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OX40 signaling favors the induction of TH9 cells and airway inflammation
The mechanisms regulating T helper 9 (TH9) cells and TH9-mediated diseases remain poorly defined. Here, we demonstrate that the receptor OX40 (Tnfrsf4) is a powerful inducer of TH9 cells in vitro and TH9-dependent airway inflammation in vivo. Under TGF-ÎČ based polarizing conditions, OX40 ligation eliminated production of induced regulatory T cells and TH17 cells, and divertedCD4+Foxp3â T cells to a TH9 phenotype. Mechanistically, OX40 activated the ubiquitin ligase TRAF6, which triggered the induction of NF-kB-inducing kinase (NIK) in CD4+ T cells and the non-canonical NF-kB pathway which subsequently lead toTH9 generation. Thus, our study identifies a previously unknown mechanism of TH9 induction and may have important clinical implications in allergic inflammation
Preliminary investigation of the eruption time of kimberlite in the Late Devonian in Mengyin, Shandong
Kimberlite in the Mengyin area serves as an excellent medium for studying the characteristics and evolutionary processes of the Paleozoic mantle. In order to determine the age of the primary calcite within the kimberlite, in situ carbonate UâPb dating was conducted in the Mengyin area. The results indicate that the primary calcite in the kimberlite originated approximately 383 ± 18 Ma (MSWD = 6.6). This age constraint suggests that the eruption of the kimberlite took place during this period, leading to the thermal alteration of limestone xenoliths, ultimately forming marble. Consequently, it can be inferred that lithospheric thinning occurred no later than the Late Devonian period. Fluid inclusions found within the marble provide further insights into its formation. The recorded formation temperature of the marble ranges from 243°C to 370°C, with a salinity range of 2.57%â14.77% (NaCl). The pressure estimates fall within the range of 3.22â20.70 MPa, indicating a depth mainly between 900 and 1,000 m. Based on these findings, it can be inferred that the overall denudation depth in the west Shandong area, since the Late Devonian, is estimated to be approximately 900â1,000 m. Furthermore, the overall crustal rise rate is estimated to be approximately 3 m/Ma
Realâworld effectiveness and safety of RC48âADC alone or in combination with PDâ1 inhibitors for patients with locally advanced or metastatic urothelial carcinoma: A multicenter, retrospective clinical study
Abstract Introduction Previous RC48 (Disitamab Vedotin) studies established that the safety and efficacy of RC48âantibodyâdrug conjugate (ADC), either alone or combined with toripalimab, for metastatic urothelial carcinoma (mUC) patients exhibiting human epidermal growth factor receptor 2 (HER2)âpositive or even HER2ânegative status after standard chemotherapy failure. Methods With locally advanced or metastatic urothelial carcinoma (la/mUC), patients who received RC48âADC monotherapy or a combination with programmed cell death protein 1 (PDâ1) inhibitors between August 2021 and October 2022 were enrolled in this retrospective observational study to evaluate the realâworld antitumor effectiveness and safety. Results Among the 38 enrolled patients (29 males; median age 67.5âyears [38â93]), 8 received RC48âADC monotherapy, while 30 received combination therapy. Initially, 63.2% (24/38) of the patients had received â„1 line of prior treatment, and 63.2% (24/38) had visceral metastasis. UC of the bladder represented the majority type in 68.4% (26/38) of cases. By the data cutoff in March 2023, the overall objective response rate (ORR) was 63.2% (95% CI, 47.1%â79.2%), with a disease control rate (DCR) of 89.5% (95% CI, 79.3%â99.7%). Median followâup time was 10.6âmonths. The median progressionâfree survival (PFS) was 8.2âmonths (95% CI, 5.9â10.5), with a 6âmonth PFS rate of 63.2% and a 12âmonth PFS rate of 34.1%. Median overall survival (OS) was not reached, with a 12âmonth OS rate of 76.7%. The median duration of response was 7.3âmonths (95% CI, 4.6â10.0) among 24 patients evaluated as partial response (PR). The most common treatmentârelated adverse events (TRAEs) included anemia (71.1%), anorexia (57.9%), asthenia (52.6%), hypoesthesia (52.6%), bone marrow suppression (47.4%), alopecia (47.4%), nausea (44.7%), proteinuria (36.8%), vomiting (34.2%), and hypoalbuminemia (31.6%). No patient experienced TRAEs of Grade â„3. One patient had an immuneârelated adverse event (irAE) of rash related to toripalimab. Conclusions Both as monotherapy and in combination with PDâ1 inhibitors, RC48âADC exhibits promising effectiveness and manageable safety profile for mUC patients in realâworld settings
Additional file 1 of Reduced gray matter volume of the hippocampal tail in melancholic depression: evidence from an MRI study
Supplementary Material 1: The schematic of the segmentation of the hippocampal and amygdala subregion
Papillary thyroid carcinoma with fibromatosis-like stroma: A case report and review of the literature
Paracoccus a cridae sp. nov., isolated from the insect Acrida cinerea living in deserted cropland
Islet allograft tolerance in the absence of invariant natural killer T cells
The invariant NKT cells are involved in both immunity and immune tolerance. However, their roles in transplant models remain controversial. We studied the role of NKT cells in the allograft response using two different strains of NKT deficient mice (CD1dâ/â and Jα18â/â mice), and found that CD1dâ/â and Jα18â/â mice rejected islet allografts with a similar kinetics as wild type B6 mice. Treatment of CD1dâ/â and Jα18â/â mice with donor specific transfusion and anti-CD154 induced donor specific tolerance, which was identical to similarly treated wt B6 mice. The islet allograft tolerance requires Foxp3+ Tregs. In the periphery, Foxp3+ Tregs in CD1dâ/â, Jα18â/â, and wt B6 mice were comparable both phenotypically and functionally. In addition, CD1dâ/â and Jα18â/â CD4+ T cells (non-Tregs) could be readily converted to Foxp3+ Tregs by TGF-ÎČ in vitro. Our data suggest that islet allograft tolerance can be successfully established without invariant NKT cells