Metagenomic Analyses Reveal Gut Microbial Profiles of Cnaphalocrocis medinalis Driven by the Infection of Baculovirus CnmeGV.

The composition of microbiota in the digestive tract gut is essential for insect physiology, homeostasis, and pathogen infection. Little is known about the interactions between microbiota load and oral infection with baculoviruses. CnmeGV is an obligative baculovirus to Cnaphalocrocis medinalis. We investigated the impact of CnmeGV infection on the structure of intestinal microbes of C. medinalis during the initial infection stage. The results revealed that the gut microbiota profiles were dynamically driven by pathogen infection of CnmeGV. The numbers of all the OTU counts were relatively higher at the early and later stages, while the microbial diversity significantly increased early but dropped sharply following the infection. The compositional abundance of domain bacteria Firmicutes developed substantially higher. The significantly enriched and depleted species can be divided into four groups at the species level. Fifteen of these species were ultimately predicted as the biomarkers of CnmeGV infection. CnmeGV infection induces significant enrichment of alterations in functional genes related to metabolism and the immune system, encompassing processes such as carbohydrate, amino acid, cofactor, and vitamin metabolism. Finally, the study may provide an in-depth analysis of the relationship between host microbiota, baculovirus infection, and pest control of C. medinalis.

Nanopore-based metagenomics analysis reveals microbial presence in amniotic fluid: A prospective study.

Background: Current research on amniotic fluid (AF) microbiota yields contradictory data, necessitating an accurate, comprehensive, and scientifically rigorous evaluation. Objective: This study aimed to characterise the microbial features of AF and explore the correlation between microbial information and clinical parameters. Methods: 76 AF samples were collected in this prospective cohort study. Fourteen samples were utilised to establish the nanopore metagenomic sequencing methodology, whereas the remaining 62 samples underwent a final statistical analysis along with clinical information. Negative controls included the operating room environment (OE), surgical instruments (SI), and laboratory experimental processes (EP) to elucidate the background contamination at each step. Simultaneously, levels of five cytokines (IL-1ß, IL-6, IL-8, TNF-α, MMP-8) in AF were assessed. Results: Among the 62 AF samples, microbial analysis identified seven without microbes and 55 with low microbial diversity and abundance. No significant clinical differences were observed between AF samples with and without microbes. The correlation between microbes and clinical parameters in AF with normal chromosomal structure revealed noteworthy findings. In particular, the third trimester exhibited richer microbial diversity. Pseudomonas demonstrated higher detection rates and relative abundance in the second trimester and Preterm Birth (PTB) groups. S. yanoikuyae in the PTB group exhibited elevated detection frequencies and relative abundance. Notably, Pseudomonas negatively correlated with activated partial thromboplastin time (APTT) (r = -0.329, P = 0.016), while Staphylococcus showed positive correlations with APTT (r = 0.395, P = 0.003). Furthermore, Staphylococcus negatively correlated with birth weight (r = -0.297, P = 0.034). Conclusion: Most AF samples exhibited low microbial diversity and abundance. Certain microbes in AF may correlate with clinical parameters such as gestational age and PTB. However, these associations require further investigation. It is essential to expand the sample size and undertake more comprehensive research to elucidate the clinical implications of microbial presence in AF.

Vemurafenib activates the sonic hedgehog pathway and promotes thyroid cancer stem cell self-renewal.

B-Raf kinase inhibitors such as vemurafenib (PLX4032) and dabrafenib have limited therapeutic efficacy on BRAF-mutated thyroid cancer. Cancer stem cells (CSCs) play important roles in tumor recurrence, drug resistance, and metastasis. Whether CSCs play a role in dampening the antitumor activity of B-Raf kinase inhibitors remains unknown. Here, we report that vemurafenib (PLX4032) induced the expression of several stemness-related genes including Gli1, Snail, BMI1, and SOX2 in two anaplastic thyroid cancer cell lines, SW1736 and 8505C, but decreased the expression of these genes in A375 cells, a human melanoma cell line. PLX4032 promoted thyroid cancer stem cell self-renewal, as evidenced by increased numbers of aldehyde dehydrogenase-positive cells and thyrospheres. Mechanistically, PLX4032 activates the PI-3 and mitogen-activated protein kinase pathways through HER3 to cross-activate Gli1, a transcription factor of the sonic hedgehog (Shh) pathway. GANT61, a specific inhibitor of Gli1, blocked the expression of the stemness-related genes in PLX4032-treated thyroid cancer cells in vitro and in vivo in two thyroid cancer xenograft models. GANT61 treatment alone weakly inhibited SW1736 tumor growth but enhanced the antitumor activity of PLX4032 when used in combination. Our study provides mechanistic insights into how thyroid cancer poorly responds to B-Raf kinase inhibitors and suggests that targeting B-Raf and the Shh pathway in combination may overcome thyroid cancer drug resistance.

Association of Allostatic Load With All-Cause Mortality in Patients With Breast Cancer.

Importance: Elevated allostatic load (AL) has been associated with adverse socioenvironmental stressors and tumor characteristics that convey poor prognosis in patients with breast cancer. Currently, the association between AL and all-cause mortality in patients with breast cancer is unknown. Objective: To examine the association between AL and all-cause mortality in patients with breast cancer. Design, Setting, and Participants: This cohort study used data from an institutional electronic medical record and cancer registry at the National Cancer Institute Comprehensive Cancer Center. Participants were patients with breast cancer diagnoses (stage I-III) between January 1, 2012, through December 31, 2020. Data were analyzed from April 2022 through November 2022. Exposure: AL was expressed as a summary score calculated by assigning 1 point for biomarkers in the worst sample quartile. High AL was defined as AL greater than the median. Main Outcomes and Measures: The main outcome was all-cause mortality. A Cox proportional hazard models with robust variance tested the association between AL and all-cause mortality. Results: There were 4459 patients (median [IQR] age, 59 [49-67] years) with an ethnoracial distribution of 3 Hispanic Black patients (0.1%), 381 non-Hispanic Black patients (8.5%), 23 Hispanic White patients (0.5%), 3861 non-Hispanic White patients (86.6%), 27 Hispanic patients with other race (0.6%), and 164 non-Hispanic patients with other race (3.7%). The mean (SD) AL was 2.6 (1.7). Black patients (adjusted relative ratio [aRR], those with 1.11; 95% CI, 1.04-1.18), single marital status (aRR, 1.06; 95% CI, 1.00-1.12), and those with government-supplied insured (Medicaid aRR, 1.14; 95% CI, 1.07-1.21; Medicare aRR, 1.11; 95% CI, 1.03-1.19) had a higher adjusted mean AL than those who were White, married/living as married, or privately insured, respectively. Adjusting for sociodemographic, clinical, and treatment factors, high AL was associated with a 46% increase in mortality risk (hazard ratio [HR], 1.46; 95% CI, 1.11-1.93) over low AL. Similarly, compared with patients in the first AL quartile, those in the third quartile (HR, 1.53; 95% CI, 1.07-2.18) and the fourth quartile (HR, 1.79; 95% CI, 1.16-2.75) had significantly increased risks of mortality. There was a significant dose-dependent association between increased AL and a higher risk of all-cause mortality. Furthermore, AL remained significantly associated with higher all-cause mortality after adjusting for the Charlson Comorbidity Index. Conclusions and Relevance: These findings suggest increased AL is reflective of socioeconomic marginalization and associated with all-cause mortality in patients with breast cancer.

Surgical Approaches to Orbital Fractures: A Practical and Systematic Review.

Orbital fractures constitute a significant percentage of all midface injuries. Here, we present a contemporary evidence-based review of the major surgical approaches for orbital wall fractures and analyze the literature to compare all major surgical procedures and their complication rates. Method: A systematic review was conducted to compare surgical approaches (subciliary, transcaruncular, transconjunctival, subtarsal, and endoscopic) and postoperative complications in patients who underwent surgical fixation of orbital wall fractures. A database search in PubMed (PubMed Central, MEDLINE and Bookshelf) was performed for all articles containing the terms "orbital," "wall," "fracture," and "surgery" with different combinations. Results: A total of 950 articles were obtained and 25 articles were included, representing an analysis of 1137 fractures. The most frequent surgical approach was the endoscopic (33.3%) followed by the external surgical approaches, specifically transconjunctival (32.8%), subciliary (13.5%), subtarsal (11.5%), and transcaruncular (8.9%). The transconjunctival approach had a statistically significantly higher rate of complications (36.19%), followed by the subciliary (21.4%), and endoscopic approach (20.2%, P < 0.0001). The subtarsal approach had a statistically significantly lower rate of complications (8.2%) followed by the transcaruncular approach (14.0%, P < 0.0001). Conclusion: The subtarsal and transcaruncular approaches were observed to have the lowest rates of complications, whereas the transconjunctival, subciliary, and endoscopic approaches were reported to have higher rates of complications.

LacNAc modification in bone marrow stromal cells enhances resistance of myelodysplastic syndrome cells to chemotherapeutic drugs.

Chemotherapeutic drugs are used routinely for treatment for myelodysplastic syndrome (MDS) patients but are ineffective in a substantial proportion of patients. Abnormal hematopoietic microenvironments, in addition to spontaneous characteristics of malignant clones, contribute to ineffective hematopoiesis. In our study, we found expression of enzyme ß1,4-galactosyltransferase 1 (ß4GalT1), which regulates N-acetyllactosamine (LacNAc) modification of proteins, is elevated in bone marrow stromal cells (BMSCs) of MDS patients, and also contributes to drug ineffectiveness through a protective effect on malignant cells. Our investigation of the underlying molecular mechanism revealed that ß4GalT1-overexpressing BMSCs promoted MDS clone cells resistant to chemotherapeutic drugs and also showed enhanced secretion of cytokine CXCL1 through degradation of tumor protein p53. Chemotherapeutic drug tolerance of myeloid cells was inhibited by application of exogenous LacNAc disaccharide and blocking of CXCL1. Our findings clarify the functional role of ß4GalT1-catalyzed LacNAc modification in BMSCs of MDS. Clinical alteration of this process is a potential new strategy that may substantially enhance effectiveness of therapies for MDS and other malignancies, by targeting a niche interaction.

Photoactivated Hydrogen Sulfide Donor with a Near-Infrared Fluorescence Report System for Accelerated Chronic Wound Healing.

Delayed wound healing is one of the major diabetes complications that occur in 25% of diabetic patients. Specific wound management and combination treatment are required to repair the wound, which still remains a challenge with few effective therapies available currently. In this work, a new H2S donor PRO-F, which is characterized by the capability to promote wound healing in diabetes, was designed. PRO-F can be activated by light without consuming endogenous substances and the accompanying fluorescent signal makes the real-time tracking of released H2S possible. PRO-F is able to deliver H2S in an intracellular environment with moderate release efficiency (50%), which presents cytoprotective effects against excessive reactive oxygen species (ROS) induced damage. Furthermore, the potential of PRO-F to enhance chronic wound healing was validated by employing diabetic models. This work provides new insights into the therapeutic role of H2S donors in complex wound conditions, which should advance the pathophysiological research associated with H2S.

Exosomal miR92a Promotes Cytarabine Resistance in Myelodysplastic Syndromes by Activating Wnt/ß-catenin Signal Pathway.

Cytarabine (Ara-C) has been one of the frontline therapies for clonal hematopoietic stem cell disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but Ara-C resistance often occurs and leads to treatment failure. Exosomal microRNAs (miRNAs, miRs) as small noncoding RNA that play important roles in post-transcriptional gene regulation, can be delivered into recipient cells by exosomes and regulate target genes' expression. miR92a has been reported to be dysregulated in many cancers, including MDS and AML. However, the effects of exosomal miR92a in hematologic malignancies have not been fully investigated. In this study, qualitative analysis showed the significantly enhanced expression of exosomal miR92a in MDS/AML plasma. Subsequent functional assays indicated that exosomal miR92a can be transported and downregulate PTEN in recipient cells and, furthermore, activate the Wnt/ß-catenin signaling pathway and interfere with the Ara-C resistance of receipt MDS/AML cells in vitro and in vivo. Altogether, our findings offer novel insights into plasma exosomal miR92a participating in Ara-C resistance in MDS/AML and we propose miR92a as a potential therapeutic target for MDS/AML.

Effects of Human-Social Capital Congruence and Environmental Dynamism on Dynamic of Encouragement and Organizational Innovation in New Ventures.

Although human capital and social capital can provide knowledge and social network for organizations, existing studies are inadequate to explore how the interaction between the two types of capital shapes organizational behaviors or organizational outcomes. The present study investigates whether the linkage of human capital to social capital was compensatory or complementary, and how they impact organizational innovation in consideration of the dynamic of encouragement. Using data from more than 200 technological new ventures in China, we analyze the associations among all the parameters through bootstrapping and response surface methods. The findings suggest that organizational innovation is stronger when human and social capital are congruent and that the dynamic of encouragement fully mediates the relationship between capital congruence and organizational innovation performance. Furthermore, environmental dynamism positively moderates the relationship between capital congruence and the dynamic of the environment, that is, the relationship is stronger for new ventures in high rather than low dynamic environments. Finally, the theoretical and managerial implications of this study are discussed.

The Gut Microbiota Composition of Cnaphalocrocis medinalis and Their Predicted Contribution to Larval Nutrition.

Intestinal bacterial flora plays an important role in the nutrition, physiology, and behavior of herbivorous insects. The composition of gut microbiota may also be affected by the food consumed. Cnaphalocrocis medinalis is an oligophagous pest, feeds on rice leaves almost exclusively and causes serious damage to rice in Asian countries. Using antibiotic treatment and metagenome sequencing, we investigated the influence of the food sources (rice and maize seedlings) on the structure and functions of intestinal bacteria of C. medinalis. Firstly, food utilization indices, relative growth rate (RGR), relative consumption rate (RCR), efficiency of conversion of ingested food (ECI), and efficiency of conversion of digested food (ECD), were all significantly adversely affected in the antibiotic treatment eliminating gut bacteria, showing that the microbiota loading in the gut were essential for the larva growth and development of C. medinalis. Further, metagenome sequencing revealed that different diets caused a variation in gut microbiota composition of C. medinalis, indicating that the gut microbiota were in part driven by the diet provided. However, the larvae of C. medinalis hosted a core microbial community in the gut, which was independent from the diets changing. The dominant bacteria in the two feeding groups were highly consistent in the gut of C. medinalis larvae, with the gut bacterial community dominated by Firmicutes at the phylum level, Enterococcus at the genus level, Enterococcus sp. FDAARGOS-375, E. casseliflavus, E. gallinarum, and E. sp. CR-Ec1 accounted for more than 96% of the gut microbiota. Functional prediction analysis demonstrated that gut bacteria encoded a series of metabolism-related enzymes involved in carbohydrate metabolism and amino acid synthesis. Carbohydrate metabolism was the most enriched function in both groups and was more abundant in rice feeding group than in maize feeding group. The core dominant Enterococcus species possessed complete pathways of 14 carbohydrates metabolism, 11 amino acids biosynthesis, and two vitamins synthesize, implied to contribute an essential role to the nutrition intake and development of C. medinalis. Finally, the study may provide an in-depth analysis of the symbiont-host co-adaptation and new insights into the management of C. medinalis.

Expression of tumour transcription factor GLI1 in canine mammary tumours tissue.

BACKGROUND: Mammary tumor is one of the most common diseases of canine in pet clinics. OBJECTIVES: This study investigates the distribution and expression of the tumor transcription factor GLI1 and the downstream proteins, Bmi1 and Sox2, in canine mammary tumors and paracancerous tissues. METHODS: Cancerous and paracancerous normal mammary tissues were detected using western blotting (WB), and immunohistochemistry. RESULTS: The results showed that the histopathology of different types in mammary tumors by microscopic observation. GLI1/Bmi1/Sox2 expression was significantly higher in canine mammary invasive carcinoma than in ductal carcinoma and adjacent normal mammary tissues (p < 0.01). The expression of GLI1 in invasive carcinoma tissues was significantly higher than Bmi1 and Sox2, while Sox2 expression in ductal carcinoma tissues was significantly higher than GLI1 and Bmi1 (p < 0.01). GLI1/Bmi1/Sox2 all showed positive reactions in both mammary tumor and adjacent normal mammary tissues with immunohistochemistry. GLI1 and Sox2 showed strong positive staining in the cytoplasm of invasive mammary carcinoma and ductal carcinoma cells, and weak positive staining in the nuclei. The positive Bmi1 reaction was mainly concentrated in the cytoplasm of invasive carcinoma and ductal carcinoma cells, while the positive reaction on the cell membrane was weak. CONCLUSIONS: We speculate that GLI1 and related proteins play an important role in regulating the proliferation and differentiation of tumors. Therefore, it provides important reference for the pathogenesis and pathogenicity of canine mammary tumor.

Variations in the life-cycle parameters and population growth of rotifer Brachionus plicatilis under the stress of microplastics and 17ß-estradiol.

The toxic effects of microplastics (MPs) on biota are related to their particle size. In addition, MPs could adsorb ambient pollutants in water, which increase the threat of MPs to organisms. In this study, the effects of different particle sizes and concentrations of MPs on the life-cycle parameters and population growth of rotifer Brachionus plicatilis were investigated, and the combined effects of MPs and 17ß-estradiol (E2) on rotifers were studied. Results showed small particle size (50 nm) MPs had negative effects on the lifespan, time to first batch of eggs, fecundity, and population growth rate of rotifers, which were dose-dependent, but large (100 nm and 500 nm) MPs were not. In addition, both life-cycle parameters and the population growth of rotifers were not affected by E2. However, the combination effects of different particle sizes of MPs and E2 on the lifespan, reproductive period, offspring per female, and population growth of rotifers were significant. Therefore, rotifers were more vulnerable to smaller particle MPs, and the coexistence of MPs and other environmental pollutants posed a serious threat to rotifers.

Inhibition of the sonic hedgehog pathway activates TGF-ß-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells.

The sonic hedgehog (Shh) pathway is highly activated in a variety of malignancies and plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. Our recent study showed that the inhibitors of the Shh pathway such as cyclopamine (CP), a Smothened (SMO) inhibitor, and GANT61, a Gli1 inhibitor, have modest inhibitory effects on thyroid tumor cell proliferation and tumor growth. The objective of this study was to determine whether autophagy was induced by inhibition of the Shh pathway and could negatively regulate GANT61-induced apoptosis. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 induced autophagy in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines; whereas Gli1 overexpression suppressed autophagy. Mechanistic investigation revealed that inhibition of the Shh pathway activated TAK1 and its two downstream kinases, the c-Jun-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). GANT61-induced autophagy was blocked by TAK1 siRNA and the inhibitors of TAK1 (5Z-7-oxozeaenol, 5Z), JNK (SP600125), and AMPK (Compound C, CC). Inhibition of autophagy by chloroquine and 5Z and by TAK1 and Beclin-1 siRNA enhanced GANT61-induced apoptosis and its antiproliferative activity. Our study has shown that inhibition of the Shh pathway induces autophagy by activating TAK1, whereas autophagy in turn suppresses GANT61-induced apoptosis. We have uncovered a previously unrecognized role of TAK1 in Shh pathway inhibition-induced autophagy and apoptosis.

Targeting the Sonic Hedgehog Pathway to Suppress the Expression of the Cancer Stem Cell (CSC)-Related Transcription Factors and CSC-Driven Thyroid Tumor Growth.

The sonic hedgehog (Shh) pathway plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. We and others have reported earlier that this pathway is highly activated in thyroid cancer. However, its role in thyroid cancer stem cell (CSC) self-renewal and tumor development remains incompletely understood. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and SRY-Box Transcription Factor 2 (SOX2) are two CSC-related transcription factors that have been implicated in promoting CSC self-renewal. The objective of our current investigation was to determine the role of the Shh pathway in regulating BMI1 and SOX2 expression in thyroid cancer and promoting thyroid tumor growth and development. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 reduced BMI1 and SOX2 expression in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines. The opposite results were obtained in cells overexpressing Gli1 or its downstream transcription factor Snail. The Shh pathway regulated SOX2 and BMI1 expression at a transcriptional and post-transcriptional level, respectively. GANT61 treatment suppressed the growth of SW1736 CSC-derived tumor xenografts but did not significantly inhibit the growth of tumors grown from bulk tumor cells. Clinicopathological analyses of thyroid tumor specimens by immunohistochemical (IHC) staining revealed that BMI1 and SOX2 were highly expressed in thyroid cancer and correlated with Gli1 expression. Our study provides evidence that activation of the Shh pathway leads to increased BMI1 and SOX2 expression in thyroid cancer and promotes thyroid CSC-driven tumor initiation. Targeting the Shh pathway may have therapeutic value for treating thyroid cancer and preventing recurrence.

Composite Inflammatory Indicators as Early Predictor of Intra-abdominal Infections after General Surgery.

OBJECTIVE: To identify rapid and accurate early diagnostic indicators for intra-abdominal infection (IAI) after general surgery. METHODS: We conducted a retrospective analysis of 3,810 general surgical patients in our hospital from August 2017 to July 2018. The predictive value of PCT, CRP, TNFα, and IL6 on postoperative days (PODs) 1 and 3 and composite indicators for complicated IAIs among surgical patients was clarified. RESULTS: There were 271 patients in the infected group and 614 patients in the uninfected group using IAI diagnostic criteria in this study. CRP, PCT, TNFα, and IL6 in the infected group were significantly higher than the uninfected group on POD1 and POD3. In the infected group, the composition of the four indicators on POD1 (AUC 0.819) and POD3 (AUC 0.848) showed higher predictive efficiency than the individual indicators (AUC 0.670-0.805). CONCLUSION: The composite of CRP, PCT, TNFα, and IL6 can be used as a predictor of postoperative abdominal infectious complications with high sensitivity and specificity on POD1 and POD3, which can provide a basis for early diagnosis of postoperative abdominal infectious complications.

Reactions of polyphenols in pomegranate peel with nitrite under simulated stomach conditions.

Punicalagin and ellagic acid are the major polyphenols present in pomegranate peels. The contents of α-punicalagin, ß-punicalagin, and ellagic acid in the pomegranate peels were approximately 75, 72, and 20 µM, respectively. The reactions of polyphenols in pomegranate peels with sodium nitrite under simulated stomach conditions were studied. The reactions decreased the polyphenolic contents of the pomegranate peels and accompanied the formation of nitroso compounds. The oxidation rates followed the order ellagic acid ＜α-punicalagin ≈ ß-punicalagin. The results suggested that the reactions can occur in the stomach after a meal, while the pH changes from 2 to 4.5.

Rutin and Its Combination With Inulin Attenuate Gut Dysbiosis, the Inflammatory Status and Endoplasmic Reticulum Stress in Paneth Cells of Obese Mice Induced by High-Fat Diet.

Gut dysbiosis induced by high fat diet (HF) or obesity is a predisposing factor to develop diverse inflammatory diseases. Polyphenols and fibers, often eaten together, have been reported to have prebiotic actions, but their health promoting benefits still need to be further characterized and defined. This study attempted to understand how polyphenol rutin and polysaccharide inulin influence intestinal health in mouse model fed a HF (60 kcal%) diet. A total of 48 C57BL/6J mice were divided into four groups fed with a low fat (10% kcal%) control diet (LC), a high fat control diet (HC), a high-fat diet supplemented with rutin (HR), or a high-fat diet supplemented rutin and inulin (HRI) for 20 weeks. Rutin supplementation reduced the HF diet-induced increase of Firmicutes/Bacteroidetes (F/B) ratio, Deferribacteraceae population and plasma lipopolysaccharide (LPS) (p < 0.05); ameliorated inflammation as indicated by the decreased circulating inflammatory cytokines (p < 0.05) and the reduced expressions of intestinal inflammatory mediators (p < 0.05); and attenuated the endoplasmic reticulum (ER) stress in Paneth cells as indicated by the decreased expressions of the ER markers (p < 0.05). Compared to the rutin supplementation alone, the co-administration of rutin with inulin improved the utilization of rutin as indicated by its decreased excretion, suppressed a number of harmful bacteria including Deferribacteraceae and Desulfovibrionaceae (p < 0.05), and further reduced the expression of the key inflammatory cytokine TNF-α and increased the production of butyrate, despite the supplementation of inulin reversed the decrease of body weight induced by rutin supplementation due to an increased food intake. Taken together, our data demonstrated that rutin supplementation ameliorated the inflammatory status and ER stress in Paneth cells under a HF-induced obese state, and its co-administration with inulin further mitigated the inflammatory status, indicating the potential to combine polyphenol rutin and the polysaccharide inulin as a dietary strategy to ameliorate gut dysbiosis, to improve inflammatory status and thereby to reduce medical disorders associated with HF-induced obesity.

Sonic Hedgehog Signaling in Thyroid Cancer.

Thyroid cancer is the most common malignancy of the endocrine system. The initiation of thyroid cancer is often triggered by a genetic mutation in the phosphortidylinositol-3 kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathway, such as RAS and BRAF, or by the rearrangement of growth factor receptor tyrosine kinase genes such as RET/PTC. The sonic hedgehog (Shh) pathway is evolutionarily conserved and plays an important role in the embryonic development of normal tissues and organs. Gene mutations in the Shh pathway are involved in basal cell carcinomas (BCC). Activation of the Shh pathway due to overexpression of the genes encoding the components of this pathway stimulates the growth and spread of a wide range of cancer types. The Shh pathway also plays an important role in cancer stem cell (CSC) self-renewal. GDC-0449 and LDE-225, two inhibitors of this pathway, have been approved for treating BCC and are being tested as a single agent or in combination with other drugs for treating various other cancers. Here, we review the recent findings on activation of the Shh pathway in thyroid cancer and its role in maintaining thyroid CSC self-renewal. We also summarize the recent developments on crosstalk of the Shh pathway with the MAPK and PI3K oncogenic pathways, and its implications for combination therapy.

Genetic Complexity of Mitral Valve Prolapse Revealed by Clinical and Genetic Evaluation of a Large Family.

BACKGROUND: A genetic component to familial mitral valve prolapse (MVP) has been proposed for decades. Despite this, very few genes have been linked to MVP. Herein is described a four-generation pedigree with numerous individuals affected with severe MVP, some at strikingly young ages. METHODS: A detailed clinical evaluation performed on all affected family members demonstrated a spectrum of MVP morphologies and associated phenotypes. RESULTS: Linkage analysis failed to identify strong candidate loci, but revealed significant regions, which were investigated further using whole-exome sequencing of one of the severely affected family members. Whole-exome sequencing identified variants in this individual that fell within linkage analysis peak regions, but none was an obvious pathogenic candidate. Follow up segregation analysis of all exome-identified variants was performed to genotype other affected and unaffected individuals in the family, but no variants emerged as clear pathogenic candidates. Two notable variants of uncertain significance in candidate genes were identified: p.I1013S in PTPRJ at 11p11.2 and FLYWCH1 p.R540Q at 16p13.3. Neither gene has been previously linked to MVP in humans, although PTPRJ mutant mice display defects in endocardial cushions, which give rise to the cardiac valves. PTPRJ and FLYWCH1 expression was detected in adult human mitral valve cells, and in-silico analysis of these variants suggests they may be deleterious. However, neither variant segregated completely with all of the affected individuals in the family, particularly when 'affected' was broadly defined. CONCLUSIONS: While a contributory role for PTPRJ and FLYWCH1 in this family cannot be excluded, the study results underscored the difficulties involved in uncovering the genomic contribution to MVP, even in apparently Mendelian families.