The composition of the fecal microbiota of UC patients differs from that of healthy individuals: we found a reduction in R hominis and F prausnitzii, both well-known butyrate-producing bacteria of the Firmicutes phylum. These results underscore the importance of dysbiosis in IBD but suggest that different bacterial species contribute to the pathogenesis of UC and CD.

Group A rotavirus classification is currently based on the molecular properties of the two outer layer proteins, VP7 and VP4, and the middle layer protein, VP6. As reassortment of all the 11 rotavirus gene segments plays a key role in generating rotavirus diversity in nature, a classification system that is based on all the rotavirus gene segments is desirable for determining which genes influence rotavirus host range restriction, replication, and virulence, as well as for studying rotavirus epidemiology and evolution. Toward establishing such a classification system, gene sequences encoding VP1 to VP3, VP6, and NSP1 to NSP5 were determined for human and animal rotavirus strains belonging to different G and P genotypes in addition to those available in databases, and they were used to define phylogenetic relationships among all rotavirus genes. Based on these phylogenetic analyses, appropriate identity cutoff values were determined for each gene. For the VP4 gene, a nucleotide identity cutoff value of 80% completely correlated with the 27 established P genotypes. For the VP7 gene, a nucleotide identity cutoff value of 80% largely coincided with the established G genotypes but identified four additional distinct genotypes comprised of murine or avian rotavirus strains. Phylogenetic analyses of the VP1 to VP3, VP6, and NSP1 to NSP5 genes showed the existence of 4, 5, 6, 11, 14, 5, 7, 11, and 6 genotypes, respectively, based on nucleotide identity cutoff values of 83%, 84%, 81%, 85%, 79%, 85%, 85%, 85%, and 91%, respectively. In accordance with these data, a revised nomenclature of rotavirus strains is proposed. The novel classification system allows the identification of (i) distinct genotypes, which probably followed separate evolutionary paths; (ii) interspecies transmissions and a plethora of reassortment events; and (iii) certain gene constellations that revealed (a) a common origin between human Wa-like rotavirus strains and porcine rotavirus strains and (b) a common origin between human DS-1-like rotavirus strains and bovine rotaviruses. These close evolutionary links between human and animal rotaviruses emphasize the need for close simultaneous monitoring of rotaviruses in animals and humans.Group A rotaviruses are major pathogens associated with acute gastroenteritis in humans and animals. Rotaviruses form a genus in the Reoviridae family and are characterized by a segmented double-stranded RNA genome (3, 16). The rotavirus genome is enclosed in a triple-layered icosahedral capsid and consists of 11 segments, encoding six viral structural proteins (VP1 to VP4, VP6, and VP7) and six nonstructural proteins (NSP1 to NSP6) (16). Each genome segment, with the exception of gene 11 that encodes two proteins (NSP5 and NSP6), codes for a single viral protein. The inner layer of the rotavirus virion is mainly composed of VP2, which encases VP1, the viral RNA-dependent RNA polymerase, and VP3, the viral capping enzyme (16). The middle layer of the virion is composed entirely of VP6 trimers, which determine rotavirus ...

Immune-checkpoint blockade (ICB) combined with neoadjuvant chemotherapy improves pathological complete response in breast cancer (BC). To understand why only a subset of tumors respond to ICB, patients with hormone receptor-positive or triple-negative BC were treated with anti-PD1 prior to surgery. Paired pre-versus on-treatment biopsies from treatment-naïve patients receiving anti-PD-1 (n=29) or patients receiving neoadjuvant chemotherapy prior to anti-PD1 (n=11) were subjected to single-cell transcriptome, T-cell receptor and proteome profiling. One-third of tumors contained PD1-expressing T-cells, which clonally expanded upon anti-PD1 treatment irrespective of tumor subtype. Expansion mainly involved CD8 + T-cells with pronounced expression of cytotoxic-activity (PRF1, GZMB), immune-cell homing (CXCL13) and exhaustion markers (HAVCR2, LAG3), and CD4 + T-cells characterized by expression of T-helper-1 (IFNG) and follicular-helper (BCL6, CXCR5) markers. In pre-treatment biopsies, the relative frequency of immunoregulatory dendritic cells (PD-L1), specific macrophage phenotypes (CCR2 or MMP9) and cancer cells exhibiting MHC class I/II expression correlated positively with T-cell expansion. Conversely, undifferentiated preeffector/memory T-cells (TCF7, GZMK) or inhibitory macrophages (CXCR3, C3) were inversely correlated. Collectively, our data identify various immunophenotypes and associated gene sets that are positively or negatively correlated with T-cell expansion following anti-PD1. We shed light on the heterogeneity in treatment response to anti-PD1 in breast cancer.

Background and aims: This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn's disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27-83). Methods: The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed. Results: 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. Conclusions: In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery.Crohn's disease (CD) is a disabling chronic relapsing inflammatory disorder of the bowel. Long-term experience with standard therapies for inflammatory bowel disease (IBD) up to the late 1990s demonstrated diverse limitations of these therapies in the treatment of IBD. Several population-based studies reported on the inability of corticosteroids to maintain remission, although these drugs have good short-term efficacy.1-5 Immunomodulators (IMMs) including azathioprine (AZA), its metabolite 6-mercaptopurine (6-MP) and the folate antagonist methotrexate (MTX) have a well-documented longterm efficacy in maintaining remission. [6][7][8][9][10]

MH induced by long-term maintenance IFX treatment is associated with an improved long-term outcome of the disease especially with a lower need for major abdominal surgeries.

G12 rotaviruses were first detected in diarrheic children in the Philippines in 1987, but no further cases were reported until 1998. However, G12 rotaviruses have been detected all over the world in recent years. Here, we report the worldwide variations of G12 rotaviruses to investigate the evolutionary mechanisms by which they managed to spread globally in a short period of time. We sequenced the complete genomes (11 segments) of nine G12 rotaviruses isolated in Bangladesh, Belgium, Thailand, and the Philippines and compared them with the genomes of other rotavirus strains. Our genetic analyses revealed that after introduction of the VP7 gene of the rare G12 genotype into more common local strains through reassortment, a vast genetic diversity was generated and several new variants with distinct gene constellations emerged. These reassortment events most likely took place in Southeast Asian countries and spread to other parts of the world. The acquirement of gene segments from human-adapted rotaviruses might allow G12 to better propagate in humans and hence to develop into an important emerging human pathogen.Group A rotaviruses are one of the major causes of severe gastroenteritis in young children and animals. More than 125 million infants and young children develop rotavirus diarrhea globally each year, resulting in 440,000 deaths among children less than 5 years of age, mostly in developing countries (29). This high disease burden motivated major efforts to develop rotavirus vaccines. However, the high degree of genetic and antigenic variation among rotaviruses hinders the vaccine development programs (5, 9, 16, 28, 34, 42).The rotavirus genome contains 11 double-stranded RNA segments, ranging in size from 664 to 3,302 nucleotides, encoding six structural viral proteins (VP) and six nonstructural proteins (NSP) (8). The viral capsid is formed by three concentric layers: a central core, an inner protein layer, and an outer protein layer (31). The outer protein layer is composed of VP4 and VP7, the two major antigens of the virus, and the middle layer is composed of VP6 molecules arranged as trimers. The central core is composed mainly of VP2 and contains the gene segments and enzyme complexes responsible for the processes of RNA transcription and replication (18).Rotaviruses are classified into G and P genotypes on the basis of the sequence diversities of the two outer layer proteins VP7 and VP4, respectively, which are the two viral proteins that elicit neutralizing antibody responses. An 89% amino acid cutoff percentage has been used to define different G and P genotypes (11,18). At least 15 G genotypes and 26 P genotypes have been reported to date in mammals and avian species (8,21,33). The segmented nature of the rotavirus genome provides an opportunity for genetic reassortment, which plays an important role in the generation of virus diversity through genetic shift as demonstrated by many investigators (1,7,12,15,22,24,36,41). In addition, "genogrouping" based on overall genomic RNA homology by hybridiz...

Background and aims: Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission.

BackgroundAntimicrobial peptides (AMPs) protect the host intestinal mucosa against microorganisms. Abnormal expression of defensins was shown in inflammatory bowel disease (IBD), but it is not clear whether this is a primary defect. We investigated the impact of anti-inflammatory therapy with infliximab on the mucosal gene expression of AMPs in IBD.Methodology/Principal FindingsMucosal gene expression of 81 AMPs was assessed in 61 IBD patients before and 4–6 weeks after their first infliximab infusion and in 12 control patients, using Affymetrix arrays. Quantitative real-time reverse-transcription PCR and immunohistochemistry were used to confirm microarray data. The dysregulation of many AMPs in colonic IBD in comparison with control colons was widely restored by infliximab therapy, and only DEFB1 expression remained significantly decreased after therapy in the colonic mucosa of IBD responders to infliximab. In ileal Crohn's disease (CD), expression of two neuropeptides with antimicrobial activity, PYY and CHGB, was significantly decreased before therapy compared to control ileums, and ileal PYY expression remained significantly decreased after therapy in CD responders. Expression of the downregulated AMPs before and after treatment (DEFB1 and PYY) correlated with villin 1 expression, a gut epithelial cell marker, indicating that the decrease is a consequence of epithelial damage.Conclusions/SignificanceOur study shows that the dysregulation of AMPs in IBD mucosa is the consequence of inflammation, but may be responsible for perpetuation of inflammation due to ineffective clearance of microorganisms.