and 8 patients achieved progressive disease (PD) after 4 cycles of atezolizumab treatment. Before treatment, there were no significant differences in the level of lymphocyte subsets between those who achieved PR/SD or PD. However, a significant difference in the level of lymphocyte subsets appeared after 4 cycles of atezolizumab treatment. Among the 22 patients who achieved PR/SD, the number of CD3+, CD4+ T, and CD4+/CD8+ indexes were significantly increased, whereas the number of CD8+ T lymphocytes was significantly decreased. Meanwhile, the 8 patients who achieved PD displayed different results. In addition, ROC curve combined detection of CD3+, CD4+, and CD8+ T [area under the curve (AUC) =0.9018, P<0.0001] showed good predictive ability for the efficacy of atezolizumab in advanced NSCLC. Conclusions: Atezolizumab may alter the level of lymphocyte subsets in patients with advanced NSCLC, and the changes in lymphocyte subsets may predict the efficacy of atezolizumab for these patients.

Habitat-based radiomics enhances the ability to predict lymphovascular space invasion in cervical cancer: a multi-center study.

Introduction: Lymphovascular space invasion (LVSI) is associated with lymph node metastasis and poor prognosis in cervical cancer. In this study, we investigated the potential of radiomics, derived from magnetic resonance (MR) images using habitat analysis, as a non-invasive surrogate biomarker for predicting LVSI in cervical cancer. Methods: This retrospective study included 300 patients with cervical cancer who underwent surgical treatment at two centres (centre 1 = 198 and centre 2 = 102). Using the k-means clustering method, contrast-enhanced T1-weighted imaging (CE-T1WI) images were segmented based on voxel and entropy values, creating sub-regions within the volume ofinterest. Radiomics features were extracted from these sub-regions. Pearson correlation coefficient and least absolute shrinkage and selection operator LASSO) regression methods were used to select features associated with LVSI in cervical cancer. Support vector machine (SVM) model was developed based on the radiomics features extracted from each sub-region in the training cohort. Results: The voxels and entropy values of the CE-T1WI images were clustered into three sub-regions. In the training cohort, the AUCs of the SVM models based on radiomics features derived from the whole tumour, habitat 1, habitat 2, and habitat 3 models were 0.805 (95% confidence interval [CI]: 0.745-0.864), 0.873(95% CI: 0.824-0.922), 0.869 (95% CI: 0.821-0.917), and 0.870 (95% CI: 0.821-0.920), respectively. Compared with whole tumour model, the predictive performances of habitat 3 model was the highest in the external test cohort (0.780 [95% CI: 0.692-0.869]). Conclusions: The radiomics model based on the tumour sub-regional habitat demonstrated superior predictive performance for an LVSI in cervical cancer than that of radiomics model derived from the whole tumour.

CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.

Transcriptomic and Metabolomic Analyses Reveal the Key Genes Related to Shade Tolerance in Soybean.

Soybean (Glycine max) is an important crop, rich in proteins, vegetable oils and several other phytochemicals, which is often affected by light during growth. However, the specific regulatory mechanisms of leaf development under shade conditions have yet to be understood. In this study, the transcriptome and metabolome sequencing of leaves from the shade-tolerant soybean 'Nanxiadou 25' under natural light (ND1) and 50% shade rate (SHND1) were carried out, respectively. A total of 265 differentially expressed genes (DEGs) were identified, including 144 down-regulated and 121 up-regulated genes. Meanwhile, KEGG enrichment analysis of DEGs was performed and 22 DEGs were significantly enriched in the top five pathways, including histidine metabolism, riboflavin metabolism, vitamin B6 metabolism, glycerolipid metabolism and cutin, suberine and wax biosynthesis. Among all the enrichment pathways, the most DEGs were enriched in plant hormone signaling pathways with 19 DEGs being enriched. Transcription factors were screened out and 34 differentially expressed TFs (DETFs) were identified. Weighted gene co-expression network analysis (WGCNA) was performed and identified 10 core hub genes. Combined analysis of transcriptome and metabolome screened out 36 DEGs, and 12 potential candidate genes were screened out and validated by quantitative real-time polymerase chain reaction (qRT-PCR) assay, which may be related to the mechanism of shade tolerance in soybean, such as ATP phosphoribosyl transferase (ATP-PRT2), phosphocholine phosphatase (PEPC), AUXIN-RESPONSIVE PROTEIN (IAA17), PURPLE ACID PHOSPHATASE (PAP), etc. Our results provide new knowledge for the identification and function of candidate genes regulating soybean shade tolerance and provide valuable resources for the genetic dissection of soybean shade tolerance molecular breeding.

Lapachol inhibits the growth of lung cancer by reversing M2-like macrophage polarization via activating NF-κB signaling pathway.

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment (TME) and improve innate and adaptive antitumor immunity. Lapachol, a naturally occurring 1,4-naphthoquinone, exhibits various pharmacological activities including antitumor, anti-leishmanial, antimalarial and antiseptic. In this study, we investigated the relevance of macrophage polarization and the antitumor effect of lapachol in Lewis lung cancer (LLC) both in vitro and in vivo. This study demonstrated that lapachol significantly reversed the polarization of M2-like macrophages thus that were endowed with the ability to kill LLC cells by activating NF-κB signaling pathway. Furthermore, lapachol effectively suppressed tumor growth in C57BL/6 mice bearing lung tumors by reducing the proportion of M2-like macrophages. Overall, our findings clearly illustrated that lapachol could reverse the polarization of M2-like macrophages to improve the immunosuppressive tumor microenvironment, and had the potential to be developed as an immunomodulatory antitumor agent.

Duplication of the transverse colon in adults: a case report and literature review.

Background: Duplication of the transverse colon is a rare gastrointestinal malformation. Its pathogenesis is still unclear, and it is extremely rare in adults. Patients often present with symptoms of tumor compression such as abdominal mass, abdominal pain, and constipation as the first manifestation. Methods and result: A patient with a duplication of the transverse colon was admitted to the Department of General Surgery of our hospital. Laparoscopic exploration found a mass at the rear of the transverse colon near the splenic flexure, and the root was connected to the middle portion of the transverse colon. Conclusion: Surgery is a radical treatment and reduces the possibility of perforation, bleeding, obstruction, and cancer.

Assessment of short-term effects of thoracic radiotherapy on the cardiovascular parasympathetic and sympathetic nervous systems.

Background: Prior research suggests that cardiovascular autonomic dysfunction might be an early marker of cardiotoxicity induced by antitumor treatment and act as an early predictor of cardiovascular disease-related morbidity and mortality. The impact of thoracic radiotherapy on the parasympathetic and sympathetic nervous systems, however, remains unclear. Therefore, this study aimed to evaluate the short-term effects of thoracic radiotherapy on the autonomic nervous system, using deceleration capacity (DC), acceleration capacity (AC) of heart rate, and heart rate variability (HRV) as assessment tools. Methods: A 5 min electrocardiogram was collected from 58 thoracic cancer patients before and after thoracic radiotherapy for DC, AC, and HRV analysis. HRV parameters employed included the standard deviation of the normal-normal interval (SDNN), root mean square of successive interval differences (RMSSD), low frequency power (LF), high frequency power (HF), total power (TP), and the LF to HF ratio. Some patients also received systemic therapies alongside radiotherapy; thus, patients were subdivided into a radiotherapy-only group (28 cases) and a combined radiotherapy and systemic therapies group (30 cases) for additional subgroup analysis. Results: Thoracic radiotherapy resulted in a significant reduction in DC (8.5 [5.0, 14.2] vs. 5.3 [3.5, 9.4], p = 0.002) and HRV parameters SDNN (9.9 [7.03, 16.0] vs. 8.2 [6.0, 12.4], p = 0.003), RMSSD (9.9 [6.9, 17.5] vs. 7.7 [4.8, 14.3], p = 0.009), LF (29 [10, 135] vs. 24 [15, 50], p = 0.005), HF (35 [12, 101] vs. 16 [9, 46], p = 0.002), TP (74 [41, 273] vs. 50 [33, 118], p < 0.001), and a significant increase in AC (-8.2 [-14.8, -4.9] vs. -5.8 [-10.1, -3.3], p = 0.003) and mean heart rate (79.8 ± 12.6 vs. 83.9 ± 13.6, p = 0.010). Subgroup analysis indicated similar trends in mean heart rate, DC, AC, and HRV parameters (SDNN, RMSSD, LF, HF, TP) in both the radiotherapy group and the combined treatment group post-radiotherapy. No statistically significant difference was noted in the changes observed in DC, AC, and HRV between the two groups pre- and post-radiotherapy. Conclusion: Thoracic radiotherapy may induce cardiovascular autonomic dysfunction by reducing parasympathetic activity and enhancing sympathetic activity. Importantly, the study found that the concurrent use of systemic therapies did not significantly amplify or contribute to the alterations in autonomic function in the short-term following thoracic radiotherapy. DC, AC and HRV are promising and feasible biomarkers for evaluating autonomic dysfunction caused by thoracic radiotherapy.

CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. EXPERIMENTAL DESIGN: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response. RESULTS: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression. CONCLUSIONS: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.

SARS-CoV-2 main protease cleaves MAGED2 to antagonize host antiviral defense.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent causing the global pandemic of COVID-19. SARS-CoV-2 genome encodes a main protease (nsp5, also called Mpro) and a papain-like protease (nsp3, also called PLpro), which are responsible for processing viral polyproteins to assemble a functional replicase complex. In this study, we found that Mpro of SARS-CoV-2 can cleave human MAGED2 and other mammalian orthologs at Gln-263. Moreover, SARS-CoV and MERS-CoV Mpro can also cleave human MAGED2, suggesting MAGED2 cleavage by Mpro is an evolutionarily conserved mechanism of coronavirus infection in mammals. Intriguingly, Mpro from Beta variant cleaves MAGED2 more efficiently than wild type, but Omicron Mpro is opposite. Further studies show that MAGED2 inhibits SARS-CoV-2 infection at viral replication step. Mechanistically, MAGED2 is associated with SARS-CoV-2 nucleocapsid protein through its N-terminal region in an RNA-dependent manner, and this disrupts the interaction between SARS-CoV-2 nucleocapsid protein and viral genome, thus inhibiting viral replication. When MAGED2 is cleaved by Mpro, the N-terminal of MAGED2 will translocate into the nucleus, and the truncated MAGED2 is unable to suppress SARS-CoV-2 replication. This work not only discovers the antiviral function of MAGED2 but also provides new insights into how SARS-CoV-2 Mpro antagonizes host antiviral response. IMPORTANCE Host factors that restrict severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain elusive. Here, we found that MAGED2 can be cleaved by SARS-CoV-2 main protease (Mpro) at Gln-263. SARS-CoV and MERS-CoV Mpro can also cleave MAGED2, and MAGED2 from multiple species can be cleaved by SARS-CoV-2 Mpro. Mpro from Beta variant cleaves MAGED2 more efficiently efficiently than wild type, but Omicron is the opposite. MAGED2 depletion enhances SARS-CoV-2 infection, suggesting its inhibitory role in SARS-CoV-2 infection. Mechanistically, MAGED2 restricts SARS-CoV-2 replication by disrupting the interaction between nucleocapsid and viral genomes. When MAGED2 is cleaved, its N-terminal will translocate into the nucleus. In this way, Mpro relieves MAGED2' inhibition on viral replication. This study improves our understanding of complex viral-host interaction and provides novel targets to treat SARS-CoV-2 infection.

Sub-minute acquisition with deep learning-based image filter in the diagnosis of colorectal cancers using total-body 18F-FDG PET/CT.

BACKGROUND: This study aimed to retrospectively evaluate the feasibility of total-body 18F-FDG PET/CT ultrafast acquisition combined with a deep learning (DL) image filter in the diagnosis of colorectal cancers (CRCs). METHODS: The clinical and preoperative imaging data of patients with CRCs were collected. All patients underwent a 300-s list-mode total-body 18F-FDG PET/CT scan. The dataset was divided into groups with acquisition durations of 10, 20, 30, 60, and 120 s. PET images were reconstructed using ordered subset expectation maximisation, and post-processing filters, including a Gaussian smoothing filter with 3 mm full width at half maximum (3 mm FWHM) and a DL image filter. The effects of the Gaussian and DL image filters on image quality, detection rate, and uptake value of primary and liver metastases of CRCs at different acquisition durations were compared using a 5-point Likert scale and semi-quantitative analysis, with the 300-s image with a Gaussian filter as the standard. RESULTS: All 34 recruited patients with CRCs had single colorectal lesions, and the diagnosis was verified pathologically. Of the total patients, 11 had liver metastases, and 113 liver metastases were detected. The 10-s dataset could not be evaluated due to high noise, regardless of whether it was filtered by Gaussian or DL image filters. The signal-to-noise ratio (SNR) of the liver and mediastinal blood pool in the images acquired for 10, 20, 30, and 60 s with a Gaussian filter was lower than that of the 300-s images (P < 0.01). The DL filter significantly improved the SNR and visual image quality score compared to the Gaussian filter (P < 0.01). There was no statistical difference in the SNR of the liver and mediastinal blood pool, SUVmax and TBR of CRCs and liver metastases, and the number of detectable liver metastases between the 20- and 30-s DL image filter and 300-s images with the Gaussian filter (P > 0.05). CONCLUSIONS: The DL filter can significantly improve the image quality of total-body 18F-FDG PET/CT ultrafast acquisition. Deep learning-based image filtering methods can significantly reduce the noise of ultrafast acquisition, making them suitable for clinical diagnosis possible.

Multi-omics analysis of expression profile and prognostic values of connexin family in LUAD.

PURPOSE: Our study first explored the expression differences and prognostic significance of Cx genes in pan-cancer and then focused on LUAD. Our objectives were to conducted a comprehensive analysis of the expression profile, prognostic significance, genetic alterations, potential biological functions and drug sensitivity of the Connexin gene family in LUAD. METHODS: We developed a comprehensive prognostic model for LUAD by combining risk scores with clinical features and created a nomogram to predict 1-, 3-, and 5-year overall survival. Using single-cell sequencing, we examined the expression and biological functions of the identified prognostic markers. RESULTS: Our risk model revealed that GJB2-5 play a critical role in the prognosis of LUAD patients, associated with many biological processes such as cell cycle, DNA damage, EMT, hypoxia, invasion, and metastasis. Furthermore, the connexin gene family is linked to transcriptional mechanisms such as the extracellular matrix (ECM), migration, mobility, angiogenesis, and the epithelial-mesenchymal transition (EMT) genetic program. CONCLUSION: The risk model can be used as a potential prognostic factor for LUAD patients and may provide new insights into cancer treatment from perspective of the expression of Cx genes.