The IRE1α/XBP1 branch of unfolded protein response (UPR) pathway has a critical function in endoplasmic reticulum (ER) expansion in plasma cells via unknown mechanisms; interestingly, another UPR branch, PERK, is suppressed during plasma cell development. Here we show that Ufbp1, a target and cofactor of the ufmylation pathway, promotes plasma cell development by suppressing the activation of PERK. By contrast, the IRE1α/XBP1 axis upregulates the expression of Ufbp1 and ufmylation pathway genes in plasma cells, while Ufbp1 deficiency impairs ER expansion in plasma cells and retards immunoglobulin production. Structure and function analysis suggests that lysine 267 of Ufbp1, the main lysine in Ufbp1 that undergoes ufmylation, is dispensable for the development of plasmablasts, but is required for immunoglobulin production and stimulation of ER expansion in IRE1α-deficient plasmablasts. Thus, Ufbp1 distinctly regulates different branches of UPR pathway to promote plasma cell development and function.

A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein–coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that Gpr109a^−/−Rag1^−/− mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17–producing Rorγt⁺ innate lymphoid cells (ILCs; ILC3). Genetic deletion of Rorγt alleviated the spontaneous colonic inflammation in Gpr109a^−/−Rag1^−/− mice. Gpr109a-deficient colonic dendritic cells produce higher amounts of IL-23 and thereby promote ILC3. Moreover, the depletion of gut microbiota by antibiotics treatment decreased IL-23 production, ILC3, and colonic inflammation in Gpr109a^−/−Rag1^−/− mice. The ceca of Gpr109a^−/−Rag1^−/− mice showed significantly increased colonization by members of Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, Streptococcaceae, Christensenellaceae, and Mogibacteriaceae, as well as IBD-associated microbiota such as Enterobacteriaceae and Mycoplasmataceae, compared with Rag1^−/− mice, housed in a facility positive for Helicobacter and murine norovirus. Niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 number in a Gpr109a-dependent manner. Collectively, our data present a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23–mediated immunopathologies.

Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types

Renal cell carcinomas (RCC) are heterogeneous and can be further classified into three major subtypes including clear cell, papillary and chromophobe. Signal transducer and activator of transcription 3 (STAT3) is commonly hyperactive in many cancers and is associated with cancer cell proliferation, invasion, migration, and angiogenesis. In renal cell carcinoma, increased STAT3 activation is associated with increased metastasis and worse survival outcomes, but clinical trials targeting the STAT3 signaling pathway have shown varying levels of success in different RCC subtypes. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we compared expression of 32 STAT3 regulated genes in 3 RCC subtypes. Our results indicate that STAT3 activation plays the most significant role in clear cell RCC relative to the other subtypes, as half of the evaluated genes were upregulated in this subtype. MMP9, BIRC5, and BCL2 were upregulated and FOS was downregulated in all three subtypes. Several genes including VEGFA, VIM, MYC, ITGB4, ICAM1, MMP1, CCND1, STMN1, TWIST1, and PIM2 had variable expression in RCC subtypes and are potential therapeutic targets for personalized medicine.

Background: Salivary gland neoplasms are uncommon in both pediatric and adult populations. Mucoepidermoid carcinoma (MEC) is one of the most common salivary gland tumors and usually presents with atypical clinical features. This study sought to evaluate the demographic and clinical factors affecting outcomes in adults and pediatric populations with MEC that could be used to risk stratification for treatment selection and clinical trial enrollment. Methods: Data on 4507 MEC patients were extracted from the Surveillance Epidemiology and End Result (SEER) database (2000–2018). Patients aged ≤ 18 years were classified into the pediatric population, and those older than 18 years were placed in the adult group. Kaplan–Meier survival curves were created to analyze survival probabilities for various independent factors. Results: The pediatric population comprised 3.7% of the entire cohort, with a predominance of females (51.5%), while the adult population constituted 96.3% of the cohort, with a predominance of female patients (52.2%). Caucasians were the predominant race overall (75.3%), while more African Americans were seen in the pediatric group. In tumor size of <2 cm overall, poorly differentiated tumors with higher metastasis rates were observed more in adults (11.3% and 9.3%) than in the pediatric population (3.0% and 4.8%, p < 0.05). Surgical resection was the most common treatment option (53.9%), making up 63.6% of the pediatric and 53.5% of the adult groups. A combination of surgical resection and radiation was used in 29.8% of the entire cohort while a combination of surgical resection, radiation, and chemotherapy made up only 3.2%. The pediatric group had a lower overall mortality rate (5.5%) than the adult group (28.6%). Females had a higher 5-year survival rate in comparison to males (86.5%, and 73.7%, respectively). Surgical resection led to a more prolonged overall survival and 5-year cancer-specific survival (98.4% (C.I, 93.7–99.6) in the pediatric group and 88.8% (C.I, 87.5–90.0) in the adult group), respectively. Metastasis to the lung, bone, brain, and/or liver was found to have significantly lower survival rates. Multivariate analysis demonstrated that adults (hazard ratio [HR] = 7.4), Asian or Pacific Islander (HR = 0.5), male (HR = 0.8), poorly differentiated histology (HR = 3.8), undifferentiated histology (HR = 4.5), regional spread (HR = 2.1), and distant spread (HR = 3.2) were associated with increased mortality (p < 0.05). Conclusions: Mucoepidermoid carcinoma of the salivary glands primarily affects Whites and is more aggressive in adults than in the pediatric population. Even with surgical resection, the overall survival is poor in the adult population as compared to its pediatric counterparts. Advanced age, larger tumor size, male sex, and lymph node invasion are associated with increased mortality.

Dendritic cells (DCs) are professional APCs that play a crucial role in initiating robust immune responses against invading pathogens while inducing regulatory responses to the body9s tissues and commensal microorganisms. A breakdown of DC-mediated immunological tolerance leads to chronic inflammation and autoimmune disorders. However, cell-intrinsic molecular regulators that are critical for programming DCs to a regulatory state rather than to an inflammatory state are not known. In this study, we show that the activation of the TCF4 transcription factor in DCs is critical for controlling the magnitude of inflammatory responses and limiting neuroinflammation. DC-specific deletion of TCF4 in mice increased Th1/Th17 responses and exacerbated experimental autoimmune encephalomyelitis pathology. Mechanistically, loss of TCF4 in DCs led to heightened activation of p38 MAPK and increased levels of proinflammatory cytokines IL-6, IL-23, IL-1β, TNF-α, and IL-12p40. Consistent with these findings, pharmacological blocking of p38 MAPK activation delayed experimental autoimmune encephalomyelitis onset and diminished CNS pathology in TCF4^ΔDC mice. Thus, manipulation of the TCF4 pathway in DCs could provide novel opportunities for regulating chronic inflammation and represents a potential therapeutic approach to control autoimmune neuroinflammation. Key Points Transcription factor TCF4 in DCs protects against autoimmune neuroinflammation. TCF4 regulates p38 MAPK activation and proinflammatory cytokine expression in DCs. TCF4 activation in DCs limits pathological effector T cell differentiation.