Study on the therapeutic effect of sintilimab combined with modified DCF regimen on advanced gastric cancer and its impact on Th1/Th2 immune balance.

The aim of this study was to observe the therapeutic effect of sintilimab combined with a modified docetaxel + cisplatin + fluorouracil (DCF) regimen on advanced gastric cancer and its effect on Th1/Th2 immune balance. Ninety-eight cases of advanced gastric cancer patients who visited our hospital from April 2020 to May 2022 were selected and divided into 48 cases each in the conventional group and the research group by random number table method; the DCF regimen was adopted in the conventional group, and sintilimab combined with modified DCF regimen was adopted in the research group, and the therapeutic effects of the patients in the two groups and the changes of Th1/Th2 immune indexes were compared. CEA, CA199, CA242, CD168 AQ3, and IL-4 in the study group were lower than those in the conventional group at the end of three cycles of treatment, and the difference was statistically significant (P < 0.001). The levels of IFN-γ and IL-4 in the study group at the end of three cycles of treatment were higher than those in the conventional group (P < 0.001). The incidence of adverse reactions during treatment in the study group was lower than that in the conventional group (P < 0.001), and the grading of adverse reactions in the study group was milder than that in the conventional group. Sintilimab combined with a modified DCF regimen in the treatment of advanced gastric cancer not only improves the therapeutic effect but also positively affects the Th1/Th2 immune balance, which provides better immune regulation for patients with advanced gastric cancer.

Record-Efficiency Printable Hole-Conductor-Free Mesoscopic Perovskite Solar Cells Enabled by the Multifunctional Schiff Base Derivative.

Tailoring multifunctional additives for performing interfacial modifications, improving crystallization, and passivating defects is instrumental for the fabrication of efficient and stable perovskite solar cells (PSCs). Here, a Schiff base derivative, (chloromethylene) dimethyliminium chloride (CDCl), is introduced as an additive to modify the interface between the mesoporous TiO2 electron transport layer and the MAPbI3 light absorber during the annealing process. CDCl chemically links to TiO2 and MAPbI3 through coordination and hydrogen bonding, respectively, and results in the construction of fast electron extraction channels. CDCl also optimizes the energy-level alignment of the TiO2/MAPbI3 heterojunction and improves the pore-filling and crystallization of MAPbI3 in the mesoscopic scaffold, which inhibits nonradiative recombination and eliminates open-circuit voltage losses. As a result, an impressive power conversion efficiency of 19.74%, which is the best one ever reported, is obtained for printable carbon-based hole-conductor-free PSCs based on MAPbI3.

Lipid metabolism in malignant tumor brain metastasis: reprogramming and therapeutic potential.

INTRODUCTION: Brain metastasis is a highly traumatic event in the progression of malignant tumors, often symbolizing higher mortality. Metabolic alterations are hallmarks of cancer, and the mask of lipid metabolic program rearrangement in cancer progression is gradually being unraveled. AREAS COVERED: In this work, we reviewed clinical and fundamental studies related to lipid expression and activity changes in brain metastases originating from lung, breast, and cutaneous melanomas, respectively. Novel roles of lipid metabolic reprogramming in the development of brain metastasis from malignant tumors were identified and its potential as a therapeutic target was evaluated. Published literature and clinical studies in databases consisting of PubMed, Embase, Scopus and www.ClinicalTrials.gov from 1990 to 2022 were searched. EXPERT OPINION: Lipid metabolic reprogramming in brain metastasis is involved in de novo lipid synthesis within low lipid availability environments, regulation of lipid uptake and storage, metabolic interactions between brain tumors and the brain microenvironment, and membrane lipid remodeling, in addition to being a second messenger for signal transduction. Although some lipid metabolism modulators work efficiently in preclinical models, there is still a long way to go from laboratory to clinic. This area of research holds assurance for the organ-targeted treatment of brain metastases through drug-regulated metabolic targets and dietary interventions.

Advances in the synthesis and modification of two-dimensional antimonene.

Antimonene with a honeycomb layered structure has great application prospects in a wide spectrum of domains due to its high carrier mobility, high thermal conductivity, and layer-dependent electrical properties. Since the first successful synthesis of antimonene by epitaxy in 2015, various fabrication methods have been proposed successively. Herein, several representative synthetic methods are described in detail, including mechanical exfoliation, epitaxial growth, liquid-phase exfoliation, electrochemical exfoliation, etc. In addition, band engineering via modification strategies of antimonene, particularly intercalation and doping, is discussed based on available theoretical studies. By comparing the achieved structure characteristics and performances of these different synthesis and modification strategies, we present promising future developments and critical challenges for antimonene.

Research progress of two-dimensional antimonene in energy storage and conversion.

Since the first proposal of antimonene in 2015, extensive research attention has been drawn to its application in energy storage and conversion because of its excellent layered structure and fast ion diffusion properties. However, in contrast to the revolutionary expansion of antimonene-based energy devices, reviews on this topic that summarize and further guide the design of 2D antimonene for energy storage and conversion are rare. In this review, the structure, physicochemical properties, and popular synthesis approaches of antimonene are first summarised. Specifically, the rational design and application of antimonene in energy storage and conversion such as electrochemical batteries and supercapacitors, electrocatalytic hydrogen evolution reaction, electrocatalytic oxygen evolution reaction, electrocatalytic carbon dioxide reduction, photocatalytic reduction of organic pollution, photocatalytic reduction of carbon dioxide (CO2), solar cells and photovoltaic devices are outlined. Finally, opportunities and challenges are presented to further advance the development and application of antimonene in energy conversion and storage.

Immune cells and RBCs derived from human induced pluripotent stem cells: method, progress, prospective challenges.

Blood has an important role in the healthcare system, particularly in blood transfusions and immunotherapy. However, the occurrence of outbreaks of infectious diseases worldwide and seasonal fluctuations, blood shortages are becoming a major challenge. Moreover, the narrow specificity of immune cells hinders the widespread application of immune cell therapy. To address this issue, researchers are actively developing strategies for differentiating induced pluripotent stem cells (iPSCs) into blood cells in vitro. The establishment of iPSCs from terminally differentiated cells such as fibroblasts and blood cells is a straightforward process. However, there is need for further refinement of the protocols for differentiating iPSCs into immune cells and red blood cells to ensure their clinical applicability. This review aims to provide a comprehensive overview of the strategies and challenges facing the generation of iPSC-derived immune cells and red blood cells.

Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis.

Lipotoxicity is a recognized pathological trigger and accelerator of nonalcoholic steatohepatitis (NASH). However, the molecular basis of lipotoxicity-induced NASH remains elusive. Here, we systematically mapped the changes in hepatic transcriptomic landscapes in response to lipotoxic insults across multiple species. Conserved and robust activation of the arachidonic acid pathway, in particular the arachidonate 12-lipoxygenase (ALOX12) gene, was closely correlated with NASH severity in humans, macaques with spontaneously developed NASH, as well as swine and mouse dietary NASH models. Using gain- and loss-of-function studies, we found that ALOX12 markedly exacerbated NASH in both mice and Bama pig models. ALOX12 was shown to induce NASH by directly targeting acetyl-CoA carboxylase 1 (ACC1) via a lysosomal degradation mechanism. Overall, our findings reveal a key molecular driver of NASH pathogenesis and suggest that ALOX12-ACC1 interaction may be a therapeutic target in NASH.

A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)­acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small molecule­based therapies for NASH.

Hepatocyte SH3RF2 Deficiency Is a Key Aggravator for NAFLD.

BACKGROUND AND AIMS: NAFLD has become the most common liver disease worldwide but lacks a well-established pharmacological therapy. Here, we aimed to investigate the role of an E3 ligase SH3 domain-containing ring finger 2 (SH3RF2) in NAFLD and to further explore the underlying mechanisms. METHODS AND RESULTS: In this study, we found that SH3RF2 was suppressed in the setting of NAFLD across mice, monkeys, and clinical individuals. Based on a genetic interruption model, we further demonstrated that hepatocyte SH3RF2 deficiency markedly deteriorates lipid accumulation in cultured hepatocytes and diet-induced NAFLD mice. Mechanistically, SH3RF2 directly binds to ATP citrate lyase, the primary enzyme promoting cytosolic acetyl-coenzyme A production, and promotes its K48-linked ubiquitination-dependent degradation. Consistently, acetyl-coenzyme A was significantly accumulated in Sh3rf2-knockout hepatocytes and livers compared with wild-type controls, leading to enhanced de novo lipogenesis, cholesterol production, and resultant lipid deposition. CONCLUSION: SH3RF2 depletion in hepatocytes is a critical aggravator for NAFLD progression and therefore represents a promising therapeutic target for related liver diseases.

Up-regulation of autophagy and apoptosis of cochlear hair cells in mouse models for deafness.

INTRODUCTION: Hearing loss is one of the most common sensory disorders. Recent findings have shown that the apoptotic program and autophagy are related to hearing loss. The aim of the study was to explore the effects of noise and cisplatin exposure on apoptosis and autophagy in the hair cells of the cochleae. MATERIAL AND METHODS: C57BL/6 mice were randomly divided into 3 groups (n = 10 for each): the control group, the noise model group and the cisplatin model group. Auditory brainstem response (ABR) measurements were used to detect the hearing thresholds. TUNEL assay was used to evaluate cell apoptosis. Western blot and immunofluorescence were performed to examine the apoptosis- and autophagy-related proteins. RESULTS: The mice exhibited substantial hearing loss after noise and cisplatin exposure. Additionally, more TUNEL positive cells were observed in the mice after noise and cisplatin exposure compared with the control group. Moreover, the protein expression levels of Beclin-1, LC3-II, Bax and cleaved caspase-3 were significantly increased, while the expression of Bcl-2 was notably decreased in the cochlea after noise (p = 0.0278, 0.0075, 0.0142, 0.0158, 0.0131 respectively) and cisplatin (p = 0.0220, 0.0075, 0.0024, 0.0161, 0.0452 respectively) exposure compared with the control group. Besides, the ratio of LC3-II/LC3-I was substantially higher in the mice treated by cisplatin (p = 0.0046) and noise (p = 0.0220) compared with the control group. CONCLUSIONS: Our findings demonstrated for the first time that noise and cisplatin exposure promoted apoptosis and autophagy in the hair cells of the cochleae. This study provides new insights into the mechanisms of noise- or cisplatin-induced hearing loss.

Pou4f3 gene mutation promotes autophagy and apoptosis of cochlear hair cells in cisplatin-induced deafness mice.

Pou4f3 plays an important role in the development of hair cells in the inner ear sensory epithelia. Autophagy is related to the auditory damage. However, the role and mechanism of Pou4f3 on drug-induced ototoxicity are incompletely understood. Hence, this study aimed to explore the effects of Pou4f3 on the apoptosis of cochlear hair cells (CHCs) and to explore whether autophagy was involved in this process. The cisplatin was used to produce a loss of CHCs to create a murine model of deafness. The AAV vectors were delivered into the scala media through the lateral wall. Compared with the control mice, the cisplatin-treated mice exhibited significantly enhanced apoptosis and autophagy in the cochleae, accompanied by a notably decreased Pou4f3 levels. Both mutation and knockdown of Pou4f3 promoted the apoptosis- and autophagy-related protein levels, and enhanced the cisplatin-induced levels of apoptosis- and autophagy-related proteins. Furthermore, the autophagy activator rapamycin promoted the apoptosis and autophagy in the cochlea. In addition, the autophagy inhibitor 3-MA overturned the promoting effect of Pou4f3 knockdown on the apoptosis and autophagy. Collectively, in cisplatin-induced deafness mice, the Pou4f3 gene mutation facilitated apoptosis of cochlear hair cells, at least partially, through inducing autophagy.

[Hemaorheology, Coagulation and Clinical Features of Malignant Lymphoma Combined with Venous Thromboembolism].

OBJECTIVE: To explore the hematological and clinical features of patients with malignant lymphoma (ML) combined with venous thromboembolism (VTE). METHODS: Sixty patients with ML combined with VTE in our hospital from May 2014 to May 2016 were enrolled in ML+VTE group, out of them 42 patients were males and 18 patients with females; another 60 patients with ML alone were enrolled in control group, out of them 43 patients were males and 17 patients females. The hematological, coagulation and clinical datas of all the patients were collected and then retrospectively analyzed. RESULTS: About 81.54% of the patients in ML+VTE group were found in Stage ⅢB-Ⅳ tumor, and about 66.67% patients were found after ML was diagnosed; about 85.00% were with deep vein thrombosis (DVT), 10.00% were with pulmonary embolism (PE), and 5.00% were complicated with both DVT and PE. Common DVT locations in 56.67% cases were the upper limb and the neck vein(56.67%); The total effective rate of the cases with DVT was 49.02%, and the rate of cases with PE was 14.29%, and 0 in the cases with both DVT and PE, the difference was statistically significant (χ2=72.650, P<0.001). Compared with the patients of control group, the levels of platelet aggregation, D-dimer, high cut blood viscosity, low cut blood viscosity, plasma viscosity, hematocrit, assembly index of erythrocyte, and rigidity index of erythrocyte were higher in patients of ML+VTE group (P<0.05), and APTT, erythrocy tesed imentation rate, deformability index of erythrocyte, and average velocity of blood flow were reduced, the differences were statistically significant (P<0.05). CONCLUSION: Hemaorheology and coagulation of patients with ML combined with VTE indicate changes in the sensitivity state of thromboembolism; DVT, which is commonly manifested in the upper limb and the neck vein, and it mainly observed in patients with end-stage.

Alleviation of Toxicity Caused by Overactivation of Pparα through Pparα-Inducible miR-181a2.

Widely varied compounds, including certain plasticizers, hypolipidemic drugs (e.g., ciprofibrate, fenofibrate, WY-14643, and clofibrate), agrochemicals, and environmental pollutants, are peroxisome proliferators (PPs). Appropriate dose of PPs causes a moderate increase in the number and size of peroxisomes and the expression of genes encoding peroxisomal lipid-metabolizing enzymes. However, high-dose PPs cause varied harmful effects. Chronic administration of PPs to mice and rats results in hepatomegaly and ultimately carcinogenesis. Nuclear receptor protein peroxisome proliferator-activated receptor-α (Pparα) was shown to be required for this process. However, biological adaptations to minimize this risk are poorly understood. In this study, we found that miR-181a2 expression was induced by the Pparα agonist WY-14643. Moreover, exogenous expression of miR-181a-5p dramatically alleviated the cell toxicity caused by overactivation of Pparα. Further studies showed that miR-181a-5p directly targeted the Pparα 3' untranslated region and depressed the Pparα protein level. This study identified a feedback loop between miR-181a-5p and Pparα, which allows biological systems to approach a balance when Pparα is overactivated.