Mitophagy-related gene signature predicts prognosis, immune infiltration and chemotherapy sensitivity in colorectal cancer.

BACKGROUND: Mitophagy plays essential role in the development and progression of colorectal cancer (CRC). However, the effect of mitophagy-related genes in CRC remains largely unknown. AIM: To develop a mitophagy-related gene signature to predict the survival, immune infiltration and chemotherapy response of CRC patients. METHODS: Non-negative matrix factorization was used to cluster CRC patients from Gene Expression Omnibus database (GSE39582, GSE17536, and GSE37892) based on mitophagy-related gene expression. The CIBERSORT method was applied for the evaluation of the relative infiltration levels of immune cell types. The performance signature in predicting chemotherapeutic sensitivity was generated using data from the Genomics of Drug Sensitivity in Cancer database. RESULTS: Three clusters with different clinicopathological features and prognosis were identified. Higher enrichment of activated B cells and CD4+ T cells were observed in cluster III patients with the most favorable prognosis. Next, a risk model based on mitophagy-related genes was developed. Patients in training and validation sets were categorized into low-risk and high-risk subgroups. Low risk patients showed significantly better prognosis, higher enrichment of immune activating cells and greater response to chemotherapy (oxaliplatin, irinotecan, and 5-fluorouracil) compared to high-risk patients. Further experiments identified CXCL3 as novel regulator of cell proliferation and mitophagy. CONCLUSION: We revealed the biological roles of mitophagy-related genes in the immune infiltration, and its ability to predict patients' prognosis and response to chemotherapy in CRC. These interesting findings would provide new insight into the therapeutic management of CRC patients.

Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease.

Dysregulated maternal fatty acid metabolism increases the risk of congenital heart disease (CHD) in offspring with an unknown mechanism, and the effect of folic acid fortification in preventing CHD is controversial. Using gas chromatography coupled to either a flame ionization detector or mass spectrometer (GC-FID/MS) analysis, we find that the palmitic acid (PA) concentration increases significantly in serum samples of pregnant women bearing children with CHD. Feeding pregnant mice with PA increased CHD risk in offspring and cannot be rescued by folic acid supplementation. We further find that PA promotes methionyl-tRNA synthetase (MARS) expression and protein lysine homocysteinylation (K-Hcy) of GATA4 and results in GATA4 inhibition and abnormal heart development. Targeting K-Hcy modification by either genetic ablation of Mars or using N-acetyl-L-cysteine (NAC) decreases CHD onset in high-PA-diet-fed mice. In summary, our work links maternal malnutrition and MARS/K-Hcy with the onset of CHD and provides a potential strategy in preventing CHD by targeting K-Hcy other than folic acid supplementation.

Pharmacological Effects of Resveratrol in Intervertebral Disc Degeneration: A Literature Review.

Intervertebral disc degeneration (IDD) is a high incidence disease of musculoskeletal system that often leads to stenosis, instability, pain and even deformity of the spinal segments. IDD is an important cause of discogenic lower back pain and often leads to large economic burden to families and society. Currently, the treatment of IDD is aimed at alleviating symptoms rather than blocking or reversing pathological progression of the damaged intervertebral disc. Resveratrol (RSV) is a polyphenol phytoalexin first extracted from the Veratrum grandiflflorum O. Loes and can be found in various plants and red wine. Owing to the in-depth study of pharmacological mechanisms, the therapeutic potential of RSV in various diseases such as osteoarthritis, neurodegenerative diseases, cardiovascular diseases and diabetes have attracted the attention of many researchers. RSV has anti-apoptotic, anti-senescent, anti-inflammatory, anti-oxidative, and anabolic activities, which can prevent further degeneration of intervertebral disc cells and enhance their regeneration. With high safety and various biological functions, RSV might be a promising candidate for the treatment of IDD. This review summarizes the biological functions of RSV in the treatment of IDD and to facilitate further research.

Short-term Outcomes of Laparoscopy-Assisted vs Open Surgery for Patients With Low Rectal Cancer: The LASRE Randomized Clinical Trial.

Importance: The efficacy of laparoscopic vs open surgery for patients with low rectal cancer has not been established. Objective: To compare the short-term efficacy of laparoscopic surgery vs open surgery for treatment of low rectal cancer. Design, Setting, and Participants: This multicenter, noninferiority randomized clinical trial was conducted in 22 tertiary hospitals across China. Patients scheduled for curative-intent resection of low rectal cancer were randomized at a 2:1 ratio to undergo laparoscopic or open surgery. Between November 2013 and June 2018, 1070 patients were randomized to laparoscopic (n = 712) or open (n = 358) surgery. The planned follow-up was 5 years. Data analysis was performed from April 2021 to March 2022. Interventions: Eligible patients were randomized to receive either laparoscopic or open surgery. Main Outcomes and Measures: The short-term outcomes included pathologic outcomes, surgical outcomes, postoperative recovery, and 30-day postoperative complications and mortality. Results: A total of 1039 patients (685 in laparoscopic and 354 in open surgery) were included in the modified intention-to-treat analysis (median [range] age, 57 [20-75] years; 620 men [59.7%]; clinical TNM stage II/III disease in 659 patients). The rate of complete mesorectal excision was 85.3% (521 of 685) in the laparoscopic group vs 85.8% (266 of 354) in the open group (difference, -0.5%; 95% CI, -5.1% to 4.5%; P = .78). The rate of negative circumferential and distal resection margins was 98.2% (673 of 685) vs 99.7% (353 of 354) (difference, -1.5%; 95% CI, -2.8% to 0.0%; P = .09) and 99.4% (681 of 685) vs 100% (354 of 354) (difference, -0.6%; 95% CI, -1.5% to 0.5%; P = .36), respectively. The median number of retrieved lymph nodes was 13.0 vs 12.0 (difference, 1.0; 95% CI, 0.1-1.9; P = .39). The laparoscopic group had a higher rate of sphincter preservation (491 of 685 [71.7%] vs 230 of 354 [65.0%]; difference, 6.7%; 95% CI, 0.8%-12.8%; P = .03) and shorter duration of hospitalization (8.0 vs 9.0 days; difference, -1.0; 95% CI, -1.7 to -0.3; P = .008). There was no significant difference in postoperative complications rate between the 2 groups (89 of 685 [13.0%] vs 61 of 354 [17.2%]; difference, -4.2%; 95% CI, -9.1% to -0.3%; P = .07). No patient died within 30 days. Conclusions and Relevance: In this randomized clinical trial of patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons was shown to provide pathologic outcomes comparable to open surgery, with a higher sphincter preservation rate and favorable postoperative recovery. Trial Registration: ClinicalTrials.gov Identifier: NCT01899547.

Insight into the pharmacological effects of andrographolide in musculoskeletal disorders.

Andrographis paniculata (A. paniculata) is a traditional herbal medicine that has been widely used in Asian countries for hundreds of years. Andrographolide (AG) is a diterpene lactone extracted from A. paniculata. Owing to the in-depth study of pharmacological mechanisms, the therapeutic potential of AG, including its anti-inflammatory, anti-tumor, and immunoregulatory attributes, has attracted the attention of many researchers. Studies testing the therapeutic effects of AG have demonstrated desirable results in the treatment of a variety of clinical diseases. With high safety and various biological functions, AG might be a promising candidate for the treatment of musculoskeletal disorders. Here, we review all available literatures to summarize the pharmacological effects of AG and facilitate further researches on musculoskeletal diseases.

Effectiveness and Safety of Apatinib Plus Chemotherapy as Neoadjuvant Treatment for Locally Advanced Gastric Cancer: A Nonrandomized Controlled Trial.

Importance: Apatinib is a novel treatment option for chemotherapy-refractory advanced gastric cancer (GC), but it has not been evaluated in patients with locally advanced GC. Objective: To investigate the effectiveness and safety of apatinib combined with S-1 plus oxaliplatin (SOX) as a neoadjuvant treatment for locally advanced GC. Design, Setting, and Participants: This multicenter, prospective, single-group, open-label, phase 2 nonrandomized controlled trial was conducted in 10 centers in southern China. Patients with M0 and either clinical T2 to T4 or N+ disease were enrolled between July 1, 2017, and June 30, 2019. Statistical analysis was performed from December 1, 2019, to January 31, 2020. Interventions: Eligible patients received apatinib (500 mg orally once daily on days 1 to 21 and discontinued in the last cycle) plus SOX (S-1: 40-60 mg orally twice daily on days 1 to 14; oxaliplatin: 130 mg/m2 intravenously on day 1) every 3 weeks for 2 to 5 cycles. A D2 gastrectomy was performed 2 to 4 weeks after the last cycle. Main Outcomes and Measures: The primary end point was R0 resection rate. Secondary end points were the response rate, toxic effects, and surgical outcome. Results: A total of 48 patients (mean [SD] age, 63.2 [8.2] years; 37 men [77.1%]) were enrolled in this study. Forty patients underwent surgery (38 had gastrectomy, and 2 had exploratory laparotomy), with an R0 resection rate of 75.0% (95% CI, 60.4%-86.4%). The radiologic response rate was 75.0%, and T downstaging was observed in 16 of 44 patients (36.4%). The pathological response rate was 54.2% (95% CI, 39.2%-68.6%); moreover, this rate was significantly higher in patients who achieved a radiologic response compared with those who did not (12 [80.0%] vs 1 [20.0%]; P = .03) and in those who had an Eastern Cooperative Oncology Group Performance Status score of 0 (20 [76.9%] vs 10 [45.5%]; P = .03) or had tumors located in the upper one-third of the stomach (16 [61.5%] vs 7 [31.8%]; P = .04). Patients who achieved a pathological response (vs those who did not) had significantly less blood loss (median [range]: 60 [10-200] mL vs 80 [20-300] mL; P = .04) and significantly more lymph nodes harvested (median [range]: 40 [24-67] vs 32 [19-51]; P = .04) during surgery. Postoperative complications were observed in 7 of 38 patients (18.4%). Grade 3 toxic effects occurred in 16 of 48 patients (33.3%), and no grade 4 toxic effects or preoperative deaths were observed. Conclusions and Relevance: This nonrandomized controlled trial found that apatinib combined with SOX was effective and had an acceptable safety profile as a neoadjuvant treatment for locally advanced GC. A large-scale randomized clinical trial may be needed to confirm the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT03192735.

Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk.

Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.

Performance of a Nomogram Based on the Integration of Inflammation Markers with Tumor Staging in Prognosis Prediction of Stage III Colorectal Cancer.

INTRODUCTION: The aim of the present study was to evaluate a nomogram model for predicting the 5-year overall survival (OS) in lymph node-metastatic colorectal cancer (CRC) patients by combining inflammation markers with some traditional prognostic factors. METHODS: A total of 399 patients with stage III (pTXN1-3M0) CRC operated from January 2007 to December 2012 were enrolled in this retrospective study. All patients underwent D2 lymphadenectomy in the hospital. A prognostic nomogram based on the integration of traditional prognostic factors and NLR (neutrophil-to-lymphocyte ratio) and PLR (platelet-to-lymphocyte ratio) was established and compared with the nomogram based on the traditional prognostic factors alone. ROC curves were further applied to verify the predictive accuracy of the established model. RESULTS: Both NLR (P=0.00) and PLR (P=0.01) predicted the 5-year OS. In multivariate analysis, age, T3 category, T4 category, N2 category, N3 category, Pgp (P-glycoprotein), NLR and PLR are proven to be independent (all P≤0.05). The established nomogram showed better predictive power than that of traditional profile (c-index: 0.66 versus 0.63) in both training and validation cohorts. External assessment by ROC curve analysis demonstrated that the established model had a good prediction accuracy of 5-year OS in stage III CRC patients, with area under curve values of 0.657 and 0.629 in training and validating sets, respectively. CONCLUSION: A nomogram based on the integration of traditional prognostic factors and inflammatory markers (NLR and PLR) could provide more precise long-term prognosis information for lymph node-metastatic CRC patients than the model based on traditional profile alone. This model might be useful for clinical application in personalized evaluation.

Inactivation of the AMPK-GATA3-ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth.

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)-GATA-binding protein 3 (GATA3)-enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of de novo FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK-GATA3-ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. SIGNIFICANCE: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK-GATA3-ECHS1 pathway as a potential therapeutic target and prognostic biomarker.

Short-term pre- and post-operative stress prolongs incision-induced pain hypersensitivity without changing basal pain perception.

BACKGROUND: Chronic stress has been reported to increase basal pain sensitivity and/or exacerbate existing persistent pain. However, most surgical patients have normal physiological and psychological health status such as normal pain perception before surgery although they do experience short-term stress during pre- and post-operative periods. Whether or not this short-term stress affects persistent postsurgical pain is unclear. RESULTS: In this study, we showed that pre- or post-surgical exposure to immobilization 6 h daily for three consecutive days did not change basal responses to mechanical, thermal, or cold stimuli or peak levels of incision-induced hypersensitivity to these stimuli; however, immobilization did prolong the duration of incision-induced hypersensitivity in both male and female rats. These phenomena were also observed in post-surgical exposure to forced swimming 25 min daily for 3 consecutive days. Short-term stress induced by immobilization was demonstrated by an elevation in the level of serum corticosterone, an increase in swim immobility, and a decrease in sucrose consumption. Blocking this short-term stress via intrathecal administration of a selective glucocorticoid receptor antagonist, RU38486, or bilateral adrenalectomy significantly attenuated the prolongation of incision-induced hypersensitivity to mechanical, thermal, and cold stimuli. CONCLUSION: Our results indicate that short-term stress during the pre- or post-operative period delays postoperative pain recovery although it does not affect basal pain perception. Prevention of short-term stress may facilitate patients' recovery from postoperative pain.

[Intracorporeal Roux-en-Y reconstruction after laparoscopic distal gastrectomy: a report of 20 cases].

OBJECTIVE: To investigate the safety and feasibility of intracorporeal Roux-en-Y reconstruction after laparoscopic distal gastrectomy. METHODS: Clinical data of 20 patients undergoing laparoscopic distal gastrectomy and intracorporeal Roux-en-Y reconstruction in our hospital from August 2012 to March 2013 were analyzed retrospectively. RESULTS: Totally laparoscopic distal gastrectomy was successfully performed in all the patients. The mean operation time was (190.8±53.6) min, the mean operative blood loss was(122.4±57.7) ml, and mean number of harvested lymph node was 31.2±5.7. Tumor-free proximal margin was confirmed by pathological examination in all the patients. The mean time to first flatus and hospital stay were (2.6±1.6) d and (8.1±2.0) d. One case developed pulmonary infection postoperatively, but no anastomosis related complication was observed. CONCLUSION: Intracorporeal Roux-en-Y reconstruction after laparoscopic distal gastrectomy is safe and feasible.

High Wilms' tumor 1 mRNA expression correlates with basal-like and ERBB2 molecular subtypes and poor prognosis of breast cancer.

The role of Wilms' tumor 1 (WT1) in breast cancer and the relationship between WT1 expression and clinicopathological factors, molecular subtypes and prognosis of breast cancer patients have not been clarified to date. We used publicly available microarray datasets of 266 early breast cancer patients to perform bioinformatics analysis on the relationship between WT1 mRNA expression and breast cancer. Results showed that WT1 mRNA expression was correlated with higher histological grades, ER-negative and basal-like and ERBB2 molecular subtypes in breast cancer. With regard to disease-free survival analysis, the WT1 high expression group showed worse prognosis than the low expression group in univariate analysis, and WT1 was demonstrated to be an independent prognostic indicator in multivariate analysis. This study confirms an oncogenic role of WT1 and demonstrates a possible relation between WT1 and progression of breast cancer.

Endoplasmic reticulum stress-mediated signaling pathway of gastric cancer apoptosis.

BACKGROUND/AIMS: To investigate ER stress-mediated CHOP-signaling pathway of gastric cancer apoptosis in vitro and in vivo. METHODOLOGY: Based on the dose-and time-response experiments about tunicamycin (TM),gastric cancer cell line BGC823 was treated with 10tg/mL of TM for 24h. BGC823 apoptosis was detected with TUNEL assay and ultrastructural changes in BGC823 cells under ER stress were observed with transmission electron microscopy (TEM). RT-PCR and western blot-ting were used to determine the expression of ERS-related proteins, glucose-regulated protein 78 (GRP78) and CHOP and apoptosis-associated protein B-cell lympho-ma 2 (Bcl-2). After the knockdown of CHOP, the changes were also observed in vitro and in vivo. RESULTS: TEM assay showed that after treatment with TM, BGC823 cell size became smaller with ER dilation, vacuolization and karyopyknosis. RT-PCR and western blotting indicated that TM up-regulated GRP78 and CHOP expression and down-regulated Bcl-2 expression. The knock-down of CHOP could convert Bcl-2 expression and reduce BGC823 apoptosis caused by ERS in vitro and in vivo, but failed to influence GRP78. CONCLUSIONS: TM can induce ESR and regulate downstream molecules CHOP up-regulation and Bcl-2 down-regulation which lead to BGC823 apoptosis. This study may provide a new theoretical basis for the pathogenesis of gastric cancer.

[Advantage of perisplenic hilar lymph node dissection by laparoscopy-assisted total gastrectomy (D2) over conventional open total gastrectomy for advanced gastric cancer].

OBJECTIVE: To compare the number of harvested perisplenic hilar lymph nodes by laparoscopy-assisted total gastrectomy (LATG) and conventional open total gastrectomy (OTG) for advanced upper and middle gastric cancer. METHODS: Three hundred twelve patients with advanced gastric cancer treated in a single institution between Sept 2008 and Jan 2011 were included in this study. They were divided into two groups: the LATG group and OTG (D2) group. All the surgical operations were performed by one surgeon or under his supervision. The lymph node clearance outcomes of the patients treated by those two surgical procedures were analyzed. RESULTS: The harvested lymph node numbers of the two groups were (29.57 ± 9.62) and (29.38 ± 11.22) respectively, statistically with no significant difference (P = 0.875). The numbers of lymph node dissected around the splenic area in the LATG group and OTG group (Section 10, 11 group) were (2.01 ± 1.34) and (1.33 ± 1.11), respectively, indicating a significant difference (P = 0.000). The numbers of lymph nodes dissected around the celiac region (Section 7, 8, 9, 11p and 12a(2) group) were (7.90 ± 3.41) and (7.22 ± 2.65), respectively, with a non-significant difference (P = 0.050). There were also no significant differences while comparing with the numbers of lymph nodes dissected in the cardiac area (group 1, 2), pyloric region (5, 6 group) and the greater and lesser omentum area (group 3 and 4) between the two groups (P = 0.605, P = 0.248, P = 0.262). CONCLUSION: Short-term results of this study indicate that laparoscopy-assisted total gastrectomy (D2) is better than conventional open surgery in perisplenic hilar lymph node dissection.

[A prospective randomized control trial of the approach for laparoscopic right hemi-colectomy:medial-to-lateral versus lateral-to-medial].

OBJECTIVE: To compare the medial-to-lateral approach with the lateral-to-medial approach in laparoscopic right hemi-colectomy for right colon cancer. METHODS: A prospective randomized controlled trial was performed in the Fujian provincial tumor hospital between January 2007 and July 2009. Forty-eight cases with right colon cancer were randomly divided into two groups:medial-to-lateral laparoscopic right hemi-colectomy group(group M) and lateral-to-medial laparoscopic right hemi-colectomy group(group L). Primary outcome(operative time) and secondary outcomes (estimated blood loss, intra-operative complication, post-operative complication, number of lymph node retrieval, hospital stay) were compared between two groups. RESULTS: Operative time was(122.5+/-25.8) min in group M and (162.9+/-30.9) min in Group L (P=0.01). Estimated blood loss was(55.8+/-36.2) ml in group M and (104.6+/-58.2) ml in group L(P=0.01). There were no significant differences between the two groups in intra-operative complications(4.2% vs 8.3%, P=1.00), post-operative complications (8.3% vs 16.7%, P=0.66), number of lymph node retrieval (17.4+/-3.2 vs 17.8+/-3.4, P=0.67), and hospital stay[(7.8+/-2.2) d vs (8.0+/-3.6) d, P=0.81]. CONCLUSION: The medial-to-lateral approach reduces operative time and blood loss in laparoscopic right hemi-colectomy as compared with the lateral-to-medial approach.

Nuclear factor-kB signaling pathway constitutively activated in esophageal squamous cell carcinoma cell lines and inhibition of growth of cells by small interfering RNA.

Although constitutive nuclear factor (NF)-kappaB activation has been reported in many human tumors, the role of the NF-kappaB pathway in esophageal squamous cell carcinoma (ESCC) has not been known. In this study, NF-kappaB pathway in two ESCC cell lines was investigated using immunocytochemistry, Western blot and reverse transcription-polymerase chain reaction. The activation of NF-kappaB DNA binding was determined by electrophoretic mobility-shift assay. RNA interference was used to specifically inhibit the expression of p65. Growth of cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The results showed that p50, p65, IkappaBalpha p-IkappaBalpha and IkappaB kinase beta were expressed and mainly localized in the cytoplasm. Reverse transcription-polymerase chain reaction results showed the constitutive expressions of p50, p65 and IkappaBalpha mRNA in the two ESCC cell lines. Furthermore, the nuclear extracts revealed that p50 and p65 translocated to the nucleus had DNA-binding activity. Finally, small interfering RNA of p65 decreased the expression of p65, and the viability of cells transfected with p65 small interfering RNA was significantly suppressed at the same concentration of 5-fluorouracil (P < 0.05) compared to untransfected cells. The results of this study showed that there was the constitutively activated NF-kB signaling pathway in the ESCC cell lines. RNA interference targeting at p65 increased the sensitivity of the ESCC cell lines to 5-fluorouracil, suggesting that NF-kappaB might be a good target for cancer treatment.