Replenishment of mitochondrial Na+ and H+ by ionophores potentiates cutaneous wound healing in diabetes.

Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na+) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na+ transporters have been identified as a functional regulator of regeneration. However, the role of Na+ in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na+ ionophores that were employed to increase intracellular Na+ content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na+ decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na+ ionophores replenish H+ to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na+, which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na+ ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.

Temperature variability associated with respiratory disease hospitalisations, hospital stays and hospital expenses the warm temperate sub-humid monsoon climate.

OBJECTIVES: The abrupt change of climate has led to an increasing trend of hospitalised patients in recent years. This study aimed to analyse the temperature variability (TV) associated with respiratory disease (RD) hospitalisations, hospital stays and hospital expenses. STUDY DESIGN: The generalized linear model combined with distributed lag non-linear model was used to investigate the association between TV and RD hospitalisations. METHODS: TV was determined by measuring the standard deviation of maximum and minimum temperatures for the current day and the previous 7 days. RD hospitalisations data were obtained from three major tertiary hospitals in Huaibei City, namely, the Huaibei People's Hospital, the Huaibei Hospital Of Traditional Chinese Medicine and the Huaibei Maternal and Child Health Care Hospital. First, using a time series decomposition model, the seasonality and long-term trend of hospitalisations, hospital stays and hospital expenses for RD were explored in this warm temperate sub-humid monsoon climate. Second, robust models were used to analyse the association between TV and RD hospitalisations, hospital stays and hospital expenses. In addition, this study stratified results by sex, age and season. Third, using the attributable fraction (AF) and attributable number (AN), hospitalisations, hospital stays and hospital expenses for RD attributed to TV were quantified. RESULTS: Overall, 0.013% of hospitalisations were attributed to TV0-1 (i.e. TV at the current day and previous 1 day), corresponding to 220 cases, 1603 days of hospital stays and 1,308,000 RMB of hospital expenses. Females were more susceptible to TV than males, and the risk increased with longer exposure (the highest risk was seen at TV0-7 [i.e. TV at the current day and previous 7 days] exposure). Higher AF and AN were observed at ages 0-5 years and ≥65 years. In addition, it was also found that TV was more strongly linked to RD in the cool season. The hot season was positively associated with hospital stays and hospital expenses at TV0-3 to TV0-7 exposure. CONCLUSIONS: Exposure to TV increased the risk of hospitalisations, longer hospital stays and higher hospital expenses for RD. The findings suggested that more attention should be paid to unstable weather conditions in the future to protect the health of vulnerable populations.

Prediction model of no-response before the first transarterial chemoembolization for hepatocellular carcinoma: TACF score.

Previous clinic models for patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE) mainly focused on the overall survival, whereas a simple-to-use tool for predicting the response to the first TACE and the management of risk classification before TACE are lacking. Our aim was to develop a scoring system calculated manually for these patients. A total of 437 patients with hepatocellular carcinoma (HCC) who underwent TACE treatment were carefully selected for analysis. They were then randomly divided into two groups: a training group comprising 350 patients and a validation group comprising 77 patients. Furthermore, 45 HCC patients who had recently undergone TACE treatment been included in the study to validate the model's efficacy and applicability. The factors selected for the predictive model were comprehensively based on the results of the LASSO, univariate and multivariate logistic regression analyses. The discrimination, calibration ability and clinic utility of models were evaluated in both the training and validation groups. A prediction model incorporated 3 objective imaging characteristics and 2 indicators of liver function. The model showed good discrimination, with AUROCs of 0.735, 0.706 and 0.884 and in the training group and validation groups, and good calibration. The model classified the patients into three groups based on the calculated score, including low risk, median risk and high-risk groups, with rates of no response to TACE of 26.3%, 40.2% and 76.8%, respectively. We derived and validated a model for predicting the response of patients with HCC before receiving the first TACE that had adequate performance and utility. This model may be a useful and layered management tool for patients with HCC undergoing TACE.

RNA demethylase ALKBH5 promotes colorectal cancer progression by posttranscriptional activation of RAB5A in an m6A-YTHDF2-dependent manner.

BACKGROUND: N6-methyladenosine (m6A) modification is an emerging epigenetic regulatory mechanism in tumourigenesis. Considering that AlkB homolog 5 (ALKBH5) is a well-described m6A demethylase in previous enzyme assays, we aimed to investigate the role of m6A methylation alteration conferred by disturbed ALKBH5 in colorectal cancer (CRC) development. METHODS: Expression of ALKBH5 and its correlation with clinicopathological characteristics of CRC were evaluated using the prospectively maintained institutional database. The molecular role and underlying mechanism of ALKBH5 in CRC were explored using in vitro and in vivo experiments with methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA-seq, MeRIP-qPCR, RIP-qPCR and luciferase reporter assays. RESULTS: ALKBH5 expression was significantly upregulated in CRC tissues compared to the paired adjacent normal tissues, and higher expression of ALKBH5 was independently associated with worse overall survival in CRC patients. Functionally, ALKBH5 promoted the proliferative, migrative and invasive abilities of CRC cells in vitro and enhanced subcutaneous tumour growth in vivo. Mechanistically, RAB5A was identified as the downstream target of ALKBH5 in CRC development, and ALKBH5 posttranscriptionally activated RAB5A by m6A demethylation, which impeded the YTHDF2-mediated degradation of RAB5A mRNA. In addition, we demonstrated that dysregulation of the ALKBH5-RAB5A axis could affect the tumourigenicity of CRC. CONCLUSIONS: ALKBH5 facilitates the progression of CRC by augmenting the expression of RAB5A via an m6A-YTHDF2-dependent manner. Our findings suggested that ALKBH5-RAB5A axis might serve as valuable biomarkers and effective therapeutic targets for CRC.

Uncovering the potential functions of lymph node metastasis-associated aberrant methylation differentially expressed genes and their association with the immune infiltration and prognosis in bladder urothelial carcinoma.

Background: Bladder urothelial carcinoma (BLCA) is a malignant tumor of the urinary system. This study aimed to explore the potential role of lymph node metastasis-associated aberrant methylation differentially expressed genes (DEGs) in BLCA. Methods: CHAMP and limma packages were used to identify lymph node metastasis-associated aberrant methylation DEGs. Univariate Cox analysis and Lasso analysis were performed to identify the signature genes, and multivariate Cox analysis was used to construct the risk score. Subsequently, the molecular characteristics of the signature genes and the relationship between risk score and prognosis, clinical characteristics and immune cell infiltration were analyzed. The signature gene AKAP7 was selected for functional verification. Results: A novel risk score model was constructed based on 12 signature genes. The risk score had a good ability to predict overall survival (OS). The nomogram constructed based on age, N stage and risk score had a higher value in predicting the prognosis of patients. It was also found that stromal activation in TIME may inhibit the antitumor effects of immune cells. Functional enrichment analysis revealed that ECM receptor interaction and focal adhesion were two important pathways involved in the regulation of BLCA. Immunohistochemistry showed that AKAP7 may be associated with the occurrence, clinical stages and grades, and lymph node metastasis of BLCA. In vitro cell experiments showed that the migration and invasion ability of EJ cells was significantly inhibited after AKAP7 overexpression, while the migration and invasion ability of T24 cells was significantly promoted after AKAP7 knockdown. Conclusion: The risk score model based on lymph node metastasis-associated aberrant methylation DEGs has a good ability to predict OS and is an independent prognostic factor for BLCA. It was also found that stromal activation in TIME may inhibit the antitumor effects of immune cells. This implicates aberrant methylation modifications as an important factor contributing to the heterogeneity and complexity of individual tumor microenvironments. Functional enrichment analysis revealed that ECM receptor interaction and focal adhesion were two important pathways involved in the regulation of BLCA, which contributed to the exploration of the pathological mechanism of BLCA. In addition, immunohistochemistry showed that AKAP7 may be associated with the occurrence, progression and lymph node metastasis of BLCA. In vitro cell experiments showed that AKAP7 could also inhibit the migration and invasion of cancer cells.

Different methods of vaginal preparation before cesarean delivery to prevent postoperative infection: a systematic review and network meta-analysis.

OBJECTIVE: Precesarean vaginal antisepsis can benefit pregnant women with ruptured membranes. However, in the general population, recent trials have shown mixed results in reducing postoperative infections. This study aimed to systematically review clinical trials and summarize the most suitable vaginal preparations for cesarean delivery in preventing postoperative infection. DATA SOURCES: We searched PubMed, Web of Science, Cochrane Library, SinoMed databases, and the ClinicalTrials.gov clinical trials registry for randomized controlled trials and conference presentations (past 20 years, 2003-2022). Reference lists of previous meta-analyses were searched manually. In addition, we conducted subgroup analysis on the basis of whether the studies were conducted in developed or developing countries, whether the membranes were ruptured, and whether patients were in labor. STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials comparing vaginal preparation methods for the prevention of postcesarean infection with each other or with negative controls. METHODS: Two reviewers independently extracted data and assessed the risk of bias and the certainty of the evidence. The effectiveness of prevention strategies was assessed by frequentist-based network meta-analysis models. The outcomes were endometritis, postoperative fever, and wound infection. RESULTS: A total of 23 trials including 10,026 cesarean delivery patients were included in this study. Vaginal preparation methods included 19 iodine-based disinfectants (1%, 5%, and 10% povidone-iodine; 0.4% and 0.5% iodophor) and 4 guanidine-based disinfectants (0.05% and 0.20% chlorhexidine acetate; 1% and 4% chlorhexidine gluconate). Overall, vaginal preparation significantly reduced the risks of endometritis (3.4% vs 8.1%; risk ratio, 0.41 [0.32-0.52]), postoperative fever (7.1% vs 11.4%; risk ratio, 0.58 [0.45-0.74]), and wound infection (4.1% vs 5.4%; risk ratio, 0.73 [0.59-0.90]). With regard to disinfectant type, iodine-based disinfectants (risk ratio, 0.45 [0.35-0.57]) and guanidine-based disinfectants (risk ratio, 0.22 [0.12-0.40]) significantly reduced the risk of endometritis, and iodine-based disinfectants reduced the risk of postoperative fever (risk ratio, 0.58 [0.44-0.77]) and wound infection (risk ratio, 0.75 [0.60-0.94]). With regard to disinfectant concentration, 1% povidone-iodine was most likely to simultaneously reduce the risks of endometritis, postoperative fever, and wound infection. CONCLUSION: Preoperative vaginal preparation can significantly reduce the risk of postcesarean infectious diseases (endometritis, postoperative fever, and wound infection); 1% povidone-iodine has particularly outstanding effects.

Erratum: In vitro and in vivo antiangiogenic activity of desacetylvinblastine monohydrazide through inhibition of VEGFR2 and Axl pathways.

[This corrects the article on p. 843 in vol. 6, PMID: 27186435.].

Analysis of the efficacy and risk factors of surgical treatment of recurrent UPJO in adults.

BACKGROUND: To compare the efficacy of secondary pyeloplasty and balloon dilation and to analyze the risk factors for secondary surgical failure in patients with recurrent uretero-pelvic junction obstruction (UPJO). METHODS: We retrospectively analyzed 65 patients with recurrent UPJO who underwent secondary surgery between September 2011 and March 2019, of whom 33 had complete baseline data and follow-up data. General clinical information, perioperative data, and follow-up results were collected from patients. Risk factors for surgical failure in patients with recurrent UPJO were analyzed using logistic regression. RESULTS: The failure rates of secondary pyeloplasty and balloon dilation in secondary surgery were 16.7% and 33.3%, respectively. Univariate analysis showed that ureteral stenosis length and operative time were associated with secondary pyeloplasty and balloon dilatation failure (p < 0.05), and ureteral stenosis length was an independent risk factor for secondary pyeloplasty failure (OR = 0.074, 95% CI: 0.006-0.864, p = 0.038). In the balloon dilation group, treatment failure rates were significantly lower in patients with stenotic segment lengths less than 1 ± 0.32 cm than in patients with stenotic segment lengths greater than 1 ± 0.32 cm (p = 0.019). CONCLUSIONS: The secondary pyeloplasty may provide better benefit. Ureteral stricture length is an independent risk factor for failure of secondary pyeloplasty and a potential risk factor for balloon dilatation. Operation time is a potential risk factor for pyeloplasty and balloon dilatation.

DNA methylation profile in CpG-depleted regions uncovers a high-risk subtype of early-stage colorectal cancer.

BACKGROUND: The current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients. METHODS: We analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation-based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively). RESULTS: The comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P < .001) and cohort 2 (hazard ratio = 3.20, 95% confidence interval = 1.92 to 5.33, P < .001). All results were further confirmed after each cohort was stratified by clinicopathological variables and molecular subtypes. CONCLUSIONS: We demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.

Autophagy in Cancer Immunotherapy.

Autophagy is a stress-induced process that eliminates damaged organelles and dysfunctional cargos in cytoplasm, including unfolded proteins. Autophagy is involved in constructing the immunosuppressive microenvironment during tumor initiation and progression. It appears to be one of the most common processes involved in cancer immunotherapy, playing bidirectional roles in immunotherapy. Accumulating evidence suggests that inducing or inhibiting autophagy contributes to immunotherapy efficacy. Hence, exploring autophagy targets and their modifiers to control autophagy in the tumor microenvironment is an emerging strategy to facilitate cancer immunotherapy. This review summarizes recent studies on the role of autophagy in cancer immunotherapy, as well as the molecular targets of autophagy that could wake up the immune response in the tumor microenvironment, aiming to shed light on its immense potential as a therapeutic target to improve immunotherapy.

Postoperative radiotherapy for thymus salivary gland carcinoma: A case report.

BACKGROUND: Salivary gland cancer is a rare disease in which cancer cells form in the tissues of the salivary glands. It mostly occurs in the glands that have secretion functions, such as the parotid gland, sublingual gland and submandibular gland. This is very rare when it occurs in other nonsecreting glands. Here, we report one case of salivary gland carcinoma occurring in the thymus and discuss related diagnoses and treatment progress. CASE SUMMARY: One 33-year-old middle-aged man presented with a thymus mass without any clinical symptoms when he underwent regular physical examination. Later, the patient was admitted to the hospital for further examination. Computed tomography (CT) showed that there was a mass of 3 cm × 2.8 cm × 1.5 cm in the thymus area. The patient had no symptom of discomfort or tumor- related medical history before. After completing the preoperative examinations, it was confirmed that the patient had indications for surgery. The surgeon performed a transthoracoscope "thymectomy + pleural mucostomy" for him. During the operation, the tumor tissue was quickly frozen, and the symptomatic section showed a malignant tumor. The final pathological result suggested thymus salivary gland carcinoma- mucoepidermoid carcinoma (MEC). In the second month after surgery, we performed local area radiotherapy for the patient, with a total radiation dose of 50.4 Gy/28Fx. After 12 mo of surgery, the patient underwent positron emission tomography-CT examination, which indicated that there was no sign of tumor recurrence or metastasis. After 16 mo of operation, CT scan re-examination showed that there was no sign of tumor recurrence or metastasis. As of the time of publication, the patient was followed up for one and a half years. He had no sign of tumor recurrence and continued to survive. CONCLUSION: The incidence of MEC in the thymus is low, and its diagnosis needs to be combined with clinical features and imaging methods. Histopathological analysis plays a key role in the diagnosis of the disease. Patients with early-stage disease have a good prognosis and long survival period. In contrast, patients with advanced-stage disease have a poor prognosis and short survival period. Combining radiotherapy and chemotherapy in inoperable patients may prolong survival.

PCSK9 Suppresses M2-Like Tumor-Associated Macrophage Polarization by Regulating the Secretion of OX40L from Hepatocellular Carcinoma Cells.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) participates in the development of various cancers, including hepatocellular carcinoma (HCC). Here, we attempted to reveal the underlying mechanism of PCSK9 in HCC. METHODS: Tumor tissues and adjacent tissues were separated from HCC patients to detect PCSK9 expression. Then, PCSK9 was overexpressed or silenced in HCC cells (MHCC97H or Huh7), and then the cell supernatant was incubated with THP-1 macrophages. OX40L neutralizing antibody (nAb) was used to inhibit OX40L activity. The expression of macrophage markers was examined by immunohistochemical staining and flow cytometry. Finally, tumor-bearing mouse model was constructed by inoculation of LV-PCSK9 infected MHCC97H cells to verify the role of PCSK in HCC. RESULTS: PCSK9 expression was decreased in tumor tissues of HCC patient specimens. HCC patients displayed M2 macrophage infiltration in tumor tissues. Moreover, PCSK9-silenced Huh7 cell supernatant promoted cell migration, and enhanced the proportion of CD206-positive cells and the expression of M2 macrophage markers IL-10 and ARG-1 in THP-1 macrophages. PCSK9-overexpressing MHCC97H cell supernatant inhibited THP-1 macrophage migration and M2-like tumor-associated macrophage (TAM) polarization, which was abolished by OX40L nAb treatment. PCSK9 overexpression enhanced the expression of OX40L in MHCC97H cells. In tumor-bearing mouse models, PCSK9 overexpression inhibited tumor growth and M2 polarization of TAMs in HCC by promoting OX40L expression. Conclusion: This work demonstrated that PCSK9 suppressed M2-like TAM polarization by regulating the secretion of OX40L from hepatocellular carcinoma cells. This study suggests that PCSK9 may be a potential target for HCC treatment.

Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages.

BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R), a classic tyrosine kinase receptor, has been identified as a proto-oncogene in multiple cancers. The CSF1/CSF1R axis is essential for the survival and differentiation of M2-phenotype tumor-associated macrophages (M2 TAMs). However, we found here that the CSF1R expression was abnormally down-regulated in colorectal cancer (CRC), and its biological functions and underlying mechanisms have become elusive in CRC progression. METHODS: The expression of class III receptor tyrosine kinases in CRC and normal intestinal mucosa was accessed using The Cancer Genome Atlas and Gene Expression Omnibus datasets and was further validated by our tested cohort. CSF1R was reconstructed in CRC cells to identify its biological functions in vitro and in vivo. We compared CSF1R expression and methylation differences between CRC cells and macrophages. Furthermore, a co-culture system was used to mimic a competitive mechanism between CSF1R-overexpressed CRC cells and M2-like macrophages. We utilized a CSF1R inhibitor PLX3397 to ablate M2 TAMs and evaluated its efficacy on CRC treatment in animal models. RESULTS: We found here that the CSF1R is silenced in CRC, and the reintroduced expression of the receptor in CRC cells can be cleaved by caspases and constrain tumor growth in vitro and in vivo, functioning as a tumor suppressor gene. We further identified CSF1R as a novel dependence receptor, which has the potential to act as either a tumor suppressor gene or an oncogene, depending on its activated state. In CRC tumors, CSF1R expression is enriched in TAMs, and its expression is associated with poor prognosis in patients ith CRC. In a co-culture system, CRC cells expressing CSF1R compete with M2-like macrophages for CSF1R ligands, resulting in a decrease in CSF1R activation and cell proliferation in macrophages. Blocking CSF1R by PLX3397 could deplete M2 TAMs and augments CD8+ T cell infiltration, effectively inhibiting tumor growth and metastasis and improving responses to chemotherapy and immunotherapy. CONCLUSION: Our findings revealed that CSF1R is a novel identified dependence receptor silenced in CRC. The silence abalienates its ligands to stimulate CSF1R expressed on M2 TAMs, which is an appealing therapeutic target for M2 TAM depletion and CRC treatment.

Partial response of metastatic cardia neuroendocrine carcinoma with the combined therapy involving PD-1 blockade after failed multi-line chemotherapies: a case report and literature review.

Cardia neuroendocrine cancer is a rare malignant tumor. The treatment regimens mainly refer to the small-cell lung cancer diagnosis and treatment guidelines and there is no standard treatment guideline specifically for neuroendocrine cancer. The use of albumin paclitaxel plus carboplatin combined with sintilimab for refractory cardia neuroendocrine carcinoma (NEC) has never been reported. This article reported a case that a 68-year-old man presented with belching without obvious reasons who was diagnosed with refractory cardia NEC by gastroscopy and pathological results. After failure of multi-line therapy including etoposide plus cisplatin as the first-line therapy, surufatinib plus toripalimab as the second-line therapy, FOLFIRI combined with bevacizumab as the third-line therapy, he received three cycles of albumin paclitaxel plus carboplatin combined with sintilimab as the fourth-line therapy and still obtained partial response of good efficiency. After the patient received this treatment regimen, the symptoms of dysphagia disappeared and the change trends of neuron-specific enolase were decreased. The computed tomography (CT) examination after three cycles of treatment was performed to show that the measured lesions have shrunk by more than 30% compared to the baseline CT. Additionally, there were no other adverse events such as nausea, vomiting, and diarrhea, except for grade III bone marrow suppression. At present, the patient is still being treated. This is the first case report that the albumin paclitaxel plus carboplatin combined with sintilimab has achieved good efficacy after failure of multi-line treatment of cardia NEC. It is very necessary to further explore the effectiveness and safety of this regimen in the treatment of NEC.

Cost-Effectiveness Analysis of First-Line Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma in the United States.

INTRODUCTION: Nivolumab plus cabozantinib improved progression-free survival and overall survival compared with sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC) according to CheckMate 9ER study. METHODS: A Markov model was developed to compare the costs and effectiveness of nivolumab plus cabozantinib with those of sunitinib in the first-line treatment of advanced RCC. Primary outcomes were costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Model uncertainty was assessed in univariable and probabilistic sensitivity analyses. RESULTS: The total cost per patient was $681,425 for nivolumab plus cabozantinib and $256,302 for sunitinib. The incremental QALY for nivolumab plus cabozantinib was 0.49 compared with sunitinib. The ICER for nivolumab plus cabozantinib was $863,720 per QALY gained versus sunitinib. The results remained robust in univariable and probabilistic sensitivity analyses. CONCLUSIONS: On the basis of a willingness-to-pay threshold of $150,000, nivolumab plus cabozantinib was not cost-effective under current drug pricing in the first-line treatment of advanced RCC from a US payer's perspective.

Comprehensive analysis of EMT-related genes and lncRNAs in the prognosis, immunity, and drug treatment of colorectal cancer.

BACKGROUND: EMT is an important biological process in the mechanism of tumor invasion and metastasis. However, there are still many unknowns about the specific mechanism of EMT in tumor. At present, a comprehensive analysis of EMT-related genes in colorectal cancer (CRC) is still lacking. METHODS: All the data were downloaded from public databases including TCGA database (488 tumor samples and 52 normal samples) as the training set and the GEO database (GSE40967 including 566 tumor samples and 19 normal samples, GSE12945 including 62 tumor samples, GSE17536 including 177 tumor samples, GSE17537 including 55 tumor samples) as the validation sets. One hundred and sixty-six EMT-related genes (EMT-RDGs) were selected from the Molecular Signatures Database. Bioinformatics methods were used to analyze the correlation between EMT-RDGs and CRC prognosis, metastasis, drug efficacy, and immunity. RESULTS: We finally obtained nine prognostic-related EMT-RDGs (FGF8, NOG, PHLDB2, SIX2, SNAI1, TBX5, TIAM1, TWIST1, TCF15) through differential expression analysis, Unicox and Lasso regression analysis, and then constructed a risk prognosis model. There were significant differences in clinical characteristics, 22 immune cells, and immune functions between the high-risk and low-risk groups and the different states of the nine prognostic-related EMT-RDGs. The methylation level and mutation status of nine prognostic-related EMT-RDGs all affect their regulation of EMT. The Cox proportional hazards regression model was also constructed by the methylation sites of nine prognostic-related EMT-RDGs. In addition, the expression of FGF8, PHLDB2, SIX2, and SNAIL was higher and the expression level of NOG and TWIST1 was lower in the non-metastasis CRC group. Nine prognostic-related EMT-RDGs also affected the drug treatment response of CRC. CONCLUSIONS: Targeting these nine prognostic-related EMT-RDGs can regulate CRC metastasis and immune, which is beneficial for the prognosis of CRC patients, improve drug sensitivity in CRC patients.

The role of non-apoptotic cell death in the treatment and drug-resistance of digestive tumors.

Tumor cell apoptosis evasion is one of the main reasons for easy metastasis occurrence, chemotherapy resistance, and the low five-year survival rate of digestive system tumors. Current research has shown that non-apoptotic cell death plays an important role in tumors of the digestive system. Therefore, increasing the proportion of non-apoptotic tumor cells is one of the effective methods of improving therapeutic efficacies for digestive system tumors. Non-apoptotic cell death modes mainly include autophagic cell death, pyroptosis, ferroptosis, in addition to other cell death modes. This review covers a systematic review relating to the research progress made into autophagic cell death, pyroptosis, ferroptosis, and other cell death modes in the treatment of digestive system tumors. It also highlights how treatment is a reasonable prospect based on clinical experience and provides reliable guidance for the further development of digestive system tumor treatments.

The Addition of Preoperative Radiation Is Insufficient for Lateral Pelvic Control in a Subgroup of Patients With Low Locally Advanced Rectal Cancer: A Post Hoc Study of a Randomized Controlled Trial.

BACKGROUND: The local recurrence of rectal cancer has been improved by total mesorectal excision following neoadjuvant chemoradiotherapy. However, in patients with low locally advanced rectal cancer, lateral pelvic recurrence remains to be addressed. OBJECTIVE: This study aimed to determine the efficiency of neoadjuvant radiotherapy in addressing lateral pelvic recurrence and which subgroup of patients might be optimal to receive lateral lymph node dissection. DESIGN: The MRI/CT images were reassessed for lateral lymph node status. The lateral lymph nodes with short axis ≥5 mm and ≥4 mm were considered positive in pretreatment and restaging MRI/CT. SETTING: This was a post hoc analysis of a prospective randomized controlled trial (FOWARC, NCT01211210). PATIENTS: A total of 495 patients with stage II or III rectal adenocarcinoma were included in the original trial. According to the excluding criteria, the finally included population consists of 253 patients; of these, 195 patients received neoadjuvant chemoradiotherapy and 94 received chemotherapy alone. MAIN OUTCOMES AND MEASURES: The primary outcome was the 5-year lateral pelvic recurrence rate. RESULTS: Compared with patients receiving chemotherapy alone, patients receiving additional radiotherapy had a marginal significance of lower lateral pelvic recurrence rate (6.6% vs 13.0%; p = 0.051). In the subset with pretreatment positive lateral lymph nodes, patients had a lateral pelvic recurrence rate of 22.6% and 45.1% after neoadjuvant chemoradiotherapy and chemotherapy alone. Of note, 34.9% of the pretreatment positive lateral lymph nodes were persistent after neoadjuvant chemoradiotherapy, culminating in a lateral pelvic recurrence rate of 63.3%. LIMITATIONS: This is a post hoc analysis, and only the patients from the leading center were included, which limited the sample size. In addition, the lateral lymph node dissection was not performed in this cohort. CONCLUSIONS: The addition of radiotherapy in neoadjuvant regimens could not address lateral pelvic recurrence adequately. Some subgroups of patients might need additional dissection. See Video Abstract at http://links.lww.com/DCR/B613. LA INCLUSION DE LA RADIOTERAPIA PREOPERATORIA ES INSUFICIIENTE EN EL CONTROL PLVICO LATERAL EN UN SUBGRUPO DE PACIENTES CON CNCER DE RECTO INFERIOR LOCALMENTE AVANZADO UN ESTUDIO POSTHOC CONTROLADO Y RANDOMIZADO: ANTECEDENTES:La recurrencia local del cancer de recto ha disminuido al efectuar una excision mesorrectal total seguida de quimioradioterapia neoadyuvante. No obstante, en pacientes con cancer de tercio inferior de recto avanzado localmente, aún está por controlarse la recurrencia pélvicaOBJETIVOS:Determinar la eficacia de la radioterapia neoadyuvante en el control de la recurrencia pélvica lateral y en que subgrupo de pacientes sería conveniente efecutar una excisión lateral de las cadenas ganglionares.DISEÑO:Se reevaluaron las imágenes tomográficas y de resonancia magnética del status de las cadenas ganglionares linfáticas laterales. Los ganglios linfáticos laterales con un eje-corto > 5 mm y ≥ 4 mm se consideraron como positivos previo al tratamiento y reestadificados con RM y TAC respectivamente.ESCENARIO:Es un análisis post hoc de un studio prospectivo randomizado controlado (FOWARC, NCT01211210).PACIENTESSe incluyeron un total de 495 pacientes en estdio II o III con adenomcarcinoma rectal en el estudio original. De acuerdo a los criterios de exclusión, la población final incluida consistió en 253 pacientes; de estos, 195 recibieron quimioradioterapia neoadyuvante y 94 quimioterapia sola.EVALUACION DE LOS RESULTADOS PRINCIPALES:El parámetro mas importante fue la tasa de recurrencia pélvica lateral a cinco años.RESULTADOS:En comparación con los pacientes que recibieron quimioterapia sola, aquellos que además fueron sometidos a radioterapia adicional presentaron un margen significativo de menor tasa de recurrencia pélvica lateral (6.6% vs. 13.0%; p=0.051). En el grupo de pacientes con ganglios linfáticos laterales positivos, los enfermos presentaron una tasa de recurrencia pélvica lateral de 22.6% y 45.1% después de quimioradiaterapia neoadyuvante en comparación con quimioterapia sola respectivamente. Cabe mencionar que el 34.9% de los pacientes con ganglios linfáticos laterales positivos antes del tratamiento persistieron después de la quimioradioterapia neoadyuvante, reportándose finalmente una recurrencia pélvica lateral de un 63.3%.LIMITACIONES:Se trata de un análisis posthoc y solo los pacientes del hospital fueron incluidos, lo que limita el tamaño de la muestra. Además, no se efectuó la disección de los ganglios linfáticos laterales en este grupo.CONCLUSIONES:La radioterapia en los esquemas de neoadyuvancia no logran controlar la recurrencia pélvica lateral en forma adecuada. Algunos subgrupos de pacientes podría requerir de disección adicional. Consulte Video Resumen en http://links.lww.com/DCR/B613.

Dysregulation of lncRNAs in Rheumatoid Arthritis: Biomarkers, Pathogenesis and Potential Therapeutic Targets.

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology, mainly manifested by persistent abnormal proliferation of fibroblast-like synoviocytes (FLSs), inflammation, synovial hyperplasia and cartilage erosion, accompanied by joint swelling and joint destruction. Abnormal expression or function of long noncoding RNAs (lncRNAs) are closely related to human diseases, including cancers, mental diseases, autoimmune diseases and others. The abnormal sequence and spatial structure of lncRNAs, the disorder expression and the abnormal interaction with the binding protein will lead to the change of gene expression in the way of epigenetic modification. Increasing evidence demonstrated that lncRNAs were involved in the activation of FLSs, which played a key role in the pathogenesis of RA. In this review, the research progress of lncRNAs in the pathogenesis of RA was systematically summarized, including the role of lncRNAs in the diagnosis of RA, the regulatory mechanism of lncRNAs in the pathogenesis of RA, and the intervention role of lncRNAs in the treatment of RA. Furthermore, the activated signal pathways, the role of DNA methylation and other mechanism have also been overview in this review.

The Effects of Autophagy-Related Genes and lncRNAs in Therapy and Prognosis of Colorectal Cancer.

Cellular autophagy plays an important role in the occurrence and development of colorectal cancer (CRC). Whether autophagy-related genes and lncRNAs can be used as ideal markers in CRC is still controversial. The purpose of this study is to identify novel treatment and prognosis markers of CRC. We downloaded transcription and clinical data of CRC from the GEO (GSE40967, GSE12954, GSE17536) and TCGA database, screened for differentially autophagy-related genes (DEAGs) and lncRNAs, constructed prognostic model, and analyzed its relationship with immune infiltration. TCGA and GEO datasets (GSE12954 and GSE17536) were used to validate the effect of the model. Oncomine database and Human Protein Atlas verified the expression of DEAGs. We obtained a total of 151 DEAGs in three verification sets collaboratively. Then we constructed a risk prognostic model through Lasso regression to obtain 15 prognostic DEAGs from the training set and verified the risk prognostic model in three verification sets. The low-risk group survived longer than the high-risk group. Age, gender, pathological stage, and TNM stage were related to the prognostic risk of CRC. On the other hand, BRAF status, RFS event, and tumor location are considered as most significant risk factors of CRC in the training set. Furthermore, we found that the immune score of the low-risk group was higher. The content of CD8 + T cells, active NK cells, macrophages M0, macrophages M1, and active dendritic cells was noted more in the high-risk group. The content of plasma cells, resting memory CD4 + T cells, resting NK cells, resting mast cells, and neutrophil cells was higher in the low-risk group. After all, the Oncomine database and immunohistochemistry verified that the expression level of most key autophagy-related genes was consistent with the results that we found. In addition, we obtained six lncRNAs co-expressed with DEAGs from the training set and found that the survival time was longer in the low-risk group. This finding was verified in the verification set and showed same trend to the results mentioned above. In the final analysis, these results indicate that autophagy-related genes and lncRNAs can be used as prognostic and therapeutic markers for CRC.