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Development of novel therapeutic antibodies that not only kill tumor cells but modulate the adaptive immune response has the potential to produce long term anti-cancer immunity and a durable clinical response. We previously reported the discovery of an anti-complement factor H (CFH) autoantibody in lung cancer patients that were associated with early stage disease and exceptional outcomes. The human monoclonal antibody GT103, produced from a single CFH autoantibody-expressing B cell of a lung cancer patient, recognizes a conformationally distinct epitope on tumor cells, kills tumor cells, and inhibits tumor growth in animal studies. Recent experiments have shown that GT103 restructures the tumor microenvironment and initiates a robust antitumoral adaptive immune response. The current study further elucidates several mechanisms by which GT103 kills tumor cells and drives the immune program. Here we show GT103 has specificity for tumor cells without binding to native soluble CFH or normal tissues. GT103 causes complement C3 split product deposition on tumor cellsin vitroandin vivo,triggers antibody-dependent cellular phagocytosis, and increases translocation of the danger associated molecular pattern molecule calreticulin to the plasma membrane.We also demonstrate that GT103 causes B cell activation and that GT103 antitumor activityin vivois B cell dependent. The complex mechanism of GT103, a tumor specific antibody that kills tumor cells and stimulates an immune response, supports further development of this human-derived antibody as a novel therapeutic option for patients with lung cancer.

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder, characterized by reciprocal translocation t(9,22) (q34; q11), leading to increased myeloid proliferation. Most cases are diagnosed in the chronic phase (CP). However, a minority of cases can be present in the blastic phase (BP). In most patients with CML-BP, the blasts have a myeloid phenotype, however, in 20–30% of cases, the blasts have a lymphoid phenotype, mostly a B-cell phenotype. It is challenging to differentiate CML B-lymphoblastic phase (CML-BLP) from Ph + primary B-acute lymphoblastic leukemia (B-ALL) especially when the CML-BLP is the initial presentation of the disease, which is uncommon. We report here an unusual case of CML-BLP as an initial presentation of the disease without typical CML morphological findings. This case demonstrates diagnostic challenges and emphasizes the importance of an integrated approach using morphology, multiparametric flow cytometry, cytogenetic studies, and molecular studies to render an accurate diagnosis.

The anharmonicity of lattice vibration is mainly responsible for the coefficient of thermal expansion (CTE) of materials. External stimuli, such as magnetic and electric fields, thus cannot effectively change the CTE, much less the sign variation from positive to negative or vice versa. In this study, we report significant magnetic field effects on the CTE of zircon- and scheelite-type DyCrO4 prepared at ambient and high pressures, respectively. At zero field, the zircon-type DyCrO4 exhibits a negative CTE below the ferromagnetic-order temperature of 23 K. With increasing field up to ≥1.0 T, however, the sign of the CTE changes from negative to positive. In the scheelite phase, magnetic field can change the initially positive CTE to be negative with a field up to 2.0 T, and then a reentrant positive CTE is induced by enhanced fields ≥3.5 T. Both zircon and scheelite phases exhibit considerable magnetostrictive effects with the absolute values as high as ~800 ppm at 2 K and 10 T. The strong spin-lattice coupling is discussed to understand the unprecedented sign changes of the CTE caused by applying magnetic fields. The current DyCrO4 provides the first example of field-induced sign change of thermal expansion, opening up a way to readily control the thermal expansion beyond the conventional chemical substitution.

The specific process of hydrogen generation by the reaction of In7 and In6Al clusters with H2O molecules is explored through density functional theory in this study. Based on the prediction of the lowest energy structure of In7 and In6Al clusters, the geometric and electronic structures of In7@H2O and In6Al@H2O are obtained by using the dispersion-corrected density functional theory B3LYP-D3. The corresponding reaction paths are constructed according to the transition states in the searched reactions. Then we discuss the reaction path, energy barrier and reaction energy release. The results show that both In7 and In6Al clusters can react with H2O molecules and release hydrogen. Both reactions are exothermic reactions, and the structure of the reaction product are very similar. The comparison of adsorption energy, energy barrier and reaction release energy show that the Al-doped In7 cluster can significantly improve its ability to react with H2O and reduce the energy barrier that has to be overcome for the reaction process. The generated H2 exists on the cluster surface in the form of physical adsorption, which is judged by the adsorption energy, the distance between the H2 molecule and the cluster surface, and the interaction region indicator.

Supplementary Figure S1. Complement regulates IL-10 production in CD8+ TILs. Supplementary Figure S2. Non-CD8+ T cell responses in tumor bearing mice. Supplementary Figure S3. T cell exhaustion markers expressed on CD8+ TILs after IL-10 culture. Supplementary Figure S4. Anaphylatoxins regulate IL-10 production through C3aR and C5aR.

Immune-checkpoint inhibitor-based combination immunotherapy has become a first-line treatment for several major types of cancer including hepatocellular carcinoma (HCC), renal cell carcinoma, lung cancer, cervical cancer, and gastric cancer. Combination immunotherapy counters several immunosuppressive elements in the tumor microenvironment and activates multiple steps of the cancer-immunity cycle. The anti-PD-L1 antibody, atezolizumab, plus the anti-vascular endothelial growth factor antibody, bevacizumab, represents a promising class of combination immunotherapy. This combination has produced unprecedented clinical efficacy in unresectable HCC and become a landmark in HCC therapy. Advanced HCC patients treated with atezolizumab plus bevacizumab demonstrated impressive improvements in multiple clinical endpoints including overall survival, progress-free survival, objective response rate, and patient-reported quality of life when compared to current first-line treatment with sorafenib. However, atezolizumab plus bevacizumab first-line therapy has limitations. First, cancer patients falling into the criteria for the combination therapy may need to be further selected to reap benefits while avoiding some potential pitfalls. Second, the treatment regimen of atezolizumab plus bevacizumab at a fixed dose may require adjustment for optimal normalization of the tumor microenvironment to obtain maximum efficacy and reduce adverse events. Third, utilization of predictive biomarkers is urgently needed to guide the entire treatment process. Here we review the current status of clinically approved combination immunotherapies and the underlying immune mechanisms. We further provide a perspective analysis of the limitations for combination immunotherapies and potential approaches to overcome the limitations.

BackgroundThe prognostic value of the tumor burden score (TBS) in patients with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remains unknown. This study aimed to investigate the impact of TBS on long-term outcomes after surgery.MethodsPatients who underwent radical-intent resection between June 2013 and December 2019 were retrospectively reviewed. Kaplan–Meier curves were used to analyze patient survival, and disease-free survival (DFS) and overall survival (OS) were examined in relation to TBS.ResultsA total of 178 patients were included in this study, with 119 in the training cohort and 59 in the validation cohort. Kaplan–Meier curves showed that TBS was a strong prognostic indicator in patients with cHCC-CCA. Elevated TBS was associated with poorer DFS and OS (both P-value < 0.001) and was identified as an independent prognostic indicator. In addition, the prognostic value of TBS outperformed tumor size and number alone, microvascular invasion, and lymph node invasion. The prognostic significance of TBS was confirmed by the internal validation cohort.ConclusionsThe present study suggested the significance of tumor morphology in assessing the prognosis of patients with cHCC-CCA who undergoing curative resection. The TBS is a promising prognostic index in patients with cHCC-CCA. Elevated TBS was related to a lower long-term survival rate and was identified as an independent risk factor for poor DFS and OS. Further research is needed to verify our results.

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Chronic pain is a disease of long-lasting pain with unpleasant feelings mediated by central and (or) peripheral sensitization, its duration usually lasts more than 3 months or longer than the expected recovery time. The patients with chronic pain are manifested with enhanced sensitivity to noxious and non-noxious stimuli. Due to an incomplete understanding of the mechanisms, patients are commonly insensitive to the treatment of first line analgesic medicine in clinic. Thus, the exploration of non-opioid-dependent analgesia are needed. Recent studies have shown that “sinomenine,” the main active ingredient in the natural plant “sinomenium acutum (Thunb.) Rehd. Et Wils,” has a powerful inhibitory effect on chronic pain, but its underlying mechanism still needs to be further elucidated. A growing number of studies have shown that various immune cells such as T cells, B cells, macrophages, astrocytes and microglia, accompanied with the relative inflammatory factors and neuropeptides, are involved in the pathogenesis of chronic pain. Notably, the interaction of the immune system and sensory neurons is essential for the development of central and (or) peripheral sensitization, as well as the progression and maintenance of chronic pain. Based on the effects of sinomenine on immune cells and their subsets, this review mainly focused on describing the potential analgesic effects of sinomenine, with rationality of regulating the neuroimmune interaction.

The generation of runaway electrons (REs) is observed during the low-density helium ohmic plasma discharge in the Experimental Advanced Superconducting Tokamak (EAST). The growth rate of hard x-ray (HXR) is inversely proportional to the line-average density. Besides, the RE generation in helium plasma is higher than deuterium plasma at the same density, which is obtained by comparing the growth rate of HXR with the same discharge conditions. The potential reason is the higher electron temperature of helium plasma in the same current and electron density plateau. Furthermore, two Alfvén eigenmodes driven by REs have been observed. The frequency evolution of the mode is not fully satisfied with the Alfvén scaling and when extension of the Alfvén frequency is towards 0, the high frequency branch is ~50 kHz. The different spatial position of the two modes and the evolution of the helium concentration could be used to understand deviation between theoretical and experimental observation.

BACKGROUND The artificial liver support system (ALSS) is an effective treatment method for liver failure, but it requires deep venous intubation and long-term indwelling catheterization. However, the coagulation mechanism disorder of basic liver failure diseases, and deep venous thrombosis (DVT) often occur. AIM To evaluate the risk factors for DVT following use of an ALSS and establish a risk assessment score. METHODS This study was divided into three stages. In the first stage, the risk factors for DVT were screened and the patient data were collected, including ALSS treatment information; biochemical indices; coagulation and hematology indices; complications; procoagulant use therapy status; and a total of 24 indicators. In the second stage, a risk assessment score for DVT after ALSS treatment was developed. In the third stage, the DVT risk assessment score was validated. RESULTS A total of 232 patients with liver failure treated with ALSS were enrolled in the first stage, including 12 with lower limb DVT. Logistic regression analysis showed that age [odds ratio (OR), 1.734; P = 0.01], successful catheterization time (OR, 1.667; P = 0.005), activity status (strict bed rest) (OR, 3.049; P = 0.005), and D-dimer level (≥ 500 ng/mL) (OR, 5.532; P < 0.001) were independent risk factors for DVT. We then established a scoring system for risk factors. In the validation group, a total of 213 patients with liver failure were treated with ALSS, including 14 with lower limb DVT. When the cutoff value of risk assessment was 3, the specificity and sensitivity of the risk assessment score were 88.9% and 85.7%, respectively. CONCLUSION A simple risk assessment scoring system was established for DVT patients with liver failure treated with ALSS and was verified to have good sensitivity and specificity.

BACKGROUND The immune-mediated invasion of IgG4-positive plasma cells in the liver is found in some autoimmune hepatitis. Giant-cell hepatitis (GCH) is a very rare pathological feature in adults, and the clinical characteristics of the simultaneous appearance of the two pathological phenomena are not clear. CASE SUMMARY A 68-year-old woman was hospitalized with fatigue, poor appetite, and yellow urine for 20 d. Liver function tests and immunological indexes were significantly abnormal and accompanied by elevated serum IgG4 levels. Liver pathology revealed severe inflammation of the interface between the portal tract and hepatocytes, portal area inflammation, plasma cell infiltration, formation of rosette cells, IgG4-positive plasma cells > 10/high-power field, IgG4/IgG > 40%, and multinucleated liver cell swelling. IgG4-related autoimmune hepatitis (AIH) combined with GCH was diagnosed, and methylprednisolone was administered at 40 mg/day. Two weeks later, the clinical symptoms disappeared, and the liver function and immunological indicators were significantly improved. Methylprednisolone was reduced at a rate of 4–8 mg per week to 8 mg/day for maintenance. A second liver biopsy 48 wk later indicated that liver inflammation and fibrosis were significantly improved. IgG4-positive plasma cells and GCH were not detected. A literature search was conducted to analyze articles reporting similar pathological phenomena. CONCLUSION AIH with simultaneous IgG4-positive plasma cell infiltration and GCH, liver inflammation, and fibrosis is possibly more severe than typical AIH but sensitive to corticosteroids.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines represent a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents including anti-PD-1 and immune adjuvant poly I:C may be combined with DC vaccines to further enhance antitumor activity. Here we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-PD-1 and poly I:C as well as a chemotherapeutic agent cyclophosphamide that were integrated with the standard chemoradiation therapy for > 5 years. The patient who received DC vaccines loaded with multiple forms of tumor antigens including mRNA-tumor associated antigens (TAAs), mRNA-neoantigens, and hypochlorous acid-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology which fuses TAAs with a destabilization domain and inserts TAAs into a full-length LAMP-1 to enhance MHC class I and II antigen presentation, respectively. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy related adverse events were observed during the treatment. Robust anti-tumor CD4+ and CD8+ T cell responses were detected. The patient remains free of disease progression as of July, 2022. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment. A large scale trial to validate these findings is warranted. Protocol numbers: 201708152377, 20202014-F-1

Complement factor H (CFH) is an abundant serum protein regulating complement activation and protecting host cells from attack by the alternative pathway of complement mediated cytotoxicity. We previously identified an anti-CFH autoantibody in early stage NSCLC patients, and cloned from single peripheral B cells a lead therapeutic mAb, GT103, for cancer immunotherapy. Although GT103 has potent antitumor activities, the underlying antitumor mechanisms remain unknown. Herein we investigated GT103-mediated antitumor effects and demonstrate that GT103 enhances antitumor immunity through multiple pathways. GT103 treatment creates a favorable tumor microenvironment (TME) by decreasing immunosuppressive regulatory T cells and myeloid-derived suppressor cells and enhancing antigen-specific effector T cells and has a synergistic antitumor effect with anti-PD-L1 mAb. Furthermore, the immune landscape of tumors from early stage patients expressing the anti-CFH autoantibody is associated with an immunologically active TME. Our results provide novel mechanistic insights into this promising human-derived immunotherapeutic agent, which is currently undergoing a Phase I/II clinical trial in patients with NSCLC.

OBJECTIVES Patients with advanced ampullary carcinoma (AC) who are unsuitable for surgery are most likely to have poor outcomes. The role of endoscopic radiofrequency ablation (RFA) in this population has not been fully defined. We aimed to assess the short- and long-term outcomes of RFA in a large cohort of AC patients. METHODS In this retrospective study, data of consecutive patients with pathologically proven AC who underwent successful endobiliary RFA and/or stent placement were collected. All patients did not undergo surgical resection. The primary outcome was overall survival (OS). The secondary outcomes included clinical success and adverse events. RESULTS A total of 85 patients, 50 in the RFA plus stenting group and 35 in the stenting alone group, were identified. The median OS was significantly longer in the RFA group than in the stenting alone group (16.9 vs. 9.8 months, P

BACKGROUND Immune checkpoint inhibitors (ICIs) can lead to immune-related hepatitis (IRH) and severe liver damage, which is life-threatening in the absence of specific treatment. CASE SUMMARY A 75-year-old man was admitted to our hospital complaining of loss of appetite, yellow urine, and abnormal liver function for the past 2 wk. Three months prior to admission, he was treated with two rounds of capecitabine in combination with camrelizumab for lymph node metastasis of esophageal cancer. Although liver function was normal before treatment, abnormal liver function appeared at week 5. Capecitabine and camrelizumab were discontinued. Ursodeoxycholic acid and methylprednisolone 40 mg daily were administered. Liver function continued to deteriorate. Prothrombin time and international normalized ratio were 19 s and 1.8, respectively. The patient was diagnosed with acute liver failure. A pathological analysis of liver biopsy indicated a strongly positive immunohistochemical staining of T8+ cells, thereby suggesting that drug-induced liver injury was related to IRH caused by camrelizumab. Subsequently, we performed sequential dual-molecule plasma adsorption system (DPMAS) treatment with plasma exchange (PE). After two rounds of treatment, the patient's appetite significantly improved, the yellow color of urine reduced, and liver function improved (total bilirubin level decreased) after five rounds of treatment. Liver function normalized 4 wk after discharge. CONCLUSION The use of sequential DPMAS with PE can reduce liver injury and systemic toxic reactions by clearing inflammatory mediators and harmful substances from blood, and regulate immune cell activity, which may be effective in the treatment of severe ICI-induced IRH.

Adrenomedullin (ADM) has beneficial effects on Leydig cells under pathological conditions, including lipopolysaccharide (LPS)-induced orchitis. Our previous studies demonstrated that ADM exerts a restorative effect on steroidogenesis in LPS-treated primary rat Leydig cells by attenuating oxidative stress, inflammation and apoptosis. In this study, we aim to investigate whether ADM inhibits Leydig cell dysfunction by rescuing steroidogenic enzymes in vivo. Rats were administered with LPS and injected with Ad-ADM, an adeno-associated virus vector that expressed ADM. Then, rat testes were collected for 3β-hydroxysteroid dehydrogenase (3β-HSD) immunofluorescence staining. Steroidogenic enzymes or steroidogenic regulatory factors or protein, including steroidogenic factor-1 (SF-1), liver receptor homologue-1 (LRH1), Nur77, steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side chain cleavage enzyme (P450scc), 3β-HSD, cytochrome P450 17α-hydroxylase/17, 20 lyase (CYP17) and 17β-hydroxysteroid dehydrogenase (17β-HSD), were detected via gene expression profiling and western blot analysis. Plasma testosterone concentrations were measured. Results showed that ADM may inhibit Leydig cell dysfunction by rescuing steroidogenic enzymes and steroidogenic regulatory factors in vivo. The reduction in the number of Leydig cells after LPS exposure was reversed by ADM. ADM rescued the gene or protein levels of SF-1, LRH1, Nur77, StAR, P450scc, 3β-HSD, CYP17 and 17β-HSD and plasma testosterone concentrations. To summarize ADM could rescue some important steroidogenic enzymes, steroidogenic regulatory factors and testosterone production in Leydig cells in vivo.

Hematopoietic stem cell transplantation (HSCT)-sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, is a clinical syndrome characterized by symptoms, such as right upper quadrant pain, jaundice, fluid retention, and hepatomegaly, and is caused by pre-treatment-related hepatotoxicity during the early stages after HSCT. Clinical diagnosis of HSCT-SOS is based on the revised Seattle or Baltimore standards. The revised standard by the European Society for Bone Marrow Transplantation in 2016 has good practicability and can be used in combination with these two standards. Eight studies have shown the value of liver stiffness measurement (LSM) in the early diagnosis of HSCT-SOS. Four studies investigated LSM specificity and sensitivity for the early diagnosis of HSCT-SOS. LSM can distinguish SOS from other post-HSCT complications, enabling a clear differential diagnosis. It has been shown that median LSM of patients with SOS is significantly higher than that of patients with other treatment-related liver complications (

Optimization of the cathode structure and exploration of a novel electrolyte system are important approaches for achieving high-performance zinc-ion batteries (ZIBs) and zinc dendrite suppression. Herein, a quasi-solid-state ZIB combining a sandwich-like MnO

The plasma-beta effect on the n = 1 resonant magnetic perturbation (RMP) field penetration in purely radio-frequency (RF) wave heated discharges has been investigated in EAST. The experimental results show that the dependence of the threshold RMP coil current for field penetration, I RMP,th , on the total absorbed power P tot scales as approximately I RMP,th ∝ P tot 0.30 , indicating that the error-field tolerance is improved with increasing RF power. This is benefited by the increased electron perpendicular flow dominated by a counter-current electron diamagnetic flow with increasing RF power. However, theoretical scaling in cylindrical geometry overestimates the power index. Assuming an additional term β N α β N for the normalized beta in the scaling, it is shown that the fitted α β N from the experimental observation is around −1, indicating a degradation effect of plasma beta. To clarify the underlying physics of the plasma-beta effect that was not included in the theoretical scaling in cylindrical geometry, the MARS-Q code with full toroidal geometry is employed for simulation of nonlinear field penetration (Liu et al 2013 Phys. Plasmas 20 042503). The MARS-Q simulation results reproduce the β N dependence well, and hence the P tot scaling of the threshold current in experimental observations. The main reason for this is that the net total torque, which is mainly contributed by the neoclassical toroidal viscosity (NTV), increases with increasing plasma β N . The results demonstrate that the nonlinear toroidal coupling effect via NTV torque plays an important role in determining field penetration, even in cases with relatively low β N ∈ [ 0.3 , 0.6 ] , which is far less than the no-wall beta limit.

Systemic sclerosis (SSc) is a fibrotic disease that initiates in the skin and progresses to internal organs, leading to a poor prognosis. Unraveling the etiology of a chronic, multifactorial disease such as SSc has been aided by various animal models that recapitulate certain aspects of the human pathology. We found that the transcription factor Snail is overexpressed in the epidermis of SSc patients and a transgenic mouse recapitulating this expression pattern is sufficient to induce many clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin (Spondin-2) in fibrogenesis. Mindin is produced by Snail transgenic skin keratinocytes and aids fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.

Hepatocellular carcinoma (HCC) is a major cause of cancer‐related death worldwide, accounting for 90% of liver cancers. Effective systemic treatments for advanced stage HCC are limited. The recent clinical application of mutated neoantigens as immunotherapeutic targets in several human cancers demonstrated that boosting host T cell responses to these antigens may help control patient tumors. With increased enthusiasm for targeting mutated neoantigens as a strategy in cancer immunotherapy, many clinical trials were initiated to apply mutated neoantigens as targets for the therapy of HCC and other solid tumors. However, recent studies suggest that targeting mutated neoantigens for the immunotherapy of HCC and other solid tumors has pitfalls and may not achieve efficacy without strategic changes. Herein, we discuss the limits of using neoantigens as targets in HCC immunotherapy and suggest alternative strategies to overcome these limits. Importantly, similar limits and alternative strategies are likely applicable to other intermediate and low tumor mutation burden cancers.

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARS-CoV-2 infection is a critical determinant for patients’ outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.

To investigate whether adrenomedullin (ADM) rescues the steroidogenic functions of Leydig cells by suppressing transforming growth factor-β1 (TGF-β1) via the Hippo signaling. Primary Leydig cells were treated with lipopolysaccharide (LPS), an adeno-associated virus vector that expressed ADM (Ad-ADM) or sh-RNA of TGF-β1 (Ad-sh-TGF-β1). Cell viability and medium concentrations of testosterone were detected. Gene expression and protein levels were detected for steroidogenic enzymes, TGF-β1, RhoA, YAP, TAZ and TEAD1. Role of Ad-ADM in the regulation of TGF-β1 promoter was confirmed by ChIP and Co-IP. Like Ad-sh-TGF-β1, Ad-ADM reversed the decreased number of Leydig cells and plasma concentrations of testosterone by rescuing the gene and protein levels of SF-1, LRH1, Nur77, StAR, P450scc, 3β-HSD, CYP17 and 17β-HSD. Similar to Ad-sh-TGF-β1, Ad-ADM inhibited the LPS-induced cytotoxicity and cell apoptosis and rescued the gene and protein levels of SF-1, LRH1, Nur77, StAR, P450scc, 3β-HSD, CYP17, 17β-HSD and the medium concentrations of testosterone in LPS-induced Leydig cells. Like Ad-sh-TGF-β1, Ad-ADM ameliorated LPS-induced TGF-β1 expression. In addition, Ad-ADM inhibited RhoA activation, enhanced the phosphorylation of YAP and TAZ, decreased TEAD1 expression which interacted with HDAC5 and then bound to TGF-β1 gene promoter in LPS-exposed Leydig cells. ADM may exert anti-apoptotic effect to rescue the steroidogenic functions of Leydig cells by suppressing TGF-β1 via the Hippo signaling.

Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3-13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).

CD4+ and CD8+ T cells are dichotomous lineages in adaptive immunity. While conventionally viewed as distinct fates that are fixed after thymic development, accumulating evidence indicates that these two populations can exhibit significant lineage plasticity, particularly upon TCR-mediated activation. We define a novel CD4-CD8αβ+ MHC II-recognizing population generated by lineage conversion from effector CD4+ T cells. CD4-CD8αβ+ effector T cells downregulated the expression of T helper cell-associated costimulatory molecules and increased the expression of cytotoxic T lymphocyte-associated cytotoxic molecules. This shift in functional potential corresponded with a CD8+-lineage skewed transcriptional profile. TCRβ repertoire sequencing and in vivo genetic lineage tracing in acutely infected wild-type mice demonstrated that CD4-CD8αβ+ effector T cells arise from fundamental lineage reprogramming of bona fide effector CD4+ T cells. Impairing autophagy via functional deletion of the initiating kinase Vps34 or the downstream enzyme Atg7 enhanced the generation of this cell population. These findings suggest that effector CD4+ T cells can exhibit a previously unreported degree of skewing towards the CD8+ T cell lineage, which may point towards a novel direction for HIV vaccine design.

The paper aimed to investigate internal mechanics between disintegration of the rockfill material and stability of the dam, and further provide scientific evidence for the design of rockfills, through the conducted disintegration of water pressure and triaxial test to analyze fractal characteristics, strength and deformation of the rockfill in whole disintegration procedure. As the results that the water pressure was low 0.2 MPa, the increasing water pressure would delay the disintegration rate of rockfill; while the water pressure was above 0.2 MPa, it would promote the disintegration rate of the rockfill. In addition, in the disintegration process, the cohesion force of rockfill rapidly slowed down at the beginning and then gradually increased. The internal friction angle increased gradually during the whole disintegration process. Furthermore, when the water pressure increased from 0 MPa to 0.6 MPa, the partial stress firstly decreased to a minimum level when the water pressure was 0.2 MPa, and then increased gradually with water pressure.