Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells.

RNA splicing is involved in cancer initiation and progression, but how it influences host antitumor immunity in the metabolically abnormal tumor microenvironment (TME) remains unclear. Here, we demonstrate that lactate modulates Foxp3-dependent RNA splicing to maintain the phenotypic and functional status of tumor-infiltrating regulatory T (Treg) cells via CTLA-4. RNA splicing in Treg cells was correlated with the Treg cell signatures in the TME. Ubiquitin-specific peptidase 39 (USP39), a component of the RNA splicing machinery, maintained RNA-splicing-mediated CTLA-4 expression to control Treg cell function. Mechanistically, lactate promoted USP39-mediated RNA splicing to facilitate CTLA-4 expression in a Foxp3-dependent manner. Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight the immunological relevance of RNA splicing in Treg cells and provide important insights into the environmental mechanism governing CTLA-4 expression in Treg cells.

VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19.

BACKGROUND: Nirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir). RESULTS: A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%). CONCLUSIONS: Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).

Opposing roles of TGFß and BMP signaling in prostate cancer development.

SMAD4 constrains progression of Pten-null prostate cancer and serves as a common downstream node of transforming growth factor ß (TGFß) and bone morphogenetic protein (BMP) pathways. Here, we dissected the roles of TGFß receptor II (TGFBR2) and BMP receptor II (BMPR2) using a Pten-null prostate cancer model. These studies demonstrated that the molecular actions of TGFBR2 result in both SMAD4-dependent constraint of proliferation and SMAD4-independent activation of apoptosis. In contrast, BMPR2 deletion extended survival relative to Pten deletion alone, establishing its promoting role in BMP6-driven prostate cancer progression. These analyses reveal the complexity of TGFß-BMP signaling and illuminate potential therapeutic targets for prostate cancer.

CircHAS2 activates CCNE2 to promote cell proliferation and sensitizes the response of colorectal cancer to anlotinib.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure. METHODS: The whole transcriptome RNA sequencing and function experiments were conducted to identify candidate anlotinib-regulated circRNAs, whose mechanism was confirmed by molecular biology experiments. CircHAS2 was profiled in a library of patient-derived CRC organoids (n = 22) and patient-derived CRC tumors in mice. Furthermore, a prospective phase II clinical study of 14 advanced CRC patients with anlotinib-based therapy was commenced to verify drug sensitivity (ClinicalTrials.gov identifier: NCT05262335). RESULTS: Anlotinib inhibits tumor growth in vitro and in vivo by downregulating circHAS2. CircHAS2 modulates CCNE2 activation by acting as a sponge for miR-1244, and binding to USP10 to facilitate p53 nuclear export as well as degradation. In parallel, circHAS2 serves as a potent biomarker predictive of anlotinib sensitivity, both in patient-derived organoids and xenograft models. Moreover, the efficacy of anlotinib inclusion into the treatment regimen yields meaningful clinical responses in patients with high levels of circHAS2. Our findings offer a promising targeted strategy for approximately 52.9% of advanced CRC patients who have high circHAS2 levels. CONCLUSIONS: CircHAS2 promotes cell proliferation via the miR-1244/CCNE2 and USP10/p53/CCNE2 bidirectional axes. Patient-derived organoids and xenograft models are employed to validate the sensitivity to anlotinib. Furthermore, our preliminary Phase II clinical study, involving advanced CRC patients treated with anlotinib, confirmed circHAS2 as a potential sensitivity marker.

Cardiac T1ρ Mapping Values Affected by Age and Sex in a Healthy Chinese Cohort.

BACKGROUND: To facilitate the clinical use of cardiac T1ρ, it is important to understand the impact of age and sex on T1ρ values of the myocardium. PURPOSE: To investigate the impact of age and gender on myocardial T1ρ values. STUDY TYPE: Cross-sectional. POPULATION: Two hundred ten healthy Han Chinese volunteers without cardiovascular risk factors (85 males, mean age 34.4 ± 12.5 years; 125 females, mean age 37.9 ± 14.8 years). FIELD STRENGTH/SEQUENCE: 1.5 T; T1ρ-prepared steady-state free precession (T1ρ mapping) sequence. ASSESSMENT: Basal, mid, and apical short-axis left ventricular T1ρ maps were acquired. T1ρ maps acquired with spin-lock frequencies of 5 and 400 Hz were subtracted to create a myocardial fibrosis index (mFI) map. T1ρ and mFI values across different age decades, sex, and slice locations were compared. STATISTICAL TESTS: Shapiro-Wilk test, Student's t test, Mann-Whitney U test, linear regression analysis, one-way analysis of variance and intraclass correlation coefficient. SIGNIFICANCE: P value <0.05. RESULTS: Women had significantly higher T1ρ and mFI values than men (50.3 ± 2.0 msec vs. 47.7 ± 2.4 msec and 4.7 ± 1.0 msec vs. 4.3 ± 1.1 msec, respectively). Additionally, in males and females combined, there was a significant positive but weak correlation between T1ρ values and age (r = 0.27), while no correlation was observed between the mFI values and age (P = 0.969). DATA CONCLUSION: We report potential reference values for cardiac T1ρ by sex, age distribution, and slice location in a Chinese population. T1ρ was significantly correlated with age and sex, while mFI was only associated with sex. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Cancer-associated fibroblast-derived exosome miR-181b-3p promotes the occurrence and development of colorectal cancer by regulating SNX2 expression.

Tumor microenvironment (TME) (e.g., stromal cells) has been closely related to the pathological process of colorectal cancer (CRC). In TME, tumor-associated fibroblasts (CAFs) are the main stromal cells. The studies have showed that CAFs promoted tumor growth and metastasis in CRC and led to poor prognosis. Mounting evidence indicates that CAFs-mediated exosomes regulate the pathological process of neighboring tumor cells through the transmission of miRNAs. In our study, we aimed to explore the function of CAFs-derived exosome miR-181b-3p in CRC. First, the expression of miR-181b-3p in CRC was found to be up-regulated and its expression was dramatically up-regulated in CRC cells after co-incubation of CAFs-mediated exosomes with CRC cells. Then, it was found that the CAFs-derived exosomes were markedly enhanced the proliferation and migration of the CRC cells, and substantially reduced apoptosis. To elucidate the influence of CAFs-derived exosome miR-181b-3p on CRC, we overexpressed and knocked down the miR-181b-3p expression in CAFs, respectively. It was found that miR-181b-3p significantly increased the proliferation and migration of CRC cells. Furthermore, we conducted in vivo experiments. Finally, we demonstrated that CAF-derived exosome miR-181b-3p regulated sorting nexin 2 (SNX2) expression in CRC cells by bioinformatics prediction combined with luciferase reporter assay. Further cellular and animal experiments jointly elucidated that miR-181b-3p promoted the pathological process of CRC by SNX2 expression. In brief, our results demonstrated that CAFs-derived exosome miR-181b-3p promoted the pathogenesis of CRC by regulating SNX2 expression, which provides a novel idea for CRC treatment.

Normal Values of Magnetic Resonance T1ρ Relaxation Times in the Adult Heart at 1.5 T MRI.

BACKGROUND: T1ρ mapping is a new quantitative MRI technique in recent years. In order to use T1ρ mapping as a noncontrast method to assess myocardial fibrosis, it is necessary to establish a range of normal values. PURPOSE: To establish a potential normal range of cardiac T1ρ values in healthy adults and to explore the influence of slice location and gender on T1ρ values. STUDY TYPE: Prospective. POPULATION: A total of 57 healthy volunteers without cardiovascular risk factors (age 26.7 ± 11.8 years; 29 males). FIELD STRENGTH/SEQUENCE: 1.5 T; modified Look-Locker inversion recovery (MOLLI) (T1 mapping), multiecho gradient-spin-echo (GraSE) (T2 mapping) and T1ρ -prepared steady-state free precession (T1ρ mapping) sequences. ASSESSMENT: Basal, mid, and apical short-axis left ventricular T1 , T2 , and T1ρ maps were acquired. T1ρ maps at spin-locking frequencies of 5 and 400 Hz were subtracted to create myocardial fibrosis index (mFI) maps. Slice-average and global average T1 , T2 , T1ρ , and mFI values were determined. STATISTICAL TESTS: Shapiro-Wilk test, Independent t-test, ANOVA test, Pearson correlation coefficient (r). SIGNIFICANCE: P value < 0.05. RESULTS: The global average values of T1 , T2 , T1ρ, and mFI were 1053 ± 34 msec, 51.9 ± 2.3 msec, 47.9 ± 2.8 msec, and 4.4 ± 1.6 msec. T1ρ values showed a significant gradual increase from the basal slice to the apical slice of the heart (basal 46.5 ± 2.7 msec, mid 48.0 ± 2.9 msec, apical 49.2 ± 3.3 msec). The T1ρ and mFI values of females (49.7 ± 2.4 msec and 5.1 ± 1.2 msec, respectively) were significantly higher than those of males (46.2 ± 1.9 msec and 3.7 ± 1.7 msec, respectively). In addition, there was a moderate positive correlation between global T1ρ values and global T1 values (r = 0.44, P < 0.05) and a moderate positive correlation between global T1ρ values and global T2 values (r = 0.42, P < 0.05). DATA CONCLUSION: In this study, the global T1ρ values of healthy adults' hearts were 47.9 ± 2.8 msec. This study found that gender and slice location of myocardium can affect the T1ρ values. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 1.

Clinical manifestations and MRI features of Danon disease: a case series.

BACKGROUND: Danon disease (DD) is an exceptionally uncommon X-linked dominant lysosomal glycogen storage disorder characterized by pronounced ventricular hypertrophy and cardiac insufficiency. The timely identification of cardiac impairment in individuals with DD holds significant clinical importance. CASE PRESENTATION: We present a case of Danon Disease in a three-generation pedigree from Anhui Province, China. Clinical features and laboratory data were collected and analyzed for a 16-year-old male proband (III-1) and two affected female family members (II-2 and II-3). The proband exhibited Wolf-Parkinson-White syndrome, hypertrophic cardiomyopathy, abnormal cognitive function, and muscle weakness. Gene sequencing confirmed a mutation (c.963G > A) in the LAMP-2 gene. CONCLUSION: Patients with DD may present both dilated and hypertrophic cardiomyopathy. Comprehensive myocardial tissue characterization by MRI plays a key role in the diagnosis of the disease.

Cancer stem cell-like cells-derived exosomal CDKN2B-AS1 stabilizes CDKN2B to promote the growth and metastasis of thyroid cancer via TGF-ß1/Smad2/3 signaling.

As CDKN2B-AS1 is demonstrated to exert promotive effects on thyroid cancer (TC), this research aims to investigate the role of cancer stem cell-like cells (CSCs)-derived exosomal CDKN2B-AS1 in TC and the underlying regulatory mechanism. Specifically, CDKN2B expression and the correlation of CDKN2B with CDKN2B-AS1 in TC were determined via bioinformatics analysis and further verified by qRT-PCR. After transfection or co-culture with CSCs-derived exosomes, viability, migration, and invasion of TPC-1 and SW579 cells were evaluated by CCK-8, wound healing, and transwell assays, respectively. The uptake of exosomes by TC cells was detected by PKH67 labeling. In vivo tumor formation and metastasis models were established. Tumor volume and weight were calculated. Metastasis loci in lung tissues were observed by hematoxylin-eosin staining. The expression levels of CDKN2B-AS1, CDKN2B, and epithelial-mesenchymal transition- and TGF-ß1/Smad2/3 signaling-related factors were detected by qRT-PCR or Western blot. Concretely, CDKN2B and CDKN2B-AS1 were highly expressed in TC, and there was a positive correlation between the two. In addition, CDKN2B-AS1 promoted the translation and stability of CDKN2B. Furthermore, CDKN2B-AS1 was highly expressed in CSCs and CSCs-derived exosomes which could be absorbed by TC cells. CDKN2B silencing inhibited viability, migration, invasion, protein levels of CDKN2B, N-cadherin and Vimentin, and TGF-ß1/Smad2/3 signaling, while promoting E-cadherin expression in TC cells. CSCs-derived exosomal CDKN2B-AS1 did oppositely and reversed the effects of CDKN2B silencing on TC cells. CDKN2B silencing impeded tumor growth and metastasis in TC mice, while TGF-ß1 performed inversely and impaired the effects of CDKN2B silencing. Collectively, CSCs-derived exosomal CDKN2B-AS1 stabilizes CDKN2B to promote growth and metastasis of TC via TGF-ß1/Smad2/3 signaling.

Deleterious effect in endothelin receptor-mediated coronary artery smooth muscle contractility in high-salt diet rats.

BACKGROUND AND AIMS: High-salt diet has been suggested to increase the risk of heart disease. However, the mechanisms underlying coronary artery tension dysfunction caused by high-salt diet are unclear. Previous studies have shown that coronary artery spasm is often induced by endothelin-1 (ET-1) and thromboxane, leading to myocardial ischemia, while the store-operated Ca2+ entry (SOCE) function of coronary smooth muscle is very important in this process. METHODS AND RESULTS: Tension measurements of endothelium-denuded coronary artery ring segments showed that vasocontraction induced by U46619, ET-1, orSTIM1/Orai1-mediated SOCE was significantly lower in 4% high-salt diet rats than in control rats fed a regular diet. The results of western blotting and immunohistochemistry assays showed lower expression levels of endothelial receptors ETA and ETB, STIM1 and Orai1 in coronary artery of high-salt intake rats compared with control rats. Fibrosis was observed by using Masson's trichrome staining and picrosirius red staining. The plasma ET-1 concentration in high-salt diet rats was significantly higher than that of controls. The interventricular septum and posterior wall of high-salt diet rats were significantly thickened. CONCLUSION: Our findings indicated that coronary artery tension was significantly decreased in 4% high-salt diet rats and that this decrease may be due to the change of endothelin receptor and its downstream pathway SOCE related protein expression in coronary artery. Coronary fibrosis was observed in rats fed with high-salt diet. This study provides potential mechanistic insights into high-salt intake-induced heart disease.

Prognostic factors in patients with thymoma who underwent surgery.

PURPOSE: Thymoma is the most common primary tumor in the anterior mediastinum. The prognostic factors of patients with thymoma still need to be clarified. In this study, we aimed to investigate the prognostic factors of patients with thymoma who received radical resection and establish the nomogram to predict the prognosis of these patients. MATERIALS AND METHODS: Patients who underwent radical resection for thymoma with complete follow-up data between 2005 and 2021 were enrolled. Their clinicopathological characteristics and treatment methods were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify the independent prognostic factors. According to the results of the univariate analysis in the Cox regression model, the predictive nomograms were created. RESULTS: A total of 137 patients with thymoma were enrolled. With a median follow-up of 52 months, the 5-year and 10-year PFS rates were 79.5% and 68.1%, respectively. The 5-year and 10-year OS rates were 88.4% and 73.1%, respectively. Smoking status (P = 0.022) and tumor size (P = 0.039) were identified as independent prognostic factors for PFS. Multivariate analysis showed that a high level of neutrophils (P = 0.040) was independently associated with OS. The nomogram showed that the World Health Organization (WHO) histological classification contributed more to the risk of recurrence than other factors. Neutrophil count was the most important predictor of OS in patients with thymoma. CONCLUSION: Smoking status and tumor size are risk factors for PFS in patients with thymoma. A high level of neutrophils is an independent prognostic factor for OS. The nomograms developed in this study accurately predict PFS and OS rates at 5 and 10 years in patients with thymoma based on individual characteristics.

Excessive HSP70/TLR2 activation leads to remodeling of the tumor immune microenvironment to resist chemotherapy sensitivity of mFOLFOX in colorectal cancer.

For locally advanced colorectal cancer (CRC), neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision or complete mesocolic excision is the standard therapeutic strategy, which is key to patient survival. Involvement of the tumor immune microenvironment is a factor that regulates tumor progression and sensitivity to nCRT in CRC. In this study, we aimed to identify the effect of heat-shock protein 70 (HSP70)/toll-like receptor-2 (TLR-2) on mFOLFOX sensitization for CRC. A total of 22 patients with advanced CRC who had received neoadjuvant mFOLFOX were enrolled and classified into the mFOLFOX-insensitive or -sensitive group, according to the tumor regression grade. The abundance of immune infiltrates was significantly higher in the post-operative pathological specimens of the mFOLFOX-insensitive group, as compared to those of the mFOLFOX-sensitive group. After transcriptome sequencing, differentially expressed genes between the two groups were annotated to inflammatory and immune responses using Gene Ontology (GO) analysis, and the TLR signaling pathway was analyzed using Kyoto Encyclopedia of Genes and Genomes pathway analysis. Significantly higher expression levels of HSP60, HSP70, HSP90, and TLR-2 in the mFOLFOX-insensitive group were detected using immunofluorescence assays. TIMER2.0 platform was introduced to further narrow the scope of HSP70 (HSPA6 or HSPA7) and TLR-2, which exhibited positive correlations with dendritic cells, Tregs, or CD4+ T cells and negative correlations with CD3+ or CD8+ T cells, implying that HSP70/TLR-2 activation mediates immunosuppressive cells to counteract CD8+ T cells, which may be a novel target of CRC treatment. A promising synergistic effect of mFOLFOX combined with a TLR-2 inhibitor was observed in vivo in mouse allograft models, which could be partly rescued by recombinant HSP70 protein. Immunohistochemical staining of allografts and immunofluorescence assays of clinical specimens corroborated the regulatory effects of the immune microenvironment. In summary, HSP70/TLR-2 activation can regulate the tumor immune microenvironment of CRC and further remodel its sensitivity to mFOLFOX. However, the specific mechanisms remain unclear and require further investigation. This study is expected to provide a new direction for the clinical treatment of CRC.

Oncologic outcomes of single-incision laparoscopic surgery versus conventional laparoscopic surgery for colorectal cancer (CSILS): study protocol for a multicentre, prospective, open-label, noninferiority, randomized controlled trial.

BACKGROUND: In most previous studies, single-incision laparoscopic surgery (SILS) for colorectal cancer (CRC) was feasible and safe in the short term. However, long-term oncologic outcomes remain uncertain, as only a few studies contained long-term survival data. SILS for CRC is still in the early stages of research. Further studies, particularly large-scale, prospective randomized controlled trials, are necessary to assess the value of SILS for CRC. METHODS: This study is a prospective, multicentre, open-label, noninferiority, parallel-group randomized controlled trial that investigates the long-term oncologic outcomes of SILS compared to conventional laparoscopic surgery (CLS) for CRC. A total of 710 eligible patients will be randomly assigned to the SILS group or the CLS group at a 1:1 ratio using a central, dynamic, and stratified block randomization method. Patients with ages ranging from 18 to 85 years old, of both sexes, with CRC above the peritoneal reflection diagnosed as cT1-4aN0-2M0 and a tumour size no larger than 5 cm will be considered for the study. The primary endpoint is 3-year disease-free survival (DFS). The secondary endpoints include: intraoperative outcomes, postoperative recovery, postoperative pain assessment, pathological outcomes, early morbidity and mortality rate, cosmetic effects, quality of life, 3-year overall survival (OS), incidence of incisional hernia, 5-year DFS and 5-year OS. The first two follow-up visits will be scheduled at one month and three months postoperatively, then every three months for the first two years and every six months for the next three years. DISCUSSION: Currently, no randomized controlled trials (RCTs) have been designed to investigate the long-term oncologic outcomes of SILS for CRC. This study is expected to provide clinical evidence of the oncologic outcomes of SILS compared to CLS for CRC to promote its widespread use. TRIAL REGISTRATION: ClinicalTrials.gov:  NCT04527861 (registered on August 27, 2020).

Clinical characteristics and patient outcomes of molecular subtypes of small cell lung cancer (SCLC).

BACKGROUND: Recent studies have shown that according to the expression levels of achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), and POU class 2 homeobox 3 (POU2F3), small cell lung cancer (SCLC) can be divided into four subtypes: SCLC-A (ASCL1-dominant), SCLC-N (NEUROD1-dominant), SCLC-P (POU2F3-dominant), and SCLC-I (triple negative or SCLC-inflamed). However, there are limited data on the clinical characteristics and prognosis of molecular subtypes of SCLC. METHODS: Immunohistochemistry (IHC) was used to detect the expression levels of ASCL1, NEUROD1, and POU2F3 in 53 patient samples of resectable SCLC. The subtype was defined by the differential expression of the transcription factors for ASCL1, NEUROD1, and POU2F3 or the low expression of all three factors with an inflamed gene signature (SCLC-A, SCLC-N, SCLC-P, and SCLC-I, respectively). The clinicopathological characteristics, immunological features (programmed death ligand 1 [PD-L1] expression and CD8+ tumor infiltrating lymphocyte [TIL] density), and patient outcomes of the four subtypes of SCLC were analyzed. RESULTS: Positive ASCL1, NEUROD1, and POU2F3 staining was detected in 43 (79.2%), 27 (51.0%), and 17 (32.1%) SCLC specimens by IHC. According to the results of IHC analysis, SCLC was divided into four subtypes: SCLC-A (39.6%), SCLC-N (28.3%), SCLC-P (17.0%), and SCLC-I (15.1%). The 5-year overall survival (OS) rates of these four subtypes were 61.9%, 69.3%, 41.7%, and 85.7%, respectively (P=0.251). There were significant differences in smoking status among different subtypes of SCLC (P= 0.031). However, we did not confirm the correlation between subtypes of SCLC and other clinicopathological factors or immune profiles. Cox multivariate analysis showed that N stage (P=0.025), CD8+ TILs (P=0.024), Ki-67 level (P=0.040), and SCLC-P (P=0.023) were independent prognostic factors for resectable SCLC. CONCLUSIONS: Our IHC-based study validated the proposed classification of SCLC using the expression patterns of key transcriptional regulatory factors. We found that SCLC-P was associated with smokers and was one of the poor prognostic factors of limited-stage SCLC. In addition, no correlation was found between PD-L1 expression or CD8+ TIL density and SCLC subtypes.

Britanin relieves ferroptosis-mediated myocardial ischaemia/reperfusion damage by upregulating GPX4 through activation of AMPK/GSK3ß/Nrf2 signalling.

CONTEXT: Ferroptosis was described as an important contributor to the myocardial ischaemia/reperfusion (MIR) injury, and britanin (Bri) was reported to exert antitumor and anti-inflammatory activities. OBJECTIVE: Our study explores the effect and mechanism of Bri on MIR damage. MATERIALS AND METHODS: The rat model of MIR was established by ligation of the left anterior descending coronary artery. Male Sprague-Dawley (SD) rats were divided into three groups: sham group (n = 6), MIR group (n = 6) and MIR + Bri group (n = 6; 50 mg/kg). Rats were intragastrically pre-treated with Bri or normal saline once daily for 3 days. To further verify the role and mechanism of Bri, H9C2 cells were subjected to hypoxia plus reoxygenation (H/R) to induce the in vitro model of MIR. RESULTS: Compared with MIR rats, Bri significantly decreased infarct area (22.50% vs. 38.67%), myocardial apoptosis (23.00% vs. 41.5%), creatine phosphokinase (0.57 U/mL vs. 0.76 U/mL), and lactate dehydrogenase levels (3.18 U/mL vs. 5.17 U/mL), concomitant with alleviation of ferroptosis. Mechanistically, Bri treatment induced the activation of the adenosine monophosphate activated protein kinase (AMPK)/glycogen synthase kinase 3ß (GSK3ß)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in vivo. In addition, the AMPK/GSK3ß/Nrf2 pathway participated in the regulation of glutathione peroxidase 4 (GPX4) expression, and silencing of Nrf2 attenuated the effect of Bri on H/R-induced cell injury. DISCUSSION AND CONCLUSIONS: Bri protected against ferroptosis-mediated MIR damage by upregulating GPX4 through activation of the AMPK/GSK3ß/Nrf2 signalling, suggesting that Bri might become a novel therapeutic agent for MIR.

Elevated Extracellular Volume Fraction and Reduced Global Longitudinal Strains in Participants Recovered from COVID-19 without Clinical Cardiac Findings.

Background It is unknown if there are cardiac abnormalities in persons who have recovered from coronavirus disease 2019 (COVID-19) without cardiac symptoms or in those who have normal biomarkers and normal electrocardiograms. Purpose To evaluate cardiac involvement in participants who had recovered from COVID-19 without clinical evidence of cardiac involvement by using cardiac MRI. Materials and Methods This prospective observational cohort study included 40 participants who had recovered from COVID-19 with moderate (n = 24) or severe (n = 16) pneumonia and who had no cardiovascular medical history, were without cardiac symptoms, had normal electrocardiograms, had normal serologic cardiac enzyme levels, and had been discharged for more than 90 days between May and September 2020. Demographic characteristics were recorded, serum cardiac enzyme levels were measured, and cardiac MRI was performed. Cardiac function, native T1, extracellular volume fraction (ECV), and two-dimensional (2D) strain were quantitatively evaluated and compared with values in control subjects (n = 25). Comparisons among the three groups were performed by using one-way analysis of variance with Bonferroni-corrected post hoc comparisons (for normal distribution) or Kruskal-Wallis tests with post hoc pairwise comparisons (for nonnormal distribution). Results Forty participants (mean age, 54 years ± 12 [standard deviation]; 24 men) were enrolled; participants had a mean time between admission and cardiac MRI of 158 days ± 18 and between discharge and cardiac MRI examination of 124 days ± 17. There were no left or right ventricular size or functional differences between participants who had recovered from COVID-19 and healthy control subjects. Only one (3%) participant had positive late gadolinium enhancement located at the mid inferior wall. Global ECV values were elevated in participants who had recovered from COVID-19 with moderate or severe pneumonia compared with those in healthy control subjects (median ECV, 29.7% vs 31.4% vs 25.0%, respectively; interquartile range, 28.0%-32.9% vs 29.3%-34.0% vs 23.7%-26.0%, respectively; P < .001 for both). The 2D global left ventricular longitudinal strain was reduced in both groups of participants (moderate COVID-19 group, -12.5% [interquartile range, -15.5% to -10.7%]; severe COVID-19 group, -12.5% [interquartile range, -15.4% to -8.7%]) compared with the healthy control group (-15.4% [interquartile range, -17.6% to -14.6%]) (P = .002 and P = .001, respectively). Conclusion Cardiac MRI myocardial tissue and strain imaging parameters suggest that a proportion of participants who had recovered from COVID-19 had subclinical myocardial abnormalities detectable months after recovery. © RSNA, 2021 Online supplemental material is available for this article.

The role of the deubiquitinating enzyme DUB3/USP17 in cancer: a narrative review.

The balance between ubiquitination and deubiquitination is critical for the degradation, transport, localization, and activity of proteins. Deubiquitinating enzymes (DUBs) greatly contribute to the balance of ubiquitination and deubiquitination, and they have been widely studied due to their fundamental role in cancer. DUB3/ubiquitin-specific protease 17 (USP17) is a type of DUB that has attracted much attention in cancer research. In this review, we summarize the biological functions and regulatory mechanisms of USP17 in central nervous system, head and neck, thoracic, breast, gastrointestinal, genitourinary, and gynecologic cancers as well as bone and soft tissue sarcomas, and we provide new insights into how USP17 can be used in the management of cancer.

Robotic colorectal cancer surgery in China: a nationwide retrospective observational study.

BACKGROUND: Robotic colorectal cancer surgery is widely accepted and applied. However, there is still no objective and comprehensive assessment on the data of nationwide multicenter series. METHOD: A total of 28 medical centers in Mainland China participated in this nationwide retrospective observational study. From the first case performed in each center to the last until December 2017, patients with robotic resection for primary tumor and pathologically confirmed colorectal adenocarcinoma were consecutively enrolled. Clinical, pathological and follow-up data were collected and analyzed. RESULTS: A total of 5389 eligible patients were finally enrolled in this study, composing 72.2% of the total robotic colorectal surgery volume of Mainland China in the same period. For resections of one bowel segment of primary tumor, the postoperative mortality rate was 0.08% (4/5063 cases), and the postoperative complication rate (Clavien-Dindo grade II or higher) was 8.6% (434/5063 cases). For multiple resections, the postoperative mortality rate was 0.6% (2/326 cases), and the postoperative complication rate was 16.3% (53/326 cases). Out of 2956 patients receiving sphincter-preserving surgery in only primary resection, 130 (4.4%) patients had anastomotic leakage. Traditional low anterior resection (tumor at middle rectum) (OR 2.384, P < 0.001), traditional low anterior resection (tumor at low rectum) (OR 1.968, P = 0.017) and intersphincteric resection (OR 5.468, P = 0.006) were significant independent risk factors for anastomotic leakage. Female gender (OR 0.557, P = 0.005), age ≥ 60 years (OR 0.684, P = 0.040), and preventive stoma (OR 0.496, P = 0.043) were significant independent protective factors. Body mass index, preoperative chemotherapy/radiotherapy, tumor size, and TNM stage did not independently affect the occurrence of anastomotic leakage. CONCLUSION: Robotic colorectal cancer surgery was safe and reliable and might have advantages in patients at high risk of anastomotic leakage.

Closed reduction and percutaneous pinning vs open reduction and internal fixation in pediatric lateral condylar humerus fractures displaced by > 4 mm: an observational cross-sectional study.

BACKGROUND: Although open reduction and internal fixation (ORIF) is recommended for lateral condylar humerus fractures (LCHFs) displaced by > 4 mm, several studies have reported the use of closed reduction and percutaneous pinning (CRPP) to treat LCHFs with significant displacement. However, little is known about the clinical differences between these two surgical techniques. This study aimed to compare the therapeutic effects of CRPP and ORIF in treating LCHFs displaced by > 4 mm. METHODS: We retrospectively reviewed pediatric LCHFs displaced by > 4 mm treated with either CRPP or ORIF at our center from June 2019 to October 2020. Song and Milch fracture classifications were used. Variables such as age at injury, sex, side injured, fracture displacement, fracture type, operating time, postoperative treatment, and complications were compared between the two techniques. RESULTS: One hundred twenty LCHFs met inclusion criteria. There were 36 Milch type I and 84 type II LCHFs, and 69 Song stage 4 and 51 stage 5 LCHFs. CRPP was performed in 45 cases and ORIF in 75 cases. No differences were found in age, sex, side injured, preoperative displacement, postoperative displacement, and length of immobilization between the CRPP and ORIF groups. There was a difference between operation time and pin duration. The CRPP group had shorter operation times and pin duration, and required no additional operations to remove internal pins. The average follow-up duration was 13.9 months. All patients achieved fracture union, and no complications such as infection, nonunion, delayed union, osteonecrosis, fishtail deformity, cubitus varus or valgus, or pain were recorded during follow-up. Bone spurs, lateral prominences, and decreased carrying angle were common complications in all groups. No obvious cubitus varus was observed. Unaesthetic scars were only observed in the ORIF groups. No differences in range of motion or elbow function was found among the different therapies. CONCLUSIONS: Both CRPP and ORIF can achieve satisfactory clinical outcomes in treating LCHFs displaced by > 4 mm. No differences were found in complications or prognoses between the two groups. However, CRPP shows some advantages over ORIF, like less invasive surgery, no obvious scarring, and no need for secondary surgery with anesthesia for pin removal.