Localized self-assembly of macroscopically structured supramolecular hydrogels through reaction-diffusion.

Localized molecular self-assembly has been developed as an effective approach for the fabrication of spatially resolved supramolecular hydrogels, showing great potential for many high-tech applications. However, the fabrication of macroscopically structured supramolecular hydrogels through molecular self-assembly remains a challenge. Herein, we report on localized self-assembly of low molecular weight hydrogelators through a simple reaction-diffusion approach, giving rise to various macroscopically patterned supramolecular hydrogels. This is achieved on the basis of an acid-catalyzed hydrazone supramolecular hydrogelator system. The acid was pre-loaded in a polydimethylsiloxane (PDMS) substrate, generating a proton gradient in the vicinity of the PDMS surface after immersing the PDMS in the aqueous solution of the hydrogelator precursors. The acid dramatically accelerates the in situ formation and self-assembly of the hydrazone hydrogelators, leading to localized formation of supramolecular hydrogels. The growth rate of the supramolecular hydrogels can be easily tuned through controlling the concentrations of the hydrogelator precursors and HCl. Importantly, differently shaped supramolecular hydrogel objects can be obtained by simply changing the shapes of PDMS. This work suggests that reaction-diffusion-mediated localized hydrogelation can serve as an approach towards macroscopically structuralized supramolecular hydrogels, which may find potential applications ranging from tissue engineering to biosensors.

Injectable temperature-sensitive hydrogel facilitating endoscopic submucosal dissection.

Purpose: Early gastrointestinal tumors can be removed by endoscopic procedures. Endoscopic mucosal dissection (ESD) requires submucosal fluid injection to provide mucosal elevation and prevent intraoperative perforation. However, the clinically applied normal saline mucosal elevation height is low for a short time, which often requires multiple intraoperative injections that increase the inconvenience and procedure time. In addition, recently researched submucosal injection materials (SIM) suffer from complex preparation, poor economy, and poor biocompatibility. Therefore, there is an urgent need for a new type of SIM that can provide long, safe and effective mucosal elevation in support of the endoscopic procedures. Methods: The FS hydrogel is based on polyethylene-polypropylene glycol (F-127) mixed with sodium alginate (SA). The different physicochemical properties of FS hydrogels were characterized through various experiments. Afterward, various biosafety assessments were carried out. Finally, the performance of FS hydrogels was evaluated by in vitro submucosal injection and in vivo swine ESD. Results: The experimental results show that the FS hydrogel is liquid at room temperature, making it easy to inject, and when injected under the mucosa, it undergoes temperature-induced cross-linking, transforming from a liquid to a solid state to provide long-lasting mucosal augmentation. At the same time, the FS hydrogel exhibits controllable gelation, stability, and biocompatibility. The results of in vitro submucosal injections and in vivo ESD procedures showed that FS achieves high mucosal augmentation and provides good submucosal cushioning in the long term. Conclusion: In summary, the F-127/SA hydrogel is simple to synthesize, cost-effective, safe, easy to store, and able to assist ESD well from the perspective of practical clinical problems, indicating that the FS hydrogel can be an ideal potent submucosal injection substitution.

Facile Electret-Based Self-Powered Soft Sensor for Noncontact Positioning and Information Translation.

Noncontact sensors have demonstrated significant potential in human-machine interactions (HMIs) in terms of hygiene and less wear and tear. The development of soft, stable, and simply structured noncontact sensors is highly desired for their practical applications in HMIs. This work reports on electret-based self-powered noncontact sensors that are soft, transparent, stable, and easy to manufacture. The sensors contain a three-layer structure with a thickness of 0.34 mm that is fabricated by simply stacking a polymeric electret layer, an electrode layer, and a substrate layer together. The fabricated sensors show high charge-retention capability, keeping over 98% of the initial surface potential even after 90 h, and can accurately and repeatedly sense external approaching objects with impressive durability. The intensity of the detected signal shows a strong dependence on the distance between the object and the sensor, capable of sensing a distance as small as 2 mm. Furthermore, the sensors can report stable signals in response to external objects over 3000 cycles. By virtue of the signal dependence on distance, an intelligent noncontact positioning system is developed that can precisely detect the location of an approaching object. Finally, by integrating with eyeglasses, the transparent sensor successfully captures the movements of blinks for information translation. This work may contribute to the development of stable and easily manufactured noncontact soft sensors for HMI applications, for instance, assisting with communication for locked-in syndrome patients.

Spatial-temporal distribution characteristics of pulmonary tuberculosis in eastern China from 2011 to 2021.

China is still among the 30 high-burden tuberculosis (TB) countries in the world. Few studies have described the spatial epidemiological characteristics of pulmonary TB (PTB) in Jiangsu Province. The registered incidence data of PTB patients in 95 counties of Jiangsu Province from 2011 to 2021 were collected from the Tuberculosis Management Information System. Three-dimensional spatial trends, spatial autocorrelation, and spatial-temporal scan analysis were conducted to explore the spatial clustering pattern of PTB. From 2011 to 2021, a total of 347,495 newly diagnosed PTB cases were registered. The registered incidence rate of PTB decreased from 49.78/100,000 in 2011 to 26.49/100,000 in 2021, exhibiting a steady downward trend (χ2 = 414.22, P < 0.001). The average annual registered incidence rate of PTB was higher in the central and northern regions. Moran's I indices of the registered incidence of PTB were all >0 (P< 0.05) except in 2016, indicating a positive spatial correlation overall. Local autocorrelation analysis showed that 'high-high' clusters were mainly distributed in northern Jiangsu, and 'low-low' clusters were mainly concentrated in southern Jiangsu. The results of this study assist in identifying settings and locations of high TB risk and inform policy-making for PTB control and prevention.

Air pollutants in bronchoalveolar lavage fluid and pulmonary tuberculosis: A mediation analysis of gene-specific methylation.

Particulate matter (PM) exposure could alter the risk of tuberculosis, but the underlying mechanism is still unclear. We enrolled 132 pulmonary tuberculosis (PTB) patients and 30 controls. Bronchoalveolar lavage fluid samples were collected from all participants to detect organochlorine pesticides, polycyclic aromatic hydrocarbons, metal elements, and DNA methylation of immunity-related genes. We observed that γ-HCH, Bap, Sr, Ag, and Sn were related to an increased risk of PTB, while Cu and Ba had a negative effect. IFN-γ, IL-17A, IL-2, and IL-23 had a higher level in the PTB group, while IL-4 was lower. The methylation of 18 CpG sites was statistically associated with PTB risk. The methylation at the IL-4_06_121 site showed a significant mediating role on γ-HCH, Sr, and Sn. Our study suggests that PM exposure can increase the risk of tuberculosis by affecting DNA methylation and cytokine expression.

Alcohol degradation, learning, and memory-enhancing effect of Acetobacter pasteurianus BP2201 in Caenorhabditis elegans model.

AIMS: This study aimed to investigate the probiotic effects of Acetobacter pasteurianus BP2201, isolated from brewing mass, for the treatment of alcohol-induced learning and memory ability impairments in a Caenorhabditis elegans model. METHODS AND RESULTS: Acetobacter pasteurianus BP2201 was examined for probiotic properties, including acid and bile salt resistance, ethanol degradation, antioxidant efficacy, hemolytic activity, and susceptibility to antibiotics. The strain displayed robust acid and bile salt tolerance, efficient ethanol degradation, potent antioxidant activity, and susceptibility to specific antibiotics. Additionally, in the C. elegans model, administering A. pasteurianus BP2201 significantly improved alcohol-induced learning and memory impairments. CONCLUSIONS: Acetobacter pasteurianus BP2201 proves to be a promising candidate strain for the treatment of learning and memory impairments induced by alcohol intake.

Coupling coefficient calculation and optimization of positive rectangular series coils in wireless power transfer systems.

In wireless power transfer (WPT) systems using magnetic coupling resonance, when there is a registration deviation between the transmitting and receiving coils, there will be significant fluctuations in the coupling coefficient, output power, and transmission efficiency, which will seriously affect the stability of the WPT system. The coupling coefficient is related to the length and width of the rectangular coil, number of turns, mutual geometric position, and space magnetic medium, making it difficult to maintain a constant value when the coil is offset. A single-emitter two-receiver positive-series rectangular coils structure and a method of calculating the structure are proposed. Then an optimization method for mutual inductance was proposed, and the structural parameters that met the design requirements were obtained using the proposed optimization method. The calculation formula for coupling coefficient was verified through simulation and experiments. The results showed that when the offset distance of the receiving coil along the Y-axis (driving direction) and X-axis reaches half of the length of the transmitting coil and 10 cm, the coupling coefficient, transmission efficiency, and output power remain almost unchanged.

Carnitine palmitoyltransferase 1A promotes mitochondrial fission by enhancing MFF succinylation in ovarian cancer.

Mitochondria are dynamic organelles that are important for cell growth and proliferation. Dysregulated mitochondrial dynamics are highly associated with the initiation and progression of various cancers, including ovarian cancer. However, the regulatory mechanism underlying mitochondrial dynamics is still not fully understood. Previously, our study showed that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer cells and promotes the development of ovarian cancer. Here, we find that CPT1A regulates mitochondrial dynamics and promotes mitochondrial fission in ovarian cancer cells. Our study futher shows that CPT1A regulates mitochondrial fission and function through mitochondrial fission factor (MFF) to promote the growth and proliferation of ovarian cancer cells. Mechanistically, we show that CPT1A promotes succinylation of MFF at lysine 302 (K302), which protects against Parkin-mediated ubiquitin-proteasomal degradation of MFF. Finally, the study shows that MFF is highly expressed in ovarian cancer cells and that high MFF expression is associated with poor prognosis in patients with ovarian cancer. MFF inhibition significantly inhibits the progression of ovarian cancer in vivo. Overall, CPT1A regulates mitochondrial dynamics through MFF succinylation to promote the development of ovarian cancer. Moreover, our findings suggest that MFF is a potential therapeutic target for ovarian cancer.

Proteomic Portrait of Human Lymphoma Reveals Protein Molecular Fingerprint of Disease Specific Subtypes and Progression.

An altered proteome in lymph nodes often suggests abnormal signaling pathways that may be associated with diverse lymphatic disorders. Current clinical biomarkers for histological classification of lymphomas have encountered many discrepancies, particularly for borderline cases. Therefore, we launched a comprehensive proteomic study aimed to establish a proteomic landscape of patients with various lymphatic disorders and identify proteomic variations associated with different disease subgroups. In this study, 109 fresh-frozen lymph node tissues from patients with various lymphatic disorders (with a focus on Non-Hodgkin's Lymphoma) were analyzed by data-independent acquisition mass spectrometry. A quantitative proteomic landscape was comprehensively characterized, leading to the identification of featured protein profiles for each subgroup. Potential correlations between clinical outcomes and expression profiles of signature proteins were also probed. Two representative signature proteins, phospholipid-binding proteins Annexin A6 (ANXA6) and Phospholipase C Gamma 2 (PLCG2), were successfully validated via immunohistochemistry. We also evaluated the capability of acquired proteomic signatures to segregate multiple lymphatic abnormalities and identified several core signature proteins, such as Sialic Acid Binding Ig Like Lectin 1 (SIGLEC1) and GTPase of immunity-associated protein 5 (GIMAP5). In summary, the established lympho-specific data resource provides a comprehensive map of protein expression in lymph nodes during multiple disease states, thus extending the existing human tissue proteome atlas. Our findings will be of great value in exploring protein expression and regulation underlying lymphatic malignancies, while also providing novel protein candidates to classify various lymphomas for more precise medical practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00075-w.

Effects of short-term PM2.5 exposure on blood lipids among 197,957 people in eastern China.

Globally, air pollution is amongst the most significant causes of premature death. Nevertheless, studies on the relationship between fine particulate matter (PM2.5) exposure and blood lipids have typically not been population-based. In a large, community-based sample of residents in Yixing city, we assessed the relationship between short-term outdoor PM2.5 exposure and blood lipid concentrations. Participants who attended the physical examination were enrolled from Yixing People's hospital from 2015 to 2020. We collected general characteristics of participants, including gender and age, as well as test results of indicators of blood lipids. Data on daily meteorological factors were collected from the National Meteorological Data Sharing Center ( http://data.cma.cn/ ) and air pollutant concentrations were collected from the China Air Quality Online Monitoring and Analysis Platform ( https://www.aqistudy.cn/ ) during this period. We applied generalized additive models to estimate short-term effects of ambient PM2.5 exposure on each measured blood lipid-related indicators and converted these indicators into dichotomous variables (non- hyperlipidemia and hyperlipidemia) to calculate risks of hyperlipidemia associated with PM2.5 exposure. A total of 197,957 participants were included in the analysis with mean age 47.90 years (± SD, 14.28). The increase in PM2.5 was significantly associated with hyperlipidemia (odds ratio (OR) 1.003, 95% CI 1.001-1.004), and it was still significant in subgroups of males and age < 60 years. For every 10 µg/m3 increase in PM2.5, triglyceride levels decreased by 0.5447% (95% CI - 0.7873, - 0.3015), the low-density lipoprotein cholesterol concentration increased by 0.0127 mmol/L (95% CI 0.0099, 0.0156), the total cholesterol concentration increased by 0.0095 mmol/L (95% CI 0.0053, 0.0136), and no significant association was observed between PM2.5 and the high-density lipoprotein cholesterol concentration. After excluding people with abnormal blood lipid concentrations, the associations remained significant except for the high-density lipoprotein cholesterol concentration. PM2.5 was positively correlated with low-density lipoprotein cholesterol and total cholesterol, and negatively correlated with triglyceride, indicating PM2.5 can potentially affect health through blood lipid levels.

Environment pollutants exposure affects the endogenous activation of within-host Mycobacterium tuberculosis.

OBJECTIVE: Epidemiological studies have linked ambient pollutants with tuberculosis (TB) risk, but the association has not been fully understood. Here, for the first time, we applied whole-genome sequencing (WGS) to assess the reproductive state of Mycobacterium tuberculosis (MTB) by profiling the mutation rate of MTB (MTBMR) during within-host endogenous reactivated progression, intending to dissect the actual effects of ambient pollutants on the endogenous reactivation. METHODS: We conducted a retrospective cohort study on bacteriologically confirmed TB patients and followed them for relapse in Jiangsu and Sichuan Province, China. Endogenous and exogenous activation were distinguished by WGS of the pathogen. The average concentration of air pollution was estimated by considering a lag of 0-1 to 0-12 months. We applied a generalized additive model with a Poisson function to evaluate the relationships between ambient pollutants exposure and MTBMR. RESULTS: In the single-pollutant adjusted models, the maximum effect for PM10 (MTBMR increase: 81.87%, 95% CI: 38.38, 139.03) and PM2.5 (MTBMR increase: 73.91%, 95% CI: 22.17, 147.55) was observed at a lag of 0-12 months for every 10 µg/m³ increase. For SO2, the maximum effect was observed at lag 0-8 months, with MTBMR increasing by 128.06% (95% CI: 45.92, 256.44); and for NO2, the maximum effect was observed at lag 0-9 months, with MTBMR increasing by 124.02% (95% CI: 34.5, 273.14). In contrast, the O3 concentration was inversely associated with MTBMR, and the maximum reduction of MTBMR was 6.18% (95% CI: -9.24, -3.02) at a lag of 0-9 months. Similar results were observed for multi-pollutant models. CONCLUSIONS: Increased exposure to ambient pollutants (PM10, PM2.5, SO2, and NO2) contributed to a faster MTBMR, indicating that MTB exhibits increased reproductive activity, thus accelerating within-host endogenous reactivation. O3 exposure could decrease the MTBMR, suggesting that MTB exerts low reproductive activity by inhibiting within-host endogenous activation.

An optofluidic platform for interrogating chemosensory behavior and brainwide neural representation in larval zebrafish.

Studying chemosensory processing desires precise chemical cue presentation, behavioral response monitoring, and large-scale neuronal activity recording. Here we present Fish-on-Chips, a set of optofluidic tools for highly-controlled chemical delivery while simultaneously imaging behavioral outputs and whole-brain neuronal activities at cellular resolution in larval zebrafish. These include a fluidics-based swimming arena and an integrated microfluidics-light sheet fluorescence microscopy (µfluidics-LSFM) system, both of which utilize laminar fluid flows to achieve spatiotemporally precise chemical cue presentation. To demonstrate the strengths of the platform, we used the navigation arena to reveal binasal input-dependent behavioral strategies that larval zebrafish adopt to evade cadaverine, a death-associated odor. The µfluidics-LSFM system enables sequential presentation of odor stimuli to individual or both nasal cavities separated by only ~100 µm. This allowed us to uncover brainwide neural representations of cadaverine sensing and binasal input summation in the vertebrate model. Fish-on-Chips is readily generalizable and will empower the investigation of neural coding in the chemical senses.

COP1 Mediates Dark-Induced Stomatal Closure by Suppressing FT, TSF and SOC1 Expression to Promote NO Accumulation in Arabidopsis Guard Cells.

RING-finger-type ubiquitin E3 ligase Constitutively Photomorphogenic 1 (COP1) and floral integrators such as FLOWERING LOCUS T (FT), TWIN SISTER OF FT (TSF) and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) have been identified as regulators of stomatal movement. However, little is known about their roles and relationship in dark-induced stomatal closure. Here, we demonstrated that COP1 is required for dark-induced stomatal closure using cop1 mutant. The cop1 mutant closed stomata in response to exogenous nitric oxide (NO) but not hydrogen peroxide (H2O2), and H2O2 but not NO accumulated in cop1 in darkness, further indicating that COP1 acts downstream of H2O2 and upstream of NO in dark-induced stomatal closure. Expression of FT, TSF and SOC1 in wild-type (WT) plants decreased significantly with dark duration time, but this process was blocked in cop1. Furthermore, ft, tsf, and soc1 mutants accumulated NO and closed stomata faster than WT plants in response to darkness. Altogether, our results indicate that COP1 transduces H2O2 signaling, promotes NO accumulation in guard cells by suppressing FT, TSF and SOC1 expression, and consequently leads to stomatal closure in darkness. These findings add new insights into the mechanisms of dark-induced stomatal closure.

Differential Alterations in Striatal Direct and Indirect Pathways Mediate Two Autism-like Behaviors in Valproate-Exposed Mice.

Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although recent studies implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, here we revealed coexisting and opposite morphologic and functional alterations in the dorsostriatal direct and indirect pathways, and such alterations in these two pathways were found to be responsible, respectively, for the two abovementioned different autism-like behaviors exhibited by male mice prenatally exposed to valproate. The alteration in direct pathway was characterized by a potentiated state of basal activity, with impairment in transient responsiveness of D1-MSNs during social exploration. Concurrent alteration in indirect pathway was a depressed state of basal activity, with enhancement in transient responsiveness of D2-MSNs during repetitive behaviors. A causal relationship linking such differential alterations in these two pathways to the coexistence of these two autism-like behaviors was demonstrated by the cell type-specific correction of abnormal basal activity in the D1-MSNs and D2-MSNs of valproate-exposed mice. The findings support those differential alterations in two striatal pathways mediate the two coexisting autism-like behavioral abnormalities, respectively. This result will help in developing therapeutic options targeting these circuit alterations.SIGNIFICANCE STATEMENT Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although a number of recent studies have implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, but social behaviors need to be processed by a series of actions, and repetitive behaviors, especially the high-order repetitive behaviors such as restrictive interests, have its scope to cognitive and emotional domains. The current study, for the first time, revealed that prenatal valproate exposure induced coexisting and differential alterations in the dorsomedial striatal direct and indirect pathways, and that these alterations mediate the two coexisting autism-like behavioral abnormalities, respectively. This result will help in developing therapeutic options targeting these circuit alterations to address the behavioral abnormalities.

GCR1 Positively Regulates UV-B- and Ethylene-Induced Stomatal Closure via Activating GPA1-Dependent ROS and NO Production.

Heterotrimeric G proteins function as key players in guard cell signaling to many stimuli, including ultraviolet B (UV-B) and ethylene, but whether guard cell G protein signaling is activated by the only one potential G protein-coupled receptor, GCR1, is still unclear. Here, we found that gcr1 null mutants showed defects in UV-B- and ethylene-induced stomatal closure and production of reactive oxygen species (ROS) and nitric oxide (NO) in guard cells, but these defects could be rescued by the application of a Gα activator or overexpression of a constitutively active form of Gα subunit GPA1 (cGPA1). Moreover, the exogenous application of hydrogen peroxide (H2O2) or NO triggered stomatal closure in gcr1 mutants and cGPA1 transgenic plants in the absence or presence of UV-B or ethylene, but exogenous ethylene could not rescue the defect of gcr1 mutants in UV-B-induced stomatal closure, and gcr1 mutants did not affect UV-B-induced ethylene production in Arabidopsis leaves. These results indicate that GCR1 positively controls UV-B- and ethylene-induced stomatal closure by activating GPA1-dependent ROS and NO production in guard cells and that ethylene acts upstream of GCR1 to transduce UV-B guard cell signaling, which establishes the existence of a classic paradigm of G protein signaling in guard cell signaling to UV-B and ethylene.

Preoperative Thyroid Peroxidase Antibody Predicts Recurrence in Papillary Thyroid Carcinoma: A Consecutive Study With 5,770 Cases.

Background: Thyroid autoimmunity is common in papillary thyroid carcinoma (PTC) and was believed to confer a better prognosis; however, controversy still remains. This study aimed to investigate the prognostic value of chronic lymphocytic thyroiditis (CLT) and preoperative thyroid peroxidase antibody (TPOAb) in PTC patients. Methods: A retrospective analysis was performed on 5,770 PTC patients who underwent surgical treatment with pathologically confirmed PTC in our institution between 2012 to 2016. The patients were divided into groups with respect to the coexistence of CLT or preoperative TPOAb levels. The clinicopathological characteristics and disease-free survival (DFS) rates were compared between the groups. Results: The coexistence of CLT was likely to have bilateral, multifocal tumors. Particularly, PTC patients with TPOAb++ (>1,000 IU/L) had a larger tumor size (p = 0.007) and higher rates of bilaterality and multifocality than those with TPOAb- (TPOAb< 100 IU/L), while for lymph node metastasis and extrathyroidal extension, there is no statistical difference. Tumor recurrence was found in 15 of 425 (3.5%), 9 of 436 (2.1%), and 56 of 3,519 (1.6%) patients with TPOAb++, TPOAb+, and TPOAb-, respectively (p = 0.017). On univariate analysis, TPOAb++ was correlated with tumor recurrence, with a hazard ratio of 2.20 [95% confidence interval (CI), 1.25-3.89], which remained as an independent risk factor at 1.98 (95% CI, 1.10-3.55) on multivariate analysis. PTC patients with TPOAb++ had the lowest DFS rates (96.5 vs. 97.9 vs. 98.4%, p = 0.020). Conclusion: CLT is not a protective factor in PTC patients. We provide initial evidence that the preoperative TPOAb instead predicts recurrence in papillary thyroid carcinoma.

Efficacy and safety of neoadjuvant sintilimab, oxaliplatin and capecitabine in patients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: early results of a phase 2 study.

Immune checkpoint inhibitors have greatly improved the prognoses of diverse advanced malignancies, including gastric and gastroesophageal junction (G/GEJ) cancer. However, the role of anti-programmed cell death protein-1 treatment in the neoadjuvant setting remains unclear. This phase 2 study aimed to evaluate sintilimab plus CapeOx as a neoadjuvant regimen in patients with advanced resectable G/GEJ adenocarcinoma. Eligible patients with resectable G/GEJ adenocarcinoma stage cT3-4NanyM0 were enrolled. Patients received neoadjuvant treatment with sintilimab (3 mg/kg for cases <60 kg or 200 mg for those ≥60 kg on day 1) plus CapeOx (oxaliplatin at 130 mg/m2 on D1 and capecitabine at 1000 mg/m2 two times per day on D1-D14) every 21 days, for three cycles before surgical resection, followed by adjuvant treatment with three cycles of CapeOx with the same dosages after surgical resection. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included objective response rate, tumor regression grade per Becker criteria, survival and safety. As of July 30, 2020, 36 patients were enrolled. Totally 7 (19.4%) patients had GEJ cancer, and 34 (94.4%) patients were clinical stage III cases. A total of 35 (97.2%) patients completed three cycles of neoadjuvant treatment, and 1 patients received two cycles due to adverse events. All patients underwent surgery and the R0 resection rate was 97.2%. In this study, pCR and major pathological response were achieved in 7 (19.4%, 95% CI: 8.8% to 35.7%; 90% CI: 10.7% to 33.1%) and 17 (47.2%, 95% CI: 31.6% to 64.3%) patients, respectively. Thirty-one patients received adjuvant treatment. By December 20, 2021, three patients died after disease relapse, and two patients were alive with relapse. Median disease-free survival (DFS) and overall survival (OS) were not reached. The 1-year DFS and OS rates were 90.3% (95% CI: 80.4% to 100.0%) and 94.1% (95% CI: 86.5% to 100.0%), respectively. The most common (>1 patient) grade 3 treatment-related adverse events during neoadjuvant treatment were anemia and neutropenia (n=5 each, 13.9%). No serious adverse events (AEs) or grade 4-5 AEs were observed. Sintilimab plus oxaliplatin/capecitabine showed promising efficacy with encouraging pCR rate and good safety profile in the neoadjuvant setting. This combination regimen might present a new option for patients with locally advanced, resectable G/GEJ adenocarcinoma. Trial registration; NCT04065282.

Progranulin promotes hippocampal neurogenesis and alleviates anxiety-like behavior and cognitive impairment in adult mice subjected to cerebral ischemia.

AIMS: Cerebral ischemia can lead to anxiety and cognitive impairment due to the loss of hippocampal neurons. Facilitation of endogenous neurogenesis in the hippocampus is a potential therapeutic strategy for alleviating ischemia-induced anxiety and cognitive impairment. Progranulin (PGRN), a secretory glycoprotein, has been reported to have a mitogentic effect on many cell types. However, it is not clear whether PGRN enhances hippocampal neurogenesis and promotes functional recovery. METHODS: Adult male C57BL/6 mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and injected intracerebroventricularly with recombinant mouse PGRN 30 min after pMCAO. Anxiety-like behavior was detected by the open field and the elevated plus maze tests, and spatial learning and memory abilities were evaluated by Morris water maze. Neurogenesis was examined by double labeling of BrdU and neural stem cells or neurons markers. For mechanism studies, the level of ERK1/2 and AKT phosphorylation were assessed by western blotting. RESULTS: Progranulin significantly alleviated anxiety-like behavior and spatial learning and memory impairment induced by cerebral ischemia in mice. Consistent with the functional recovery, PGRN promoted neural stem cells (NSCs) proliferation and neuronal differentiation in the dentate gyrus (DG) after cerebral ischemia. PGRN upregulated the expression of phosphorylated ERK1/2 and Akt in the DG after cerebral ischemia. CONCLUSIONS: Progranulin alleviates ischemia-induced anxiety-like behavior and spatial learning and memory impairment in mice, probably via stimulation of hippocampal neurogenesis mediated by activation of MAPK/ERK and PI3K/Akt pathways. PGRN might be a promising candidate for coping with ischemic stroke-induced mood and cognitive impairment in clinic.