What is the Risk for Peritoneal Metastases and Survival Afterwards in T4 Colon Cancers?

BACKGROUND: Patients with T4 colon adenocarcinomas have an increased risk of peritoneal metastases (PM) but the histopathologic risk factors for its development are not well-described. OBJECTIVE: The purpose of this study was to determine factors associated with PM, time to recurrence, and survival after recurrence among patients with T4 colon cancer. PATIENTS AND METHODS: Patients with pathologic T4 colon cancer who underwent curative resection from 2005 to 2017 were identified from a prospectively maintained institutional database and classified by recurrence pattern: (a) none - 68.8%; (b) peritoneal only - 7.9%; (c) peritoneal and extraperitoneal - 9.9%; and (d) extraperitoneal only - 13.2%. Associations between PM development and patient, primary tumor, and treatment factors were assessed. RESULTS: Overall, 151 patients were analyzed, with a median follow-up of 66.2 months; 27 patients (18%) developed PM (Groups B and C) and 20 (13%) patients recurred at non-peritoneal sites only (Group D). Median time to developing metastases was shorter for Groups B and C compared with Group D (B and C: 13.7 months; D: 46.7 months; p = 0.022). Tumor deposits (TDs) and nodal stage were associated with PM (p < 0.05), and TDs (p = 0.048) and LVI (p = 0.015) were associated with additional extraperitoneal recurrence. Eleven (41%) patients with PM underwent salvage surgery, and median survival after recurrence was associated with the ability to undergo cytoreduction (risk ratio 0.20, confidence interval 0.06-0.70). CONCLUSION: PM risk after resection of T4 colon cancer is independently associated with factors related to lymphatic spread, such as N stage and TDs. Well-selected patients can undergo cytoreduction with long-term survival. These findings support frequent postoperative surveillance and aggressive early intervention, including cytoreduction.

The protective effect of MANF on intestinal epithelial cell injury induced by endoplasmic reticulum stress / 中国药理学通报

Aim To observe the proteetive effect of meseneephalie astrocyte-de rived neurotrophic faetor (MANF) on intestinal epithelial eells under endoplas- mic reticulum stress (EH stress).Methods Normal human intestinal epithelial cell line FHs74Int was stimulated with EH stress inducers, tunicmycin (TM) and TNF-cx, then the expression of endogenous MANF was observed.The recombinant plasmids MANF-GFP and GFP were transfected into FHs74Int cells individually, the transfection efficiency was observed by fluorescence j j microscopy, and the effect of MANF on EH stress was observed by Western blot.The effect of MANF on the proliferation of intestinal epithelial cells stimulated by TM was detected via CCK-8 assay.The effect of MANF on apoptosis after EH stress was detected by Western blot and flow cytometry.Results EH stress could induce the expression of endogenous MANE in intestinal epithelial cells.Overexpression of MANE significantly inhibited the expression of the EH stress-related proteins, Bip and CHOP, and promoted the proliferation of intestinal epithelial cells.At the same time, it could reduce the production of the proapoptotic proteins cleaved-c a spa se-3 and Bax, increase the expression of the antiapoptotic protein Bcl-2, and inhibit the proportion of early and late apoptosis of intestinal epithelial cells.Conclusions MANF plays a protective role in inhibiting EH stress in intestinal epithelial cells by promoting cell proliferation and reducing apoptosis.

[Analysis on adult health life expectancy in Shanghai].

Objective: To investigate health status and calculate health life expectancy (HE) of residents in Shanghai, analyze health related factors and provided foundation of health policy. Methods: A multi-stage stratified random sampling was used to obtain self-reported health survey in Shanghai. WHO questionnaire was used to evaluate the health quality of life which was designed for the world health survey, Sullivan's method was used to calculate HE. Results: The self-assessment disability measure for adults over 18 years old in Shanghai was 0.25, higher for women (0.28) than for men (0.23). LE was 65.76 years for adults over 18 years old, higher for women (68.22) than for men (63.39). HE for adults over 18 years old was 47.99 years old, higher for men (49.05) than women (47.14). HE's proportion in LE gradually decreases with age. It accounts for 72.97% in the 18 years old and 39.00% in the 85 years old. Conclusions: The health of adult male in Shanghai is higher than that of female, and the proportion of HE loss of elderly is higher than young people. It is necessary to focus on the aging problem and strengthen the long-term care and health support system for the elderly. Improve the prevention and control of major diseases such as chronic diseases,which affect the quality of life expectancy seriously. Promotes the health level and quality of life in Shanghai.

CEA as a blood-based biomarker in anal cancer.

BACKGROUND: The clinical utility of a blood-based biomarker in squamous cell carcinoma of the anus (SCCA) is unknown. We analyzed carcinoembryonic antigen (CEA), a commonly employed assay for patients with colorectal adenocarcinoma, as a serum biomarker for patients with biopsy-proven SCCA. MATERIALS AND METHODS: Medical records from 219 patients with biopsy-proven SCCA at the University of Texas MD Anderson Cancer Center were reviewed under an IRB-approved protocol from 2013 to 2020 to assess for correlations between CEA levels and corresponding clinical and pathologic characteristics. RESULTS: The mean CEA among subgroups by clinical status at the time of presentation to our institution was highest among those patients with metastatic SCCA to visceral organs (M-V, 20.7 ng/mL), however this finding was not statistically significant by ANOVA (p = .74). By clinical subgroup, the percentage of patients with an abnormally elevated CEA was highest in those patients with metastatic disease to lymph nodes (M-L, 41.2%) followed by recurrent/unresectable SCCA (36.8%), and metastatic SCCA to visceral organs (M-V, 35.2%), and was statistically significant between groups (Fisher's exact test p = .02). Using RECIST criteria for tumor progression and disease response, the mean change in CEA for patients with progression was an increase in 19 ng/mL, compared to a change of -7.3 ng/mL in those with disease response (p = .004). We likewise assessed whether CEA levels were associated with survival outcomes for all patients with metastatic SCCA, and found no correlation between CEA and likelihood for survival in a ROC analysis (multivariate, age-adjusted analysis for CEA cutoff of 8, HR = 1.01, 95% CI 0.52-1.96). CONCLUSIONS: Despite interesting patterns of abnormally high CEA in SCCA patients with advanced disease, and correlation of increased CEA with disease progression (and conversely decreased CEA with disease response), CEA is not associated with survival outcomes in SCCA, and is not a clinically relevant biomarker in this disease.

Genomic and Transcriptomic Characterisation of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT), followed by surgical resection. However, >70% of patients do not achieve a complete pathological response and have higher rates of relapse and death. There are no validated pre- or on-treatment factors that predict response to NACRT besides tumour stage and size. We characterised the response of 33 LARC patients to NACRT, collected tumour samples from patients prior to, during and after NACRT, and performed whole exome, transcriptome and high-depth targeted sequencing. The pre-treatment LARC genome was not predictive of response to NACRT. However, in line with the increasing recognition of microbial influence in cancer, RNA analysis of pre-treatment tumours suggested a greater abundance of Fusobacteria in intermediate and poor responders. In addition, we investigated tumour heterogeneity and evolution in response to NACRT. While matched pre-treatment, on-treatment and post-treatment tumours revealed minimal genome evolution overall, we identified cases in which microsatellite instability developed or was selected for during NACRT. Recent research has suggested a role for adaptive mutability to targeted therapy in colorectal cancer cells. We provide preliminary evidence of selection for mismatch repair deficiency in response to NACRT. Furthermore, pre-NACRT genomic landscapes do not predict treatment response but pre-NACRT microbiome characteristics may be informative.

The re-emerging of SADS-CoV infection in pig herds in Southern China.

A new highly virulent swine acute diarrhoea syndrome coronavirus (SADS-CoV) emerged in Guangdong province in 2017 followed by fatal diarrhoea that involved the death of 24,693 piglets. And yet from May 2017 to January 2019, there were no new SADS cases arising in pig herds in Guangdong. In this study, we reported the recent diarrhoea outbreak of SADS-CoV in Southern China on February 2019. Intestinal samples collected from diarrhoeal piglets were detected for common swine virus and confirmed that SADS-CoV was responsible for the diarrhoea case. Meanwhile, serological investigation of sows' sera implied that SADS-CoV has existed in the farm and PEDV antibody may not directly contribute to the amplification of SADS-CoV. Homology and phylogenetic analysis of the whole genome showed that the re-emerging SADS-CoV strain shared high sequence identities with existing SADS-CoV strains and all strains clustered together in Alpha coronavirus. All in all, the report herein emphasized the re-emerging of SADS-CoV and highlights continuous monitoring for this virus.

Expression profile analysis of 5-day-old neonatal piglets infected with porcine Deltacoronavirus.

BACKGROUND: Porcine deltacoronavirus (PDCoV) is a novel coronavirus that can cause diarrhea in nursing piglets. This study was aimed to investigate the roles of host differentially expressed genes on metabolic pathways in PDCoV infections. RESULTS: Twenty thousand six hundred seventy-four differentially expressed mRNAs were identified in 5-day-old piglets responded to PDCoV experimental infections. Many of these genes were correlated to the basic metabolism, such as the peroxisome proliferator-activated receptor (PPAR) signaling pathway which plays a critical role in digestion. At the same time, in the PPAR pathway genes of fatty acid-binding protein (FABP) family members were observed with remarkably differential expressions. The differential expressed genes were associated with appetite decrease and weight loss of PDCoV- affected piglets. DISCUSSION: Fatty acid-binding protein 1 (FABP1) and fatty acid-binding protein 3 (FABP3) were found to be regulated by PDCoV. These two genes not only mediate fatty acid transportation to different cell organelles such as mitochondria, peroxisome, endoplasmic reticulum and nucleus, but also modulate fatty acid metabolism and storage as a signaling molecule outside the cell. Therefore, it can be preliminarily concluded that PPAR differential expression caused by PDCoV was mostly associated with weight loss and death from emaciation. CONCLUSIONS: The host differentially expressed genes were associated with infection response, metabolism signaling and organismal systems signaling pathways. The genes of FABP family members in the PPAR signaling pathway were the most highly altered and played important roles in metabolism. Alteration of these genes were most likely the reason of weight loss and other clinical symptoms. Our results provided new insights into the metabolic mechanisms and pathogenesis of PDCoV infection. METHODS: Animal experiment, Determination of viral growth by real-time RT-PCR, Histopathology, Immunohistochemical staining, Microarray analysis.

Preclinical development of peptide vaccination combined with oncolytic MG1-E6E7 for HPV-associated cancer.

Human papilloma virus (HPV)-associated cancer is a significant global health burden and despite the presence of viral transforming antigens within neoplastic cells, therapeutic vaccinations are ineffective for advanced disease. HPV positive TC1 cells are susceptible to viral oncolysis by MG1-E6E7, a custom designed oncolytic Maraba virus. Epitope mapping of mice vaccinated with MG1-E6E7 enabled the rational design of synthetic long peptide (SLP) vaccines against HPV16 and HPV18 antigens. SLPs were able to induce specific CD8+ immune responses and the magnitude of these responses significantly increased when boosted by MG1-E6E7. Logically designed vaccination induced multi-functional CD8+ T cells and provided complete sterilising immunity of mice challenged with TC1 cells. In mice bearing large HPV-positive tumours, SLP vaccination combined with MG1-E6E7 was able to clear tumours in 60% of mice and these mice were completely protected against a long term aggressive re-challenge with the TC1 tumour model. Combining conventional SLPs with the multi-functional oncolytic MG1-E6E7 represents a promising approach against advanced HPV positive neoplasia.

Glucocorticoids impair bone formation of bone marrow stromal stem cells by reciprocally regulating microRNA-34a-5p.

UNLABELLED: The inhibitory effects of glucocorticoids (GCs) on bone marrow stromal stem cell (BMSC) proliferation and osteoblastic differentiation are an important pathway through which GCs decrease bone formation. We found that microRNA-34a-5p was a critical player in dexamethasone (Dex)-inhibited BMSC proliferation and osteogenic differentiation. MicroRNA-34a-5p might be used as a therapeutic target for GC-impaired bone formation. INTRODUCTION: The inhibitory effects of glucocorticoids (GCs) on bone marrow stromal stem cell (BMSC) proliferation and osteoblastic differentiation are an important pathway through which GCs decrease bone formation. The mechanisms of this process are still not completely understood. Recent studies implicated an important role of microRNAs in GC-mediated responses in various cellular processes, including cell proliferation and differentiation. Therefore, we hypothesized that these regulatory molecules might be implicated in the process of GC-decreased BMSC proliferation and osteoblastic differentiation. METHODS: Western blot, quantitative real-time PCR, and cell proliferation and osteoblastic differentiation assays were employed to investigate the role of microRNAs in GC-inhibited BMSC proliferation and osteoblastic differentiation. RESULTS: We found that microRNA-34a-5p was reciprocally regulated by Dex during the process of BMSC proliferation and osteoblastic differentiation. Furthermore, we confirmed that microRNA-34a-5p was a critical player in Dex-inhibited BMSC proliferation and osteogenic differentiation. Mechanistic studies showed that Dex inhibited BMSC proliferation by microRNA-34a-5p targeting cell cycle factors, including CDK4, CDK6, and Cyclin D1. Furthermore, downregulation of microRNA-34a-5p by Dex leads to Notch signaling activation, resulting in inhibition of BMSC osteogenic differentiation. CONCLUSIONS: These results showed that microRNA-34a-5p, a crucial regulator for BMSC proliferation and osteogenic differentiation, might be used as a therapeutic target for GC-impaired bone formation.

Detection and clinical significance of lymph node micrometastasis in gastric cardia adenocarcinoma.

OBJECTIVES: Lymph node micro metastasis was investigated in gastric cardia adenocarcinoma (GCA) patients without lymph node metastasis on routine pathological examination. The relationship between micrometastasis and clinicopathological features was also evaluated. METHODS: A total of 349 lymph nodes were obtained from 45 patients with GCA. Micrometastases were detected by immunohistochemical staining for the markers cytokeratin 19 (CK19) and CD44 variant 6 (CD44v6). RESULTS: A total of 33 lymph nodes (9.5%) from 15 patients (33.3%) were positive for CK19. Of these, 27 lymph nodes (7.7%) from 12 patients (26.7%) were also positive for CD44v6. Micrometastasis was significantly related to depth of tumour invasion and Lauren classification (intestinal or diffuse). The recurrence rate was significantly higher and 2-year survival rate significantly lower in patients with than in those without lymph node micrometastasis, showing the necessity of detecting micrometastasis in GCA patients who test negative for lymph node metastasis on routine examination. CONCLUSION: CK19 and CD44v6 were shown to be good markers for micrometastasis detection.

Quantitative studies of the distribution pattern for Salmonella Enteritidis in the internal organs of chicken after oral challenge by a real-time PCR.

This research was undertaken to identify and understand the regular distribution pattern for Salmonella Enteritidis (S. enteritidis) in the internal organs of chicken after oral challenge over a 3 wk period. We used a real-time, fluorescence-based quantitative polymerase chain reaction (FQ-PCR) to detect genomic DNA of S. enteritidis in the blood and the internal organs, including heart, liver, spleen, kidney, pancreas, and gallbladder, from chicken after oral challenge at different time points. The results showed that the spleen was positive at 12 h post inoculation (PI), and the blood was at 14 h PI. The organism was detected in the liver and heart at 16 h PI, pancrea was positive at 20 h PI, and the final organ to show a positive results were the kidney and gallbladder at 22 h PI. The copy number of S. enteritidis DNA in each tissue reached a peak at 24 h-36 h PI, with the liver and spleen containing high concentrations of S. enteritidis, whereas the blood, heart, kidney, pancreas, and gallbladder had low concentrations. S. enteritidis populations began to decrease and were not detectable at 3 d PI, but were still present up to 12 d PI in the gallbladder, 2 wk for the liver, and 3 wk for the spleen without causing apparent symptoms. The results showed that the liver and spleen may be the primary sites for S. enteritidis setting itself up as a commensa over a long time after oral challenge. Interestingly, it may be the first time reported that the gallbladder is a site of carriage for S. enteritidis over a 12 d period. This study will help to understand the mechanisms of action of S. enteritidis infection in vivo.

Statistical methods for the analysis of relapse data in MS clinical trials.

Patients with multiple sclerosis (MS) often experience unpredictable recurrent relapses with periods of remission. The modeling of MS relapse data is complicated because both within-subject serial dependence between relapses and between-patient heterogeneity may exist. We compare six statistical methods for assessing the treatment efficacy in reducing the frequency of relapses in MS clinical trials. All methods can be implemented in SAS, and are grouped into two classes, one based on Poisson-type regressions for count data and the other on Cox proportional hazards models for time to relapse. We apply these models to the data of a Tysabri (Natalizumab) MS trial and interpret the differences in results based on the underlying assumptions. Negative binomial regression is recommended for evaluating the overall treatment effect because of its simplicity and efficiency.

Clinical and molecular survey in 124 Chinese patients with Leigh or Leigh-like syndrome.

Leigh syndrome is the most common mitochondrial disorder in children characterized by necrotic lesions in the central nervous system. Both mitochondrial DNA (mtDNA) and nuclear DNA defects in the mitochondrial respiratory chain can lead to this disease. To characterize the clinical and genetic traits of Leigh or Leigh-like syndrome patients in China, 124 unrelated cases were collected between 1992 and 2005. Seventy-seven cases (62.1%) met the typical criteria of Leigh syndrome, including symmetrical bilateral abnormal signals in the basal ganglia, thalamus and brain stem, etc. Other cases (37.9%) belonged to Leigh-like syndrome with atypical clinical or radiological manifestations. Late-onset patients accounted for 20.2%, which is more than previously reported. Movement disorder was the most common symptoms in our patients. Thirty-two patients (25.8%) were confirmed to carry mutant genes. Among them, six cases (4.8%) have been demonstrated to have point mutations in mitochondrial DNA. Two separate patients were detected to have mutations on A8344G and A3243G. The T8993G point mutation was identified in one patient and T8993C in one other patient. SURF1 mutations associated with cytochrome-c oxidase deficiency were identified in 25 patients (20.2%). Four unreported variations have been identified in SURF1 gene from three patients. G604C was found in 22 patients. Only one patient had C214T mutation in the pyruvate dehydrogenase E1alpha subunit gene. In the remaining 92 patients (74.2%), a specific molecular dysfunction or underlying metabolic abnormality could not be identified.

Relationship between LAPTM4B gene polymorphism and susceptibility of gastric cancer.

BACKGROUND: A novel gene called LAPTM4B (lysosome-associated protein transmembrane 4beta) was mapped to 8q22, and contains seven exons. The 2.25-kb messenger RNA of the gene encodes a putative lysosome-associated protein with four transmembrane regions. There are two alleles of the gene, named as LAPTM4B*1 and LAPTM4B*2. Allele *1 differs from allele *2 in that it contains only one copy of a 19-bp sequence in the 5' untranslated region (UTR), whereas this sequence is duplicated and tandemly arranged in allele *2. Studies showed that the allelic variation of LAPTM4B was associated with the genetic susceptibility of hepatocellular carcinoma but not with that of esophageal squamous cell carcinoma. This study was designed to investigate the possible association between the allelic variation of LAPTM4B and the genetic susceptibility of gastric cancer. MATERIALS AND METHODS: The genotype of LAPTM4B was analyzed in 350 unrelated healthy adult individuals and 214 patients with gastric cancer by utilizing polymerase chain reaction based on specific primers. The genotypic distribution of LAPTM4B was analyzed by chi(2) test. RESULTS: The allelic frequencies of the *2 were 33.88% and 24.14% in the gastric cancer group and the healthy control group, respectively, which was significantly different between the two groups (P < 0.001). There was a significant difference in the overall genotypic distribution between the patients and the controls (P = 0.023). The risk of suffering from gastric cancer was increased 1.819 times in the individuals of the *1/2 genotype [95% confidence interval (CI) 1.273-2.601] and 2.387 times in the individuals of the *2/2 genotype of LAPTM4B (95% CI 1.195-4.767) compared with the *1/1 genotype. No association between the genotypic distribution of LAPTM4B and the clinical information on patients of gastric cancer such as age, pathological type, differentiation classification of TNM, and infection of hepatitis B virus was shown. CONCLUSION: This study indicated that allele *2 of LAPTM4B might be the risk factor of gastric cancer, which could be associated with genetic susceptibility of gastric cancer.

Analysis of polycyclic aromatic hydrocarbons in the particulate phase of cigarette smoke using a gas chromatographic-high-resolution mass spectrometric technique.

A new procedure is developed for the extraction of polycyclic aromatic hydrocarbons (PAHs) from the particulate phase of cigarette smoke. The procedure applies solid-phase extraction using a Bond Elut CH cartridge as a sample preparation step. The efficiency of the cleanup procedure is verified using a gas chromatographic (GC)-high-resolution mass spectrometric (MS) technique, proving that no interference occurs in the PAHs' determination. The efficient cleanup allows GC detection using either high- or low-resolution MS detection. Enhanced sensitivity is obtained using GC-MS and selected ion monitoring. This new technique has several advantages over other reported techniques. The method is simple and robust and has good repeatability and accuracy. The estimated detection limit is 0.1 ng/cigarette for benzo[a]pyrene. In addition to that, the recovery from the smoke pad in which the smoke is collected is approximately 97% for all PAHs. Results for the PAH analyses for 1R5F, 1R4F, and 1R3 Kentucky reference cigarettes are reported in this study. These results provide useful evidence for clarifying the controversy about previously reported data.

Motion rivalry impairs motion repulsion.

In their classic study on motion repulsion, Marshak and Sekuler (Science 205 (1979) 1399) reported a repulsion of up to 10 degrees when two different directions of motion were presented dichoptically. However, subjects in that study did not experience binocular rivalry, presumably because of the brief presentation time. In the present study, we measured repulsion during binocular rivalry by requiring subjects to dichoptically view the stimuli until one direction of motion appeared to exclusively dominate the other (Blake, Yu, Lokey, & Norman (1998). J. Cogn. Neurosci., 10, 46-60). We found that motion repulsion was significantly reduced during exclusive dominance. Indeed, after controlling for reference repulsion--the misjudgment of a single direction of motion (Rauber & Treue (1998). Perception, 27, 393-402)--we found no significant motion repulsion during exclusive dominance. These data suggest that motion repulsion may require the perception, rather than merely the physical presence, of multiple directions.

Transcranial magnetic stimulation differentially affects speed and direction judgments.

This study was conducted to determine whether humans' judgments about the speed and direction of moving stimuli was differentially affected by transcranial magnetic stimulation (TMS). Subjects viewed two successively presented moving stimuli that differed from each other both in speed and direction of motion. Single-pulse TMS was applied either medially (approximately 2 cm above the inion) or laterally (approximately 5 cm lateral to and 4 cm above the inion), while subjects judged the speed and direction differences. The physical stimulation (visual and TMS) was identical on the two tasks, as was discriminability (d') when TMS was not applied. We found significant criterion (beta) shifts on the speed discrimination task at both stimulation sites. Specifically, on TMS trials the proportion of "slower" judgments increased significantly, consistent with subjective reports that stimuli often appeared to slow when TMS was applied. The subjective reports indicated no corresponding change in perceived direction. We also found that speed discriminability was impaired significantly more than direction discriminability, but only when TMS was applied medially. Indeed, after controlling for TMS-related changes in reaction time, speed discriminability was impaired significantly, while direction discriminability remained largely intact. This dissociation suggests that the sensory response constraining speed discrimination is at least partially independent from the sensory response constraining direction discrimination. Combined with previous psychophysical data, the present data suggest a double dissociation between speed and direction discrimination in humans.