Nicotinamide mononucleotide enhances fracture healing by promoting skeletal stem cell proliferation.

The process of skeletal regeneration initiated by stem cells following injury, especially in fractures, is significantly impaired by aging and adverse factors. Nicotinamide mononucleotide (NMN), a critical endogenous precursor of nicotinamide adenine dinucleotide (NAD), has garnered extensive attention for its multifaceted regulatory functions in living organisms and its wide-ranging therapeutic potential. However, whether NMN contributes to trauma-induced skeletal regeneration remains unclear. Methods: The transverse femoral shaft fracture model was employed to evaluate the potential advantages of NMN administration for overall repair during the initial fracture stages in male mice through micro-CT analysis, histochemistry, and biomechanical testing. The pro-proliferative function of NMN on skeletal stem cells (SSCs) was investigated through flow cytometry, qRT-PCR, NAD content measurement, and cell proliferation assay. Results: In this study, we observed that the administration of NMN during the initial phase of fracture in mice led to a larger callus and corresponding improvement in micro-CT parameters. NMN enhances the cartilaginous component of the callus by elevating the NAD content, consequently accelerating subsequent endochondral ossification and the fracture healing process. Subsequent analyses elucidated that NMN was beneficial in promoting the expansion of diverse stem cells in vivo and in vitro potentially via modulation of the Notch signaling pathway. Moreover, the depletion of macrophages profoundly obstructs the proliferation of SSCs. Conclusion: Our discoveries provide a potential strategy for enhancing fracture healing through stimulation of callus SSC proliferation at an early stage, shedding light on the translational value of NMN as an enhancer for skeletal regeneration and highlighting the pivotal role of macrophage-stem cell interactions in governing the regenerative influence of NMN on stem cells.

Modifications in the Composition of the Gut Microbiota in Rats Induced by Chronic Sleep Deprivation: Potential Relation to Mental Disorders.

Introduction: Sleep deprivation(SD) has numerous negative effects on mental health. A growing body of research has confirmed the implication of gut microbiota in mental disorders. However, the specific modifications in mammalian gut microbiota following SD exhibit variations across different studies. Methods: Male specific-pathogen-free Wistar rats were given a modified multiple-platform exposure for 7 days of SD. Fecal samples were obtained from the control and SD groups both at baseline and after 7 days of SD. We utilized 16S rDNA gene sequencing to investigate the gut microbial composition and functional pathways in rats. Results: Analysis of the microbiota composition revealed a significant change in gut microbial composition after chronic SD, especially at the phylum level. The relative abundances of p_Firmicutes, g_Romboutsia, and g_Enterococcus increased, whereas those of p_Bacteroidetes, p_Verrucomicrobia, p_Fusobacteria, g_Akkermansia, and g_Cetobacterium decreased in animals after chronic SD compared with controls or animals before SD. The ratio of Firmicutes to Bacteroidetes exhibited an increase following SD. The relative abundance of gut microbiota related to the functional pathways of GABAergic and glutamatergic synapses was observed to be diminished in rats following SD compared to pre-SD. Conclusion: Collectively, these findings suggest that chronic SD causes significant alterations in both the structural composition and functional pathways of the gut microbiome. Further researches are necessary to investigate the chronological and causal connections among SD, the gut microbiota and mental disorders.

Ultraflat single-crystal hexagonal boron nitride for wafer-scale integration of a 2D-compatible high-κ metal gate.

Hexagonal boron nitride (hBN) has emerged as a promising protection layer for dielectric integration in the next-generation large-scale integrated electronics. Although numerous efforts have been devoted to growing single-crystal hBN film, wafer-scale ultraflat hBN has still not been achieved. Here, we report the epitaxial growth of 4 in. ultraflat single-crystal hBN on Cu0.8Ni0.2(111)/sapphire wafers. The strong coupling between hBN and Cu0.8Ni0.2(111) suppresses the formation of wrinkles and ensures the seamless stitching of parallelly aligned hBN domains, resulting in an ultraflat single-crystal hBN film on a wafer scale. Using the ultraflat hBN as a protective layer, we integrate the wafer-scale ultrathin high-κ dielectrics onto two-dimensional (2D) materials with a damage-free interface. The obtained hBN/HfO2 composite dielectric exhibits an ultralow current leakage (2.36 × 10-6 A cm-2) and an ultrathin equivalent oxide thickness of 0.52 nm, which meets the targets of the International Roadmap for Devices and Systems. Our findings pave the way to the synthesis of ultraflat 2D materials and integration of future 2D electronics.

Insulin-Induced Gene 1-Enhance Secretion of BMSC Exosome Enriched in miR-132-3p Promoting Wound Healing in Diabetic Mice.

Chronic diabetic wounds represent a significant clinical challenge because of impaired healing processes, which require innovative therapeutic strategies. This study explores the therapeutic efficacy of insulin-induced gene 1-induced bone marrow mesenchymal stem cell exosomes (Insig1-exos) in promoting wound healing in diabetic mice. We demonstrated that Insig1 enhanced the secretion of bone marrow mesenchymal stem cell-derived exosomes, which are enriched with miR-132-3p. Through a series of in vitro and in vivo experiments, these exosomes significantly promoted the proliferation, migration, and angiogenesis of dermal fibroblasts under high-glucose conditions. They also regulated key wound-healing factors, including matrix metalloproteinase-9, platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor-ß1, and platelet endothelial cell adhesion molecule-1, thereby accelerating wound closure in diabetic mice. Histological analysis showed that Insig1-exos were more effective in promoting epithelialization, enhancing collagen deposition, and reducing inflammation. Additionally, inhibition of miR-132-3p notably diminished these therapeutic effects, underscoring its pivotal role in the wound-healing mechanism facilitated by Insig1-exos. This study elucidates the molecular mechanisms through which Insig1-exos promotes diabetic wound healing, highlighting miR-132-3p as a key mediator. These findings provide new strategies and theoretical foundations for treating diabetes-related skin injuries.

Self-assembled superstructure alleviates air-water interface effect in cryo-EM.

Cryo-electron microscopy (cryo-EM) has been widely used to reveal the structures of proteins at atomic resolution. One key challenge is that almost all proteins are predominantly adsorbed to the air-water interface during standard cryo-EM specimen preparation. The interaction of proteins with air-water interface will significantly impede the success of reconstruction and achievable resolution. Here, we highlight the critical role of impenetrable surfactant monolayers in passivating the air-water interface problems, and develop a robust effective method for high-resolution cryo-EM analysis, by using the superstructure GSAMs which comprises surfactant self-assembled monolayers (SAMs) and graphene membrane. The GSAMs works well in enriching the orientations and improving particle utilization ratio of multiple proteins, facilitating the 3.3-Å resolution reconstruction of a 100-kDa protein complex (ACE2-RBD), which shows strong preferential orientation using traditional specimen preparation protocol. Additionally, we demonstrate that GSAMs enables the successful determinations of small proteins (<100 kDa) at near-atomic resolution. This study expands the understanding of SAMs and provides a key to better control the interaction of protein with air-water interface.

Pathophysiological role of ion channels and transporters in hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) has continued to increase annually worldwide, and HCC has become a common cause of cancer-related death. Despite great progress in understanding the molecular mechanisms underlying HCC development, the treatment of HCC remains a considerable challenge. Thus, the survival and prognosis of HCC patients remain extremely poor. In recent years, the role of ion channels in the pathogenesis of diseases has become a hot topic. In normal liver tissue, ion channels and transporters maintain water and electrolyte balance and acid‒base homeostasis. However, dysfunction of these ion channels and transporters can lead to the development and progression of HCC, and thus these ion channels and transporters are expected to become new therapeutic targets. In this review, ion channels and transporters associated with HCC are reviewed, and potential targets for new and effective therapies are proposed.

Traditional Chinese herbal formulas modulate gut microbiome and improve insomnia in patients with distinct syndrome types: insights from an interventional clinical study.

Background: Traditional Chinese medicine (TCM) comprising herbal formulas has been used for millennia to treat various diseases, such as insomnia, based on distinct syndrome types. Although TCM has been proposed to be effective in insomnia through gut microbiota modulation in animal models, human studies remain limited. Therefore, this study employs machine learning and integrative network techniques to elucidate the role of the gut microbiome in the efficacies of two TCM formulas - center-supplementing and qi-boosting decoction (CSQBD) and spleen-tonifying and yin heat-clearing decoction (STYHCD) - in treating insomnia patients diagnosed with spleen qi deficiency and spleen qi deficiency with stomach heat. Methods: Sixty-three insomnia patients with these two specific TCM syndromes were enrolled and treated with CSQBD or STYHCD for 4 weeks. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) every 2 weeks. In addition, variations in gut microbiota were evaluated through 16S rRNA gene sequencing. Stress and inflammatory markers were measured pre- and post-treatment. Results: At baseline, patients exhibiting only spleen qi deficiency showed slightly lesser severe insomnia, lower IFN-α levels, and higher cortisol levels than those with spleen qi deficiency with stomach heat. Both TCM syndromes displayed distinct gut microbiome profiles despite baseline adjustment of PSQI, ISI, and IFN-α scores. The nested stratified 10-fold cross-validated random forest classifier showed that patients with spleen qi deficiency had a higher abundance of Bifidobacterium longum than those with spleen qi deficiency with stomach heat, negatively associated with plasma IFN-α concentration. Both CSQBD and STYHCD treatments significantly improved sleep quality within 2 weeks, which lasted throughout the study. Moreover, the gut microbiome and inflammatory markers were significantly altered post-treatment. The longitudinal integrative network analysis revealed interconnections between sleep quality, gut microbes, such as Phascolarctobacterium and Ruminococcaceae, and inflammatory markers. Conclusion: This study reveals distinct microbiome profiles associated with different TCM syndrome types and underscores the link between the gut microbiome and efficacies of Chinese herbal formulas in improving insomnia. These findings deepen our understanding of the gut-brain axis in relation to insomnia and pave the way for precision treatment approaches leveraging TCM herbal remedies.

Research trends of bio-application of major components in lignocellulosic biomass (cellulose, hemicellulose and lignin) in orthopedics fields based on the bibliometric analysis: A review.

Cellulose, hemicellulose, and lignin are the major bio-components in lignocellulosic biomass (BC-LB), which possess excellent biomechanical properties and biocompatibility to satisfy the demands of orthopedic applications. To understand the basis and trends in the development of major bio-components in BC-LB in orthopedics, the bibliometric technology was applied to get unique insights based on the published papers (741) in the Web of Science (WOS) database from January 1st, 2001, to February 14th, 2023. The analysis includes the annual distributions of publications, keywords co-linearity, research hotspots exploration, author collaboration networks, published journals, and clustering of co-cited literature. The results reveal a steady growth in publications focusing on the application of BC-LB in orthopedics, with China and the United States leading in research output. The "International Journal of Biological Macromolecules" was identified as the most cited journal for BC-LB research in orthopedics. The research hotspots encompassed bone tissue engineering, cartilage tissue engineering, and drug delivery systems, indicating the fundamental research and potential development in these areas. This study also highlights the challenges associated with the clinical application of BC-LB in orthopedics and provides valuable insights for future advancements in the field.

Study on the Influence of Supercritical CO2 with High Temperature and Pressure on Pore-Throat Structure and Minerals of Shale.

Injection of carbon dioxide offers substantial social and economic advantages for reduction of carbon emission reduction. Utilizing CO2 in shale formations can significantly enhance the extraction of shale oil or gas. Conducting fundamental research on how CO2 affects shale rock's physical properties is crucial for enhancing its porosity and permeability. Particularly for deep shale layers, the effects of supercritical CO2 on shale physical properties should be investigated at a high temperature and pressure, differing from the standard conditions applied in shallower layers. A study examined the impact of supercritical CO2 under such conditions on the pore-throat structure and mineral composition of the shale. The experimental parameters included immersing shale rock in supercritical CO2 at pressures ranging from 10 to 70 MPa and temperatures between 55 and 95 °C. This study evaluated changes in mineral composition, pore-throat structure (using scanning electron microscopy and nitrogen adsorption tests), and the porosity and permeability of the shale rocks. Findings indicated that the dissolution of CO2 altered the relative content of certain minerals. The average quartz content rose and, potassium feldspar and the average contents of plagioclase declined conversely. When increasing the pressure, an increase in the relative content of I/S mixed layer and a decrease in illite content were observed and kaolinite content experienced minor changes. When increasing the temperature, kaolinite, I/S mixed layer, and chlorite all exhibited a decreasing trend with increasing temperature, while the relative contents of illite increased. Some of the pores become rounded in a high-magnification view under the impact of CO2 dissolution. Additionally, the Brunauer-Emmett-Teller specific surface area, pore volume, porosity, and permeability generally improved with increasing pressure and temperature. With the temperature and pressure of CO2 increased, the curves of nitrogen absorption had moved first upward and then downward. However, under specific CO2 conditions, the permeability enhancement effect could diminish or even negatively impact the shale's permeability. These findings underscore the need to optimize supercritical CO2 injection parameters under high-temperature and high-pressure conditions. This research aims to provide theoretical guidance for the efficient use of CO2 in deep shale applications to increase the shale gas output.

Association between chitinase-3-like protein 1 and metabolic-associated fatty liver disease in patients with type 2 diabetes mellitus.

BACKGROUND AND AIM: Early identification of liver fibrosis is essential for the prognosis of metabolic-associated fatty liver disease (MAFLD), particularly in type 2 diabetes mellitus (T2DM) patients. Here, we explored the association of chitinase-3-like protein 1 (CHI3L1) and liver fibrosis in T2DM-MAFLD patients. METHODS: Liver fibrosis was staged in T2DM-MAFLD patients, and a liver stiffness measurement (LSM) of ≥ 8 kPa was used to differentiate between non-significant (NSLF) and significant liver fibrosis (SLF) subgroups. The two subgroups were compared for serum CHI3L1 and other parameters. Linear correlation, logistic regression, and restricted cubic spline (RCS) analyses were performed to evaluate the association between CHI3L1 and liver fibrosis. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic accuracy of CHI3L1. RESULTS: Among T2DM-MAFLD, SLF patients had higher CHI3L1 compared to NSLF patients. CHI3L1 was found to be positively correlated with LSM. Multivariate logistic regression analysis suggested that CHI3L1 may be a potential independent risk factor for SLF. Further stratified analysis indicated that the odds ratios of SLF in the high CHI3L1 group were higher than in the low CHI3L1 group in the subgroups. RCS analysis suggested an increasing trend in the incidence of significant fibrosis with the rising level of CHI3L1. The area under the ROC curve for detecting significant fibrosis was 0.749 (95% CI: 0.668-0.829). CONCLUSIONS: Serum CHI3L1 demonstrates an association with significant liver fibrosis. High serum levels of CHI3L1 may indicate the existence of significant liver fibrosis in T2DM-MAFLD patients.

Engineered MgO nanoparticles for cartilage-bone synergistic therapy.

The emerging therapeutic strategies for osteoarthritis (OA) are shifting toward comprehensive approaches that target periarticular tissues, involving both cartilage and subchondral bone. This shift drives the development of single-component therapeutics capable of acting on multiple tissues and cells. Magnesium, an element essential for maintaining skeletal health, shows promise in treating OA. However, the precise effects of magnesium on cartilage and subchondral bone are not yet clear. Here, we investigated the therapeutic effect of Mg2+ on OA, unveiling its protective effects on both cartilage and bone at the cellular and animal levels. The beneficial effect on the cartilage-bone interaction is primarily mediated by the PI3K/AKT pathway. In addition, we developed poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with nano-magnesium oxide modified with stearic acid (SA), MgO&SA@PLGA, for intra-articular injection. These microspheres demonstrated remarkable efficacy in alleviating OA in rat models, highlighting their translational potential in clinical applications.

Alteration of serum bile acid profiles of HBV-related hepatocellular carcinoma identified by LC-MS/MS.

BACKGROUND: Hepatocellular carcinoma closely related to metabolic disorders is a common and aggressive liver malignancy. The dysregulation of bile acid homeostasis has emerged as a key factor for the development and progression of HCC. We aimed to investigate the relationship between bile acids and HCC diagnosis and progression. METHODS: A total of 744 HBV-related patients (including 396 HCC patients and 348 patients with chronic liver diseases) were enrolled in the current study. The baseline characteristics of patients were collected from electronic medical records, and the levels of bile acid profiles were determined by LC-MS/MS. Propensity score matching analysis was conducted to reduce the effect of selection bias, and receiver operating characteristic analysis was performed to evaluate the clinical application values of bile acid. RESULTS: Significant differences were observed for most characteristics between the HCC group and the CLD group before PSM analysis. Patients with HCC were older and fatter (p < 0.05). After adjusting with a 1:1 ratio for age, gender and BMI, 42 HCC patients and 42 non-HCC patients were matched in 2 groups, respectively. The total bile acid level in HCC patients was lower than that in patients with chronic liver diseases before and after PSM analysis (p < 0.05). However, patients with HCC had significantly higher levels of DCA, LCA, and GLCA and lower levels of TCDCA, GUDCA, and TUDCA (p < 0.05, respectively). Besides, the TCDCA, TUDCA, GLCA, and GUDCA were significantly correlated with tumor procession. Moreover, the BAs profiles had a superior predictive ability for predicting the development of HCC even in patients with low serum AFP levels. CONCLUSION: Patients with HCC had significantly lower levels of total bile acid, but higher levels of secondary bile acids (DCA, LCA, and GLCA). The levels of primary bile acid (TCDCA) were closely related to tumor size and stage, which indicated that the bile acids were involved in the HCC procession and had important clinical application values.

JMJD3 regulate H3K27me3 modification via interacting directly with TET1 to affect spermatogonia self-renewal and proliferation.

BACKGROUND: In epigenetic modification, histone modification and DNA methylation coordinate the regulation of spermatogonium. Not only can methylcytosine dioxygenase 1 (TET1) function as a DNA demethylase, converting 5-methylcytosine to 5-hydroxymethylcytosine, it can also form complexes with other proteins to regulate gene expression. H3K27me3, one of the common histone modifications, is involved in the regulation of stem cell maintenance and tumorigenesis by inhibiting gene transcription. METHODS: we examined JMJD3 at both mRNA and protein levels and performed Chip-seq sequencing of H3K27me3 in TET1 overexpressing cells to search for target genes and signaling pathways of its action. RESULTS: This study has found that JMJD3 plays a leading role in spermatogonia self-renewal and proliferation: at one extreme, the expression of the self-renewal gene GFRA1 and the proliferation-promoting gene PCNA was upregulated following the overexpression of JMJD3 in spermatogonia; at the other end of the spectrum, the expression of differentiation-promoting gene DAZL was down-regulated. Furthermore, the fact that TET1 and JMJD3 can form a protein complex to interact with H3K27me3 has also been fully proven. Then, through analyzing the sequencing results of CHIP-Seq, we found that TET1 targeted Pramel3 when it interacted with H3K27me3. Besides, TET1 overexpression not only reduced H3K27me3 deposition at Pramel3, but promoted its transcriptional activation as well, and the up-regulation of Pramel3 expression was verified in JMJD3-overexpressing spermatogonia. CONCLUSION: In summary, our study identified a novel link between TET1 and H3K27me3 and established a Tet1-JMJD3-H3K27me3-Pramel3 axis to regulate spermatogonia self-renewal and proliferation. Judging from the evidence offered above, we can safely conclude that this study provides new ideas for further research regarding the mechanism of spermatogenesis and spermatogenesis disorders on an apparent spectrum.

Osteocyte-derived sclerostin impairs cognitive function during ageing and Alzheimer's disease progression.

Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-ß-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-ß-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-ß-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid ß (Aß) production through ß-catenin-ß-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αß production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD.

Graphene sandwich-based biological specimen preparation for cryo-EM analysis.

High-quality specimen preparation plays a crucial role in cryo-electron microscopy (cryo-EM) structural analysis. In this study, we have developed a reliable and convenient technique called the graphene sandwich method for preparing cryo-EM specimens. This method involves using two layers of graphene films that enclose macromolecules on both sides, allowing for an appropriate ice thickness for cryo-EM analysis. The graphene sandwich helps to mitigate beam-induced charging effect and reduce particle motion compared to specimens prepared using the traditional method with graphene support on only one side, therefore improving the cryo-EM data quality. These advancements may open new opportunities to expand the use of graphene in the field of biological electron microscopy.

Intracellular chloride channel 1 and tumor.

As the major intracellular anion, chloride plays an important role in maintaining intracellular and extracellular ion homeostasis, osmotic pressure, and cell volume. Intracellular chloride channel 1, which has the physiological role of forming membrane proteins in the lipid bilayer and playing ion channels, is a hot research topic in recent years. It has been found that CLIC1 does not only act as an ion channel but also participates in cell cycle regulation, apoptosis, and intracellular oxidation; thus, it participates in the proliferation, invasion, and migration of various tumor cells in various systems throughout the body. At the same time, CLIC1 is highly expressed in tumor cells and is associated with malignancy and a poor prognosis. This paper reviews the pathological mechanisms of CLIC1 in systemic diseases, which is important for the early diagnosis, treatment, and prognosis of systemic diseases associated with CLIC1 expression.

Potassium channels as novel molecular targets in hepatocellular carcinoma (Review).

Hepatocellular carcinoma (HCC) poses a serious health burden worldwide. It is often not diagnosed until the patient is at an advanced stage of the disease, when treatment options are limited and the prognosis is poor. Therefore, novel treatment strategies are urgently required. Potassium (K+) channels have an important role in HCC, including regulating the proliferation, migration, invasion and drug resistance of HCC cells. The aim of the present review was therefore to survey the relevant publications that have investigated K+ channels not only as markers for the early diagnosis of HCC, but also as potential therapeutic targets for the treatment of HCC. Several of these channels have been indicated to be the sites of action for natural products previously known to inhibit HCC; however, more systematic studies are required to determine which K+ channels may be utilized for the clinical treatment of HCC, particularly in the advanced stages of the disease and in cases where patients are resistant to the existing drugs.

A potential tumor marker: Chaperonin containing TCP­1 controls the development of malignant tumors (Review).

Due to concealment, high invasiveness and a lack of indicators, malignant tumors have emerged as one of the deadliest diseases worldwide and their incidence is rising yearly. Research has revealed that the chaperonin family member, chaperonin containing TCP­1 (CCT), serves a crucial role in malignant tumors. CCT is involved in the growth of numerous malignant tumors such as lung cancer, breast cancer, hepatocellular carcinoma and colorectal cancer and assists the folding of a number of proteins linked to cancer, such as KRAS, p53 and STAT3. According to clinical data, CCT is highly expressed in a range of tumor cells and is associated with poor patient prognosis. In addition, through controlling the cell cycle or interacting with other proteins (including YAP1, HoXB2 and SMAD2), CCT has an effect on the proliferation, invasion and migration of cancer cells. As a result, it is possible that CCT will become a new tumor marker or therapeutic target, which will provide some guidance for early tumor screening or late tumor prognosis. In the present review, the molecular properties of CCT are introduced, alongside a summary of its interactions with other cancer­related proteins and a discussion of its function in common malignant tumors. It is expected that the present review will offer fresh approaches to the treatment of cancer.

Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial.

In this multicenter, single-arm phase 2 trial (ChiCTR1900024428), patients with locally advanced gastric/gastroesophageal junction cancers receive one cycle of sintilimab (anti-PD1) and chemotherapy (S-1 and nab-paclitaxel), followed by 5 weeks of concurrent chemoradiotherapy and sintilimab, and another cycle of sintilimab and chemotherapy thereafter. Surgery is preferably scheduled within one to three weeks, and three cycles of adjuvant sintilimab and chemotherapy are administrated. The primary endpoint is the pathological complete response. Our results meet the pre-specified primary endpoint. Thirteen of 34 (38.2%) enrolled patients achieve pathological complete response (95% CI: 22.2-56.4). The secondary objectives include disease-free survival (DFS), major pathological response, R0 resection rate, overall survival (OS), event-free survival (EFS), and safety profile. The median DFS and EFS were 17.0 (95%CI: 11.1-20.9) and 21.1 (95%CI: 14.7-26.1) months, respectively, while the median OS was not reached, and the 1-year OS rate was 92.6% (95%CI: 50.1-99.5%). Seventeen patients (50.0%) have grade ≥3 adverse events during preoperative therapy. In prespecified exploratory biomarker analysis, CD3+ T cells, CD56+ NK cells, and the M1/M1 + M2-like macrophage infiltration at baseline are associated with pathological complete response. Here, we show the promising efficacy and manageable safety profile of sintilimab in combination with concurrent chemoradiotherapy for the perioperative treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma.