Involvement of Rictor/mTORC2/Akt/GLUT4 pathway in the regulation of energy metabolism in the gastric smooth muscle of diabetic rats.

Diabetes mellitus can be accompanied by a variety of complications. The purpose of the present study was to characterize the Rictor/mTOR complex 2 (mTORC2)/Akt/glucose transporter 4 (GLUT4) pathway and its effects on energy metabolism in the gastric smooth muscle of diabetic rats. Diabetes was induced in rats using streptozotocin and their phenotype was compared with untreated rats. The relationship between gastric motility and energy metabolism was analyzed by comparing the contraction and ATP metabolism of muscle strips. Western blotting was used to detect the expression of key proteins in the pathway. The diabetic rats demonstrated less frequent and less powerful gastric smooth muscle contractions. The concentrations of ADP, AMP, and ATP, and the energy charge in gastric smooth muscle changed in different periods of diabetes, and these changes were consistent with changes in mechanistic target of rapamycin (mTOR) protein content. The expression of the key intermediates in signal transduction in the Rictor/mTORC2/Akt/GLUT4 pathway also underwent significant changes. Rictor protein expression increased during the development of diabetes, but the activation of mTORC2 did not increase with the increase in Rictor expression. GLUT4 translocation is regulated by Akt and its expression change during the development of diabetes. These findings suggest that altered energy metabolism is present in gastric smooth muscle that is associated with changes in the Rictor/mTORC2/Akt/GLUT4 pathway. Rictor/mTORC2/Akt/GLUT4 pathway may be involved in the regulation of energy metabolism in the gastric smooth muscle of diabetic rats and the development of diabetic gastroparesis.

Assessing transfer of aluminum during tea brewing and associated population health risks.

Tea is consumed widely around the world owing to its refreshing taste and potential health benefits. However, drinking tea is considered a major route for dietary aluminum exposure in areas where tea consumption is relatively large. To assess the health risk associated with drinking tea, the contamination level of aluminum was determined in 81 tea samples. The transfer rate of aluminum during tea brewing was investigated. Then based on the site-specific exposure parameters such as consumption data and body weight for six different subpopulations in Fujian, the exposure risks were estimated using a probabilistic approach. Results demonstrate that the contents of aluminum in green tea, white tea, oolong tea, and black tea were significantly different according to the one-way ANOVA analysis (p < 0.05). The transfer rate of aluminum were 32.6%, 31.6%, 26.3%, and 14% for white tea, black tea, oolong tea, and green tea, respectively. With respect to the oral reference dose, the exposure of inhabitants in Fujian to aluminum through drinking tea is under control (even at the 99th percentile).

Influence of sports elective courses on college students' physical health / Influência dos cursos eletivos esportivos sobre a saúde física dos estudantes universitários / Influencia de las asignaturas deportivas optativas en la salud física de los estudiantes universitarios

ABSTRACT Introduction The college sports environment is characterized by breadth, diversity, and personality. This is an important period to develop students' physical ability and improve their personality. Objective Compare the effects of different exercise methods on students' health status. Methods 2991 college students participated in different sports activities. These sports were conducted based on the selection course (PE), all during one semester. The students' physical health status was observed through experiments performed before and after the intervention. Results Activities such as basketball and soccer showed high effectiveness in improving students' vital capacity index, volleyball expressively improved students' performance in the long jump, tennis and table tennis were effective in improving students' strength and adherence index, being lower in other indices. Martial arts also stood out in improving the students' vital capacity index. Conclusion Improving physical health should be an overall process of students' fitness development, and universities should actively encourage college students to participate in long-term sports to improve their health. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução O ambiente do esporte universitário é caracterizado pela abrangência, diversidade e personalidade. Este é um período importante para desenvolver a capacidade física dos estudantes e melhorar a sua personalidade. Objetivo Comparar os efeitos de diferentes métodos de exercício sobre o estado de saúde dos estudantes. Métodos 2991 estudantes universitários participaram de diferentes atividades esportivas. Estes esportes foram conduzidos com base no curso de seleção (PE), todos durante um semestre. O estado de saúde física dos estudantes foi observado através de experimentos executados previa e posteriormente à intervenção. Resultados Atividades como basquetebol e futebol demonstraram alta efetividade para melhorar o índice de capacidade vital dos estudantes, voleibol melhorou expressivamente o desempenho dos alunos no salto em distância, o tênis e o tênis de mesa foram efetivos para aprimorar o índice de força e de adesão dos alunos, sendo inferior noutros índices. Também as artes marciais se destacaram ao melhorar o índice de capacidade vital dos alunos. Conclusão O aprimoramento da saúde física deve ser um processo global de desenvolvimento da aptidão física dos estudantes e as universidades devem encorajar ativamente os estudantes universitários a participar de esportes de longo prazo para melhorar sua saúde. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción El entorno del deporte universitario se caracteriza por su alcance, diversidad y personalidad. Es un periodo importante para desarrollar la capacidad física de los alumnos y mejorar su personalidad. Objetivo Comparar los efectos de diferentes métodos de ejercicio sobre el estado de salud de los estudiantes. Métodos 2991 estudiantes universitarios participaron en diferentes actividades deportivas. Estos deportes se llevaron a cabo basándose en el curso de selección (PE), todo ello durante un semestre. El estado de salud física de los alumnos se observó mediante experimentos realizados antes y después de la intervención. Resultados Actividades como el baloncesto y el fútbol mostraron una alta eficacia para mejorar el índice de capacidad vital de los alumnos, el voleibol mejoró expresivamente el rendimiento de los alumnos en salto de longitud, el tenis y el tenis de mesa fueron eficaces para mejorar el índice de fuerza y adherencia de los alumnos, siendo inferiores en otros índices. También las artes marciales se destacaron en la mejora del índice de capacidad vital de los alumnos. Conclusión La mejora de la salud física debería ser un proceso global del desarrollo de la forma física de los estudiantes y las universidades deberían animar activamente a los universitarios a participar en deportes de larga duración para mejorar su salud. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Uptake of atmospherically deposited cadmium by leaves of vegetables: Subcellular localization by NanoSIMS and potential risks.

Atmospherically deposited cadmium (Cd) may accumulate in plants through foliar uptake; however, the foliar uptake, accumulation, and distribution processes of Cd are still under discussion. Atmospherically deposited Cd was simulated using cadmium sulfide (CdS) with various particle sizes and solubility. Water spinach (Ipomoea aquatica Forsk, WS) and pak choi (Brassica chinensis L., PC) leaves were treated with suspensions of CdS nanoparticles (CdSN), which entered the leaves via the stomata. Cd concentrations of WS and PC leaves treated with 125 mg L-1 CdSN reached up to 39.8 and 11.0 mg kg-1, respectively, which are higher than the critical leaf concentration for toxicity. Slight changes were observed in fresh biomass, photosynthetic parameters, lipid peroxidation, and mineral nutrient uptake. Exposure concentration, rather than particle size or solubility, regulated the foliar uptake and accumulation of Cd. Subcellular and the high-resolution secondary ion mass spectrometry (NanoSIMS) results revealed that Cd was majorly stored in the soluble fraction and cell walls, which is an important Cd detoxification mechanism in leaves. The potential health risks associated with consuming CdS-containing vegetables were highlighted. These findings facilitate a better understanding of the fate of atmospheric Cd in plants, which is critical in ensuring food security.

Copper exposure disrupts ovarian steroidogenesis in human ovarian granulosa cells via the FSHR/CYP19A1 pathway and alters methylation patterns on the SF-1 gene promoter.

Information on the effects of copper on reproduction is limited. Our previous study indicated that copper induces abnormal steroidogenesis in human ovarian granulosa cells, but the underlying mechanism remains unclear. In this study, human ovarian granulosa cells were treated with multiple concentrations of copper for 24 h. After treatment, the 17-estradiol levels were significantly increased (29.83 % and 45.12 %, respectively) in the 1.0 and 2.0 µg/mL groups but decreased (23.06 % and 31.56 %, respectively) in the 20.0 and 40.0 µg/mL groups (P < 0.05). Similar changes in the levels of FSHR, StAR, CYP11A1, CYP19A1, HSD3ß1, and SF-1 were observed. The protein levels of FSHR were increased in the 2.0 µg/mL group but decreased in the 20.0 and 40.0 µg/mL groups (P < 0.05). Moreover, copper partially reversed the FSH-induced increase in FSHR, CYP19A1 and 17-estradiol levels, and the decreased effect of the FSH receptor binding inhibitor fragment on FSHR, CYP19A1, and 17-estradiol became more apparent after adding copper. Additionally, the total methylation levels of the SF-1 promoter and DNMTs expression were significantly decreased following copper treatment. Overall, our results indicate that copper exposure induces steroidogenesis disorders via the FSHR/CYP19A1 pathway and changes DNA methylation on the SF-1 promoter in human ovarian granulosa cells.

Occurrence of pesticides in white tea and a corresponding risk exposure assessment for the different residents in Fujian, China.

White tea has been of increasing public interest worldwide owing to its health benefits. Based on 2 years of surveillance, the long-term and cumulative chronic exposure risks of pesticide residues through white tea drinking were assessed for different subpopulations in Fujian, China. Twenty-five different pesticides were found, and 74.8% of samples contained at least one pesticide residue. The most frequently detected pesticide was bifenthrin with detection rates of 61.6%. Risk assessment was performed using both the deterministic approach and semiprobabilistic model under the best-case and the worst-case scenarios. The results demonstrated that the dietary risks were extremely low for six different subpopulations in which the risks for adults over the age of 41 were relatively higher. The risk ranking scheme indicated that isocarbophos and triazophos were considered to be of medium risk. The different use suggestions for the 25 positive pesticides are proposed to further minimize the exposure risk to consumer health. PRACTICAL APPLICATION: Tea is the second most popular nonalcoholic beverage throughout the world. Pesticides are used to improve the yield of tea. Pesticide residues in tea could be one of the exposure pathways for consumers. Monitoring residual levels and assessing the health risk assessment in tea are thus in an urge.

Fisetin protects against high fat diet-induced nephropathy by inhibiting inflammation and oxidative stress via the blockage of iRhom2/NF-κB signaling.

Promoted inflammation enhances the development of nephropathy in obesity. Fisetin (3,3',4',7-tetrahydroxyflavone, FIS) is a naturally occurring dietary flavonoid, and exhibits anti-inflammatory and anti-oxidative properties. Inactive rhomboid protein 2 (iRhom2), an inactive member of the rhomboid intramembrane proteinase family, is an essential inflammation-associated regulator. Here, we attempted to investigate the protective mechanisms of FIS against high fat diet (HFD)-induced nephropathy, with particular focus on iRhom2. We found that HFD induced systematic and renal pro-inflammatory cytokine production. Furthermore, iRhom2 expression was markedly elevated in kidney of HFD-fed mice, and in PAL-incubated macrophages, accompanied with high phosphorylation of NF-κB. Significant oxidative stress was observed in kidney of HFD-fed mice through suppressing Nrf-2/HO-1 signaling. Moreover, activation of iRhom2/NF-κB signaling and oxidative stress by PAL was detected in macrophages, which were effectively reversed by FIS. Importantly, we showed that iRhom2 knockdown significantly abrogated the ability of FIS to restrain inflammation and oxidative stress induced by PAL in macrophages, indicating that iRhom2 might be a potential therapeutic target for FIS during nephropathy treatment. Together, these results revealed that FIS could mitigate HFD-induced renal injury by regulating iRhom2/NF-κB and Nrf-2/HO-1 signaling pathways.

A radiologic parameter that could be applied in the development of sleep apnea in rheumatoid arthritis patients undergoing occipitocervical fusion.

BACKGROUND: The prevalence of sleep apnea in rheumatoid arthritis (RA) patients with occipitocervical lesions was 79%. Occipitocervical fusion (OCF) could incur sleep apnea or worsen this condition. Recent studies reported that this complication is caused by stenosis of the oropharyngeal airway accompanying a decrease in the occipitoaxial angle (O-C2a). However, there are several limitations to the application of the O-C2a, which decreases its effectiveness. Therefore, we aimed to evaluate the association between a new radiologic parameter, the CVT/NSL angle (CVT: craniocervical inclination in the second and fourth vertebrae; NSL: Nasion-Sella line), and sleep apnea in RA patients accepting OCF. METHODS: A total of 35 patients who underwent OCF due to upper cervical lesions secondary to RA and had sleep apnea before surgery were analyzed. Those who have a postoperative apnea-hypopnea index (AHI) < 15 and a ΔAHI ≥50% were considered "responders"; patients were otherwise considered "non-responders." They were analyzed whether pre- and postoperative radiologic parameters and their differences in plain lateral radiographs were correlated to the parameter related to sleep apnea. RESULTS: The included patients have a mean AHI of 21.9 (range, 10 to 52) before surgery. The mean postoperative CVT/NSLa, ΔCVT/NSLa, andΔO-C2a in complete responders were significantly greater compared with non-responders (p < 0.05). Both the changes in the CVT/NSLa and O-C2a were linearly correlated within patients. However, the R2 value for the CVT/NSLa was greater compared with the O-C2a (0.403 vs. 0.203). CONCLUSIONS: The usefulness of the new craniovertebral angle, CVT/NSLa, as an intraoperative indicator during OCF, is more valuable in comparison with the conventional method of measuring the O-C2a. Measuring the craniovertebral angle is extremely important in the planning of surgical treatment for the development of sleep apnea in rheumatoid arthritis patients undergoing occipitocervical fusion.

NEAT1/miR-200b-3p/SMAD2 axis promotes progression of melanoma.

Melanoma is a skin malignancy with a high mutation frequency of genetic alterations. MicroRNA (miR)-200b-3p is involved in various cancers, while in melanoma its bio-function remains unknown. In this study, we found that miR-200b-3p was down-regulated in melanoma tissues and cell lines compared to benign nevus cells. Overexpression of miR-200b-3p significantly inhibited the proliferation and invasion of melanoma cells. According to bioinformatics analysis and sequencing data, we supposed that SMAD family member 2 (SMAD2) was the target gene and nuclear enriched abundant transcript 1 (NEAT1) was the upstream long non-coding RNA (lncRNA) of miR-200b-3p. These predictions were verified by western blotting and quantitative real-time reverse transcription PCR (RT-qPCR). Luciferase reporter assays revealed that NEAT1 up-regulated SMAD2 by directly sponging miR-200b-3p. In vitro and in vivo, we demonstrated that both NEAT1 and SMAD2 could promote the proliferation and invasion of melanoma cells, and these effects were reversed by up-regulating miR-200b-3p. In addition, NEAT1/miR-200b-3p/SMAD2 axis promoted melanoma progression by activating EMT signaling pathway and immune responses. Taken together, the NEAT1/miR-200b-3p/SMAD2 signaling pathway promotes melanoma via activation of EMT, cell invasion and is related with immune responses, which provides new insights into the molecular mechanisms and therapeutic targets for melanoma.

Comparative proteomics analysis indicates that palmatine contributes to transepithelial migration by regulating cellular adhesion.

CONTEXT: Palmatine, a biologically active isoquinoline alkaloid, possesses multiple pharmaceutical activities against mucosal infection and inflammation. OBJECTIVE: There are no reports about the influence of palmatine on uterine mucosal epithelial cells. MATERIALS AND METHODS: We used proteomics to analyse differentially expressed proteins (DEPs) in goat endometrial epithelial cells (EECs) stimulated by lipopolysaccharide (LPS, 5 µg/mL, the dosage can induce inflammatory response, according to our previous study) for 12 h and then treated with palmatine (80 µg/mL) for 8 h; the dosage was selected based on MTT assay. The EECs without any treatment were used as controls. Every group was treated in triplicate. RESULTS: A total of 428 DEPs in LPS-stimulated group and 486 DEPs in the palmatine-treated group were identified. Functional annotation analysis showed that palmatine mainly regulated the protein expression of structural molecules involved in the response to stimuli. Pathway analysis showed that cell adhesion molecule (CaM) pathways were most significant enriched due to palmatine treatment. Junction adhesion molecule 1 (JAM1), nectin 1 (NECT1) and cadherin 5 (CDH5), which play important roles in the transepithelial migration (TEpM) of leukocytes, were significantly downregulated by palmatine. Meanwhile, other proteins essential to the maintenance of cell adhesion and those that facilitate leukocyte migration were upregulated after palmatine treatment. Discussion and conclusions: The results suggested that palmatine regulates the expression of CaMs to affect TEpM during uterine mucosal inflammation and provides novel insight to understanding and developing palmatine pharmacology. Palmatine is a promising drug for treatment of mucosal inflammation.

Prognostic significance of high triglyceride and apolipoprotein B levels in patients with stage III and high-risk stage II colorectal cancer undergoing curative surgery.

Although epidemiologic studies suggest that dyslipidemia increases the risk of colorectal cancer (CRC), the prognostic value of blood lipid and apolipoprotein levels in CRC remains unclear. The aim of the present study was to investigate the impact of blood lipid and apolipoprotein levels on the prognosis of patients with stage III and high-risk stage II CRC undergoing curative surgery. Preoperative levels of total cholesterol, triglycerides (TG), high-density lipoprotein, low-density lipoprotein, very-low-density lipoprotein, apolipoprotein A1 and apolipoprotein B (APO-B) in patients with CRC undergoing surgery were evaluated. The cut-off values of these factors were determined by the maximal x2 method and were used to classify patients into two prognostic groups: Poor and good prognosis groups. The patients prognostic values were assessed using the Kaplan-Meier curve and Cox regression analysis. In addition, the impact of these parameters on the prognosis and their predictive accuracy were evaluated using nomograms and Harrells concordance index, respectively. In total, 246 patients were included in this evaluation. Based on the cut-off points for TG (1.53 mmol/l in men and 1.58 mmol/l in women) and APO-B (0.73 mmol/l in men and women), the present study determined that both TG and APO-B were predictors of disease-free survival (DFS) and overall survival (OS). Multivariate analysis demonstrated that high TG (men, ≥1.53 mmol/l; women, ≥1.58 mmol/l) and high APO-B (≥0.73 mmol/l) levels were significantly associated with decreased DFS and OS. Nomograms that included values for TG and APO-B levels demonstrated higher predictive accuracy compared with that of nomograms without these values. These results indicated that TG and APO-B levels may be good independent prognostic biomarkers after radical CRC surgery. Therefore, adjusting these parameters to moderate levels may be beneficial.

Lipocalin-2-The myth of its expression and function.

Lipocalin-2 is a functional biomarker for acute and chronic kidney diseases, heart failure and obesity-related medical complications. It is rapidly induced in epithelial cells under stress conditions, but constitutively produced from pre-adipocytes and mature adipocytes. Measuring the lipocalin-2 levels represents an effective approach for risk prediction, patient stratification and disease management. Nevertheless, due to ligand-binding, post-translational modification and protein-protein interaction, lipocalin-2 exists as multiple variants that elicit different pathophysiological functions. To characterize the specific structure-functional relationships of lipocalin-2 variants is critical for the development of biomarker assays with sufficient precision and reliability. Moreover, identifying the pathological forms of lipocalin-2 will provide new therapeutic targets and treatment approaches for obesity-related complications.

Silencing of long noncoding RNA XIST attenuated Alzheimer's disease-related BACE1 alteration through miR-124.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder. However, its pathogenetic mechanism is still poorly understood. An increasing number of studies have evidenced the important role of long noncoding RNAs (lncRNAs) in AD. The aim of the current study was to investigate the effect and molecular mechanism of the lncRNA X-inactive specific transcript (XIST) in AD. Bilateral common carotid artery occlusion (2VO) was used to induce an AD model in mice. Hydrogen peroxide (H2 O2 ) was used to induce an AD model in N2a cells. The lncRNA XIST, miR-124, and BACE1 messenger RNA expression levels were detected by a real-time polymerase chain reaction. The BACE1 protein expression level was detected by western blot and immunofluorescence assay. The Aß1-42 expression level was detected using an enzyme-linked immunosorbent assay kit. The expression level of lncRNA XIST was significantly upregulated in AD models, both in vivo and in vitro. Silencing of lncRNA XIST negatively regulated miR-124 and positively regulated BACE1 expression in N2a cells, which is attenuated by cotransfection of anti-miR-124 oligodeoxyribonucleotide (AMO-124). Silencing of lncRNA XIST reversed the effect of H2 O2 on miR-124, BACE1, and Aß1-42 expression in N2a cells, which was reversed by cotransfection of AMO-124. Silencing of lncRNA XIST attenuated AD-related BACE1 alteration through miR-124. LncRNA XIST may be a new potential target for the treatment of AD.

Hypermethylation of mismatch repair gene hMSH2 associates with platinum-resistant disease in epithelial ovarian cancer.

PURPOSE: One major reason of the high mortality of epithelial ovarian cancer (EOC) is due to platinum-based chemotherapy resistance. Aberrant DNA methylation may be a potential mechanism underlying the development of platinum resistance in EOC. The purpose of this study is to discover potential aberrant DNA methylation that contributes to drug resistance. METHODS: By initially screening of 16 platinum-sensitive/resistant samples from EOC patients with reduced representation bisulfite sequencing (RRBS), the upstream region of the hMSH2 gene was discovered hypermethylated in the platinum-resistant group. The effect of hMSH2 methylation on the cellular response to cisplatin was explored by demethylation and knockdown assays in ovarian cancer cell line A2780. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was employed to examine the methylation levels of hMSH2 upstream region in additional 40 EOC patient samples. RT-qPCR and IHC assay was used to detect the hMSH2 mRNA and protein expression in extended 150 patients. RESULTS: RRBS assay discovered an upstream region from - 1193 to - 1125 of hMSH2 was significant hypermethylated in resistant EOC patients (P = 1.06 × 10-14). In vitro analysis demonstrated that global demethylation increased cisplatin sensitivity along with a higher expression of the hMSH2 mRNA and protein. Knockdown hMSH2 reduced the cell sensitivity to cisplatin. MALDI-TOF mass spectrometry assay validated the strong association of hypermethylation of hMSH2 upstream region with platinum resistance. Spearman's correlation analysis revealed a significantly negative connection between methylation level of hMSH2 upstream region and its expression. The Kaplan-Meier analyses showed the high methylation of hMSH2 promoter region, and its low expressions are associated with worse survival. In multivariable models, hMSH2 low expression was an independent factor predicting poor outcome (P = 0.03, HR = 1.91, 95%CI = 1.85-2.31). CONCLUSION: The hypermethylation of hMSH2 upstream region is associated with platinum resistant in EOC, and low expression of hMSH2 may be an index for the poor prognosis.

Zinc inhibited LPS-induced inflammatory responses by upregulating A20 expression in microglia BV2 cells.

BACKGROUND: Our previous studies have proved that zinc supplement effectively alleviate depression symptoms in mice, but the mechanisms are still uncertain. Neuroinflammation is considered as an important aspect in pathogenesis of depression. To elucidate the role of zinc on neuroinflammation, in this study, we investigated effects of zinc on lipopolysaccharide (LPS)-induced inflammation in BV2 microglia cells, a kind of innate immune cells in central nervous system. METHODS: BV2 cells were treated by 100 ng/ml LPS to induce inflammatory responses and the effects of zinc sulfate (ZnSO4) addition on LPS-induced inflammation were observed. Besides, through culturing HT-22 hippocampus cells by using medium transferred from zinc-intervened BV2 cells, the protective roles of zinc on hippocampus cells were identified. RESULTS: LPS treatment up-regulated expressions of CD11b, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) and level of reactive oxygen species (ROS). Meaningfully, zinc was capable of blocking ROS generation and reducing expressions of the above inflammatory cytokines at both 10 µM and 30 µM. In addition, it was proved that zinc intervention to BV2 cells could increase the viabilities of hippocampal HT-22 cells cultured by medium of BV2 cells. Furthermore, the zinc-finger protein A20, an anti-inflammation factor, was increased by zinc supplement, while levels of p65, p-IκB and p-p65 were significantly decreased. LIMITATIONS: More compelling proofs were needed to ensure roles of A20 in anti-inflammatory effects of zinc. CONCLUSIONS: The present results suggested that zinc inhibits inflammatory responses mediated by microglia cells via upregulation of zinc-finger A20. It was proposed that this anti-inflammatory action might be underlying mechanism of previously observed anti-depressive effects of zinc.

Strategy to targeting the immune resistance and novel therapy in colorectal cancer.

Assessing the CRC subtypes that can predict the outcome of colorectal cancer (CRC) in patients with immunogenicity seems to be a promising strategy to develop new drugs that target the antitumoral immune response. In particular, the disinhibition of the antitumoral T-cell response by immune checkpoint blockade has shown remarkable therapeutic promise for patients with mismatch repair (MMR) deficient CRC. In this review, the authors provide the update of the molecular features and immunogenicity of CRC, discuss the role of possible predictive biomarkers, illustrate the modern immunotherapeutic approaches, and introduce the most relevant ongoing preclinical study and clinical trials such as the use of the combination therapy with immunotherapy. Furthermore, this work is further to understand the complex interactions between the immune surveillance and develop resistance in tumor cells. As expected, if the promise of these developments is fulfilled, it could develop the effective therapeutic strategies and novel combinations to overcome immune resistance and enhance effector responses, which guide clinicians toward a more "personalized" treatment for advanced CRC patients.

The Pex4p-Pex22p complex from Hansenula polymorpha: biophysical analysis, crystallization and X-ray diffraction characterization.

Peroxisomes are a major cellular compartment of eukaryotic cells, and are involved in a variety of metabolic functions and pathways according to species, cell type and environmental conditions. Their biogenesis relies on conserved genes known as PEX genes that encode peroxin proteins. Peroxisomal membrane proteins and peroxisomal matrix proteins are generated in the cytosol and are subsequently imported into the peroxisome post-translationally. Matrix proteins containing a peroxisomal targeting signal type 1 (PTS1) are recognized by the cycling receptor Pex5p and transported to the peroxisomal lumen. Pex5p docking, release of the cargo into the lumen and recycling involve a number of peroxins, but a key player is the Pex4p-Pex22p complex described in this manuscript. Pex4p from the yeast Saccharomyces cerevisiae is a ubiquitin-conjugating enzyme that is anchored on the cytosolic side of the peroxisomal membrane through its binding partner Pex22p, which acts as both a docking site and a co-activator of Pex4p. As Pex5p undergoes recycling and release, the Pex4p-Pex22p complex is essential for monoubiquitination at the conserved cysteine residue of Pex5p. The absence of Pex4p-Pex22p inhibits Pex5p recycling and hence PTS1 protein import. This article reports the crystallization of Pex4p and of the Pex4p-Pex22p complex from the yeast Hansenula polymorpha, and data collection from their crystals to 2.0 and 2.85 Šresolution, respectively. The resulting structures are likely to provide important insights to understand the molecular mechanism of the Pex4p-Pex22p complex and its role in peroxisome biogenesis.

[Clinical significance of CD44 and CD133 expression in oral potentially malignant disorder and oral squamous cell carcinoma].

OBJECTIVE: This study aims to investigate the expression and relationship of CD44 and CD133 in normal oral mucosa, oral potentially malignant disorder (OPMD), and oral squamous cell carcinoma (OSCC). This work also analyzes the relationship between such expression and clinical factors. This study intends to evaluate the clinical value of using CD44 and CD133 as indices to evaluate the carcinogenic potential of OPMD. METHODS: Clinical data from 60 patients with OPMD, 60 patients with OSCC, and 10 cases of normal oral mucosa were analyzed. Double immunohistochemical analysis was applied to investigate the expression of CD44 and CD133 in paraffin sections of normal oral mucosa, OPMD, and OSCC tissues. Subsequently, the relationships between such expression and clinical factors were analyzed. RESULTS: The positive rates of CD44 expression in the normal oral mucosa, OPMD, and OSCC tissues were 100.00%, 96.67%, and 71.67% (P<0.05), respectively. Meanwhile, the positive rates of CD133 expression in the normal oral mucosa, OPMD, and OSCC tissues were 0.00%, 35.00%, and 63.33% (P<0.05), respectively. The expression of CD44 and CD133 was found to be correlated (P<0.05). Such expression was related to the clinical stages and lymphatic metastasis of OSCC (P<0.05). CONCLUSIONS: CD44 and CD133 can be used individually as clinical indices to evaluate the carcinogenic potential of OPMD.
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Peripherally Inserted Central Catheter-Related Vein Thrombosis in Patients With Lung Cancer.

BACKGROUND: Peripherally inserted central venous catheters (PICCs) are widely used in patients with cancer. Catheter usage is one of the risk factors for venous thromboembolism. We aimed to scrutinize the incidence and risk factors for PICC-related upper extremity venous thrombosis (UEVT) in patients with lung cancer receiving chemotherapy. PATIENTS AND METHODS: We performed a retrospective cohort study of patients with lung cancer with PICC insertion undergoing chemotherapy. Symptomatic PICC-UEVT was diagnosed by ultrasound. The relationship between chemotherapeutic agent exposure and PICC-UEVT was evaluated. Patient-, catheter-, and insertion-related factors were analyzed in univariable and multivariable logistic regression to identify significant independent risk factors for PICC-UEVT in patients with lung cancer. RESULTS: A total of 328 patients with lung cancer having PICC undergoing chemotherapy were included, for a total of 34 895 catheter days. Seventeen (5.2%) patients developed PICC-related UEVT, with an incidence of 0.49 per 1000 catheter days. In multivariable logistic analysis, advanced disease was shown to be a significant risk factor for PICC-UEVT (odds ratio [OR]: 4.9; 95% confidence interval [CI]: 1.4-16.7; P = .011). Patients treated with etoposide had a higher risk of PICC-related UEVT (OR: 3.6; 95% CI: 1.1-12.1; P = .042). Patients were followed up after PICC removal for a median duration of 246 days. None of the patients developed pulmonary embolism. CONCLUSION: Patients with lung cancer harboring an advanced disease or treating with etoposide were at higher risk of PICC-UEVT.

Massive cryptogenic hemoptysis undergoing pulmonary resection: clinical and pathological characteristics and management.

Massive cryptogenic hemoptysis is a common presenting symptom and cause of hospitalization for respiratory diseases, and represents a challenging condition in the clinical. This study aimed to analyze the clinical and pathologic data and management of patients with massive cryptogenic hemoptysis. We retrospectively reviewed 12 patients with massive cryptogenic hemotysis in our hospital between January 2003 and December 2012. Bronchoscopy showed submucosal vascular abnormalities in 4 patients. Of 6 patients managed with conservative measures, bleeding was completely controlled in 2 patients. Of 10 hemoptysis patients, three were controlled by bronchial arterial embolization, and seven by surgery. Pathological examination showed a superficial dysplastic, tortuous and dilated bronchial artery under the bronchial epithelium in 4 patients, and bronchiole dilation in 2 patients, indicating Dieulafoy's disease of the bronchus and bronchiectasis. No malignance developed within the follow-up. In conclusion, Dieulafoy's disease of the bronchus and bronchiectasis should be suspected in patients with massive cryptogenic hemoptysis. BAE and surgical treatment should be considered in case that massive hemoptysis could not be controlled by conservative management.