Endoplasmic Reticulum Stress Response Mediator IRE-1α Promotes Host Dendritic Cells in Graft-versus-Host Disease Development.

Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.

The Absence of IL-12Rß2 Expression on Recipient Nonhematopoietic Cells Diminishes Acute Graft-versus-Host Disease in the Gastrointestinal Tract.

The gastrointestinal (GI) tract is a frequent target organ in acute graft-versus-host disease (aGVHD), which can determine the morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells recognize allogeneic Ags presented by host APCs, proliferate, and differentiate into Th1 and Th17 cells that drive GVHD pathogenesis. IL-12 has been shown to play an important role in amplifying the allogeneic response in preclinical and clinical studies. This study demonstrates that IL-12Rß2 expression on recipient nonhematopoietic cells is required for optimal development of aGVHD in murine models of allo-HCT. aGVHD attenuation by genetic depletion of IL-12R signaling is associated with reduced MHC class II expression by intestinal epithelial cells and maintenance of intestinal integrity. We verified IL-12Rß2 expression on activated T cells and in the GI tract. This study, to our knowledge, reveals a novel function of IL-12Rß2 in GVHD pathogenesis and suggests that selectively targeting IL-12Rß2 on host nonhematopoietic cells may preserve the GI tract after allo-HCT.

Assessment of radial artery atherosclerosis in acute coronary syndrome patients: an in vivo study using optical coherence tomography.

BACKGROUND: Radial artery (RA) atherosclerosis in acute coronary syndrome (ACS) patients has not been systematically observed in vivo. The study aims to characterize plaque morphology and intimal hyperplasia of the RA in patients with ACS, using optical coherence tomography (OCT). METHODS: In this retrospective study involving 239 ACS patients underwent RA OCT without guidewire shadow, 3 groups were divided according to the following criteria: radial artery plaque (RAP) group included patients with fibrous, lipid or calcified plaque; patients without RAP were further classified into radial intimal hyperplasia (RIH) group (intima media thickness ratio [IMR] ≥ 1) or normal group (IMR < 1). The presence and characteristics of RAP and its related risk factors were identified. RESULTS: The RAP, RIH and normal groups included 76 (31.8%), 69 (28.9%) and 94 (39.3%) patients, respectively. Patients in RAP group were the oldest, compared with those in the RIH and normal groups (p < 0.001), and more frequently had triple vessel disease (p = 0.004). The percentage of plaque rupture (72.4% vs. 56.4%, p = 0.018) and calcification (42.1% vs. 27.6%, p = 0.026) at culprit lesion were significantly higher in patients with RAP than those without RAP. A total of 148 RAP were revealed by OCT, including fibrous (72, 48.6%), lipid (50, 33.8%) and calcified plaques (26, 17.6%). The microvessels were also frequently observed in the RAP group than that in RIH and normal groups (59.2% vs. 8.7% vs. 9.6%, p < 0.001). Multivariate logistic regression analysis showed that age, diabetes, and smoking history (all p < 0.05) were independent risk factors for RAP. CONCLUSIONS: In terms of insights gained from OCT, RA atherosclerosis is not uncommon in ACS patients by OCT, sharing several morphological characters with early coronary atherosclerosis. Aging, diabetes, and smoking are risk factors for RAP.

Interleukin-23 receptor signaling by interleukin-39 potentiates T cell pathogenicity in acute graft-versus-host disease.

IL-12 (p35/p40) and IL-23 (p19/p40) signal through IL-12R (IL-12Rß2/ß1) and IL-23R (IL-23Rα/IL-12Rß1), respectively, which can promote pathogenic T lymphocyte activation, differentiation, and function in graft-versus-host disease (GVHD). With the use of murine models of allogeneic hematopoietic cell transplantation (HCT), we found that IL-12Rß1 on donor T cells was dispensable to induce acute GVHD development in certain circumstances, while IL-23Rα was commonly required. This observation challenges the current paradigm regarding IL-12Rß1 as a prerequisite to transmit IL-23 signaling. We hypothesized that p19/EBI3 (IL-39) may have an important role during acute GVHD. With the use of gene transfection and immunoprecipitation approaches, we verified that p19 and EBI3 can form biological heterodimers. We found that IL-39 levels in recipient serum positively correlated with development of acute GVHD in experimental models and in clinical settings, thereby implicating IL-39 in the pathogenesis of acute GVHD. Furthermore, we observed that human T cells can signal in response to IL-39. In chronic GVHD, IL-23Rα and IL-12Rß1 were similarly required for donor T cell pathogenicity, and IL-39 levels were not significantly different from controls without GVHD. Collectively, we identify a novel cytokine, IL-39, as a pathogenic factor in acute GVHD, which represents a novel potential therapeutic target to control GVHD and other inflammatory disorders.

Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation.

Janus kinase 2 (JAK2) signal transduction is a critical mediator of the immune response. JAK2 is implicated in the onset of graft-versus-host disease (GVHD), which is a significant cause of transplant-related mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Transfer of JAK2-/- donor T cells to allogeneic recipients leads to attenuated GVHD yet maintains graft-versus-leukemia. Th1 differentiation among JAK2-/- T cells is significantly decreased compared with wild-type controls. Conversely, iTreg and Th2 polarization is significantly increased among JAK2-/- T cells. Pacritinib is a multikinase inhibitor with potent activity against JAK2. Pacritinib significantly reduces GVHD and xenogeneic skin graft rejection in distinct rodent models and maintains donor antitumor immunity. Moreover, pacritinib spares iTregs and polarizes Th2 responses as observed among JAK2-/- T cells. Collectively, these data clearly identify JAK2 as a therapeutic target to control donor alloreactivity and promote iTreg responses after allo-HCT or solid organ transplantation. As such, a phase I/II acute GVHD prevention trial combining pacritinib with standard immune suppression after allo-HCT is actively being investigated (https://clinicaltrials.gov/ct2/show/NCT02891603).

MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice.

Chronic graft-versus-host disease (cGVHD) is characterized as autoimmune-like fibrosis and antibody production mediated by pathogenic T cells and B cells. MicroRNA-17-92 (miR-17-92) influences the survival, differentiation, and function of lymphocytes in cancer, infections, and autoimmunity. To determine whether miR-17-92 regulates T- and B-cell responses in cGVHD, we generated mice conditionally deficient for miR-17-92 in T cells, B cells, or both. Using murine models of allogeneic bone marrow transplantation, we demonstrate that expression of miR-17-92 in donor T and B cells is essential for the induction of both scleroderma and bronchiolitis obliterans in cGVHD. Mechanistically, miR-17-92 expressed in T cells not only enhances the differentiation of pathogenic T helper 1 (Th1) and Th17 cells, but also promotes the generation of follicular Th cells, germinal center (GC) B cells, and plasma cells. In B cells, miR-17-92 expression is required for autoantibody production and immunoglobulin G deposition in the skin. Furthermore, we evaluated a translational approach using antagomirs specific for either miR-17 or miR-19, key members in miR-17-92 cluster. In a lupus-like cGVHD model, systemic administration of anti-miR-17, but not anti-miR-19, alleviates clinical manifestations and proteinuria incidence in recipients through inhibiting donor lymphocyte expansion, B-cell activation, and GC responses. Blockade of miR-17 also ameliorates skin damage by reducing Th17 differentiation in a scleroderma-cGVHD model. Taken together, our work reveals that miR-17-92 is required for T-cell and B-cell differentiation and function, and thus for the development of cGVHD. Furthermore, pharmacological inhibition of miR-17 represents a potential therapeutic strategy for the prevention of cGVHD.

Bivalirudin vs. Heparin on Radial Artery Thrombosis during Transradial Coronary Intervention: An Optical Coherence Tomography Study.

OBJECTIVES: This study aimed to evaluate the antithrombotic efficacy between bivalirudin and unfractionated heparin (UFH) on radial artery thrombosis (RAT) during transradial coronary intervention (TRI) by optical coherence tomography (OCT). METHODS AND RESULTS: We consecutively reviewed a total of 307 patients who underwent radial artery OCT inspection after TRI in our centre from October 2017 to January 2019; afterwards, 211 screened patients were divided into the UFH group (n = 144) and the bivalirudin group (n = 67) according to their anticoagulation strategy during TRI. The thrombosis in the radial artery was observed in 51 cases (24.17%) with a median thrombus volume of 0.054 mm3 (0.024, 0.334) and median thrombus score of 7 (4, 15). Thrombus occurred in 28 cases in the bivalirudin group with an incidence of 41.8%, which was significantly higher than that in the UFH group (n = 23, 16.0%, P < 0.001). This difference was even more remarkable after propensity score matching (bivalirudin group n = 22, 42.3% vs. UHF group n = 11, 13.9%, P < 0.001). Multivariate logistic analysis revealed that bivalirudin increased the RAT risk by 3.872 times (95% CI 2.006-8.354, P < 0.001) after adjustment for the other predictors. CONCLUSION: In this present study, the use of bivalirudin was associated with a higher risk of RAT than UFH. It highlighted UFH should be a more considerable choice to prevent radial artery access thrombosis in TRI.

T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model.

Histone acetylation and the families of enzymes responsible for controlling these epigenetic marks have been implicated in regulating T-cell maturation and phenotype. Here, we demonstrate a previously undefined role of histone deacetylase 11 (HDAC11) in regulating T-cell effector functions. Using EGFP-HDAC11 transgenic reporter mice, we found that HDAC11 expression was lower in effector relative to naive and central memory T-cell populations, and activation of resting T cells resulted in its decreased expression. Experiments using HDAC11 knockout (KO) mice revealed that T cells from these mice displayed enhanced proliferation, proinflammatory cytokine production, and effector molecule expression. In addition, HDAC11KO T cells had increased expression of Eomesodermin (Eomes) and TBX21 (Tbet), transcription factors previously shown to regulate inflammatory cytokine and effector molecule production. Conversely, overexpression of HDAC11 resulted in decreased expression of these genes. Chromatin immunoprecipitation showed the presence of HDAC11 at the Eomes and Tbet gene promoters in resting T cells, where it rapidly disassociated following T-cell activation. In vivo, HDAC11KO T cells were refractory to tolerance induction. HDAC11KO T cells also mediated accelerated onset of acute graft-versus-host disease (GVHD) in a murine model, characterized by increased proliferation of T cells and expression of interferon-γ, tumor necrosis factor, and EOMES. In addition, adoptive transfer of HDAC11KO T cells resulted in significantly reduced tumor burden in a murine B-cell lymphoma model. Taken together, these data demonstrate a previously unknown role of HDAC11 as a negative epigenetic regulator of T-cell effector phenotype and function.

T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice.

Beyond its critical role in T cells, T-bet regulates the functions of APCs including dendritic cells and B cells, as well as NK cells. Given that recipient APCs are essential for priming allogeneic T cells and recipient NK or T cells are able to reject allogeneic donor cells, we evaluated the role of T-bet on the host in acute graft-versus-host disease (GVHD) using murine models of allogeneic bone marrow transplantation. T-bet(-/-) recipients developed significantly milder GVHD than their wild type counterparts in MHC-mismatched or CD4-dependent minor histocompatibility Ag-mismatched models. Allogeneic donor T cells, in particular, CD4 subset, significantly reduced IFN-γ production, proliferation and migration, and caused less injury in liver and gut of T-bet(-/-) recipients. We further observed that T-bet on recipient hematopoietic cells was primarily responsible for the donor T cell response and pathogenicity in GVHD. T-bet(-/-) dendritic cells expressed higher levels of Trail, whereas they produced lower levels of IFN-γ and IL-12/23 p40, as well as chemokine CXCL9, resulting in significantly higher levels of apoptosis, less priming, and infiltration of donor T cells. Meanwhile, NK cells in T-bet(-/-) hosts partially contribute to the decreased donor T cell proliferation. Furthermore, although T-bet on hematopoietic cells was required for GVHD development, it was largely dispensable for the graft-versus-leukemia effect. Taken together with our previous findings, we propose that T-bet is a potential therapeutic target for the control of GVHD through regulating donor T cells and recipient hematopoietic cells.

MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice.

MicroRNAs (miRs) play important roles in orchestrating many aspects of the immune response. The miR-17-92 cluster, which encodes 6 miRs including 17, 18a, 19a, 20a, 19b-1, and 92-1, is among the best characterized of these miRs. The miR-17-92 cluster has been shown to regulate a variety of immune responses including infection, tumor, and autoimmunity, but the role of this cluster in T-cell response to alloantigens has not been previously explored. By using major histocompatibility complex (MHC)-matched, -mismatched, and haploidentical murine models of allogeneic bone marrow transplantation (allo-BMT), we demonstrate that the expression of miR-17-92 on donor T cells is essential for the induction of graft-versus-host disease (GVHD), but dispensable for the graft-versus-leukemia (GVL) effect. The miR-17-92 plays a major role in promoting CD4 T-cell activation, proliferation, survival, and Th1 differentiation, while inhibiting Th2 and iTreg differentiation. Alternatively, miR-17-92 may promote migration of CD8 T cells to GVHD target organs, but has minimal impact on CD8 T-cell proliferation, survival, or cytolytic function, which could contribute to the preserved GVL effect mediated by T cells deficient for miR-17-92. Furthermore, we evaluated a translational approach and found that systemic administration of antagomir to block miR-17 or miR-19b in this cluster significantly inhibited alloreactive T-cell expansion and interferon-γ (IFNγ) production, and prolonged the survival in recipients afflicted with GVHD while preserving the GVL effect. Taken together, the current work provides a strong rationale and demonstrates the feasibility to target miR-17-92 for the control of GVHD while preserving GVL activity after allo-BMT.

T-bet is critical for the development of acute graft-versus-host disease through controlling T cell differentiation and function.

T-bet is a master regulator for IFN-γ production and Th1 differentiation. We evaluated the roles of T-bet and IFN-γ in T cell responses in acute graft-versus-host disease (GVHD) and found that T-bet(-/-) T cells induced significantly less GVHD compared with wild-type or IFN-γ(-/-) counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility Ag-mismatched models driven by CD4 T cells. T-bet(-/-), but not IFN-γ(-/-), CD4 T cells had a markedly reduced ability to cause tissue damage in liver and gut. This distinct outcome is reflected by the differential gene expression on donor CD4 T cells deficient for T-bet or IFN-γ. At mRNA and protein levels, we defined several T-bet-dependent molecules that may account for the impaired ability of T-bet(-/-) T cells to migrate into target organs and to produce Th1-related cytokines. Moreover, these molecules were independent of either endogenous IFN-γ, such as CXCR3 and programmed death-1, or systematic IFN-γ, such as NKG2D, I-A(b), and granzyme B. Although both T-bet(-/-) and IFN-γ(-/-) CD4 T cells are prone to differentiate into Th17 cells, polarized Th17 cells deficient for T-bet but not for IFN-γ had a significantly reduced ability to cause GVHD. Finally, T-bet(-/-) T cells had a compromised graft-versus-leukemia effect, which could be essentially reversed by neutralization of IL-17 in the recipients. We conclude that T-bet is required for Th1 differentiation and migration, as well as for optimal function of Th17 cells. Thus, targeting T-bet or regulating its downstream effectors independent of IFN-γ may be a promising strategy to control GVHD in the clinic.

Essential Role of Interleukin-12/23p40 in the Development of Graft-versus-Host Disease in Mice.

Graft-versus-host disease (GVHD), in both its acute (aGVHD) and chronic (cGVHD) forms, remains a major obstacle impeding successful allogeneic hematopoietic stem cell transplantation (allo-HSCT). T cells, in particular pathogenic T helper (Th) 1 and Th17 subsets, are a driving force for the induction of GVHD. IL-12 and IL-23 cytokines share a common p40 subunit and play a critical role in driving Th1 differentiation and in stabilizing the Th17 phenotype, respectively. In our current study, we hypothesized that p40 is an essential cytokine in the development of GVHD. By using p40-deficient mice, we found that both donor- and host-derived p40 contribute to the development of aGVHD. Neutralization of p40 with an anti-p40 mAb inhibited Th1- and Th17-polarization in vitro. Furthermore, anti-p40 treatment reduced aGVHD severity while preserving the graft-versus-leukemia (GVL) activity. Alleviation of aGVHD was associated with an increase of Th2 differentiation and a decrease of Th1 and Th17 effector T cells in the GVHD target organs. In addition, anti-p40 treatment attenuated the severity of sclerodermatous cGVHD. These results provide a strong rationale that blockade of p40 may represent a promising therapeutic strategy in preventing and treating aGVHD and cGVHD while sparing the GVL effect after allo-HSCT.

Tolerance induction between two different strains of parental mice prevents graft-versus-host disease in haploidentical hematopoietic stem cell transplantation to F1 mice.

Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) has been employed worldwide in recent years and led to favorable outcome in a group of patients who do not have human leukocyte antigen (HLA)-matched donors. However, the high incidence of severe graft-versus-host disease (GVHD) is a major problem for Haplo-HSCT. In the current study, we performed a proof of concept mouse study to test whether induction of allogeneic tolerance between two different parental strains was able to attenuate GVHD in Haplo-HSCT to the F1 mice. We induced alloantigen tolerance in C3H mice (H-2k) using ultraviolet B (UVB) irradiated immature dendritic cells (iDCs) derived from the cultures of Balb/c bone marrow cells. Then, we performed Haplo-HSCT using tolerant C3H mice as donors to F1 mice (C3H×Balb/c). The results demonstrated that this approach markedly reduced GVHD-associated death and significantly prolonged the survival of recipient mice in contrast to the groups with donors (C3H mice) that received infusion of non-UVB-irradiated DCs. Further studies showed that there were enhanced Tregs in the tolerant mice and alloantigen-specific T cell response was skewed to more IL-10-producing T cells, suggesting that these regulatory T cells might have contributed to the attenuation of GVHD. This study suggests that it is a feasible approach to preventing GVHD in Haplo-HSCT in children by pre-induction of alloantigen tolerance between the two parents. This concept may also lead to more opportunities in cell-based immunotherapy for GVHD post Haplo-HSCT.

Feeding a high-concentrate corn straw diet increased the release of endotoxin in the rumen and pro-inflammatory cytokines in the mammary gland of dairy cows.

BACKGROUND: The objective of this study was to investigate the effects of feeding a high-concentrate corn straw diet on the release of endotoxin in the rumen and the changes of pro-inflammatory cytokines in the mammary gland of dairy cows in comparison with a low-concentrate corn straw diet and a low-concentrate mixed forage diet. Thirty second-parity Chinese Holstein cows in mid-lactation with a body condition score of 2.86 ± 0.29, weighing 543 ± 57 kg and producing 24.32 ± 3.86 kg milk per day were randomly assigned to 1 of the 3 diets (n = 10 per treatment): 1) low-concentrate mixed forage diet (LCF) with a concentrate to roughage ratio of 46 : 54; 2) high-concentrate corn straw diet (HCS) with a concentrate to roughage ratio of 65 : 35; 3) low-concentrate corn straw diet (LCS) with the same concentrate to roughage ratio (46 : 54) as LCF. The experiment lasted 6 weeks, and samples were collected in the last week. Milk samples were analyzed for conventional components, rumen fluid samples were analyzed for pH and endotoxin, and mammary arterial and venous plasma samples were analyzed for concentrations of interleukin (IL)-1ß, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α). RESULTS: Concentrations of endotoxin in rumen fluid and feces of cows fed HCS were significantly higher than those of cows fed LCS and LCF. Feeding HCS increased the release of IL-1ß, IL-6 and IL-8 in the mammary gland compared with feeding LCS. Concentrations of cytokines (IL-1ß and IL-8) in mammary venous plasma had a negative correlation with milk production efficiencies. CONCLUSIONS: Results indicated that the high-concentrate corn straw diet increased the concentrations of endotoxin in rumen fluid and feces. Furthermore, feeding the high-concentrate corn straw diet stimulated the mammary gland to release more pro-inflammatory cytokines. The results suggest that feeding a high-concentrate corn straw diet induce a higher pro-inflammatory response in the mammary gland and thus may partly decrease the milk production efficiencies in dairy cows.

Characterization of radial artery perforation patterns using optical coherence tomography.

BACKGROUND: The characterization of radial artery perforation (RAP) patterns using optical coherence tomography (OCT) has not been well established. This study aimed to identify the characteristic RAP patterns in patients diagnosed through post-procedural OCT examination. METHODS: This retrospective study included 1936 consecutive patients who underwent radial artery (RA) OCT following OCT-guided transradial coronary intervention (TRI) from January 2016 to July 2022. Data regarding RAP characteristics were collected through OCT, including the perforation site as well as dimensions such as the length, width, and arc. Furthermore, RAP types were classified as small or large perforations, with a cut-off arc value of ≤90°. RESULTS: RAP, as identified by RA angiography (RAA) during TRI and on post-procedural OCT, was found in 16 out of 1936 patients (0.83 %). RA OCT imaging showed that the median distance between the RA ostium and the perforation site, the perforation length, width, and arc were 30.6 (14.4-42.2) mm, 1.55 (1.03-1.92) mm, 0.74 (0.60-1.14) mm, and 42.5 (25.0-58.1) °, respectively. Small perforations (arc ≤90°) were observed in 14 out of the 16 (87.5 %) patients with RAP. Post-procedural RAA revealed that 15 out of the 16 (93.7 %) patients with RAP had sealed perforations, with the remaining patient requiring external compression. CONCLUSIONS: Our findings demonstrated that RAP is uncommon during TRI, with clearly defined characteristic patterns on OCT. Most RAPs are small and tend to spontaneous seal through catheter tamponade.

Tipping the GVH/GVL balance by targeting HIF1α.

Promoting GVL activity while eliminating GVHD is the utmost goal to treat hematological malignancies with allo-HCT. Bailey et al. demonstrate that targeting HIF1α can favor GVL activity while limiting GVHD after allo-HCT even in combination with immune checkpoint inhibition.1.

The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis.

Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis.

Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance.

Elucidating the mechanisms of resistance to immunotherapy and developing strategies to improve its efficacy are challenging goals. Bioinformatics analysis demonstrates that high CDK6 expression in melanoma is associated with poor progression-free survival of patients receiving single-agent immunotherapy. Depletion of CDK6 or cyclin D3 (but not of CDK4, cyclin D1, or D2) in cells of the tumor microenvironment inhibits tumor growth. CDK6 depletion reshapes the tumor immune microenvironment, and the host anti-tumor effect depends on cyclin D3/CDK6-expressing CD8+ and CD4+ T cells. This occurs by CDK6 phosphorylating and increasing the activities of PTP1B and T cell protein tyrosine phosphatase (TCPTP), which, in turn, decreases tyrosine phosphorylation of CD3ζ, reducing the signal transduction for T cell activation. Administration of a PTP1B and TCPTP inhibitor prove more efficacious than using a CDK6 degrader in enhancing T cell-mediated immunotherapy. Targeting protein tyrosine phosphatases (PTPs) might be an effective strategy for cancer patients who resist immunotherapy treatment.

Effects of rosuvastatin and atorvastatin on renal function: meta-analysis.

BACKGROUND: Several clinical trials have reported inconsistent findings for the effects of rosuvastatin (RSV) and atorvastatin (ATV) on renal function. The aim of this meta-analysis was to investigate the effects of these 2 statins on glomerular filtration rate (GFR) and proteinuria respectively, and determine which is better. METHODS AND RESULTS: PubMed, CENTRAL, Web of Knowledge, and ClinicalTrials.gov website were searched for randomized controlled trials. Eligible studies reported GFR and/or proteinuria during treatment with RSV or ATV compared with control (placebo, no statins, or usual care), or RSV compared with ATV head to head. Trials that enrolled dialysis participants and teenagers were excluded. Statistical heterogeneity was assessed using the I(2) statistic, and pooled results using the random-effects model. The standardized mean differences (SMD) and ratio of means (ROM) were measured, respectively, to analyze GFR and proteinuria. Sixteen trials with a total number of 24,278 participants were identified. Compared with control, changes in the SMD of GFR were 0.04 (95% confidence interval [CI]: 0.01-0.07) and 0.59 (95%CI: 0.12-1.06) for RSV and ATV, respectively. The ROMs of proteinuria were 0.59 (95%CI: 0.46-0.74) for RSV vs. the control group, and 1.23 (95%CI: 1.05-1.43) in the head-to-head comparison. CONCLUSIONS: Both RSV and ATV improve GFR, and ATV seems to be more effective in reducing proteinuria. The validity and clinical significance require high-quality intensive studies with composite clinic endpoints of kidney and death.

Variation in blood microbial lipopolysaccharide (LPS) contributes to immune reconstitution in response to suppressive antiretroviral therapy in HIV.

BACKGROUND: In HIV infection, even under long-term antiretroviral therapy (ART), up to 20% of HIV-infected individuals fail to restore CD4+ T cell counts to the levels similar to those of healthy controls. The mechanisms of poor CD4+ T cell reconstitution on suppressive ART are not fully understood. METHODS: Here, we tested the hypothesis that lipopolysaccharide (LPS) from bacteria enriched in the plasma from immune non-responders (INRs) contributes to blunted CD4+ T cell recovery on suppressive ART in HIV. We characterized plasma microbiome in HIV INRs (aviremic, CD4+ T cell counts < 350 cells/µl), immune responders (IRs, CD4+ T cell counts > 500 cells/µl), and healthy controls. Next, we analyzed the structure of the lipid A domain of three bacterial species identified by mass spectrometry (MS) and evaluated the LPS function through LPS induced proinflammatory responses and CD4+ T cell apoptosis in PBMCs. In comparison, we also evaluated plasma levels of proinflammatory cytokine and chemokine patterns in these three groups. At last, to study the causality of microbiome-blunted CD4+ T cell recovery in HIV, B6 mice were intraperitoneally (i.p.) injected with heat-killed Burkholderia fungorum, Serratia marcescens, or Phyllobacterium myrsinacearum, twice per week for total of eight weeks. FINDINGS: INRs exhibited elevated plasma levels of total microbial translocation compared to the IRs and healthy controls. The most enriched bacteria were Burkholderia and Serratia in INRs and were Phyllobacterium in IRs. Further, unlike P. myrsinacearum LPS, B. fungorum and S. marcescens LPS induced proinflammatory responses and CD4+ T cell apoptosis in PBMCs, and gene profiles of bacteria-mediated cell activation pathways in THP-1 cells in vitro. Notably, LPS structural analysis by mass spectrometry revealed that lipid A from P. myrsinacearum exhibited a divergent structure consistent with weak toll-like receptor (TLR) 4 agonism, similar to the biological profile of probiotic bacteria. In contrast, lipid A from B. fungorum and S. marcescens showed structures more consistent with canonical TLR4 agonists stemming from proinflammatory bacterial strains. Finally, intraperitoneal (i.p.) injection of inactivated B. fungorum and S. marcescens but not P. myrsinacearum resulted in cell apoptosis in mesenteric lymph nodes of C57BL/6 mice in vivo. INTERPRETATION: These results suggest that the microbial products are causally associated with INR phenotype. In summary, variation in blood microbial LPS immunogenicity may contribute to immune reconstitution in response to suppressive ART. Collectively, this work is consistent with immunologically silencing microbiome being causal and targetable with therapy in HIV. FUNDING: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID; R01 AI128864, Jiang) (NIAID; P30 AI027767, Saag/Health), the Medical Research Service at the Ralph H. Johnson VA Medical Center (merit grant VA CSRD MERIT I01 CX-002422, Jiang), and the National Institute of Aging (R21 AG074331, Scott). The SCOPE cohort was supported by the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763, Gandhi) and the CFAR Network of Integrated Clinical Systems (R24 AI067039, Saag). The National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001450 (the pilot grant, Jiang). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.