Potential drug targets for gastroesophageal reflux disease and Barrett's esophagus identified through Mendelian randomization analysis.

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.

Intracellular Protein Adsorption Behavior and Biological Effects of Polystyrene Nanoplastics in THP-1 Cells.

Micro(nano)plastics (MNPs) are emerging pollutants that can adsorb pollutants in the environment and biological molecules and ultimately affect human health. However, the aspects of adsorption of intracellular proteins onto MNPs and its biological effects in cells have not been investigated to date. The present study revealed that 100 nm polystyrene nanoplastics (NPs) could be internalized by THP-1 cells and specifically adsorbed intracellular proteins. In total, 773 proteins adsorbed onto NPs with high reliability were identified using the proteomics approach and analyzed via bioinformatics to predict the route and distribution of NPs following cellular internalization. The representative proteins identified via the Kyoto Encyclopedia of Genes and Genomes pathway analysis were further investigated to characterize protein adsorption onto NPs and its biological effects. The analysis revealed that NPs affect glycolysis through pyruvate kinase M (PKM) adsorption, trigger the unfolded protein response through the adsorption of ribophorin 1 (RPN1) and heat shock 70 protein 8 (HSPA8), and are chiefly internalized into cells through clathrin-mediated endocytosis with concomitant clathrin heavy chain (CLTC) adsorption. Therefore, this work provides new insights and research strategies for the study of the biological effects caused by NPs.

Mapping and ablation of ventricular arrhythmias arising from the left ventricular summit.

The left ventricular summit (LVS) refers to the highest portion of the left ventricular outflow tract (LVOT). It is an epicardially delimited triangular area by the left coronary arteries and the coronary venous circulation. Its deep myocardium correlates closely with the left coronary cusp, aortic-mitral continuity, and right ventricular outflow tract (RVOT), complicating the anatomical relationship. Ventricular arrhythmias (VAs) originating from this area are common, accounting for 14.5% of all VAs origin from left ventricle. Specific electrocardiogram (ECG) characteristics may assist in locating LVS-VAs pre-procedure and facilitate procedure planning. However, catheter ablation of LVS-VAs remains challenging because of anatomical constraints. This paper reviews the recent understanding of LVS anatomy, concludes ECG characteristics, and summarizes current mapping and ablation methods for LVS-VAs.

Dynamic patterns of particulate matter concentration and size distribution in urban street canyons: insights into diurnal and short-term seasonal variations.

Time-varying characteristics of particulate matter (PM) pollution play a crucial role in shaping atmospheric dynamics, which impact the health and welfare of urban commuters. Previously published studies on the diurnal patterns of PMs are not consistent, especially in the context of field experiments in central China, and most field studies have only focused on particles with a single particle size. This study conducted regional-scale studies across 72 street canyon sets in Wuhan, China, investigated diurnal and seasonal PM concentration variations while also evaluating various PM size and the key driving factors. During summer (July, August, and September), evergreen tree-lined street canyons maintained a stable linear trend for smaller dp particulates (i.e., PM1, PM2.5, and PM4), while deciduous street canyons exhibited a bimodal distribution. In winter (January and February), fine particulates (i.e., PM1 and PM2.5) remained a linear trend in evergreen street canyons, while deciduous street canyons show a slightly wavy fluctuating pattern. Meanwhile, it exhibited quadrimodal-peak and triple-trough patterns in both PM7, PM10, and TSP concentrations. The lowest PM concentrations were observed between 14:00 and 16:00 for all particle sizes, with decreased summer pollution (7.81% lower in PM2.5, 53.47% lower in PM10, and 50.3% lower in TSP) noted in our seasonal analysis. Among the various meteorological factors, relative humidity (RH) was identified as the dominant influencing PM factor in both summer and winter. Results from this study will help us better understand field-based air pollutant dispersion processes within pedestrian spaces while laying the groundwork for future research into street PM experiments.

Random Lasing from Label-Free Living Cells for Rapid Cytometry of Apoptosis.

A random laser carrying the scattering information on a biological host is a promising tool for the characterization of biophysical properties. In this work, random lasing from label-free living cells is proposed to achieve rapid cytometry of apoptosis. Random lasing is achieved by adding biocompatible gain medium to a confocal dish containing cells under optically pumped conditions. The random lasing characteristics are distinct at different stages of cell apoptosis after drug treatment. By analyzing the power Fourier transform results of the random lasing spectra, the percentage of apoptotic cells could be distinguished within two seconds, which is more than an order of magnitude faster than traditional flow cytometry. These results provide a label-free approach for rapid cytometry of apoptosis, which is advantageous for further research of random lasers in the biological field.

Prognostic significance of lateral pelvic lymph node dissection for middle-low rectal cancer patients with lateral pelvic lymph node metastasis: a propensity score matching study.

BACKGROUND: There is still controversy regarding the clinical value and significance of lateral pelvic lymph node (LPN) dissection (LPND). The present study aimed to investigate whether the addition of LPND to total mesorectal excision (TME) confers survival benefits in rectal cancer patients with clinical lateral pelvic node metastasis (LPNM). METHODS: From January 2015 to January 2021, a total of 141 rectal cancer patients with clinical evidence of LPNM who underwent TME + LPND were retrospectively analysed and divided into the LPNM group (n = 29) and the non-LPNM group (n = 112). The LPNM group was further subdivided into a high-risk LPNM group (n = 14) and a low-risk LPNM group (n = 15). Propensity score matching (PSM) was performed to minimize selection bias. The primary outcomes of this study were 3-year overall survival (OS) and disease-free survival (DFS). RESULTS: Of the 141 patients undergoing LPND, the local recurrence rate of patients with LPNM was significantly higher than that of patients without LPNM both before (27.6% vs. 4.5%, P = 0.001) and after (27.6% vs. 3.4%, P = 0.025) PSM. Multivariate analysis revealed that LPNM was an independent risk factor for not only OS (HR: 3.06; 95% CI, 1.15-8.17; P = 0.025) but also DFS (HR: 2.39; 95% CI, 1.18-4.87; P = 0.016) in patients with LPNM after TME + LPND. When the LPNM group was further subdivided, multivariate logistic regression analysis showed that OS and DFS were significantly better in the low-risk group (obturator/internal iliac artery region and < 2 positive LPNs). CONCLUSION: Even after LPND, LPNM patients have a poor prognosis. Moreover, LPNM is an independent poor prognostic factor affecting OS and DFS after TME + LPND. However, LPND appears to confer survival benefits to specific patients with single LPN involvement in the obturator region or internal iliac vessel region. Furthermore, LPND may have no indication in stage IV patients and should be selected carefully.

The role of adipose tissue-derived hydrogen sulfide in inhibiting atherosclerosis.

Hydrogen sulfide (H2S) is the third gaseous signaling molecule discovered in the body after NO and CO and plays an important organismal protective role in various diseases. Within adipose tissue, related catalytic enzymes (cystathionine-ß-synthetase, cystathionine-γ-lyase, and 3-mercaptopyruvate transsulfuration enzyme) can produce and release endogenous H2S. Atherosclerosis (As) is a pathological change in arterial vessels that is closely related to abnormal glucose and lipid metabolism and a chronic inflammatory response. Previous studies have shown that H2S can act on the cardiovascular system, exerting effects such as improving disorders of glycolipid metabolism, alleviating insulin resistance, protecting the function of vascular endothelial cells, inhibiting vascular smooth muscle cell proliferation and migration, regulating vascular tone, inhibiting the inflammatory response, and antagonizing the occurrence and development of As.

Gene expression in human umbilical vein endothelial cells exposed to fine particulate matter: RNA sequencing analysis.

Exposure to airborne particulate matter (PM2.5) is associated with cardiovascular diseases. In order to investigate the molecular mechanisms of air pollution-induced CVDs toxicity, human umbilical vein endothelial cells (HUVECs) were exposed to PM2.5 collected from January, 2016 winter in Beijing, China. We performed RNA sequencing to elucidate key molecular mechanism of PM 2.5-mediated toxicity in HUVECs. A total of 1753 genes, 864 up-regulated and 889 down-regulated, were observed to be differentially expressed genes (DEGs). Among these, genes involved in metabolic response, oxidative stress, inflammatory response, and vascular dysfunction were significantly differentially expressed (log2 FC > 4). The results were validated by quantitative real-time PCR (qPCR) and Western blot for CYP1B1, HMOX1, IL8, and GJA4. Pathway analysis revealed that DEGs were involved in the biological processes related to metabolism, inflammation, and host defense against environmental insults. This research is providing a further understanding of the mechanisms underlying PM2.5-induced cardiovascular diseases (CVDs).

High-grade postoperative complications affect survival outcomes of patients with colorectal Cancer peritoneal metastases treated with Cytoreductive surgery and Hyperthermic Intraperitoneal chemotherapy.

BACKGROUND: This study aimed to evaluate the impact of postoperative complications on long-term survival in patients with peritoneal metastasis (PM) arising from colorectal cancer (CRC) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Patients with PM arising from CRC treated with CRS and HIPEC were systematically reviewed at the China National Cancer Center and Huanxing Cancer Hospital from June 2017 to June 2019. High-grade complications that occurred within 30 days were defined as grade 3 to 4 events according to the Common Terminology Criteria for Adverse Events (CTCAE) classification. Univariate and multivariable Cox regression models for overall survival were created. Predictors of high-grade postoperative complications were evaluated with univariate and multivariate logistic regression analyses. RESULTS: In all, 86 consecutive cases were included in this study. Forty-one patients (47.7%) developed postoperative complications, while 22 patients (25.6%) experienced high-grade complications. No mortality occurred during the postoperative period. The median survival of all patients was 25 months, and the estimated 3-year overall survival (OS) rate was 35.0%. In the multivariable Cox regression analysis, a high peritoneal carcinomatosis index (PCI) score (HR, 1.07, 95% CI, 1.01-1.14; P=0.015) and grade 3-4 postoperative complications (HR, 1.86, 95% CI, 1.22-3.51; P=0.044) correlated with worse overall survival. High estimated blood loss (OR, 1.01, 95% CI, 1.01-1.02; P< 0.001) was identified as an independent risk factor for developing high-grade complications. CONCLUSION: Careful patient selection, high levels of technical skill and improved perioperative management are crucial to ensure patient survival benefits after CRS+HIPEC.

Neoadjuvant chemoradiotherapy followed by lateral pelvic lymph node dissection for rectal cancer patients: A retrospective study of its safety and indications.

BACKGROUND AND OBJECTIVES: There is no consensus on the safety and indications of lateral pelvic lymph node dissection (LPND) for patients with clinical lateral pelvic node metastasis (LPNM) after neoadjuvant chemoradiotherapy (nCRT). METHODS: We retrospectively analyzed 151 patients who underwent total mesorectal excision (TME) + LPND and divided them into two groups: nCRT group (n = 73) and non-nCRT group (n = 78). RESULTS: Thirty-one (20.5%) patients had LPNM by pathology. The operative time was significantly longer in the nCRT group (291.9 vs. 237.0 min, p < 0.001); however, the two groups had comparable intraoperative blood loss (87.3 vs. 78.9 ml, p = 0.607) and morbidity (19.2% vs. 15.7%, p = 0.537). Additionally, in the nCRT group, multivariate logistic regression analysis showed that poor/mucinous/signet adenocarcinoma (odds ratio [OR] = 6.65, 95% confidence interval [CI] = 1.03-43.03, p = 0.047) and post-nCRT LPN size ≥7 mm (OR = 26.67, 95% CI = 2.87-247.91, p = 0.004) were independent risk factors for pathological LPNM. CONCLUSION: nCRT before TME + LPND is safe and feasible with a comparably low mortality and acceptable morbidity. Poor/mucinous/signet adenocarcinoma and post-nCRT LPN size ≥7 mm were independent predictive factors of pathological LPNM after nCRT for rectal cancer patients with clinical LPNM, and patients with these characteristics should consider LPND after nCRT.

Neoadjuvant chemotherapy followed by hyperthermic intraperitoneal chemotherapy for patients with colorectal peritoneal metastasis: a retrospective study of its safety and efficacy.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are effective routine treatments for colorectal peritoneal metastasis (PM). However, the safety and efficacy of neoadjuvant chemotherapy (NAC) before CRS+HIPEC are poorly understood. Therefore, this study aimed to assess the perioperative safety and long-term efficacy of NAC prior to CRS+HIPEC for patients with synchronous colorectal PM. METHODS: Patients with synchronous colorectal PM who received NAC prior to CRS+HIPEC were systematically reviewed at the China National Cancer Center and Huanxing Cancer Hospital from June 2017 to June 2019. The clinicopathologic characteristics, perioperative parameters, and survival rates of patients who underwent CRS+HIPEC with NAC (NAC group) and patients who underwent CRS+HIPEC without NAC (non-NAC group) were compared. RESULTS: The study enrolled 52 patients, with 20 patients in the NAC group and 32 in the non-NAC group. In the NAC group, the proportion of patients with a peritoneal carcinomatosis index (PCI) score < 12 was significantly higher than that in the non-NAC group (80.0% vs 50.0%, P = 0.031), and more patients achieved complete cytoreduction (80.0% vs 46.9%, P = 0.018). The two groups had comparable grade III/IV complications and similar reoperation and mortality rates (P > 0.05). However, patients who received NAC had lower platelet counts (151.9 vs 197.7 × 109/L, P = 0.036) and neutrophil counts (4.7 vs 7.2 × 109/L, P = 0.030) on postoperative day 1. More patients survived for 2 years in the NAC group than in the non-NAC group (67.4% vs 32.2%, respectively, P = 0.044). However, the completeness of cytoreduction score (HR, 2.99; 95% CI, 1.14-7.84; P = 0.026), rather than NAC, was independently associated with overall survival (OS) in the multivariate analysis after controlling for confounding factors. CONCLUSION: NAC administration before CRS+HIPEC can be regarded as safe and feasible for patients with colorectal PM with comparably low mortality rates and acceptable morbidity rates. Nevertheless, large-sample randomized controlled studies are needed to confirm whether the administration of NAC before CRS+HIPEC confers a survival benefit to patients.

Does the primary tumour location affect the prognosis of patients with colorectal cancer peritoneal metastases treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy?

BACKGROUND: The impact of primary tumour location on the prognosis of patients with peritoneal metastasis (PM) arising from colorectal cancer (CRC) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is rarely discussed, and the evidence is still limited. METHODS: Patients with PM arising from CRC treated with CRS and HIPEC at the China National Cancer Center and Huanxing Cancer Hospital between June 2017 and June 2019 were systematically reviewed. Clinical characteristics, pathological features, perioperative parameters, and prognostic data were collected and analysed. RESULTS: A total of 70 patients were divided into two groups according to either colonic or rectal origin (18 patients in the rectum group and 52 patients in the colon group). Patients with PM of a colonic origin were more likely to develop grade 3-4 postoperative complications after CRS+HIPEC (38.9% vs 19.2%, P = 0.094), but this difference was not statistically significant. Patients with colon cancer had a longer median overall survival (OS) than patients with rectal cancer (27.0 vs 15.0 months, P = 0.011). In the multivariate analysis, the independent prognostic factors of reduced OS were a rectal origin (HR 2.15, 95% CI 1.15-4.93, P = 0.035) and incomplete cytoreduction (HR 1.99, 95% CI 1.06-4.17, P = 0.047). CONCLUSION: CRS is a complex and potentially life-threatening procedure, and we suggest that the indications for CRS+HIPEC in patients with PM of rectal origin be more restrictive and that clinicians approach these cases with caution.

Risk factors and prognostic significance of lateral pelvic lymph node dissection after neoadjuvant chemoradiotherapy for rectal patients with clinically suspected lateral lymph node metastasis.

AIM: It is still controversial whether the addition of lateral pelvic lymph node (LPN) dissection (LPND) to total mesorectal excision (TME) can provide a survival benefit after neoadjuvant chemoradiotherapy (nCRT) in rectal cancer patients with pathological lateral lymph node metastasis (LPNM). METHODS: Patients with clinically suspected LPNM who underwent nCRT followed by TME + LPND were systematically reviewed and divided into the positive LPN group (n = 15) and the negative LPN group (n = 58). Baseline characteristics, clinicopathological data and survival outcomes were collected and analysed. RESULTS: Of the 73 patients undergoing TME + LPND after nCRT, the pathological LPNM rate was 20.5% (15/73). Multivariate analysis showed that a post-nCRT LPN short diameter ≥ 7 mm (OR 49.65; 95% CI 3.98-619.1; P = 0.002) and lymphatic invasion (OR 9.23; 95% CI 1.28-66.35; P = 0.027) were independent risk factors for pathological LPNM. The overall recurrence rate of patients with LPNM was significantly higher than that of patients without LPNM (60.0% vs 27.6%, P = 0.018). Multivariate regression analysis identified that LPNM was an independent risk factor not only for overall survival (OS) (HR 3.82; 95% CI 1.19-12.25; P = 0.024) but also for disease-free survival (DFS) (HR 2.33; 95% CI 1.02-5.14; P = 0.044). Moreover, N1-N2 stage was another independent risk factor for OS (HR 7.41; 95% CI 1.63-33.75; P = 0.010). CONCLUSIONS: Post-nCRT LPN short diameter ≥ 7 mm and lymphatic invasion were risk factors for pathological LPNM after nCRT. Furthermore, patients with pathological LPNM still show an elevated overall recurrence rate and poor prognosis after TME + LPND. Strict patient selection and intensive perioperative chemotherapy are crucial factors to ensure the efficacy of LPND.

Can transanal natural orifice specimen extraction after laparoscopic anterior resection for colorectal cancer reduce the inflammatory response?

BACKGROUND AND AIM: Avoiding abdominal incisions is one of the unique features of natural orifice specimen extraction (NOSE) surgery. There has been no consensus on whether the avoidance of abdominal incisions can reduce the systemic inflammatory response after NOSE surgery. This study was designed to evaluate the safety and feasibility of transanal NOSE, especially the inflammatory response after transanal NOSE versus mini-laparotomy (LAP). METHODS: A total of 172 colorectal cancer patients who underwent transanal NOSE were matched with 172 patients who underwent LAP for colorectal cancer. Clinical characteristics, pathological features, perioperative parameters, and indicators of the inflammatory response were collected and compared. The inflammatory response was assessed by measuring body temperature, neutrophil count, C-reactive protein levels, and procalcitonin levels. RESULTS: Patients in the NOSE group had better short-term outcomes, such as lower incidence of wound infection, less postoperative pain, less need for anesthetic drugs, and faster recovery of intestinal function. Regarding the inflammatory response, the average body temperature of patients in the NOSE group was higher on postoperative day (POD) 2 than that in the LAP group. A higher median neutrophil count and C-reactive protein levels were observed in the NOSE group on POD3 and POD5 than was observed in the LAP group. CONCLUSIONS: Transanal NOSE is safe and feasible for colorectal cancer, with better short-term outcomes. Although transanal NOSE produced a larger systemic inflammatory response than LAP in the early postoperative stages, this response did not appear to translate into infectious morbidity.

The feasibility and safety of complete laparoscopic extended right hemicolectomy with preservation of the ileocecal junction in right-transverse colon cancer.

BACKGROUND: To evaluate the feasibility and safety of a new surgical method, complete laparoscopic extended right hemicolectomy with preservation of the ileocecal junction in right-transverse colon cancer. METHODS: We retrospectively analyzed and compared the data of consecutive patients with right-transverse colon cancer who underwent complete laparoscopic extended right hemicolectomy with preservation of the ileocecal junction (n = 23) and conventional complete laparoscopic extended right hemicolectomy (n = 34) in our hospital between October 2017 to May 2019, respectively. RESULTS: The overall operation time of the ileocecal junction-preserved group was significantly shorter than that of the control group (p = 0.048). There was no difference in the number of harvested lymph nodes, metastatic lymph nodes, and rate of metastatic lymph nodes (p > 0.05). The ileocecal junction-preserved group showed shorter time of first flatus, lower frequency of postoperative diarrhea, and shorter duration of postoperative hospitalization. Furthermore, it also showed that the defecation frequency was lower in the ileocecal junction-preserved group than the control group on the 1st, 3rd, and 6th month (p < 0.05), and the number of patients who defecated at night or defecated four times or more a day was less in the ileocecal junction-preserved group than control group on the 1st month (p < 0.05). CONCLUSION: The complete laparoscopic extended right hemicolectomy with preservation of the ileocecal junction promises as a safe and feasible surgical procedure for right-transverse colon cancer, associated with earlier recovery of bowel function, shorter operation time, and similar pathological outcomes when compared to the conventional laparoscopic procedure.

Indocyanine green fluorescence imaging to assess bowel perfusion during totally laparoscopic surgery for colon cancer.

BACKGROUND: To retrospectively evaluate the feasibility and safety of intraoperative assessment of bowel perfusion in totally laparoscopic surgery for colon cancer using indocyanine green fluorescence imaging (IGFI). METHODS: From October 2017 to June 2019, consecutive patients with colon cancer who underwent totally laparoscopic surgery were enrolled retrospectively and grouped into the IGFI group (n = 84) and control group (n = 105). In the IGFI group, indocyanine green (ICG) was injected intravenously, and the bowel perfusion was observed using a fluorescence camera system prior to and after completion of the anastomosis. RESULTS: The two groups were demographically comparable. The IGFI group exhibited a significantly shorter operative time (p = 0.0374) while intraoperative blood loss did not significantly differ among the groups (p = 0.062). In the IGFI group, average time to perfusion fluorescence was 48.4 ± 14.0 s after ICG injection, and four patients (4.8%) were required to choose a more proximal point of resection due to the lack of adequate fluorescence at the point previously selected. There were no differences in terms of pathological outcomes, postoperative recovery and the postoperative complication rates between the groups (p>0.05). CONCLUSION: IGFI shows promise as a safe and feasible tool to assess bowel perfusion during a totally laparoscopic surgery for colon cancer and may reduce the operative time.

Experiment of Structural Geometric Morphology Monitoring for Bridges Using Holographic Visual Sensor.

To further improve the precision and efficiency of structural health monitoring technology and the theory of large-scale structures, full-field non-contact structural geometry morphology monitoring is expected to be a breakthrough technology in structural safety state monitoring and digital twins, owing to its economic, credible, high frequency, and holographic advantages. This study validates a proposed holographic visual sensor and algorithms in a computer-vision-based full-field non-contact displacement and vibration measurement. Using an automatic camera patrol experimental device, original segmental dynamic and static video monitoring data of a model bridge under various damage/activities were collected. According to the temporal and spatial characteristics of the series data, the holographic geometric morphology tracking algorithm was introduced. Additionally, the feature points set of the structural holography geometry and the holography feature contours were established. Experimental results show that the holographic visual sensor and the proposed algorithms can extract an accurate holographic full-field displacement signal, and factually and sensitively accomplish vibration measurement, while accurately reflecting the real change in structural properties under various damage/action conditions. The proposed method can serve as a foundation for further research on digital twins for large-scale structures, structural condition assessment, and intelligent damage identification.

Wip1 cooperates with KPNA2 to modulate the cell proliferation and migration of colorectal cancer via a p53-dependent manner.

Due to the increasing incidence and mortality, the early diagnosis, specific targeted therapies, and prognosis for colorectal cancer (CRC) attract more and more attention. Wild-type p53-induced phosphatase 1 (Wip1) and karyopherin α2 (KPNA2) have been regarded as oncogenes in many cancers, including CRC. Wip1 dephosphorylates p53 to inactivate it. TP53 activator and Wip1 inhibitor downregulate KPNA2 expression. Therefore, we speculate that Wip1 may co-operate with KPNA2 to modulate CRC progression in a p53-dependent manner. Here, Wip1 and KPNA2 messenger RNA expression and protein levels are significantly increased in CRC tissues and cell lines and are positively correlated with each other. Wip1 silence increases p53 phosphorylation while decreases KPNA2 protein. Wip1 knockdown remarkably suppresses CRC cell proliferation and migration while KPNA2 overexpression exerts an opposing effect. KPNA2 overexpression could partially rescue Wip1 silence-inhibited CRC cell proliferation and migration. Finally, Wip1 interacts with KPNA2 to modulate the activation of AKT/GSK-3ß signaling and metastasis-related factors. In summary, Wip1 could co-operate with KPNA2 to modulate CRC cell proliferation and migration, possibly via a p53-dependent manner, through downstream AKT/GSK-3ß pathway. We provided a novel mechanism of Wip1 interacting with KPNA2, therefore modulating CRC cell proliferation and migration.

Mitochondrial dysfunction in endothelial cells induced by airborne fine particulate matter (<2.5 µm).

Exposure to ambient fine particulate matter (<2.5 µm; PM2.5 ) increases the risk of the physiopathology of vascular diseases. However, the underlying mechanism, particularly the mitochondrial damage mechanism, of PM2.5 -induced vascular dysfunction is still unclear. In this study, we examined PM2.5 -induced alterations of mitochondrial morphology, and further demonstrated the adverse effects on mitochondrial dynamics and function in vascular endothelial cells. Consequently, cultured EA.hy926 cells were subjected to PM2.5 collected from Beijing. A Cell Counting Assay Kit-8 demonstrated that PM2.5 exposure decreased the proliferation of EA.hy926 cells in a dose-dependent manner. The exposure caused an increment of abnormal mitochondria coupled with the decrease of fusion protein MFN2 and the increase of fission protein FIS1, suggesting that PM2.5 inhibits mitochondrial fusion. Further analyses revealed PM2.5 decreased the mitochondrial membrane potential (ΔΨm) and increased the mitochondrial permeability transport pore opening, eventually resulting in impairments in adenosine triphosphate synthesis. Therefore, it is clearly shown that PM2.5 triggered endothelial toxicity through mitochondria as the target, including the damage of mitochondrial homeostasis.

Predictive risk factors for anastomotic leakage after anterior resection of rectal cancer in elderly patients over 80 years old: an analysis of 288 consecutive patients.

BACKGROUND: Anastomotic leakage (AL) is a common complication after anterior resection of rectal cancer. Few studies have been conducted to determine whether the traditional predictors of AL can be applied to elderly patients (age ≥ 80) undergoing anterior resection (AR) or low anterior resection (LAR) of rectal cancer. This study was designed to explore the predictive factors for AL after anterior resection of rectal cancer in patients over 80 years old. METHODS: From January 2007 to May 2019, consecutive elderly (age ≥ 80) rectal cancer patients undergoing AR or LAR at our institution were systematically reviewed. The general information, perioperative outcomes, and comorbidities were collected. RESULTS: A total of 288 consecutive patients were included in this study. The average age was 82.8 ± 2.4 years, and 30 (10.4%) patients developed AL. The univariate analyses showed that neoadjuvant therapy (50.0% vs. 27.9%, P = 0.013), the number of stapler firings ≥ 3 (60.0% vs. 36.0%, P = 0.011), and coronary heart disease (CHD) (46.7% vs. 17.8%, P < 0.001) were associated with an increased incidence of AL. The multivariate analysis showed that the number of stapler firings ≥ 3 (OR = 4.77, 95% CI = 1.33-15.21, P = 0.035) and CHD (OR = 8.33, 95% CI = 1.94-13.05, P = 0.003) were independent risk factors for AL. CONCLUSION: The number of stapler firings ≥ 3 and CHD were independent risk factors for AL in elderly patients (age ≥ 80) with rectal cancer. A temporary ileostomy or the Hartmann procedure is recommended for patients with CHD, male patients, patients considered to be obese, and patients with a lower tumor location, which may increase the number of stapler firings. Certainly, we recommend that the number of stapler firings should be minimized to alleviate the economic and physical burden of patients.