Accumulating evidence indicates that circular RNAs (circRNAs) act as microRNA (miRNA) sponges to directly inhibit specific miRNAs and alter their ability to regulate gene expression at the ...post-transcriptional level; this mechanism is believed to occur in various cancers. However, the expression level, precise function and mechanism of circ_001680 in colorectal carcinoma (CRC) are largely unknown.
qRT-PCR was used to detect the expression of circ_001680 and miR-340 in human CRC tissues and their matched normal tissues. Bioinformatics analyses and dual-fluorescence reporter assays were used to evaluate whether circ_001680 could bind to miR-340. Circ_001680 overexpression and knockdown cell lines were constructed to investigate the proliferation and migration abilities in vivo and in vitro through function-based experiments, including CCK8, plate clone formation, transwell, and wounding healing assays. The relationships among circ_001680, miR-340 and BMI1 were investigated by bioinformatics analyses, dual-fluorescence reporter system, FISH, RIP and RNA pull down assays. Sphere forming assays and flow cytometry analyses were used to assess the effect of circ_001680 on the stemness characteristics of CRC cells.
Circ_001680 was more highly expressed in of CRC tissue than in matched adjacent normal tissues from the same patients. Circ_001680 was observed to enhance the proliferation and migration capacity of CRC cells. Furthermore, dual-fluorescence reporter assays confirmed that circ_001680 affects the expression of BMI1 by targeting miR-340. More importantly, we also found that circ_001680 could promote the cancer stem cell (CSC) population in CRC and induce irinotecan therapeutic resistance by regulating the miR-340 target gene BMI1.
Our results demonstrated that circ_001680 is a part of a novel strategy to induce chemotherapy resistance in CRC through BMI1 upregulation. Moreover, circ_001680 may be a promising diagnostic and prognostic marker to determine the success of irinotecan-based chemotherapy.
Controlling the relaxation dynamics of excitons is key to improving the efficiencies of semiconductor-based applications. Confined semiconductor nanocrystals (NCs) offer additional handles to control ...the properties of excitons, for example, by changing their size or shape, resulting in a mismatch between excitonic gaps and phonon frequencies. This has led to the hypothesis of a significant slowing-down of exciton relaxation in strongly confined NCs, but in practice due to increasing exciton-phonon coupling and rapid multiphonon relaxation channels, the exciton relaxation depends only weakly on the size or shape. Here, we focus on elucidating the nonradiative relaxation of excitons in NCs placed in an optical cavity. We find that multiphonon emission of carrier governs the decay, resulting in a polariton-induced phonon bottleneck with relaxation time scales that are slower by orders of magnitude compared to the cavity-free case, while the photon fraction plays a secondary role.
The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the ...importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was
) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was
mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation.
Was
mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was
mice, Helicobacter relative abundance was positively correlated with fecal lipocalin-2 (LCN2), a marker of intestinal inflammation. In contrast, WT mice colonized with ASF and Helicobacter were free of inflammation and strikingly, Helicobacter relative abundance was negatively correlated with LCN2. In Was
colons, bacteria breach the mucus layer, and the mucosal relative abundance of ASF457 Mucispirillum schaedleri was positively correlated with fecal LCN2. Meta-transcriptomic analyses revealed that ASF457 had higher expression of genes predicted to enhance fitness and immunogenicity in Was
compared to WT mice. In contrast, ASF519 Parabacteroides goldsteinii's relative abundance was negatively correlated with LCN2 in Was
mice, and transcriptional analyses showed lower expression of genes predicted to facilitate stress adaptation by ASF519 in Was
compared to WT mice.
These studies indicate that the effect of a microbe on the immune system can be context dependent, with the same bacteria eliciting a tolerogenic response under homeostatic conditions but promoting inflammation in immune-dysregulated hosts. Furthermore, in inflamed environments, some bacteria up-regulate genes that enhance their fitness and immunogenicity, while other bacteria are less able to adapt and decrease in abundance. These findings highlight the importance of studying host-microbe interactions in different contexts and considering how the transcriptional profile and fitness of bacteria may change in different hosts when developing microbiota-based therapeutics. Video abstract.
Surface functionalization with atoms serves as an important strategy to modulate the catalytic activities of low-dimensional nanomaterials. Herein, we developed a facile hydrogen incorporation ...strategy for improving the catalytic activities of SnS2 nanosheets toward CO2 electroreduction. Compared with SnS2 nanosheets, the hydrogen-incorporated SnS2 (denoted as H-SnS2) nanosheets exhibited high current density and Faradaic efficiency (FE) for formate. At −0.9 V vs RHE, H-SnS2 nanosheets displayed a maximum FE of 93% for carbonaceous product, which rivals the activities of most Sn-based catalysts in CO2 electroreduction. Mechanistic studies disclosed that the incorporation of surface hydrogen induced the electron injection into the structures of H-SnS2 nanosheets, which largely facilitates the process of CO2 activation. Density functional theory (DFT) calculations further revealed that hydrogen incorporation decreased the energy barrier for the formation of HCOO* intermediates, thus contributing to the CO2-to-formate conversion on H-SnS2 nanosheets.
Very early onset inflammatory bowel disease (VEO-IBD) reflects IBD presenting before 6 years of age. We provide an approach to diagnosis and management of patients with VEO-IBD, based on expert ...opinion from members of the VEO-IBD Consortium (www.VEOIBD.org).
Abstract
Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.
Interleukin-10 (IL10) signaling plays an important role in the pathogenesis of very early onset inflammatory bowel disease (VEO-IBD) in children. However, little is known about the role of the IL10 ...axis in children with VEO-IBD in China.
The Chinese VEO-IBD Collaboration Group was created to collect clinical and genetic data from patients deficient in IL10 and the IL10 receptor. High-throughput sequencing was performed to identify mutations in these genes.
We identified 32 compound heterozygous mutations and 9 homozygous mutations in IL10 receptor subunit alpha and 1 homozygous mutation in IL10 receptor subunit beta. Among these mutations, 10 novel mutations were identified, and 6 pathogenic mutations had been previously described. In patients with IL10 receptor subunit alpha mutations, c.301C>T (p.R101RW) and c.537 G>A (p.T179T) were the most common mutations. For 88.1% of the patients, the initial symptom was diarrhea, with a time of onset of 10.4 ± 8.0 days. Oral ulcers were the first symptom in 23.8% of the patients, with a time of onset of 9.7 ± 2.8 days. Extraintestinal manifestations included perianal abscesses (22/42), perianal fistulas (23/42), oral ulcers (20/42), and recurrent eczema (15/42). Twelve patients underwent enterostomy. These patients also had lower average Z scores in height-for-age and weight-for-age. Various treatment strategies were used, including fecal microbiota transplantation; however, only hematopoietic stem cell transplantation was efficacious.
This study identified genotypes and phenotypes of Chinese VEO-IBD infants with IL10 receptor mutations. Our study expands the current knowledge on the involvement of the IL10 axis in patients with VEO-IBD.
Abstract
Background
Hematopoietic stem cell transplantation is considered the only curative therapy for very early-onset inflammatory bowel disease with specific immune defects, such as ...interleukin-10 receptor deficiency. We performed reduced-intensity conditioning before umbilical cord blood transplantation in patients with interleukin-10 receptor-A deficiency.
Methods
We enrolled 9 very early-onset inflammatory bowel disease patients with typical manifestations. We diagnosed the patients with interleukin-10 receptor-A deficiency by whole-exome sequencing. Umbilical cord blood transplantation was performed in all 9 patients. Eight patients received the reduced-intensity conditioning regimen, and 1 patient received the myeloablative conditioning regimen.
Results
All 9 patients received transplantation between the ages of 6 months to 43 months (average, 16.8 months) with body weights ranging from 3 to 10.4 kg (average, 6.6 kg). The patients displayed complete chimerism at 2-8 weeks after transplantation; 6 patients achieved complete remission without evidence of graft-vs-host disease or infections; 1 patient died of chronic lung graft-vs-host disease at 6 months post-transplantation; and the other 2 patients died of sepsis post-transplantation because of unsuccessful engraftments. Severe malnutrition and growth retardation associated with interleukin-10 receptor-A deficiency were significantly improved post-transplantation.
Conclusions
We recommend umbilical cord blood transplantation as a potential treatment for very early-onset inflammatory bowel disease with a defined monogenic immunodeficiency, and we suggest that reduced-intensity conditioning chemotherapy is more suitable than myeloablative conditioning for patients with severe malnutrition and bowel disease. We have demonstrated success with reduced-intensity conditioning for interleukin-10 receptor-A deficiency in pediatric patients with severe clinical conditions.
10.1093/ibd/izy028_video1
izy028.video1
5786489183001
Abstract
Background
Interleukin-10 (IL10)/interleukin-10 receptor (IL10R) deficiency is a rare disease with life-threatening infantile-onset colitis. We sought to accurately phenotype this disorder ...based on a large cohort of patients with a proven defect of IL10 signaling and to clarify the effects of allogeneic hematopoietic stem cell transplantation (HSCT).
Methods
We analyzed the phenotypes of our 61 patients and reviewed 78 other previously reported cases with identified mutations in the genes encoding IL10 or IL10R. We also compared the clinical features of patients with interleukin-10 receptor B (IL10RB), interleukin-10 receptor A (IL10RA), and IL10 mutations. The therapeutic effects of allogeneic HSCT were evaluated.
Results
We found that the disease onset time was extremely early: 70.3% within 30 days postnatal and 94.9% within the first 6 months of life. In addition, 94.2% of patients typically presented with perianal lesions. Oral ulcers and skin rash were common extra-intestinal manifestations (33.8% and 51.8%, respectively). There was no statistically significant difference in disease onset time, perianal lesion involvement, or mortality rate among patients with IL10RB, IL10RA, or IL10 deficiency. However, the surgery rate was higher in patients with IL10RB mutations than in those with IL10 or IL10RA mutations (P < 0.05). Compared with those with IL10RA deficiency, a higher percentage (32%, 9 of 28) of patients with IL10RB mutations developed B-cell lymphoma (P < 0.01). Compared with other regions, a higher percentage (98.7%) of IL10RA mutations was detected among patients in East Asia countries (P < 0.01), with hot-spot mutation sites of c.C301T and c.G537A. Allogeneic HSCT is efficacious but has a high mortality rate (17.5%, 7 of 40).
Conclusions
Our study expands the current knowledge on the genotype-correlated phenotypes with a defect of IL10 signaling. B-cell lymphoma was more frequent than would be expected in patients with IL10RB mutations. There may be a unique genetic architecture among Eastern Asia compared with other populations. Although allogeneic HSCT represents a causal therapeutic approach for IL10-and IL10R-deficient patients, a word of caution is warranted.
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