No abstract

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Inflammation contributes to cancer development and inflammatory bowel disease is an important risk factor for CRC. The aim of this study is to assess whether a widely used probiotic Enterococcus faecalis can modulate the NLRP3 inflammasome and protect against colitis and colitis-associated CRC. We studied the effect of heat-killed cells of E. faecalis on NLRP3 inflammasome activation in THP-1-derived macrophages. Pretreatment of E. faecalis or NLRP3 siRNA can inhibit NLRP3 inflammasome activation in macrophages in response to fecal content or commensal microbes, P. mirabilis or E. coli, according to the reduction of caspase-1 activation and IL-1β maturation. Mechanistically, E. faecalis attenuates the phagocytosis that is required for the full activation of the NLRP3 inflammasome. In in vivo mouse experiments, E. faecalis can ameliorate the severity of intestinal inflammation and thereby protect mice from dextran sodium sulfate (DSS)-induced colitis and the formation of CRC in wild type mice. On the other hand, E. faecalis cannot prevent DSS-induced colitis in NLRP3 knockout mice. Our findings indicate that application of the inactivated probiotic, E. faecalis, may be a useful and safe strategy for attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis.

Pre-mRNA alternative splicing is an important mechanism for the generation of synaptic protein diversity, but few factors governing this process have been identified. From a screen for Drosophila mutants with aberrant synaptic development, we identified beag, a mutant with fewer synaptic boutons and decreased neurotransmitter release. Beag encodes a spliceosomal protein similar to splicing factors in humans and C. elegans. We find that both beag mutants and mutants of an interacting gene dsmu1 have changes in the synaptic levels of specific splice isoforms of Fasciclin II (FasII), the Drosophila ortholog of Neural Cell Adhesion Molecule (NCAM). We show that restoration of one splice isoform of FasII can rescue synaptic morphology in beag mutants while expression of other isoforms cannot. We further demonstrate that this FasII isoform has unique functions in synaptic development independent of trans-synaptic adhesion. beag and dsmu1 mutants demonstrate an essential role for these previously uncharacterized splicing factors in the regulation of synapse development and function.

The clinicopathologic relevance of various gene rearrangements underlying dermatofibrosarcoma protuberans (DFSP) remains insufficiently characterized. In 188 DFSPs, we determined PDGFB, COL1A1, PDGFD, COL6A3, and EMILIN2 rearrangements by fluorescence in situ hybridization (FISH). The clinicopathologic significance of rearrangement types and factors related to recurrence and metastasis were statistically analyzed. In all, classic PDGFB rearrangement, cryptic COL1A1-PDGFB fusion, and PDGFD rearrangement were identified in 172 (91.4%), 8 (4.3%), and 8 (4.3%: 4 COL6A3-PDFGD, 4 EMILIN2-PDGFD) cases, respectively. In an index DFSP harboring the cryptic fusion, the COL1A1-PDGFB transcript was confirmed by both RNA sequencing and reverse transcription-polymerase chain reaction. In comparison with cases harboring classic PDGFB rearrangement, cryptic PDGFB-rearranged DFSPs usually exhibited higher 5′-COL1A1 copy numbers. In a combined reappraisal of published and current cases, COL6A3-PDGFD-positive DFSPs (n = 16) predominated in females (n = 14, 88%) and torso (n = 14, 88%), especially the breast (n = 7, 44%); EMILIN2-PDGFD-positive DFSPs (n = 6) preferentially demonstrated near exclusively subcutaneous growth (n = 5, 83%) and fibrosarcomatous transformation (n = 5, 83%). In our cohort, local recurrence was related to fibrosarcomatous variant (P = 0.029, odds ratio = 3.478) and head and neck location (P = 0.046, odds ratio = 3.508). Distant metastasis only occurred in the fibrosarcomatous variant (9/73, 12.3%) but not in other cases. In conclusion, 8.6% of DFSPs are negative for PDGFB break-apart FISH, which, especially those with challenging subcutaneous and circumscribed manifestation, require complementary diagnosis by FISH assays targeting COL1A1 and PDGFD. The types of fusion gene rearrangements, head and neck location, and fibrosarcomatous transformation may account for clinicopathologic and prognostic variations in DFSPs and warrant future independent validation.

Immunohistochemical examination of HSPs and HSF1 provides useful prognostic information that may contribute to the design of therapeutic strategies for patients with ccRCC.

Reprogramming of cellular energy metabolism, such as lipid metabolism, is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). However, whether protein expression related to fatty acid oxidation (FAO) affects survival in SCCHN remains unclear. We aimed to investigate FAO-related enzyme expression and determine its correlation with clinicopathological variables in SCCHN patients. Immunohistochemical analysis (IHC) of FAO-related protein expression, including carnitine palmitoyltransferase 1 (CPT1), the acyl-CoA dehydrogenase family, and fatty acid synthase (FAS), was performed using tissue microarrays from 102 resected SCCHN tumors. Expressions were categorized according to IHC scores, and the statistical association with clinicopathological factors was determined. Moderate-to-high expression of long-chain acyl-CoA dehydrogenase (LCAD) had a protective role against cancer-related death (adjusted hazard ratio (HR), 0.2; 95% confidence interval (CI), 0.05–0.87) after covariate adjustment. Age and clinical stage remained independent predictors of survival (adjusted HR, 1.75; 95% CI, 1.22–2.49 for age; adjusted HR, 14.33; 95% CI, 1.89–108.60 for stage III/IV disease). Overexpression of medium-chain acyl-CoA dehydrogenase and FAS correlated with advanced tumor stage (T3/T4); however, none of these factors were independent predictors of survival. Several FAO-related enzymes were upregulated and LCAD overexpression had a protective effect on overall survival in advanced SCCHN patients. FAO-related-enzyme expression might have a prognostic impact on survival outcomes in SCCHN.

Rationale: Multiseptate gallbladder (MSG) is a rare congenital gallbladder anomaly. Between 1963 and June 2021, only 56 cases were reported. There is currently no treatment guideline for pediatric or adult cases of MSG. Patient concerns: A 14-year-old woman visited our out-patient clinic in September 2020 for epigastric pain that last for 6 months. Honeycomb appearance of the gallbladder was noted under ultrasonography. Diagnosis: The patient was diagnosed with MSG. The diagnosis was confirmed through computed tomography and magnetic resonance cholangiopancreatography. Interventions: Cholecystectomy was performed. Outcomes: Epigastric pain showed limited improvement after the surgery. Since she was diagnosed with gastritis at the same time, a proton-pump inhibitor was prescribed. Epigastric pain was eventually resolved. Lessons: MSG cases can undergo cholecystectomy and show good recovery without complications. However, concomitant treatment may be required to resolve in the presence of other symptoms such as epigastric pain.

a sharp border separating the two tumors ( Figure 1D). Both components lack conspicuous mitotic activity, prominent cellular atypia, hemorrhage, or necrosis. Immunohistochemically, both tumors express vimentin, and both components were negative for broad spectrum cytokeratin (AE1/AE3) (data not shown). Calretinin highlighted the rounded, short spindled, bland-looking cells component while absent in the signet-ring cell component ( Figure 1E). Taken together, the findings indicate that the tumor is a combination of a sclerosing stromal tumor and a signet-ring stromal tumor of the ovary. Both sclerosing stromal tumor and signet-ring stromal tumor are very rare benign sex-cord stromal tumor in ovary. Sclerosing stromal tumor is an uncommon pure stromal tumor of ovary and almost all tumors occur unilaterally, and patients usually do not have hormonal symptoms. 4 The incidence of signet-ring stromal tumor is not clear due to its rarity. 4 It is characterized by aggregates of signet-ring cell with large intracytoplasmic vacuole which lacks of mucin, an important feature to differentiate from Krukenberg tumor. Immunohistochemically, the absence of calretinin or inhibin expression is another feature of the tumor. 4 Interestingly, in one case report, He et al., showed that a sclerosing stromal tumor with characteristics of signet-ring stromal tumor in a 4-year-old girl. They have proposed that sclerosing stromal tumor and signet-ring stromal tumor may represent a spectrum of ovarian stromal tumor evolution. 5 However, in our case, there is a distinct border between two tumors and no area shows admixture of the two components, supporting the scenario of a collision tumor. Albeit rare, pathologists should be aware of the possibility of collision tumor when confronting a neoplasm exhibiting two entirely distinct morphological features.