Causal association between lipid-lowering drugs and cancers: A drug target Mendelian randomization study.

Accumulating evidences have indicated that lipid-lowering drugs have effect for the treatment of cancers. However, causal associations between lipid-lowering drugs and the risk of cancers are still unclear. In our study, we utilized single nucleotide polymorphisms of proprotein convertase subtilis kexin 9 (PCSK9) inhibitors and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors and performed a drug target Mendelian randomization to explore the causal association between lipid-lowering drugs and the risk of cancers. Five regression methods were carried out, including inverse variance weighted (IVW) method, MR Egger, weighted median, simple mode and weighted mode methods, of which IVW method was considered as the main analysis. Our outcome dataset contained the risk of breast cancer (BC), colorectal cancer, endometrial cancer, gastric cancer (GC), hepatocellular carcinoma (HCC), lung cancer, esophageal cancer, prostate cancer (PC), and skin cancer (SC). Our results demonstrated that PCSK9 inhibitors were significant associated with a decreased effect of GC [IVW: OR = 0.482, 95% CI: 0.264-0.879, P = .017]. Besides, genetic inhibitions of HMGCR were significant correlated with an increased effect of BC [IVW: OR = 1.421, 95% CI: 1.056-1.911, P = .020], PC [IVW: OR = 1.617, 95% CI: 1.234-2.120, P = .0005] and SC [IVW: OR = 1.266, 95% CI: 1.022-1.569, P = .031]. For GC [IVW: OR = 0.559, 95% CI: 0.382-0.820, P = .0029] and HCC [IVW: OR = 0.241, 95% CI: 0.085-0.686, P = .0077], HMGCR inhibitors had a protective risk. Our method suggested that PCSK9 inhibitors were significant associated with a protective effect of GC. Genetic inhibitions of HMGCR were significant correlated with an increased effect of BC, PC and SC. Meanwhile, HMGCR inhibitors had a protective risk of GC and HCC. Subsequent studies still needed to assess potential effects between lipid-lowering drugs and the risk of cancers with clinical trials.

Causal relationships between gut microbrome and digestive system diseases: A two-sample Mendelian randomization study.

Growing evidences of recent studies have shown that gut microbrome are causally related to digestive system diseases (DSDs). However, causal relationships between the gut microbiota and the risk of DSDs still remain unclear. We utilized identified gut microbiota based on class, family, genus, order and phylum information and digestive system diseases genome-wide association study (GWAS) dataset for two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was used to evaluate causal relationships between gut microbiota and 7 DSDs, including chronic gastritis, colorectal cancer, Crohn's disease, gastric cancer, gastric ulcer, irritable bowel syndrome and esophageal cancer. Finally, we verified the robustness of MR results based on heterogeneity and pleiotropy analysis. We discovered 15 causal associations with genetic liabilities in the gut microbiota and DSDs, such as genus Victivallis, genus RuminococcaceaeUCG005, genus Ruminococcusgauvreauiigroup, genus Oxalobacter and so on. Our MR analysis revealed that the gut microbiota is causally associated with DSDs. Further researches of the gut microbiota and the pathogenesis of DSDs are still significant and provide new methods for the prevention and treatment of DSDs.

Hepatic Transcriptomic Responses to Ethinylestradiol in Embryonic Japanese Quail and Double-Crested Cormorant.

Understanding species differences in sensitivity to toxicants is a critical issue in ecotoxicology. We recently established that double-crested cormorant (DCCO) embryos are more sensitive than Japanese quail (JQ) to the developmental effects of ethinylestradiol (EE2). We explored how this difference in sensitivity between species is reflected at a transcriptomic level. The EE2 was dissolved in dimethyl sulfoxide and injected into the air cell of eggs prior to incubation at nominal concentrations of 0, 3.33, and 33.3 µg/g egg weight. At midincubation (JQ 9 days; DCCO 16 days), livers were collected from five embryos/treatment group for RNA sequencing. Data were processed and analyzed using EcoOmicsAnalyst and ExpressAnalyst. The EE2 exposure dysregulated 238 and 1,987 genes in JQ and DCCO, respectively, with 78 genes in common between the two species. These included classic biomarkers of estrogen exposure such as vitellogenin and apovitellenin. We also report DCCO-specific dysregulation of Phase I/II enzyme-coding genes and species-specific transcriptional ontogeny of vitellogenin-2. Twelve Kyoto Encyclopedia of Genes and Genomes pathways and two EcoToxModules were dysregulated in common in both species including the peroxisome proliferator-activated receptor (PPAR) signaling pathway and fatty acid metabolism. Similar to previously reported differences at the organismal level, DCCO were more responsive to EE2 exposure than JQ at the gene expression level. Our description of differences in transcriptional responses to EE2 in early life stage birds may contribute to a better understanding of the molecular basis for species differences. Environ Toxicol Chem 2024;43:772-783. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Implanting Iodine-125 Seed Strand Inside the Portal Vein Stent: An Improved Approach to Endovascular Brachytherapy for Treatment of Patients with Hepatocellular Carcinoma and Main Portal Vein Tumor Thrombus.

Purpose: To investigate the feasibility and efficacy of implanting an iodine-125 (125I) seed strand inside a portal vein stent (PVS) in the treatment of patients with hepatocellular carcinoma (HCC) and main portal vein tumor thrombus (mPVTT). Patients and Methods: Twenty-three patients who diagnosed with HCC and mPVTT and underwent endovascular implantation 125I seed strands and portal vein stenting were included in this study. Patients were divided into two groups. For patients in group A (n = 12), the 125I seed strand was placed outside the PVS, and for those in group B (n = 11), the strand was placed inside the PVS. Technical success, pain intensity during the procedure (numeric rating scale), procedure-related complications, changes in liver function, stent patency, and survival rates were recorded and analyzed. Results: The procedures were successful in all patients, and no serious procedure-related complications occurred in either group. Pain intensity during the procedure was significantly lower in group B than in group A (2.64 ± 1.50 vs 4.08 ± 1.78, p = 0.048), and there were no significant differences between pre- and post-procedure liver function in either group. The median duration of stent patency was 9 months (95% CI 2.21-15.79 months) in group A and 12 months (95% CI 3.63-18.37 months) in group B (p = 0.670). Median survival was 12 months (95% CI 10.30-13.70 months) in group A and 13 months (95% CI 10.03-15.97 months) in group B (p = 0.822). The cumulative stent patency and survival rates at 3, 6, and 12 months were 75%, 50%, and 41.7%, and 83.3%, 75%, and 50% in group A and 72.7%, 62.3%, and 31.2%, and 90.9%, 80.8%, and 50.5%, respectively. Conclusion: Implantation of 125I seed strand inside the PVS is effective and feasible for treating patients with HCC and mPVTT.

Comparing Transcriptomic Responses to Chemicals Across Six Species Using the EcoToxChip RNASeq Database.

The EcoToxChip project includes RNA-sequencing data from experiments involving model (Japanese quail, fathead minnow, African clawed frog) and ecological (double-crested cormorant, rainbow trout, northern leopard frog) species at multiple life stages (whole embryo and adult) exposed to eight chemicals of environmental concern known to perturb a wide range of biological systems (ethinyl estradiol, hexabromocyclododecane, lead, selenomethionine, 17ß trenbolone, chlorpyrifos, fluoxetine, and benzo[a]pyrene). The objectives of this short communication were to (1) present and make available this RNA-sequencing database (i.e., 724 samples from 49 experiments) under the FAIR principles (FAIR data are data which meet principles of findability, accessibility, interoperability, and reusability), while also summarizing key meta-data attributes and (2) use ExpressAnalyst (including the Seq2Fun algorithm and EcoOmicsDB) to perform a comparative transcriptomics analysis of this database focusing on baseline and differential transcriptomic changes across species-life stage-chemical combinations. The database is available in NCBI GEO under accession number GSE239776. Across all species, the number of raw reads per sample ranged between 13 and 58 million, with 30% to 79% of clean reads mapped to the "vertebrate" subgroup database in EcoOmicsDB. Principal component analyses of the reads illustrated separation across the three taxonomic groups as well as some between tissue types. The most common differentially expressed gene was CYP1A1 followed by CTSE, FAM20CL, MYC, ST1S3, RIPK4, VTG1, and VIT2. The most common enriched pathways were metabolic pathways, biosynthesis of cofactors and biosynthesis of secondary metabolites, and chemical carcinogenesis, drug metabolism, and metabolism of xenobiotics by cytochrome P450. The RNA-sequencing database in the present study may be used by the research community for multiple purposes, including, for example, cross-species investigations, in-depth analyses of a particular test compound, and transcriptomic meta-analyses. Environ Toxicol Chem 2024;00:1-6. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer.

This study aimed to explore the value of color Doppler ultrasonography combined with carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in differential diagnosis of gastric stromal tumor (GST) and gastric cancer (GC). An analysis of the clinical data of 180 patients with clinically suspected gastric space occupying lesions. According to the postoperative pathological results, 180 suspected gastric space-occupying lesion patients were divided into GST group (n = 83) and GC group (n = 97). Color Doppler ultrasonography, serum tumor markers CEA and CA19-9 were compared. The research results showed that serum CEA and CA19-9 levels were lower in patients with GST group than those with GC group (both P < 0.001). With postoperative pathology as the gold standard, detection rates of GST and GC by combination of color Doppler ultrasound (CDUS), serum CEA, and CA19-9 were higher than those of each index alone (both P < 0.001). There was no difference between detection rates of GST and GC by combination of CDUS, serum CEA, and CA19-9 (P = 0.058). Color Doppler ultrasonography combined with serum tumor markers CEA and CA19-9 tests has a certain differential diagnostic value for GST and GC, which may provide a reliable reference basis for clinical diagnosis and treatment.

Spectral CT - a new supplementary method for preoperative assessment of pathological grades of esophageal squamous cell carcinoma.

BACKGROUND: Spectral CT imaging parameters have been reported to be useful in the differentiation of pathological grades in different malignancies. This study aims to investigate the value of spectral CT in the quantitative assessment of esophageal squamous cell carcinoma (ESCC) with different degrees of differentiation. METHODS: There were 191 patients with proven ESCC who underwent enhanced spectral CT from June 2018 to March 2020 retrospectively enrolled. These patients were divided into three groups based on pathological results: well differentiated ESCC, moderately differentiated ESCC, and poorly differentiated ESCC. Virtual monoenergetic 40 keV-equivalent image (VMI40keV), iodine concentration (IC), water concentration (WC), effective atomic number (Eff-Z), and the slope of the spectral curve(λHU) of the arterial phase (AP) and venous phase (VP) were measured or calculated. The quantitative parameters of the three groups were compared by using one-way ANOVA and pairwise comparisons were performed with LSD. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of these parameters in poorly differentiated groups and non-poorly differentiated groups. RESULTS: There were significant differences in VMI40keV, IC, Eff-Z, and λHU in AP and VP among the three groups (all p < 0.05) except for WC (p > 0.05). The VMI40keV, IC, Eff-Z, and λHU in the poorly differentiated group were significantly higher than those in the other groups both in AP and VP (all p < 0.05). In the ROC analysis, IC performed the best in the identification of the poorly differentiated group and non-poorly differentiated group in VP (AUC = 0.729, Sensitivity = 0.829, and Specificity = 0.569 under the threshold of 21.08 mg/ml). CONCLUSIONS: Quantitative parameters of spectral CT could offer supplemental information for the preoperative differential diagnosis of ESCC with different degrees of differentiation.

Indole-3-Propionic Acid, a Gut Microbiota Metabolite, Protects Against the Development of Postoperative Delirium.

OBJECTIVE: The aim was to determine preoperative gut microbiota metabolites that may be associated with postoperative delirium (POD) development in patients and further study in rodents. SUMMARY BACKGROUND DATA: POD occurs in 9% to 50% of older patients undergoing anesthesia/surgery but lacks effective treatments or prevention. High-throughput metabolomics using liquid chromatography with tandem mass spectrometry has accelerated disease-related biomarkers discovery. We performed metabolomic studies in humans to identify potential metabolite biomarkers linked to POD and examined potential mechanisms in rodents. METHODS: We performed a prospective observational cohort study to examine the metabolomic changes that were associated with the development of POD. Then the gut microbiota-related metabolomic changes were recapitulated by gut microbiota perturbation in rodents. POD was assessed in mice using a battery of behavioral tests including novel objective test, Y-maze test, open-field test, and buried food test. The mechanisms through which gut microbiota-related metabolomic changes influenced POD were examined using chemogenetics. RESULTS: Indole-3-propionic acid (IPA) is a gut microbiota metabolite that belongs to the indole family. Baseline plasma levels of IPA were significantly inversely correlated with the onset of POD in 103 (17 cases) human individuals. This relationship was validated in preclinical mouse models for POD: reducing IPA levels through gut microbiota perturbation promoted POD-like behavior. More importantly, IPA administration deterred POD-like behavior. Colonization of germ-free mice with mutant Clostridium sporogenes that did not produce IPA-promoted POD-like behavior. Chemogenetic studies revealed that the protective effect of IPA in mice was mediated, in part, by peroxisome proliferator-activated receptor gamma coactivator 1-alpha in hippocampal interneurons. CONCLUSIONS: Gut microbiota-derived IPA is an important molecule implicated in the pathogenesis of POD, which could potentially be harnessed for POD prevention.

Immunogenic change after percutaneous microwave ablation in pulmonary malignancies: Variation in immune cell subsets and cytokines in peripheral blood.

Introduction: To investigate immunogenic changes after percutaneous microwave ablation (MWA) in pulmonary malignancies. Methods: Twenty-two consecutive patients with pulmonary malignancies who underwent percutaneous lung tumor MWA were prospectively enrolled in this study. Peripheral blood samples were collected on the day before (D0) and one month (M1) after MWA. Changes in immune cell subsets (CD3+, CD4+, and CD8+ T cells, and B, natural killer, regulatory T (Treg), and CD3-CD20+ cells) and cytokines (interleukin [IL]-2, 4, 6, 10, 17A, tumor necrosis factor [TNF]-α, and interferon-γ) were noted and compared. Progression-free survival (PFS) and potentially related factors were analyzed. Results: The proportion of CD8+ T cells increased from 22.95 ± 7.38% (D0) to 25.95 ± 9.16% (M1) (p = 0.031). The proportion of Treg cells decreased from 10.82 ± 4.52% (D0) to 8.77 ± 2.05% (M1) (p = 0.049). The IL-2 concentration was also decreased from 1.58 ± 0.46 pg/mL (D0) to 1.26 ± 0.60 pg/mL (M1) (p = 0.028). The reduction in Treg cells predicted PFS independently of clinical prognostic features in multivariate analysis (hazard ratio = 4.97, 95% confidence interval: 1.32-18.66, p = 0.018). A reduction in the proportion of Treg cells was observed in 15 patients (68.2%) and the average of the reduction was 2.05 ± 4.60%. Those patients with a reduction in the proportion of Treg cells that was more than average showed a significantly longer median PFS time than those with a reduction that was less than average (16 months vs. 8.5 months, p = 0.025). Discussion: Percutaneous MWA of pulmonary malignancies leads to immunogenic changes. The reduction in the proportion of Treg cells was independently associated with PFS.

Alterations in degree centrality and cognitive function in breast cancer patients after chemotherapy.

The goal of this study was to determine the presence or absence of persistent functional impairments in specific brain regions in breast cancer patients during the recovery period after chemotherapy. We calculated degree centrality (DC) and explored the correlation between brain changes and cognitive scores in 29 female patients with breast cancer who had completed chemotherapy within 1-6 years (C + group) and in 28 age-matched patients with breast cancer who did not receive chemotherapy (C- group). All patients underwent rs-fMRI and cognitive testing. Differences in brain functional activity were explored using DC parameters. Correlations between brain features and cognitive scores were analyzed via correlation analysis. Compared with the C- group, the C + group obtained significantly lower motor and cognitive subscores on the Fatigue Scale for Motor and Cognitive Functions and four subscale scores of the Functional Assessment of Cancer Therapy-Cognitive Function (P < 0.05). Furthermore, the C + group exhibited a significantly higher DC z-score (zDC) in the right superior temporal gyrus and left postcentral gyrus (P < 0.01, FWE-corrected), and a lower zDC in the left caudate nucleus (P < 0.01, FWE-corrected). We found a positive correlation between digit symbol test (DST) scores and zDC values in the right superior temporal gyrus (r = 0.709, P < 0.001), and a negative correlation between DST scores and zDC values in the right angular gyrus (r = -0.784, P < 0.001) and left superior parietal gyrus (r = -0.739, P < 0.001). Chemotherapy can cause abnormal brain activity and cognitive decline in patients with breast cancer, and these effects are likely to persist. DC can be used as an imaging marker for chemotherapy-related cognitive impairment after chemotherapy in breast cancer patients.

Oxidative stress suppression in C. elegans by peptides from dogfish skin via regulation of transcription factors DAF-16 and HSF-1.

Functional peptides were obtained via enzymatic hydrolysis of smooth dogfish (Mustelus canis) skin. The enzyme-assisted process was optimized to achieve high yield of smooth dogfish skin peptides (SDSP). Fractions of SDSP (MW < 2 kDa, 2-5 kDa, 5-10 kDa and >10 kDa) showed in vitro antioxidant activities. The peptides <2 kDa (SDSP<2 kDa) significantly improved motility, reduced ROS and H2O2 levels of Caenorhabditis elegans, and increased its resistance to oxidative stress compared to the other peptide fractions. In vivo function of SDSP<2 kDa could be explained by their capacity to increase the expression of stress-response genes. The enhanced resistance to oxidative stress mediated by SDSP<2 kDa was dependent on DAF-16 and HSF-1. The amino acid residues and sequences of SDSP<2 kDa were characterized and revealed a higher content of hydrophobic versus polar amino acid contents. This study (especially the in vivo investigation) explored new potent antioxidant peptides derived from dogfish skin.

Assessing the Toxicity of 17α-Ethinylestradiol in Rainbow Trout Using a 4-Day Transcriptomics Benchmark Dose (BMD) Embryo Assay.

There is an urgent demand for more efficient and ethical approaches in ecological risk assessment. Using 17α-ethinylestradiol (EE2) as a model compound, this study established an embryo benchmark dose (BMD) assay for rainbow trout (RBT; Oncorhynchus mykiss) to derive transcriptomic points-of-departure (tPODs) as an alternative to live-animal tests. Embryos were exposed to graded concentrations of EE2 (measured: 0, 1.13, 1.57, 6.22, 16.3, 55.1, and 169 ng/L) from hatch to 4 and up to 60 days post-hatch (dph) to assess molecular and apical responses, respectively. Whole proteome analyses of alevins did not show clear estrogenic effects. In contrast, transcriptomics revealed responses that were in agreement with apical effects, including excessive accumulation of intravascular and hepatic proteinaceous fluid and significant increases in mortality at 55.1 and 169 ng/L EE2 at later time points. Transcriptomic BMD analysis estimated the median of the 20th lowest geneBMD to be 0.18 ng/L, the most sensitive tPOD. Other estimates (0.78, 3.64, and 1.63 ng/L for the 10th percentile geneBMD, first peak geneBMD distribution, and median geneBMD of the most sensitive over-represented pathway, respectively) were within the same order of magnitude as empirically derived apical PODs for EE2 in the literature. This 4-day alternative RBT embryonic assay was effective in deriving tPODs that are protective of chronic effects of EE2.

Identify the triple-negative and non-triple-negative breast cancer by using texture features of medicale ultrasonic image: A STROBE-compliant study.

ABSTRACT: The study aimed to explore the value of ultrasound (US) texture analysis in the differential diagnosis of triple-negative breast cancer (TNBC) and non-TNBC.Retrospective analysis was done on 93 patients with breast cancer (35 patients with TNBC and 38 patients with non-TNBC) who were admitted to Taizhou people's hospital from July 2015 to June 2019. All lesions were pathologically proven at surgery. US images of all patients were collected. Texture analysis of US images was performed using MaZda software package. The differences between textural features in TNBC and non-TNBC were assessed. Receiver operating characteristic curve analysis was used to compare the diagnostic performance of textural parameters showing significant difference.Five optimal texture feature parameters were extracted from gray level run-length matrix, including gray level non-uniformity (GLNU) in horizontal direction, vertical gray level non-uniformity, GLNU in the 45 degree direction, run length non-uniformity in 135 degree direction, GLNU in the 135 degree direction. All these texture parameters were statistically higher in TNBC than in non-TNBC (P <.05). Receiver operating characteristic curve analysis indicated that at a threshold of 268.9068, GLNU in horizontal direction exhibited best diagnostic performance for differentiating TNBC from non-TNBC. Logistic regression model established based on all these parameters showed a sensitivity of 69.3%, specificity of 91.4% and area under the curve of 0.834.US texture features were significantly different between TNBC and non-TNBC, US texture analysis can be used for preliminary differentiation of TNBC from non-TNBC.

The symbiotic relationship between Caenorhabditis elegans and members of its microbiome contributes to worm fitness and lifespan extension.

BACKGROUND: A healthy microbiome influences host physiology through a mutualistic relationship, which can be important for the host to cope with cellular stress by promoting fitness and survival. The mammalian microbiome is highly complex and attributing host phenotypes to a specific member of the microbiome can be difficult. The model organism Caenorhabditis elegans and its native microbiome, discovered recently, can serve as a more tractable, experimental model system to study host-microbiome interactions. In this study, we investigated whether certain members of C. elegans native microbiome would offer a benefit to their host and putative molecular mechanisms using a combination of phenotype screening, omics profiling and functional validation. RESULTS: A total of 16 members of C. elegans microbiome were screened under chemically-induced toxicity. Worms grown with Chryseobacterium sp. CHNTR56 MYb120 or Comamonas sp. 12022 MYb131, were most resistant to oxidative chemical stress (SiO2 nanoparticles and juglone), as measured by progeny output. Further investigation showed that Chryseobacterium sp. CHNTR56 positively influenced the worm's lifespan, whereas the combination of both isolates had a synergistic effect. RNAseq analysis of young adult worms, grown with either isolate, revealed the enrichment of cellular detoxification mechanisms (glutathione metabolism, drug metabolism and metabolism of xenobiotics) and signaling pathways (TGF-beta and Wnt signaling pathways). Upregulation of cysteine synthases (cysl genes) in the worms, associated with glutathione metabolism, was also observed. Nanopore sequencing uncovered that the genomes of the two isolates have evolved to favor the specific route of the de novo synthesis pathway of vitamin B6 (cofactor of cysl enzymes) through serC or pdxA2 homologs. Finally, co-culture with vitamin B6 extended worm lifespan. CONCLUSIONS: In summary, our study indicates that certain colonizing members of C. elegans have genomic diversity in vitamin B6 synthesis and promote host fitness and lifespan extension. The regulation of host cellular detoxification genes (i.e. gst) along with cysl genes at the transcriptome level and the bacterium-specific vitamin B6 synthesis mechanism at the genome level are in an agreement with enhanced host glutathione-based cellular detoxification due to this interspecies relationship. C. elegans is therefore a promising alternative model to study host-microbiome interactions in host fitness and lifespan.

Preoperative Hepatic and Regional Arterial Chemotherapy in Patients Who Underwent Curative Colorectal Cancer Resection: A Prospective, Multi-center, Randomized Controlled Trial.

OBJECTIVE: To evaluate the effects of the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis of stage II and III colorectal cancer (CRC) in a multicenter setting. SUMMARY OF BACKGROUND DATA: Our previous single-center pilot trial suggested that PHRAC in combination with surgical resection could reduce the occurrence of liver metastasis (LM) and improve survival in CRC patients. METHODS: A prospective multi-center randomized controlled trial was conducted from December 2008 to December 2012 at 5 hospitals in China. Eligible patients with clinical stage II or III CRC who underwent curative resection were randomized to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary endpoint was DFS. Secondary endpoints were cumulative LM rates, overall survival (OS), and safety (NCT00643877). RESULTS: A total of 688 patients from 5 centers in China were randomly assigned (1:1) to each arm. The five-year DFS rate was 77% in the PHRAC arm and 65% in the control arm (HR = 0.61, 95% CI 0.46-0.81; P = 0.001). The 5-year LM rates were 7% and 16% in the PHRAC and control arms, respectively (HR = 0.37, 95% CI 0.22-0.63; P < 0.001). The 5-year OS rate was 84% in the PHRAC arm and 76% in the control arm (HR = 0.61, 95% CI 0.43-0.86; P = 0.005). There were no significant differences regarding treatment related morbidity or mortality between the two arms. CONCLUSIONS: The addition of PHRAC could improve DFS in patients with stage II and III CRC. It reduced the incidence of LM and improved OS without compromising patient safety. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00643877.

A giant hemolymphangioma of the pancreas: A case report and literature review.

RATIONALE: Hemolymphangioma of the pancreas is an extremely rare benign tumor; only 10 patients with this disease have been reported to date, the majority of whom were women. PATIENT CONCERNS: We describe a 28-year-old man who presented with abdominal pain and discomfort. Computed tomography and magnetic resonance imaging data showed a huge heterogeneous solid cystic mass at the retroperitoneal pancreatic head. The maximum cross-sectional lengths of the pancreatic lesion were approximately 12 × 8.5 × 12 cm. DIAGNOSIS: Hemolymphangioma of the pancreas. INTERVENTIONS: The patient underwent a pylorus-preserving pancreatoduodenectomy; surgical excision is the main treatment for this type of tumor. OUTCOMES: The patient followed up regularly in the outpatient department for 6 months after surgery, and no sign of recurrence was found. LESSONS: Although it is uncommon, clinicians ought to consider the diagnosis of hemolymphangioma of the pancreas upon detection of a pancreatic cystic lesion exhibiting fat or calcification.

Loss of disease tolerance during Citrobacter rodentium infection is associated with impaired epithelial differentiation and hyperactivation of T cell responses.

Citrobacter rodentium is an intestinal mouse pathogen widely used as a model to study the mucosal response to infection. Inbred mouse strains suffer one of two fates following infection: self-limiting colitis or fatal diarrheal disease. We previously reported that Rspo2 is a major genetic determinant of the outcome of C. rodentium infection; Rspo2 induction during infection of susceptible mice leads to loss of intestinal function and mortality. Rspo2 induction does not impact bacterial colonization, but rather, impedes the ability of the host to tolerate C. rodentium infection. Here, we performed deep RNA sequencing and systematically analyzed the global gene expression profiles of C. rodentium-infected colon tissues from susceptible and resistant congenic mice strains to determine the common responses to infection and the Rspo2-mediated dysfunction pathway signatures associated with loss of disease tolerance. Our results highlight changes in metabolism, tissue remodeling, and host defence as common responses to infection. Conversely, increased Wnt and stem cell signatures, loss of epithelial differentiation, and exaggerated CD4+ T cell activation through increased antigen processing and presentation were specifically associated with the response to infection in susceptible mice. These data provide insights into the molecular mechanisms underlying intestinal dysfunction and disease tolerance during C. rodentium infection.

Genetic profiles of ten Dirofilaria immitis isolates susceptible or resistant to macrocyclic lactone heartworm preventives.

BACKGROUND: For dogs and cats, chemoprophylaxis with macrocyclic lactone (ML) preventives for heartworm disease is widely used in the United States and other countries. Since 2005, cases of loss of efficacy (LOE) of heartworm preventives have been reported in the U.S. More recently, ML-resistant D. immitis isolates were confirmed. Previous work identified 42 genetic markers that could predict ML response in individual samples. For field surveillance, it would be more appropriate to work on microfilarial pools from individual dogs with a smaller subset of genetic markers. METHODS: MiSeq technology was used to identify allele frequencies with the 42 genetic markers previously reported. Microfilaria from ten well-characterized new isolates called ZoeKY, ZoeMI, ZoeGCFL, ZoeAL, ZoeMP3, ZoeMO, ZoeAMAL, ZoeLA, ZoeJYD-34, and Metairie were extracted from fresh blood from dogs. DNA were extracted and sequenced with MiSeq technology. Allele frequencies were calculated and compared with the previously reported susceptible, LOE, and resistant D. immitis populations. RESULTS: The allele frequencies identified in the current resistant and susceptible isolates were in accordance with the allele frequencies previously reported in related phenotypes. The ZoeMO population, a subset of the ZoeJYD-34 population, showed a genetic profile that was consistent with some reversion towards susceptibility compared with the parental ZoeJYD-34 population. The Random Forest algorithm was used to create a predictive model using different SNPs. The model with a combination of three SNPs (NODE_42411_RC, NODE_21554_RC, and NODE_45689) appears to be suitable for future monitoring. CONCLUSIONS: MiSeq technology provided a suitable methodology to work with the microfilarial samples. The list of SNPs that showed good predictability for ML resistance was narrowed. Additional phenotypically well characterized D. immitis isolates are required to finalize the best set of SNPs to be used for large scale ML resistance screening.

Computed tomography and magnetic resonance features of intracranial hemangioendothelioma: A study of 7 cases.

The current study aimed to present the neuroradiological and histopathological features of intracranial hemangioendothelioma (HE). The computed tomography (CT; n=3) and magnetic resonance imaging (MRI; n=7) features, and the clinical presentations of 7 patients with pathologically documented HEs were retrospectively analyzed. Lesions were observed in the right side of the skull (the frontal bone in 1 patient and the parietal bone in 1 patient), the tentorium (2 patients), the cerebral falx (1 patient), the right cavernous sinus (1 patient) and the right temporal lobe (1 patient). The tumor was lobulated in 5 cases and round in 2 cases. The majority of tumors appeared isointense or hypointense with multiple scattered hyperintensities on T1-weighted MRI. Moreover, the lesions appeared as inhomogeneous hyperintense regions with multiple enlarged and tortuous blood flow voids on T2-weighted MRI. The lesions also showed marked gadolinium enhancement in a honeycomb pattern. CT scan results showed a isoattenuation region (32-47 HU), with numerous small, round, high-density foci. The 2 cases with skull lesions presented with local bone destruction and discontinuous bone lines of the tabula interna ossis cranii. In 1 case, MR angiography revealed abnormal vessels in the basilar region. A total of 4 cases were epithelial HE, 2 were retiform HE and 1 was kaposiform HE. Histological examination revealed endothelial cell proliferation with vascular lesions and a mucous matrix or dense fibrous mesenchyme. In conclusion, intracranial HE is rare, but should be considered in the differential diagnosis when evaluating intracranial neoplasms. A well-defined lobulated mass and imaging features that include internal heterogeneity, small scattered hemorrhages and thromboses, signal voids of vessels, and marked and delayed enhancement may confirm the diagnosis of HE.

Intercellular transfer of messenger RNAs in multiorgan tumorigenesis by tumor cell-derived exosomes.

Exosomes are small membrane vesicles of endocytic origin. They are derived from various cells, including tumor cells, and may serve as important modulators of intercellular communication. The present study established a U­87 MG human glioblastoma cell line that showed a stable expression of green fluorescent protein (GFP; U­87­GFP). Two types of human tumor cell lines, U­87­GFP and LoVo human colon cancer cells, were demonstrated to communicate through the transfer of GFP messenger (m)RNA by exosomes. Furthermore, GFP mRNAs delivered by the U­87­GFP cell­derived exosomes were translated into functional proteins in the recipient LoVo cells. In addition, LoVo cells were demonstrated to uptake exosomes derived from the U­87­GFP cells by clathrin­mediated endocytosis. These results indicate that tumor cell­derived exosomes may represent vesicular carriers that regulate gene expression, which may provide a pathway of intercellular communication in the tumor microenvironment during multiorgan tumorigenesis. The exosome uptake pathway may have potential therapeutic applications in multiorgan tumorigenesis.