CPE correlates with poor prognosis in gastric cancer by promoting tumourigenesis.

Aims: To investigate the potential functions and mechanisms of tumourigenesis in carboxypeptidase E (CPE) and its prognostic value in gastric cancer, and to develop a predictive model for prognosis based on CPE. Results: Transcriptome level variation and the prognostic value of CPE in different types of cancers were investigated using bioinformatics analyses. The association between CPE and clinicopathological characteristics was specifically explored in gastric cancer. Elevated CPE expression was associated with poor survival and recurrence prognosis and was found in cases with a later clinical stage of gastric cancer. The CPE was considered an independent prognostic factor, as assessed using Cox regression analysis. The prognostic value of CPE was further verified through immunohistochemistry and haematoxylin staining. Enrichment analysis provided a preliminary confirmation of the potential functions and mechanisms of CPE. Immune cell infiltration analysis revealed a significant correlation between CPE and macrophage infiltration. Eventually, a prognosis prediction nomogram model based on CPE was developed. Conclusion: CPE was identified as an independent biomarker associated with poor prognosis in gastric cancer. This suggests that CPE overexpression promoted epithelial-mesenchymal transition via the activation of the Erk/Wnt pathways, leading to proliferation, invasion, and metastasis. Targeted therapeutic strategies for gastric cancer may benefit from these findings.

Predicting surgical benefit of primary tumor resection in patients with stage IV colorectal cancer.

BACKGROUND: There exists continuous controversy regarding the benefit of primary tumor resection (PTR) for stage IV colorectal cancer (CRC) patients. Little is known about how to predict the patients' benefit from PTR. This study aimed to develop a tool for surgical benefit prediction. METHODS: Stage IV CRC patients diagnosed between 2010 and 2015 from the Surveillance, Epidemiology and End Results database were included. Patients receiving PTR who survived longer than the median cancer-specific survival (CSS) time of those who did not undergo PTR were considered to benefit from surgery. Logistic regression analysis identified prognostic factors influencing surgical benefit, based on which a nomogram was constructed. The data of patients who underwent PTR from our institution was used for external validation. A user-friendly webserver was then built for convenient clinical use. RESULTS: The median CSS of the PTR group was 23 months, significantly longer than that of the non-PTR group (7 months, P < 0.001). In the PTR group, 23.3% of patients did not benefit from surgery. Logistic regression analysis identified age, marital status, tumor location, CEA level, chemotherapy, metastasectomy, tumor size, tumor deposits, number of examined lymph nodes, N stage, histological grade and number of distant metastases as independently associated with surgical benefit. The established prognostic nomogram demonstrated satisfactory performance in both the internal and external validation. CONCLUSION: PTR was associated with prolonged CSS in stage IV CRC. The proposed nomogram could be used as an evidenced-based platform for risk-to-benefit assessment to select appropriate patients for undergoing PTR.

Circular RNA circTATDN3 promotes the Warburg effect and proliferation in colorectal cancer.

As one of the key metabolic enzymes in the glycolytic pathway, lactate dehydrogenase A (LDHA) might be linked to tumor proliferation by driving the Warburg effect. Circular RNAs (circRNAs) are widely implicated in tumor progression. Here, we report that circTATDN3, a circular RNA that interacts with LDHA, plays a critical role in proliferation and energy metabolism in CRC. We found that circTATDN3 expression was increased in CRC cells and tumor tissues and that high circTATDN3 expression was positively associated with poor postoperative prognosis in CRC patients. Additionally, circTATDN3 promoted the proliferation of CRC cells in vivo and vitro. Mechanistically, circTATDN3 was shown to function as an adaptor molecule that enhances the binding of LDHA to FGFR1, leading to increased LDHA phosphorylation and consequently promoting the Warburg effect. Moreover, circTATDN3 increased the expression of LDHA by sponging miR-511-5p, which synergistically promoted CRC progression and the Warburg effect. In conclusion, circTATDN3 may be a target for the treatment of CRC.

Comparative single-cell analysis reveals heterogeneous immune landscapes in adenocarcinoma of the esophagogastric junction and gastric adenocarcinoma.

Adenocarcinoma of the esophagogastric junction (AEG) is a type of tumor that arises at the anatomical junction of the esophagus and stomach. Although AEG is commonly classified as a subtype of gastric adenocarcinoma (GAC), the tumor microenvironment (TME) of AEG remains poorly understood. To address this issue, we conducted single-cell RNA sequencing (scRNA-seq) on tumor and adjacent normal tissues from four AEG patients and performed integrated analysis with publicly available GAC single-cell datasets. Our study for the first time comprehensively deciphered the TME landscape of AEG, where heterogeneous AEG malignant cells were identified with diverse biological functions and intrinsic malignant nature. We also depicted transcriptional signatures and T cell receptor (TCR) repertoires for T cell subclusters, revealing enhanced exhaustion and reduced clone expansion along the developmental trajectory of tumor-infiltrating T cells within AEG. Notably, we observed prominent enrichment of tumorigenic cancer-associated fibroblasts (CAFs) in the AEG TME compared to GAC. These CAFs played a critical regulatory role in the intercellular communication network with other cell types in the AEG TME. Furthermore, we identified that the accumulation of CAFs in AEG might be induced by malignant cells through FGF-FGFR axes. Our findings provide a comprehensive depiction of the AEG TME, which underlies potential therapeutic targets for AEG patient treatment.

Prognostic impact of tumor budding in rectal cancer after neoadjuvant therapy: a systematic review and meta-analysis.

BACKGROUND: Tumor budding (TB) is a negative prognostic factor in colorectal cancer; however, its prognostic impact following neoadjuvant therapy for patients with rectal cancer remains unclear. This study aims to assess the prognostic impact of TB and the correlation between TB and other pathological features in patients with rectal cancer after neoadjuvant therapy. METHODS: A comprehensive search of PubMed, Embase, Cochrane, Scopus, CNKI, Wanfang, and ClinicalKey databases was conducted for studies on the prognosis of TB in rectal cancer after neoadjuvant therapy from the inception of the databases to January 2023, and the final literature included was determined using predefined criteria. Quality assessment of the studies included, extraction of general and prognostic information from them, and meta-analyses were carried out progressively. RESULTS: A total of 11 studies were included, and the results of the meta-analysis showed that high-grade tumor budding (TB-1) increased the risk of poor 5-year disease-free survival (HR = 1.75, 95% CI 1.38-2.22, P < 0.00001), 5-year overall survival (HR = 1.77, 95% CI 1.21-2.59, P = 0.003), local recurrence (OR = 4.15, 95% CI 1.47-11.75, P = 0.007), and distant metastasis (OR = 5.36, 95% CI 2.51-11.44, P < 0.0001) in patients with rectal cancer after neoadjuvant therapy. TB-1 was significantly associated with poor differentiation and lymphatic, perineural, and venous invasion. CONCLUSION: Tumor budding is significantly correlated with unfavorable prognosis and poor pathological characteristics following neoadjuvant therapy for rectal cancer. We anticipate more high-quality, prospective studies in the future to confirm our findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022377564.

Reproductive Profile of Neuronal Androgen Receptor Knockout Female Mice With a Low Dose of DHT.

Hyperandrogenism and polycystic ovarian syndrome result from the imbalance or increase of androgen levels in females. Androgen receptor (AR) mediates the effects of androgens, and this study examines whether neuronal AR plays a role in reproduction under normal and increased androgen conditions in female mice. The neuron-specific AR knockout (KO) mouse (SynARKO) was generated from a female mouse (synapsin promoter driven Cre) and a male mouse (Ar fl/y). Puberty onset and the levels of reproductive hormones such as LH, FSH, testosterone, and estradiol were comparable between the control and the SynARKO mice. There were no differences in cyclicity and fertility between the control and SynARKO mice, with similar impairment in both groups on DHT treatment. Neuronal AR KO, as in this SynARKO mouse model, did not alleviate the infertility associated with DHT treatment. These studies suggest that neuronal AR KO neither altered reproductive function under physiological androgen levels, nor restored fertility under hyperandrogenic conditions.

Pathological-Features-Modified TNM Staging System Improves Prognostic Accuracy for Rectal Cancer.

BACKGROUND: Variations in survival outcomes are observed in the eighth edition of the American Joint Committee on Cancer TNM staging system. OBJECTIVE: Machine learning ensemble methods were used to develop and evaluate the effectiveness of a pathological-features-modified TNM staging system in predicting survival for patients with rectal cancer by use of commonly reported pathological features, such as histological grade, tumor deposits, and perineural invasion, to improve the prognostic accuracy. DESIGN: This was a retrospective population-based study. SETTINGS: Data were assessed from the database of the Surveillance, Epidemiology, and End Results Program. PATIENTS: The study cohort comprised 14,468 patients with rectal cancer diagnosed between 2010 and 2015. The development cohort included those who underwent surgery as the primary treatment, whereas patients who received neoadjuvant therapy were assigned to the validation cohort. MAIN OUTCOME MEASURES: The primary outcome measures included cumulative rectal cancer survival, adjusted HRs, and both calibration and discrimination statistics to evaluate model performance and internal validation. RESULTS: Multivariable Cox regression analysis identified all 3 pathological features as prognostic factors, after which patients were categorized into 4 pathological groups based on the number of pathological features (ie, 0, 1, 2, and 3). Distinct survival differences were observed among the groups, especially with patients with stage III rectal cancer. The proposed pathological-features-modified TNM staging outperformed the TNM staging in both the development and validation cohorts. LIMITATIONS: Retrospective in design and lack of external validation. CONCLUSIONS: The proposed pathological-features-modified TNM staging could complement the current TNM staging by improving the accuracy of survival estimation of patients with rectal cancer. See Video Abstract . EL SISTEMA DE ESTADIFICACIN TNM CON CARACTERSTICAS PATOLGICAS MODIFICADO MEJORA LA PRECISIN DEL PRONSTICO DEL CNCER DE RECTO: ANTECEDENTES:Se observan variaciones en los resultados de supervivencia en el sistema de estadificación TNM del Comité Conjunto Americano del Cáncer 8º ediciónOBJETIVO:Se utilizaron métodos conjuntos de aprendizaje automático para desarrollar y evaluar la eficacia de un sistema de estadificación con características patológicas modificadas de tumores, ganglios y metástasis para predecir la supervivencia de pacientes con cáncer de recto, utilizando algunas características patológicas comúnmente informadas, como el grado histológico, depósitos tumorales e invasión perineural, para mejorar la precisión del pronóstico.DISEÑO:Este fue un estudio retrospectivo de base poblacional.ENTERNO CLINICO:Se recuperaron y evaluaron datos de la base de datos de Vigilancia, Epidemiología y Resultados Finales.PACIENTES:La cohorte del estudio estuvo compuesta por 14,468 pacientes con cáncer de recto diagnosticados entre 2010 y 2015. La cohorte de desarrollo incluyó a aquellos que se sometieron a cirugía como tratamiento primario, mientras que los pacientes que recibieron terapia neoadyuvante fueron asignados a la cohorte de validación.PRINCIPALES MEDIDAS DE RESULTADO:Las medidas de resultado primarias incluyeron supervivencia acumulada del cáncer de recto, índices de riesgo ajustados y estadísticas de calibración y discriminación para evaluar el rendimiento del modelo y la validación interna.RESULTADOS:El análisis de regresión multivariable de Cox identificó las tres características patológicas como factores pronósticos, después de lo cual los pacientes se clasificaron en cuatro grupos patológicos según el número de características patológicas (es decir, 0, 1, 2 y 3). Se observaron distintas diferencias en la supervivencia entre los grupos, especialmente en los pacientes en estadio III. La estadificación propuesta con características patológicas modificadas de tumores-ganglios-metástasis superó a la estadificación TNM tanto en las cohortes de desarrollo como en las de validación.LIMITACIONES:Diseño retrospectivo y falta de validación externa.CONCLUSIONES:La estadificación propuesta con características patológicas modificadas de tumores-ganglios-metástasis podría complementar la estadificación TNM actual al mejorar la precisión de la estimación de supervivencia de los pacientes con cáncer de recto. (Traducción- Dr. Francisco M. Abarca-Rendon ).

NF-κB downstream miR-1262 disturbs colon cancer cell malignant behaviors by targeting FGFR1.

Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions in vitro using cancer cells and in vivo using a subcutaneous xenograft model. miRNA downstream targets are analyzed, and predicted binding and regulation are verified. miR-1262, an antitumor miRNA, is downregulated in colon cancer tissue samples and cell lines. miR-1262 overexpression suppresses colon cancer malignant behaviors in vitro and tumor development and metastasis in a subcutaneous xenograft model and a lung metastasis mouse model in vivo. miR-1262 directly targets fibroblast growth factor receptor 1 (FGFR1) and inhibits FGFR1 expression. FGFR1 overexpression shows oncogenic functions through the regulation of cancer cell proliferation, invasion, and migration; when cotransfected, lv-FGFR1 partially attenuates the antitumor effects of agomir-1262. NF-κB binds to the miR-1262 promoter region and inhibits transcription activity. The NF-κB inhibitor CAPE exerts antitumor effects; miR-1262 inhibition partially reverses CAPE effects on colon cancer cells. Conclusively, miR-1262 serves as an antitumor miRNA in colon cancer by targeting FGFR1. The NF-κB/miR-1262/FGFR1 axis modulates colon cancer cell phenotypes, including proliferation, invasion, and migration.

SIK1 suppresses colorectal cancer metastasis and chemoresistance via the TGF-ß signaling pathway.

In the present study, we investigated the role of salt-induced kinase 1 (SIK1), a serine/threonine kinase protein, in colorectal cancer (CRC). Despite the reported association of SIK1 with tumor malignancy suppression in various cancers, limited research has been conducted on its function in CRC. Our findings revealed that SIK1 expression was low in CRC cells. The results of a KEGG pathway analysis showed a strong association between SIK1 and the TGF-ß signaling pathway. In addition, a coimmunoprecipitation assay validated the interaction between SIK1 and Smad7. Our data indicate that SIK1 inhibited the phosphorylation of Smad2, a critical molecule in the Smad-related TGF-ß pathway, and downstream target genes of the TGF-ß pathway. Furthermore, SIK1 was found to inhibit indicators of epithelial-mesenchymal transition (EMT) and reverse oxaliplatin resistance in CRC. Additionally, SIK1 reduced cell migration and invasion. Our results suggest that the inhibitory effect of SIK1 on the TGF-ß pathway contributes to the suppression of metastasis and oxaliplatin chemoresistance in CRC. However, this effect was reversed by galunisertib (LY2157299). In conclusion, our findings provide novel insights into the role of SIK1 in the regulation of the TGF-ß pathway in CRC, suggesting its potential as a therapeutic target for the treatment of CRC. Further studies are required to fully characterize the mechanism underlying these observations and to validate these findings in animal models.

Neuronal AR Regulates Glucose Homeostasis and Energy Expenditure in Lean Female Mice With Androgen Excess.

Hyperandrogenemia and polycystic ovary syndrome are a result of the imbalance of androgen levels in females. Androgen receptor (Ar) mediates the effect of androgen, and this study examines how neuronal Ar in the central nervous system mediates metabolism under normal and increased androgen conditions in female mice. The neuron-specific ARKO mouse (SynARKO) was created from female (Ar fl/wt; synapsin promoter driven Cre) and male (Ar fl/y) mice. A glucose tolerance test revealed impaired glucose tolerance that was partially alleviated in the SynARKO-dihydrotestosterone (DHT) mice compared with Con-DHT mice after 4 months of DHT treatment. Heat production and food intake was higher in Con-DHT mice than in Con-veh mice; these effects were not altered between SynARKO-veh and SynARKO-DHT mice, indicating that excess androgens may partially alter calorie intake and energy expenditure in females via the neuronal Ar. The pAkt/Akt activity was higher in the hypothalamus in Con-DHT mice than in Con-veh mice, and this effect was attenuated in SynARKO-DHT mice. Western blot studies show that markers of inflammation and microglia activation, such as NF-kB p-65 and IBA1, increased in the hypothalamus of Con-DHT mice compared with Con-veh. These studies suggest that neuronal Ar mediates the metabolic impacts of androgen excess in females.

Which treatment strategy is optimal for acute left-sided malignant colonic obstruction? A Bayesian meta-analysis.

PURPOSE: This study aimed to determine the best treatment for acute left-sided malignant colonic obstruction (ALMCO) among emergency surgery (ES), self-expanding metallic stent (SEMS), transanal drainage tube (TD), and decompressive stoma (DS). METHOD: Articles that compared two or more treatments of ALMCO were searched from PubMed, Cochrane Library, and Embase. Network meta-analyses were performed to calculate the outcomes of primary anastomosis, stoma creation, morbidity, mortality, and 5-year survival. RESULTS: Fifty-one articles met inclusion criteria. TD was the optimal treatment in performing primary anastomosis [probability of ranking first (Pro-1) 0.96], while ES was the worst [probability of ranking fourth (Pro-4) 0.99]. More permanent stoma was formed in ES and TD groups than in SEMS and DS groups [OR (95%CI): TD vs SEMS: 4.12 (1.89, 9.45); TD vs DS: 3.39 (1.46, 8.75); ES vs DS: 2.55 (1.73, 4.17); SEMS vs ES: 0.33 (0.24, 0.42)]. More morbidity occurred in ES group than in SEMS group [OR (95%CI): ES vs SEMS: 1.44 (1.14, 1.82)]. Besides, SEMS was ranked first in avoiding infection (Pro-4 0.95). For in-hospital mortality, ES was ranked first (Pro-1 0.93). TD was ranked first in recurrence (Pro-1 0.97) and metastasis (Pro-1 0.98). There was no discrepancy in 5-year overall and disease-free survival among all strategies. CONCLUSION: SEMS as a bridge to surgery reduces stoma formation, and morbidity especially the infection rate with relatively great oncological outcomes. Therefore, SEMS should be recommended first for ALMCO in the medical center with experience and conditions.

Constructing and Validating a Dynamic Nomogram to Predict Response to Bariatric Surgery: A Multicenter Retrospective Study.

PURPOSE: Suboptimal response is one of the major problems for bariatric surgery, and constructing an individualized model for predicting outcomes of bariatric surgery is essential. Thus, the aim of this study is to develop a nomogram to predict the response to bariatric surgery. MATERIALS AND METHODS: 509 patients who underwent bariatric surgery between 2019 to 2020 from 6 centers were retrieved and assessed. Multiple Imputation was used to replace missing data. Patients with %TWL ≥ 20% 1 year after bariatric surgery were classified as patients with optimal response, while the others were patients with suboptimal response. A web-based nomogram was constructed and validated. ROC curve and calibration curve were used to determine the predictive ability of our model. RESULTS: 56 (11.0%) patients were classified as patients with suboptimal response, and they showed advanced age, lower pre-operative BMI, smaller waist circumference, higher fasting glucose, higher HbA1c and lower fasting insulin compared to patients with optimal response. A forward likelihood ratio logistic regression analysis indicated that age (OR = 0.943, 95% CI: 0.915-0.971, p < 0.001), pre-operative BMI (OR = 1.109, 95% CI: 1.002-1.228, p = 0.046) and waist circumference (OR = 1.043, 95% CI: 1.000-1.088, p = 0.048) were essential factors contributing to the response to bariatric surgery. Lastly, a web-based nomogram was constructed to predict the response to bariatric surgery and demonstrated an AUC of 0.829 and 0.798 upon internal and external validation. CONCLUSION: Age, BMI and fasting glucose were proved to be essential factors influencing the response to bariatric surgery. The nomogram constructed in this study demonstrated good adaptivity.

Development of a prognostic model based on ferroptosis-related genes for colorectal cancer patients and exploration of the biological functions of NOS2 in vivo and in vitro.

Background: Ferroptosis is involved in many malignant tumors and has been implicated in important mechanisms of colorectal cancer (CRC) suppression. However, the prognostic and predictive values of the ferroptosis activation pattern in CRC patients have not been noted. Here, we aimed to construct and validate a prediction model based on ferroptosis-related genes (FRGs) for CRC patients and investigated the expression pattern and biological function of the most significantly altered gene. Methods: A total of 112 FRGs were obtained from the FerrDb website, and the clinical characteristics of 545 CRC patients and their global gene expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Survival-related FRGs were identified by Cox proportional hazards regression analysis. Finally, the expression pattern and biological function of NOS2, the most implicated gene was explored in vitro and in vivo. Results: The prediction model was established based on 8 FRGs. Patients in the high- or low-risk group were stratified based on the median risk value calculated by our model, and patients in the high-risk group experienced poor overall survival (p<0.01). Further validation demonstrated that the FRG model acted as an independent prognostic indicator for CRC patients (HR=1.428, 95% CI, 1.341-1.627; p<0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for 5-year survival was 0.741. NOS2 was one of the most significantly affected FRGs and was highly expressed in malignant tissue, but it inhibited tumor growth and induced tumor cell death in vitro and in vivo, possibly by repressing the NF-κB pathway. Conclusion: Our study revealed that FRGs have potential prognostic value in CRC patients and that NOS2 suppresses tumor progression, providing a novel therapeutic target for CRC treatment based on ferroptosis.

Evaluation of early liquid drinking after radical gastrectomy in gastric cancer: a Chinese multicenter propensity score matching analysis.

Background: Enhanced recovery after surgery is used in gastrointestinal surgery. This study aimed to access the effects of early liquid drinking (ELD) on gastrointestinal function recovery in patients with gastric cancer (GC) who underwent radical gastrectomy, as high-quality evidence on the outcomes of ELD after gastrectomy is currently lacking. Methods: Clinicopathological data of patients with GC from 11 centers were retrospectively analysed. Clinical outcomes were investigated in 555 patients, including 225 who started drinking liquid within 48 h (ELD group) of surgery and 330 who started drinking liquid after flatus resumption (traditional liquid drinking [TLD] group). Propensity score matching (PSM) analysis was performed using a match ratio of 1:1 and 201 patients were selected from each group for the analysis. Primary outcome was time to first passage of flatus. Secondary outcomes included time to first defecation, post-operative hospitalization days, occurrence of short-term post-operative complications, and hospitalization costs. Results: After PSM, baseline characteristics were not significantly different between the two groups. The time to first flatus (2.72 ± 1.08 vs 3.36 ± 1.39 days), first defecation (4.34 ± 1.85 vs 4.77 ± 1.61 days), and post-operative hospital stay (8.27 ± 4.02 vs 12.94 ± 4.43 days) were shorter in the ELD group than in the TLD group (all P < 0.05). The ELD group had lower hospitalization costs than the TLD group ([7.83 ± 2.44 vs 8.78 ± 3.41] × 104 RMB, P = 0.041). No significant differences were observed in the incidence of post-operative complications. Conclusions: Compared with TLD, post-operative ELD could promote rapid recovery of gastrointestinal function and reduce hospitalization costs; moreover, ELD does not increase the risk of post-operative complications.

Delivery of Engineered Primary Tumor-Derived Exosomes Effectively Suppressed the Colorectal Cancer Chemoresistance and Liver Metastasis.

Liver metastasis is one of the major causes of colorectal cancer (CRC)-related morbidity and mortality. Delivering small interfering RNAs (siRNAs) or noncoding RNAs has been reported as a promising method to target liver metastasis and chemoresistance in CRC. Here, we report a noncoding RNA delivery system using exosomes derived from primary patient cells. Coiled-coil domain-containing protein 80 (CCDC80) was strongly associated with CRC liver metastasis and chemoresistance, a finding validated by bioinformatic analysis and clinical specimens. Silencing CCDC80 significantly increased sensitivity to chemotherapy agents in OXA-resistant cell lines and a mouse model. The primary cell-derived exosome delivery system was designed to simultaneously deliver siRNAs targeting CCDC80 and increase chemotherapy sensitivity in the distant CRC liver metastasis mouse models and patient-derived xenograft mouse models. We further validated the antitumor effect in an ex vivo model of chemoresistant CRC organoids and a patient-derived organoid xenograft model. Tumor-bearing mice treated with the siRNA-delivering exosomes and hepatectomy showed ideal overall survival. Our results provide a therapeutic target and represent a possible therapeutic alternative for patients with CRC and distant metastasis and in cases of chemoresistance.

A Novel Protein Encoded by Exosomal CircATG4B Induces Oxaliplatin Resistance in Colorectal Cancer by Promoting Autophagy.

Oxaliplatin is commonly used in chemotherapeutic regimens for colorectal cancer (CRC) after surgical resection. However, acquired chemoresistance seriously affects the curative effect in CRC patients, and the mechanism is still unclear. Here, a circular RNA, circATG4B is identified, which plays an important role in oxaliplatin resistance in CRC. circATG4B expression is found to be increased in exosomes secreted by oxaliplatin-resistant CRC cells. In addition, the results suggest that circATG4B induces oxaliplatin resistance by promoting autophagy. Further in vivo and in vitro studies indicate that the effect of circATG4B is attributed to its potential to encode a novel protein, circATG4B-222aa. Next, circATG4B-222aa is found to function as a decoy to competitively interact with TMED10 and prevent TMED10 from binding to ATG4B, which leads to increased autophagy followed by induction of chemoresistance. Therefore, this study reveals that exosomal circATG4B participates in the decreased chemosensitivity of CRC cells, providing a new rationale for a potential therapeutic target for oxaliplatin resistance in CRC.

Targeting histone demethylases as a potential cancer therapy (Review).

Post­translational modifications of histones by histone demethylases have an important role in the regulation of gene transcription and are implicated in cancers. Recently, the family of lysine (K)­specific demethylase (KDM) proteins, referring to histone demethylases that dynamically regulate histone methylation, were indicated to be involved in various pathways related to cancer development. To date, numerous studies have been conducted to explore the effects of KDMs on cancer growth, metastasis and drug resistance, and a majority of KDMs have been indicated to be oncogenes in both leukemia and solid tumors. In addition, certain KDM inhibitors have been developed and have become the subject of clinical trials to explore their safety and efficacy in cancer therapy. However, most of them focus on hematopoietic malignancy. This review summarizes the effects of KDMs on tumor growth, drug resistance and the current status of KDM inhibitors in clinical trials.

Effects of Preoperative Radiotherapy on Long-Term Bowel Function in Patients With Rectal Cancer Treated With Anterior Resection: A Systematic Review and Meta-analysis.

Background: Anterior resection is a common surgical approach used in rectal cancer surgery; however, this procedure is known to cause bowel injury and dysfunction. Neoadjuvant therapy is widely used in patients with locally advanced rectal cancer. In this study, we determined the effect of preoperative radiotherapy on long-term bowel function in patients who underwent anterior resection for treatment of rectal cancer. Methods: We performed a comprehensive literature search of the PubMed, Embase, Web of Science, and the Cochrane Library databases. A random-effects model was used in the meta-analysis by the Review Manager software, version 5.3. Results: This systematic review and meta-analysis included 12 studies, which used low anterior resection syndrome score with a total of 2349 patients. Based on them, we concluded that low anterior resection syndrome was significantly more common in the preoperative radiotherapy group (odds ratio 3.59, 95% confidence interval 2.68-4.81, P < .00001) and that major low anterior resection syndrome also occurred significantly more frequently in the preoperative radiotherapy group (odds ratio 3.28, 95% confidence interval 2.05-5.26, P < .00001). Subgroup analyses of long-course radiation, total mesorectal excision, and non-metastatic tumors were performed, and the results met the conclusions of the primary outcomes. Conclusions: Preoperative radiotherapy negatively affects long-term bowel function in patients who undergo anterior resection for rectal cancer.

The ratio of serum C-reactive protein level on postoperative day 3 to day 2 is a good marker to predict postoperative complications after laparoscopic radical gastrectomy for gastric cancer.

PURPOSE: Study reported that C-reactive protein (CRP) would peak at 48 h after the initiation of an acute inflammatory response. We proposed that the ratio of CRP level on postoperative day 3 to day 2 (POD3/2 CRP) can be used to early predict major postoperative complications (PCs) for patients who underwent laparoscopic radical gastrectomy. METHODS: Patients were randomized into training cohort and validation cohort at a ratio of 7:3. PCs greater than grade II or more, according to Clavien-Dindo classification, were defined as major PCs. Three predictive models for major PCs based on CRP level were constructed, including POD3/2 CRP, the CRP level on POD3 (POD3 CRP), and the ratio of CRP level on POD3 to POD1 (POD3/1 CRP). The performances of three prediction models were assessed by AUC. Univariate and multivariate logistic regression analyses were performed to identify risk factors of major PCs. RESULTS: 344 patients were included. Major PCs were observed in 57 patients (16.6%). In the training cohort, POD3/2 CRP provided the best diagnostic accuracy with an AUC of 0.929 at an optimal cut-off value of 1.08, and the sensitivity and specificity were 0.902 and 0.880, respectively. In the validation cohort, the corresponding AUC was 0.917. BMI ≥ 25 kg/m2 and POD3/2 CRP > 1 were identified as risk factors for major PCs. CONCLUSION: POD3/2 CRP is a reliable marker to predict major PCs after laparoscopic radical gastrectomy. If CRP is higher on POD3 than on POD2, major PCs are highly likely.

Tumor Deposits and Perineural Invasion had Comparable Impacts on the Survival of Patients With Non-metastatic Colorectal Adenocarcinoma: A Population-Based Propensity Score Matching and Competing Risk Analysis.

BACKGROUND: Both tumor deposits (TD) and perineural invasion (PNI) have been identified as risk factors for poor survival in patients with non-metastatic colorectal adenocarcinoma (CRC). However, the adverse impacts of TD and PNI on the survival of patients with non-metastatic CRC have not been compared. METHOD: Patients with non-metastatic CRC with known TD and PNI status were selected from the Surveillance, Epidemiology, and End Results (SEER) database. First, bivariate logistic regression analysis was utilized to identify the factors associated with TD and PNI status. Then, patients were divided into four groups, according to TD and PNI status. Propensity score matching (PSM) was performed to balance the baseline covariates. The impact of TD and PNI on survival was assessed by analyzing overall survival (OS) and cancer-specific mortality (CSM) rates. OS was calculated by the Kaplan-Meier method with log-rank analysis. CSM was estimated by competing risk analysis using the Fine and Gray model. RESULTS: A total of 70 689 patients with CRC met the inclusion and exclusion criteria. The positive rates of TD and PNI were 9.37% and 9.91%, respectively. For TD, the most important risk factor was N stage. With respect to PNI, the most significant factor was T stage. Tumor location, tumor size, differentiation grade, and serum CEA level were also correlated with TD and PNI status. After PSM, 1849 pairs were selected. Patients with TD+PNI+ status had the worst 5 year CSM and 5 year OS. In addition, the long-term survival outcomes of patients with TD+PNI- and TD-PNI+ status were comparable. CONCLUSION: The adverse impacts of TD and PNI on the survival of patients with non-metastatic CRC were comparable. CRC patients with both TD and PNI positive had the worst survival outcome.