Nomogram to Predict Recurrence and Guide a Pragmatic Surveillance Strategy After Resection of Hepatoid Adenocarcinoma of the Stomach: A Retrospective Multicenter Study.

BACKGROUND: An accurate recurrence risk assessment system and surveillance strategy for hepatoid adenocarcinoma of the stomach (HAS) remain poorly defined. This study aimed to develop a nomogram to predict postoperative recurrence of HAS and guide individually tailored surveillance strategies. METHODS: The study enrolled all patients with primary HAS who had undergone curative-intent resection at 14 institutions from 2004 to 2019. Clinicopathologic variables with statistical significance in the multivariate Cox regression were incorporated into a nomogram to build a recurrence predictive model. RESULTS: The nomogram of recurrence-free survival (RFS) based on independent prognostic factors, including age, preoperative carcinoembryonic antigen, number of examined lymph nodes, perineural invasion, and lymph node ratio, achieved a C-index of 0.723 (95% confidence interval [CI], 0.674-0.772) in the whole cohort, which was significantly higher than those of the eighth American Joint Committed on Cancer (AJCC) staging system (C-index, 0.629; 95% CI, 0.573-0.685; P < 0.001). The nomogram accurately stratified patients into low-, middle-, and high-risk groups of postoperative recurrence. The postoperative recurrence risk rates for patients in the middle- and high-risk groups were respectively 3 and 10 times higher than for the low-risk group. The patients in the middle- and high-risk groups showed more recurrence and metastasis, particularly multiple site metastasis, within 36 months after the operation than those in the low-risk group (low, 2.2%; middle, 8.6%; high, 24.0%; P = 0.003). CONCLUSIONS: The nomogram achieved good prediction of postoperative recurrence for the patients with HAS after radical resection. For the middle- and high-risk patients, more active surveillance and targeted examination methods should be adopted within 36 months after the operation, particularly for liver and multiple metastases.

Surface Subsidence Monitoring of Mining Areas in Hunan Province Based on Sentinel-1A and DS-InSAR.

Monitoring the surface subsidence in mining areas is conducive to the prevention and control of geological disasters, and the prediction and early warning of accidents. Hunan Province is located in South China. The mineral resource reserves are abundant; however, large and medium-sized mines account for a low proportion of the total, and the concentration of mineral resource distribution is low, meaning that traditional mining monitoring struggles to meet the needs of large-scale monitoring of mining areas in the province. The advantages of Interferometric Synthetic Aperture Radar (InSAR) technology in large-scale deformation monitoring were applied to identify and monitor the surface subsidence of coal mining fields in Hunan Province based on a Sentinel-1A dataset of 86 images taken from 2018 to 2020, and the process of developing surface subsidence was inverted by selecting typical mining areas. The results show that there are 14 places of surface subsidence in the study area, and accidents have occurred in 2 mining areas. In addition, the railway passing through the mining area of Zhouyuan Mountain is affected by the surface subsidence, presenting a potential safety hazard.

Novel nomogram for predicting risk of early postoperative small bowel obstruction after right colectomy for cancer.

BACKGROUND: Early postoperative small bowel obstruction (EPSBO) is a common complication after colorectal cancer surgery. Few studies have specifically studied risk factors for early small bowel obstruction after right colectomy, especially in establishing predictive models. The purpose of the current study was to establish an effective nomogram to predict the incidence of EPSBO after right colectomy. METHODS: The current study retrospectively analyzed data from a total of 424 patients who underwent right colectomy in a local hospital from January 2014 to March 2021. A logistic regression model was used to identify potential risk factors for EPSBO after right colectomy. A nomogram was established by independent risk factors, and the prediction performance of the model was evaluated using an area under the receiver operating characteristic (ROC) curve and calibration chart. RESULTS: A total of 45 patients (10.6%) developed early small bowel obstruction after right colectomy. Male sex, emergency operation, history of abdominal surgery, open surgery, long operative time, anastomotic leakage, and preoperative albumin were closely related to EPSBO. Analysis of postoperative rehabilitation indices showed that EPSBO remarkably slowed the postoperative rehabilitation speed of patients. Multivariate logistic regression analysis showed that male sex, open surgery, operative time, and anastomotic leakage were independent risk factors (P < 0.05), and the operation time had the greatest impact on EPSBO. On the basis of multivariate logistic regression, a nomogram was constructed, which showed moderate accuracy in predicting EPSBO, with a C-statistic of 0.716. The calibration chart showed good consistency between the predicted probability and ideal probability. CONCLUSION: The current study constructed a nomogram based on the clinical data of patients who underwent right colectomy, which had moderate predictability and could provide reference value for clinicians to evaluate the risk of EPSBO.

Loss of BMI-1 dampens migration and EMT of colorectal cancer in inflammatory microenvironment through TLR4/MD-2/MyD88-mediated NF-κB signaling.

Increasing evidence from various clinical and experimental studies has demonstrated that the inflammatory microenvironment created by immune cells facilitates tumor migration. Epithelial-mesenchymal transition (EMT) is involved in the progression of cancer invasion and metastasis in an inflammatory microenvironment. B-lymphoma Moloney murine leukemia virus insertion region 1 (BMI-1) acts as an oncogene in various tumors. Ectopic expression of Bmi-1 have an effect on EMT and invasiveness. The purpose of this study was to investigate the efficacy of BMI-1 on inflammation-induced tumor migration and EMT and the underlying mechanism. We observed that the expression of BMI-1, TNF-α, and IL-1ß was significantly increased in HT29 and HCT116 cells after THP-1 Conditioned-Medium (THP-1-CM) stimulation. Additionally, inhibition of BMI-1 impeded cell invasion induced by THP-1-CM-stimulation in both HT29 and HCT116 cells. BMI-1 knockdown remarkably repressed THP-1-CM-induced EMT by regulating the expression of EMT biomarkers with an increase in E-cadherin accompanied by decrease in N-cadherin and vimentin. Furthermore, downregulation of BMI-1 dramatically impeded THP-1-CM-triggered Toll-like receptor 4(TLR4)/myeloid differentiation protein 2(MD-2)/myeloid differentiation factor 88(MyD88) activity by repressing the expression of the TLR4/MD-2 complex and MyD88. Further data demonstrated that knockout of BMI-1 also dampened NF-κB THP-1-CM-triggered activity. Taken all data together, our findings established that BMI-1 modulated TLR4/MD-2/MyD88 complex-mediated NF-κB signaling involved in inflammation-induced cancer cells invasion and EMT, and therefore, could be a potential chemopreventive agent against inflammation-associated colorectal cancer. HIGHLIGHTS: Establishment of an inflammatory microenvironment. Suppression of BMI-1 reverses THP-1-CM-induced inflammatory cytokine production in CRC. Loss of BMI-1 suppressed TLR4/MD-2/MyD88 complex-mediated NF-κB signaling.

Variation and treatment of vessels in laparoscopic right hemicolectomy.

BACKGROUND: With the introduction of complete mesocolic excision (CME) and the application of laparoscopic technique, surgery for colon cancer has become more standardized and the curative effect has improved [1]. The key points in laparoscopic right hemicolectomy are high ligation of main vessels and root dissection of lymph nodes. The wide range of variations in vascular architecture and intraoperative bleeding are common causes of prolonged surgical time, wound hemorrhage, and even transfer to the opening operation. METHODS: The superior mesenteric vein (SMV) is the most important anatomical landmark in CME for the right colon, and guides all the steps of lymph node dissection. The SMV appears as a pale blue bulge on laparoscopy, which enables accurate positioning. The ileocolic vessel pedicle is relatively constant and facilitates accurate positioning. The intersection of the ileocolic vessel pedicle and the SMV is the optimal starting point in laparoscopic right hemicolectomy using a medial-to-lateral approach. A sheath with an avascular plane can be reached after opening the SMV vascular sheath, which results in less bleeding and enables vascular root and thorough lymph node dissection. The first step is to manage the ileocolic vessels. The ileocolic artery (ICA) is located anterior to the ileocolic vein (ICV) for about one-third of the incidence. The ileocolic vessels are relatively long and are easy to work with. In the vast majority of cases, the ICV drains into the SMV, and into the gastrocolic trunk (GCT) in about 2.5% of cases. The reported incidence of a right colic artery (RCA) is controversial; the RCA is absent in about 50% of cases and often crosses the SMV. The right colic vein (RCV) usually drains into the GCT, but sometimes drains directly into the SMV. The middle colic vessels have great variability and a close anatomical relationship with the pancreas, duodenum, and GCT. Moreover, the transverse colon and mesentery are long, and root positioning and processing of the middle colic vein (MCV) are relatively difficult. With the SMV and pancreas as anatomic landmarks, it is more feasible to locate the blood vessels in the neck of the pancreas. The middle colic artery (MCA) originates from the superior mesenteric artery (SMA), and the distance from the inferior border of the pancreas differs slightly in the literature, but is at the most 5 cm. Identification of the MCA trunk and branches, as well as the common origin of the MCA and RCA, is of great importance for the maintaining the blood supply during surgery for primary colon cancer. The MCV mainly drains into the SMV and GCT; however, if branching variation drains into the jejunal vein, inferior mesenteric vein, or splenic vein, the effect is serious when a vessel is torn. Isolation of the GCT is the step at which bleeding will likely occur in standard right resection and is a difficult stage of the surgery. The GCT has five origins including the right gastroepiploic vein (RGV), right colic vein (RCV), accessory right colic vein (ARCV), pancreaticduodenal vein (PDV), and MCV, which can have 2, 3, or 4 branches; therefore, familiarity with variants may be helpful to avoid bleeding. Approximately 5-10% of colon cancers at the hepatic flexure have No. 6 group lymph node metastasis, and laparoscopic radical extended right hemicolectomy requires thorough dissection of No. 6 group lymph nodes and the omental arcade 10 cm from the pylorus. The inferior arteriovenous vessels are a common source of bleeding, and the RGV can serve as a clue to finding the artery. CONCLUSIONS: The core area of laparoscopic radical extended right hemicolectomy includes the pancreatic neck, duodenum, and right gastroepiploic vessels. The difficulty lies with the standard treatment of the GCT. A medial-to-lateral approach is more in line with the principle of no-touch in tumor surgery and is applied from lower to upper, inside to outside, and left to right, for both the vessels and plane of dissection. Familiarity with vascular variation and the management of vessels in key areas are essential for successful surgery.

The dynamic nature of assimilation and accommodation procedures in the brains of Chinese-English and English-Chinese bilinguals.

The framework of assimilation and accommodation has been proposed to explain the brain mechanisms supporting second language reading acquisition (Perfetti et al. [2007]: Bilingual Lang Cogn 10:131). Assimilation refers to using the procedures of the native language network in the acquisition of a new writing system, whereas accommodation refers to using second language procedures for reading the newly acquired writing system. We investigated assimilation and accommodation patterns in the brains of bilingual individuals by recruiting a group of Chinese-English bilinguals and a group of English-Chinese bilinguals to perform lexical decision tasks in both English and Chinese. The key question was whether the assimilation/accommodation procedures supporting second language reading in the brains of Chinese-English and English-Chinese bilinguals were dynamic, i.e., modulated by proficiency in the second language and perceptual features of the second language's script. Perceptual features of the scripts were manipulated through orthographic degradation by inserting spaces between the radicals of a Chinese character or between the syllables of an English word. This manipulation disrupts the visual configuration of the orthography but does not change its more fundamental design principles. We found that for English-Chinese bilinguals, higher proficiency was associated with greater accommodation, suggesting that the accommodation procedure in a bilingual individual's brain is modulated by second language proficiency. Most interestingly, we found that the assimilation/accommodation effects vanished or diminished when orthographically degraded scripts were processed by both Chinese-English and English-Chinese bilinguals, suggesting that the assimilation/accommodation procedures in a bilingual individual's brain are modulated by perceptual features of orthography. This work therefore offers a new, dynamic perspective for our understanding of the assimilation/accommodation framework for second language acquisition.

Construction of a diagnostic nomogram model for predicting the risk of lymph node metastasis in clinical T1 or T2 colon cancer based on the SEER database.

Background: There are few methods related to predicting lymph node metastasis (LNM) in patients with clinically staged T1 or T2 colon cancer. In this study, we aimed to discover independent risk factors for patients with pathologic T-stage 1 (pT1) or pT2 colon cancer with LNM and to develop a nomogram for predicting the probability of LNM for patients with clinically staged T1 or T2 colon cancer. Methods: All data were drawn from the Surveillance, Epidemiology, and End Results (SEER) database. Independent risk factors for LNM were identified using univariate and multivariate logistic regression analyses, and these factors were used to construct a nomogram. The discriminatory power, accuracy, and clinical utility of the model were evaluated using receiver operating characteristic (ROC), calibration, and decision curve analysis (DCA), respectively. Results: According to the inclusion and exclusion criteria, 32,803 patients with stage pT1 or pT2 colon cancer who had undergone surgery were selected from the SEER database. The data showed that the incidence of LNM in patients with pT1 and pT2 colon cancer was 17.11%. The age, histological grade, histological type, T classification, M classification, and tumour location were independent risk factors identified through univariate and multivariate analyses, and these factors were used to construct a nomogram. The ROC curve analysis showed that the area under the curve (AUC) of the ROC of the predictive nomogram for LNM risk was 0.6714 [95% confidence interval (CI): 0.6621-0.6806] in the training set and 0.6567 (95% CI: 0.6422-0.6712) in the validation set, indicative of good discriminatory power of the model. Calibration curve analysis demonstrated good agreement between the nomogram prediction and actual observation. DCA showed excellent clinical utility of the prediction model. Conclusions: The incidence of LNM was high in patients with pT1 and pT2 colon cancer. The nomogram established in this study can accurately predict the risk of LNM in patients with clinically staged T1 or T2 colon cancer before further clinical intervention, which allows clinicians to develop optimal treatment.

A novel MAMLD1 variant in a newborn with hypospadias and elevated 17-hydroxyprogesterone.

PURPOSE: Disorders of sex development (DSD) have complex pathogenesis, and evidence suggests an association between MAMLD1 defects and DSD. MAMLD1 is expressed in gonadal tissues and affected males exhibit hypospadias, steroid hormone abnormalities, or gonadal underdevelopment. We performed genetic testing on a newborn patient with severe hypospadias and an elevation of 17-hydroxyprogesterone (17α-OH) for the diagnosis of DSD. METHODS: Genetic testing of the proband and parents was conducted using whole-exome and Sanger sequencing. The identified variant was transfected into HEK293T cells to assess mutant protein expression using western blot (WB) and into steroidogenic NCI-H295R cells to assess MAMLD1 and CYP17A1 transcript levels using qPCR. Molecular dynamics simulations were performed to construct a structural model and analyze potential biological implications. RESULTS: A novel heterozygous variant was identified in the proband's MAMLD1, NM_005491.5: c.1619_1637del (p.Gln540Alafs*72), inherited from the mother. In transfected cells, the wild-type and mutant proteins were 86.2 and 68.3 kDa, respectively, indicating the formation of a truncated protein. While MAMLD1 transcription was not affected, CYP17A1 transcription levels decreased with the variant compared to wild-type, suggesting an impact on the transactivation of CYP17A1. The truncated protein exhibited enhanced hydrophobicity, owing to the absence of the C-terminal structural portion, resulting in a looser protein structure. CONCLUSION: Severe hypospadias in the proband may be attributed to a novel MAMLD1 variant, whereas the 17α-OH elevation might be related to interference with CYP17A1 transcriptional activation. This study expands the spectrum of MAMLD1 variants and underscores the critical role of genetic testing in the diagnosis of DSD.

Experimental Study of the Airflow Field and Fiber Motion in the Melt-Blowing Process.

The melt-blowing process involves high velocity airflow and fiber motion, which have a significant effect on fiber attenuation. In this paper, the three-dimensional airflow field for a melt-blowing slot die was measured using the hot-wire anemometry in an experiment. The fiber motion was captured online using a high-speed camera. The characteristics of the airflow distribution and fiber motion were analyzed. The results show that the melt-blowing airflow field is asymmetrically distributed. The centerline air velocity is higher than that around it and decays quickly. The maximum airflow velocity exists near the die face, in the range of 130-160 m/s. In the region of -0.3 cm < y < 0.3 cm and 0 < z < 2 cm, the airflow has a high velocity (>100 m/s). As the distance of z reaches 5 cm and 7 cm, the maximum airflow velocity reduces to 70 m/s. The amplitude of fibers is calculated, and it increases with the increase in air dispersion area which has a significant influence on fiber attenuation. At z = 1.5 cm, 2.5 cm, 4 cm, and 5.5 cm, the average fiber amplitudes are 1.05 mm, 1.71 mm, 2.83 mm, and 3.97 mm, respectively. In the vicinity of the die, the fibers move vertically downward as straight segments. With the increase in distance from the spinneret, the fiber appears to bend significantly and forms a fiber loop. The fiber loop morphology affects the velocity of the fiber movement, causing crossover, folding, and bonding of the moving fiber. The study investigated the interaction between the fiber and airflow fields. It indicates that the airflow velocity, velocity difference, and dispersion area can affect the motion of fiber which plays an important role in fiber attenuation during the melt-blowing process.

Long-term prognostic benefit of adjuvant chemotherapy for patients with hepatoid adenocarcinoma of the stomach after radical resection: A national multicenter study.

BACKGROUND: There is no consensus on whether adjuvant chemotherapy (AC) is effective for hepatoid adenocarcinoma of the stomach (HAS). The aim of this study was to investigate the relationship between AC and the long-term prognosis of patients with HAS. METHODS: The clinicopathological data of 239 patients with primary HAS who underwent radical surgery from April 1, 2004 to December 31, 2019 in 14 centers in China were retrospectively analyzed. Patients were divided into the AC group (127 patients) and the nonadjuvant chemotherapy (NAC) group (112 patients). RESULTS: Kaplan‒Meier (KM) analysis showed that there were no significant differences in the 1-year3-year overall survival rate (OS) and 1-year, 3-year recurrence-free survival rate (RFS) between the AC group and the NAC group (1-year OS: 85.6% vs. 79.8%, 3-year OS: 59.8% vs. 62.4%, 1-year RFS: 69.8% vs. 74.4%, 3-year RFS: 57.2% vs. 55.9%, all P > 0.05). The subpopulation treatment effect pattern plots (STEPP) did not show treatment heterogeneity of AC in patients with HAS. The proportions of local recurrence and metastasis sites in the two groups were similar. Although the smoothed hazard curves of the NAC and AC groups crossed, the peak hazard time was later in the AC group (5.9 and 4.7 months), and the peak hazard rate was lower (0.032 and 0.038, P = 0.987). CONCLUSION: The current AC regimen may not significantly improve the survival of patients with HAS after radical surgery.

Gallium ions incorporated silk fibroin hydrogel with antibacterial efficacy for promoting healing of Pseudomonas aeruginosa-infected wound.

The continual resistance to antibiotics and the generation of a series of bacterial infections has emerged as a global concern, which requires appropriate measures and therapeutics to address such a menace. Herein, we report on Silk fibroin (SF) hydrogel with good biocompatibility and biodegradability fabricated through the crosslinking of the SF of different concentrations with Gallium nitrate (Ga (NO3)3) against Pseudomonas aeruginosa. However, the SF: Ga = 500: 1 (w/w) (SF/Ga) demonstrated a good bactericidal and wound healing effect as a result of the moderate and prolonged release of the Ga3+ following the gradual degradation of the hydrogel. The Ga3+, known for its innovative nature acted as a crosslinked agent and a therapeutic agent employing the "Trojan horse" strategy to effectively deal with the bacteria. Also, the Ga3+, which is positively charged neutralizes the negative potential value of the SF particles to reduce the charge and further induce the ß-sheet formation in the protein structure, a characteristic of gelation in SF. The morphology showed a fabricated homogenous structure with greater storage modulus- G' with low loss modulus- G'' modulus demonstrating the mechanical performance and the ability of the SF/Ga hydrogel to hold their shape, at the same time allowing for the gradual release of Ga3+. A demonstration of biocompatibility, biodegradability, bactericidal effect and wound healing in in vitro and in vivo present the SF/Ga hydrogel as an appropriate platform for therapeutic and for antibacterial wound dressing.

Analysis of 20 patients with laparoscopic extended right colectomy.

BACKGROUND: Currently, the standard surgical procedure for right colon cancer is complete mesocolic excision. Whether preventive extended lymph node dissection for colon cancer located in the hepatic flexure or right transverse colon should be performed remains controversial because the safety and effectiveness of the operation have not been proven, and infrapyloric lymph nodes (No. 206) and lymph nodes in the greater curvature of the stomach (No. 204) have not been strictly defined and distinguished as surgical indicators in previous studies. AIM: To analyze the metastatic status of infrapyloric lymph nodes and lymph nodes of the greater curvature of the stomach and perioperative complications and systematically evaluate the feasibility and safety of laparoscopic extended right colectomy using prospective data collected retrospectively. METHODS: The study was a clinical study. Twenty patients with colon cancer who underwent laparoscopic extended right colon resection in our hospital from June 2020 to May 2021 were included. RESULTS: Among the patients who underwent extended right colon resection, there were no intraoperative complications or conversion to laparotomy; 2 patients had gastrocolic ligament lymph node metastasis, and 5 patients had postoperative complications. The patients with postoperative complications received conservative treatment. CONCLUSION: Laparoscopic extended right colon resection is safe. However, malignant tumors located in the liver flexure or the right-side transverse colon are more likely to metastasize to the gastrocolic ligament lymph nodes, and notably, the incidence of gastroparesis was high. The number of patients was small, and the follow-up time was short. It is necessary to further increase the sample size to evaluate the No. 204 and No. 206 lymph node metastasis rates and the long-term survival impact.

Splenosis masquerading as gastric stromal tumor: A case report.

BACKGROUND: Splenosis is a rare benign disease that often disguises itself as a malignant tumor. There are few articles providing a comprehensive description of splenosis, especially cases located in the stomach being treated by laparoscopic surgery. CASE SUMMARY: A 44-year-old man presented with recurrent upper abdominal pain for more than half a year. The patient had splenic rupture caused by trauma more than 10 years ago and underwent splenectomy. An abdominal contrast-enhanced computed tomography scan revealed an irregular soft tissue density. Gastroscopy revealed an approximately 3.0 cm × 3.0 cm mucosal eminence at the posterior wall of the upper segment of the gastric body. Biopsy was not performed since the lesion was found under the mucosa and the gastric mucosa appeared normal. According to these findings, a diagnosis of gastric stromal tumor was made, although a definitive differential diagnosis was not known before surgery. When laparoscopic resection of the gastric stromal tumor was performed, an astonishing finding was made when postoperative pathology showed that the lesion comprised typical spleen tissue. CONCLUSION: This case highlights the strong similarities between splenosis and malignant tumors. A detailed medical history combined with various effective auxiliary examinations can help improve differential diagnosis.

Nomogram for predicting chylous ascites after right colectomy.

BACKGROUND: Chylous ascites following right colectomy has a high incidence which is a critical challenge. At present, there are few studies on the factors affecting chylous ascites after right colectomy and especially after D3 Lymphadenectomy. A predictive model for chylous ascites has not yet been established. Therefore, we created the first nomogram to predict the incidence of chylous ascites after right hemicolectomy. AIM: To analyze the risk factors for chylous ascites after right colectomy and establish a nomogram to predict the incidence of chylous ascites. METHODS: We retrospectively collected patients who underwent right hemicolectomy between January 2012 and May 2021 and were pathologically diagnosed with cancer. Multivariate logistic regression was used to analyze the influencing factors of chylous ascites and a nomogram was established. The predictive ability was assessed by the area under the receiver operating characteristic (ROC) curve. RESULTS: Operative time, the type of operation (standard or extended), the number of lymph nodes retrieved, and somatostatin administration were considered important risk factors. Multivariate logistic regression and nomograms can be used to accurately predict whether chylous ascites occurs. The area under the ROC curve of the model is 0.770. The C-statistic of this model is 0.770 which indicates that it has a relatively moderate ability to predict the risk of chylous ascites. CONCLUSION: We found a novel set of risk factors, created a nomogram, and validated it. The nomogram had a relatively accurate forecasting ability for chylous ascites after right hemicolectomy and can be used as a reference for risk assessment of chylous ascites and whether to prevent it after surgery.

Assessment of Clinicopathological Characteristics and Development of an Individualized Prognostic Model for Patients With Hepatoid Adenocarcinoma of the Stomach.

Importance: Few studies have examined the clinicopathological characteristics and prognoses of patients with hepatoid adenocarcinoma of the stomach (HAS). Objective: To explore the clinicopathological characteristics and prognoses of patients with HAS and develop a nomogram to predict overall survival (OS). Design, Setting, and Participants: This prognostic study involved a retrospective analysis of data from 315 patients who received a diagnosis of primary HAS between April 1, 2004, and December 31, 2019, at 14 centers in China. Main Outcomes and Measures: OS and prognostic factors. Patients were randomly assigned to a derivation cohort (n = 220) and a validation cohort (n = 95). A nomogram was developed based on independent prognostic factors identified through a multivariable Cox mixed-effects model. Results: Among 315 patients with HAS (mean [SD] age, 61.9 [10.2] years; 240 men [76.2%]), 137 patients had simple HAS (defined as the presence of histologically contained hepatoid differentiation areas only), and 178 patients had mixed HAS (defined as the presence of hepatoid differentiation areas plus common adenocarcinoma areas). Patients with simple HAS had a higher median preoperative α-fetoprotein level than those with mixed HAS (195.9 ng/mL vs 48.9 ng/mL, respectively; P < .001) and a higher rate of preoperative liver metastasis (23 of 137 patients [16.8%] vs 11 of 178 patients [6.2%]; P = .003). The 3-year OS rates of patients with simple vs mixed HAS were comparable (56.0% vs 60.0%; log-rank P = .98). A multivariable Cox analysis of the derivation cohort found that the presence of perineural invasion (hazard ratio [HR], 2.13; 95% CI, 1.27-3.55; P = .009), preoperative carcinoembryonic antigen levels of 5 ng/mL or greater (HR, 1.72; 95% CI, 1.08-2.74; P = .03), and pathological node category 3b (HR, 3.72; 95% CI, 1.34-10.32; P = .01) were independent risk factors for worse OS. Based on these factors, a nomogram to predict postoperative OS was developed. The concordance indices of the nomogram (derivation cohort: 0.72 [95% CI, 0.66-0.78]; validation cohort: 0.72 [95% CI, 0.63-0.81]; whole cohort: 0.71 [95% CI, 0.66-0.76]) were higher than those derived using the American Joint Committee on Cancer's AJCC Cancer Staging Manual (8th edition) pathological tumor-node-metastasis (pTNM) staging system (derivation cohort: 0.63 [95% CI, 0.57-0.69]; validation cohort: 0.65 [95% CI, 0.56-0.75]; whole cohort: 0.64 [95% CI, 0.59-0.69]) and those derived using a clinical model that included pTNM stage and receipt of adjuvant chemotherapy (derivation cohort: 0.64 [95% CI, 0.58-0.69]; validation cohort: 0.65 [95% CI, 0.56-0.75]; whole cohort: 0.64 [95% CI, 0.59-0.69]). Based on the nomogram cutoff of 10 points, the whole cohort was divided into high-risk and low-risk groups. The 3-year OS rate of patients in the high-risk group was significantly lower than that of patients in the low-risk group (29.7% vs 75.9%, respectively; log-rank P < .001), and the 3-year prognosis of high-risk and low-risk groups could be further distinguished into pTNM stage I to II (33.3% vs 80.2%; exact log-rank P = .15), stage III (34.3% vs 71.3%; log-rank P < .001), and stage IV (15.5% vs 70.3%; log-rank P = .009). Conclusions and Relevance: This study found that perineural invasion, preoperative carcinoembryonic antigen levels of 5 ng/mL or greater, and pathological node category 3b were independent risk factors associated with worse OS. An individualized nomogram was developed to predict OS among patients with HAS. This nomogram had good prognostic value and may be useful as a supplement to the current American Joint Committee on Cancer TNM staging system.

S-nitrosylation of PTEN Invovled in ischemic brain injury in rat hippocampal CA1 region.

The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is not only a protein, but also a lipid phosphatase that can negatively regulate the serine/threonine kinase Akt. It has been reported that PTEN can be regulated by means of phosphorylation. However, whether PTEN can be regulated by another post-translational protein modification (S-nitrosylation) was not fully elucidated. In this study, we investigated the S-nitrosylation of PTEN during transient cerebral ischemia/reperfusion in rat hippocampus. Transient brain ischemia was induced by the four-vessel occlusion in Sprague-Dawley rats. Our data show that S-nitrosylation of PTEN was increased significantly after 12 h of reperfusion compared with sham control. Pretreatment with the inhibitor of nNOS (7-NI) and the inhibitor of iNOS could inhibit PTEN's activity and decrease S-nitrosylation of PTEN. Taken together, these results indicate that nitric oxide could regulate PTEN's activity via S-nitrosylation during transient global ischemia in rat hippocampus.

Bufothionine Promotes Apoptosis via Triggering ER Stress and Synergizes with Temozolomide in Glioblastoma Multiforme Cells.

Glioblastoma multiforme (GBM) is the most common type of malignant glioma. Bufothionine is one of the major active ingredients of Cinobufacini. Although the antitumor activities of bufothionine have been reported, the underlying mechanism remains unclear. The present study showed that bufothionine exhibited antigrowth activities in GBM cell lines U87 and U373. Further investigation showed that bufothionine triggered endoplasmic reticulum (ER) stress to promote apoptosis in U87 and U373 cells. Moreover, our results showed that bufothionine exhibited synergistic activities with Temozolomide (TMZ) to suppress the growth of U87 and U373 cells. The findings in the present study provide basis for further investigation of the therapeutic potential of bufothionine in GBM. Anat Rec, 302:1950-1957, 2019. © 2019 American Association for Anatomy.

Inhibition of JAK1 mitigates postoperative ileus in mice.

BACKGROUND: Intestinal inflammation is the predominant contributor to the genesis of postoperative ileus. Janus kinase 1 plays an important role during inflammation. Here, we investigated the role of Janus kinase 1 in postoperative ileus and whether inhibition of Janus kinase 1 could mitigate postoperative ileus. METHODS: A mouse model of postoperative ileus was induced by intestinal manipulation. Janus kinase 1 inhibitor GLPG0634 or placebo was administered orally before intestinal manipulation. At the indicated time points post operation, neutrophil infiltration was assessed by immunohistochemistry and enzyme-linked immunosorbent assay; proinflammatory gene expression was quantified by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay; and Janus kinase 1 activation was detected by Western blot. Functional studies were conducted to evaluate intestinal motility. RESULTS: We found that intestinal manipulation led to marked activation of Janus kinase 1, with increased proinflammatory gene expression and upregulated myeloperoxidase level. Moreover, intestinal manipulation resulted in an impairment of intestinal transit in vivo and inhibition of smooth muscle contractility in vitro. Preoperative administration of GLPG0634 markedly lowered the expression of proinflammatory cytokines, the myeloperoxidase level in the muscularis layer after bowel manipulation, and significantly ameliorated smooth muscle contractile function and intestinal transit ability. CONCLUSION: Our data showed that Janus kinase 1 activation mediated intestinal manipulation-induced resident macrophage activation after intestinal manipulation, and subsequent complex inflammatory cascade and gut dysmotility. Janus kinase 1 inhibition appears to be a prospective and convenient approach for the prevention of postoperative ileus.

Opposing effects of Bad phosphorylation at two distinct sites by Akt1 and JNK1/2 on ischemic brain injury.

Increasing evidence suggests that the Bcl-2 family proteins play pivotal roles in regulation of the mitochondria cell-death pathway on transient cerebral ischemia. Bad, a BH3-only proapoptotic Bcl-2 family protein, has been shown to be phosphorylated extensively on serine by kinds of kinases. However, the exact mechanisms of the upstream kinases in regulation of Bad signaling pathway remain unknown. Here, we reported that Bad could be phosphorylated not only by Akt1 but also by JNK1/2 after transient global ischemia in rat hippocampal CA1 region. Our data demonstrated that Akt1 mediated the phosphorylation of Bad at serine 136, which increased the interaction of serine 136-phosphorylated Bad with 14-3-3 proteins and prevented the dimerization of Bad with Bcl-Xl, inhibited the release of cytochrome c to the cytosol and the death effector caspase-3 activation, leading to the survival of neuron. In contrast, JNK1/2 induced the phosphorylation of Bad at a novel site of serine 128 after brain ischemia/reperfusion, which inhibited the interaction of PI3K/Akt-induced serine 136-phosphorylated Bad with 14-3-3 proteins, thereby promoted the apoptotic effect of Bad. In addition, activated Akt1 inhibited the activation of Bad(S128) through downregulating JNK1/2 activation, thus inhibiting JNK-mediated Bad apoptosis pathway. Furthermore, the fate of cell to survive or to die was determined by a balance between prosurvival and proapoptotic signals. Taken together, our studies reveal that Bad phosphorylation at two distinct sites induced by Akt1 and JNK1/2 have opposing effects on ischemic brain injury, and present the possibility of Bad as a potential therapeutic target for stroke treatment.