Atlas of Metastatic Gastric Cancer Links Ferroptosis to Disease Progression and Immunotherapy Response.

BACKGROUND & AIMS: Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve patients with GAC poses a significant challenge, limiting the scope of current research, which has focused predominantly on localized tumors. This gap hinders deeper insight into the metastatic dynamics of GAC. METHODS: We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, using cell lines and multiple patient-derived xenograft and novel mouse models of GAC. RESULTS: Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of tumor microenvironment phenotypes, supporting the notion that cancer cells and their local tumor microenvironments co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 up-regulation during GAC progression. Conditional depletion of Gpx4 or pharmacologic inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. In addition, ferroptosis-resensitizing treatments augmented the efficacy of chimeric antigen receptor T-cell therapy. CONCLUSIONS: This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with chimeric antigen receptor T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.

CRISPR/Cas9-mediated generation of a mutant library of cotton CDPK gene family for identifying insect-resistant genes.

Calcium-dependent protein kinases (CDPKs) are pivotal signaling transduction enzymes in plants, especially responsive to diverse stress, including herbivory. In this study, through comprehensive analysis of CDPK gene family in upland cotton, we showed that GhCPKs are widely expressed in multiple tissues of cotton and positively respond to various biotic and abiotic stress. We developed a strategy for screening insect-resistant genes based on the CRISPR/Cas9 mutant library of GhCPKs. The library contains 82 members of the GhCPKs using 246 sgRNAs to generate 518 independent T0 plants. The coverage rate of target genes reached to 86.18%, the genome editing rate reached to 89.49%, and the editing heritability reached 82%. Through field insect bioassay, 14 GhCPK mutants resistant or susceptible to insect were identified. The most obvious insect-resistant mutant, cpk33/74 (simultaneously knocking out the homologous genes GhCPK33 and GhCPK74), was selected for further study. Oral secretions (OS) from Spodoptera litura induced a rapid influx of Ca2+ in cpk33/74 leaves, resulting in a significant increase in jasmonic acid (JA) content. S-adenosylmethionine synthase (SAMS) is an important protein involved in plant stress response, protein interaction experiments provided evidence of interactions between GhCPK33 and GhCPK74 with GhSAMS1 and GhSAM2, respectively. Additionally, silencing GhSAMS1 and GhSAM2 in cotton using VIGS resulted in decreased defense against S. litura. This study provides an effective strategy for constructing a mutant library of gene families in polyploid plant species and valuable insights into the role of CDPKs in the interaction between plants and herbivorous insects.

Three biomarkers (HER2, PD-L1, and microsatellite status) in a large cohort of metastatic gastroesophageal adenocarcinomas: The MD Anderson Cancer Center experience.

Human epidermal growth factor receptor-2 (HER2), programmed death-ligand 1 (PD-L1), and microsatellite (MS) status are well-established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD-L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis.

Objective measure of binaural processing: Acoustic change complex in response to interaural phase differences.

Combining cochlear implants with binaural acoustic hearing via preserved hearing in the implanted ear(s) is commonly referred to as combined electric and acoustic stimulation (EAS). EAS fittings can provide patients with significant benefit for speech recognition in complex noise, perceived listening difficulty, and horizontal-plane localization as compared to traditional bimodal hearing conditions with contralateral and monaural acoustic hearing. However, EAS benefit varies across patients and the degree of benefit is not reliably related to the underlying audiogram. Previous research has indicated that EAS benefit for speech recognition in complex listening scenarios and localization is significantly correlated with the patients' binaural cue sensitivity, namely interaural time differences (ITD). In the context of pure tones, interaural phase differences (IPD) and ITD can be understood as two perspectives on the same phenomenon. Through simple mathematical conversion, one can be transformed into the other, illustrating their inherent interrelation for spatial hearing abilities. However, assessing binaural cue sensitivity is not part of a clinical assessment battery as psychophysical tasks are time consuming, require training to achieve performance asymptote, and specialized programming and software all of which render this clinically unfeasible. In this study, we investigated the possibility of using an objective measure of binaural cue sensitivity by the acoustic change complex (ACC) via imposition of an IPD of varying degrees at stimulus midpoint. Ten adult listeners with normal hearing were assessed on tasks of behavioral and objective binaural cue sensitivity for carrier frequencies of 250 and 1000 Hz. Results suggest that 1) ACC amplitude increases with IPD; 2) ACC-based IPD sensitivity for 250 Hz is significantly correlated with behavioral ITD sensitivity; 3) Participants were more sensitive to IPDs at 250 Hz as compared to 1000 Hz. Thus, this objective measure of IPD sensitivity may hold clinical application for pre- and post-operative assessment for individuals meeting candidacy indications for cochlear implantation with low-frequency acoustic hearing preservation as this relatively quick and objective measure may provide clinicians with information identifying patients most likely to derive benefit from EAS technology.

SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel.

BACKGROUND: The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. This study aimed to examine the association of SMARCA4ms with clinical outcomes and co-occurrence with other gene mutations identified through a next-generation sequencing (NGS) panel in GEA patients. METHODS: A total of 256 patients with metastatic or recurrent GEA who underwent NGS panel profiling at the MD Anderson Cancer Center between 2016 and 2022 were included. Comparative analyses were performed to assess clinical outcomes related to SMARCA4ms. The frequency and types of SMARCA4ms and their co-occurrence with other gene mutations were also examined. RESULTS: SMARCA4ms were identified in 19 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046). No difference in survival between the SMARCA4m and SMARCA4-normal group was observed (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. CONCLUSIONS: These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA.

Comprehensive analysis of MAPK gene family in upland cotton (Gossypium hirsutum) and functional characterization of GhMPK31 in regulating defense response to insect infestation.

KEY MESSAGE: The transcriptomic, phenotypic and metabolomic analysis of transgenic plants overexpressing GhMPK31 in upland cotton revealed the regulation of H2O2 burst and the synthesis of defensive metabolites by GhMPK31. Mitogen-activated protein kinases (MAPKs) are a crucial class of protein kinases, which play an essential role in various biological processes in plants. Upland cotton (G. hirsutum) is the most widely cultivated cotton species with high economic value. To gain a better understanding of the role of the MAPK gene family, we conducted a comprehensive analysis of the MAPK gene family in cotton. In this study, a total of 55 GhMPK genes were identified from the whole genome of G. hirsutum. Through an investigation of the expression patterns under diverse stress conditions, we discovered that the majority of GhMPK family members demonstrated robust responses to abiotic stress, pathogen stress and pest stress. Furthermore, the overexpression of GhMPK31 in cotton leaves led to a hypersensitive response (HR)-like cell death phenotype and impaired the defense capability of cotton against herbivorous insects. Transcriptome and metabolomics data analysis showed that overexpression of GhMPK31 enhanced the expression of H2O2-related genes and reduced the accumulation of defensive related metabolites. The direct evidence of GhMPK31 interacting with GhRBOHB (H2O2-generating protein) were found by Y2H, BiFC, and LCI. Therefore, we propose that the increase of H2O2 content caused by overexpression of GhMPK31 resulted in HR-like cell death in cotton leaves while reducing the accumulation of defensive metabolites, ultimately leading to a decrease in the defense ability of cotton against herbivorous insects. This study provides valuable insights into the function of MAPK genes in plant resistance to herbivorous insects.

PixRevive: Latent Feature Diffusion Model for Compressed Video Quality Enhancement.

In recent years, the rapid prevalence of high-definition video in Internet of Things (IoT) systems has been directly facilitated by advances in imaging sensor technology. To adapt to limited uplink bandwidth, most media platforms opt to compress videos to bitrate streams for transmission. However, this compression often leads to significant texture loss and artifacts, which severely degrade the Quality of Experience (QoE). We propose a latent feature diffusion model (LFDM) for compressed video quality enhancement, which comprises a compact edge latent feature prior network (ELPN) and a conditional noise prediction network (CNPN). Specifically, we first pre-train ELPNet to construct a latent feature space that captures rich detail information for representing sharpness latent variables. Second, we incorporate these latent variables into the prediction network to iteratively guide the generation direction, thus resolving the problem that the direct application of diffusion models to temporal prediction disrupts inter-frame dependencies, thereby completing the modeling of temporal correlations. Lastly, we innovatively develop a Grouped Domain Fusion module that effectively addresses the challenges of diffusion distortion caused by naive cross-domain information fusion. Comparative experiments on the MFQEv2 benchmark validate our algorithm's superior performance in terms of both objective and subjective metrics. By integrating with codecs and image sensors, our method can provide higher video quality.

E-cadherin loss drives diffuse-type gastric tumorigenesis via EZH2-mediated reprogramming.

Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared with KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.

Mesothelial cells with mesenchymal features enhance peritoneal dissemination by forming a protumorigenic microenvironment.

Malignant ascites accompanied by peritoneal dissemination contain various factors and cell populations as well as cancer cells; however, how the tumor microenvironment is shaped in ascites remains unclear. Single-cell proteomic profiling and a comprehensive proteomic analysis are conducted to comprehensively characterize malignant ascites. Here, we find defects in immune effectors along with immunosuppressive cell accumulation in ascites of patients with gastric cancer (GC) and identify five distinct subpopulations of CD45(-)/EpCAM(-) cells. Mesothelial cells with mesenchymal features in CD45(-)/EpCAM(-) cells are the predominant source of chemokines involved in immunosuppressive myeloid cell (IMC) recruitment. Moreover, mesothelial-mesenchymal transition (MMT)-induced mesothelial cells strongly express extracellular matrix (ECM)-related genes, including tenascin-C (TNC), enhancing metastatic colonization. These findings highlight the definite roles of the mesenchymal cell population in the development of a protumorigenic microenvironment to promote peritoneal dissemination.

Engineered immunomodulatory extracellular vesicles derived from epithelial cells acquire capacity for positive and negative T cell co-stimulation in cancer and autoimmunity.

Extracellular vesicles (EVs) are generated by all cells and systemic administration of allogenic EVs derived from epithelial and mesenchymal cells have been shown to be safe, despite carrying an array of functional molecules, including thousands of proteins. To address whether epithelial cells derived EVs can be modified to acquire the capacity to induce immune response, we engineered 293T EVs to harbor the immunomodulatory CD80, OX40L and PD-L1 molecules. We demonstrated abundant levels of these proteins on the engineered cells and EVs. Functionally, the engineered EVs efficiently elicit positive and negative co-stimulation in human and murine T cells. In the setting of cancer and auto-immune hepatitis, the engineered EVs modulate T cell functions and alter disease progression. Moreover, OX40L EVs provide additional benefit to anti-CTLA-4 treatment in melanoma-bearing mice. Our work provides evidence that epithelial cell derived EVs can be engineered to induce immune responses with translational potential to modulate T cell functions in distinct pathological settings.

Galectin-3 Cooperates with CD47 to Suppress Phagocytosis and T-cell Immunity in Gastric Cancer Peritoneal Metastases.

The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor prognosis, highlighting the need to identify new therapeutic targets. CD47 conveys a "don't eat me" signal to myeloid cells upon binding its receptor signal regulatory protein alpha (SIRPα), which helps tumor cells circumvent macrophage phagocytosis and evade innate immune responses. Previous studies demonstrated that the blockade of CD47 alone results in limited clinical benefits, suggesting that other target(s) might need to be inhibited simultaneously with CD47 to elicit a strong antitumor response. Here, we found that CD47 was highly expressed on malignant PC cells, and elevated CD47 was associated with poor prognosis. Galectin-3 (Gal3) expression correlated with CD47 expression, and coexpression of Gal3 and CD47 was significantly associated with diffuse type, poor differentiation, and tumor relapse. Depletion of Gal3 reduced expression of CD47 through inhibition of c-Myc binding to the CD47 promoter. Furthermore, injection of Gal3-deficient tumor cells into either wild-type and Lgals3-/- mice led to a reduction in M2 macrophages and increased T-cell responses compared with Gal3 wild-type tumor cells, indicating that tumor cell-derived Gal3 plays a more important role in GAC progression and phagocytosis than host-derived Gal3. Dual blockade of Gal3 and CD47 collaboratively suppressed tumor growth, increased phagocytosis, repolarized macrophages, and boosted T-cell immune responses. These data uncovered that Gal3 functions together with CD47 to suppress phagocytosis and orchestrate immunosuppression in GAC with PC, which supports exploring a novel combination therapy targeting Gal3 and CD47. SIGNIFICANCE: Dual inhibition of CD47 and Gal3 enhances tumor cell phagocytosis and reprograms macrophages to overcome the immunosuppressive microenvironment and suppress tumor growth in peritoneal metastasis of gastric adenocarcinoma.

Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression.

Understanding tumor microenvironment (TME) reprogramming in gastric adenocarcinoma (GAC) progression may uncover novel therapeutic targets. Here, we performed single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and compositions as GAC progresses. Abundant IgA+ plasma cells exist in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominate late-stage GACs. We identified six TME ecotypes (EC1-6). EC1 is exclusive to blood, while EC4, EC5, and EC2 are highly enriched in uninvolved tissues, premalignant lesions, and metastases, respectively. EC3 and EC6, two distinct ecotypes in primary GACs, associate with histopathological and genomic characteristics, and survival outcomes. Extensive stromal remodeling occurs in GAC progression. High SDC2 expression in cancer-associated fibroblasts (CAFs) is linked to aggressive phenotypes and poor survival, and SDC2 overexpression in CAFs contributes to tumor growth. Our study provides a high-resolution GAC TME atlas and underscores potential targets for further investigation.

A new intronic quantitative PCR method led to the discovery of transformation from human ascites to murine malignancy in a mouse model.

Purpose: To establish a fast and accurate detection method for interspecies contaminations in the patient-derived xenograft (PDX) models and cell lines, and to elucidate possible mechanisms if interspecies oncogenic transformation is detected. Methods: A fast and highly sensitive intronic qPCR method detecting Gapdh intronic genomic copies was developed to quantify if cells were human or murine or a mixture. By this method, we documented that murine stromal cells were abundant in the PDXs; we also authenticated our cell lines to be human or murine. Results: In one mouse model, GA0825-PDX transformed murine stromal cells into a malignant tumorigenic murine P0825 cell line. We traced the timeline of this transformation and discovered three subpopulations descended from the same GA0825-PDX model: epithelium-like human H0825, fibroblast-like murine M0825, and main passaged murine P0825 displayed differences in tumorigenic capability in vivo. P0825 was the most aggressive and H0825 was weakly tumorigenic. Immunofluorescence (IF) staining revealed that P0825 cells highly expressed several oncogenic and cancer stem cell markers. Whole exosome sequencing (WES) analysis revealed that TP53 mutation in the human ascites IP116-generated GA0825-PDX may have played a role in the human-to-murine oncogenic transformation. Conclusion: This intronic qPCR is able to quantify human/mouse genomic copies with high sensitivity and within a time frame of a few hours. We are the first to use intronic genomic qPCR for authentication and quantification of biosamples. Human ascites transformed murine stroma into malignancy in a PDX model.

CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion.

Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 gene mutations, causing E-Cadherin loss, its role in sporadic DGAC is unclear. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared to KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.

A novel fluorescent probe for the detection of formaldehyde in real food samples, animal serum samples and gaseous formaldehyde.

Formaldehyde (FA) is widely used as an adhesion promoter and dyeing aid in industrial production. Ingestion of a certain amount of formaldehyde may cause corrosive burns in the mouth, throat, and digestive tract. Therefore, it is very necessary to use simple and effective detection methods to ensure human health and food safety. Herein, a novel fluorescent probe NFD based on naphthalimide for the detection of formaldehyde in food was designed and synthesized. The probe had a remarkable fluorescence response to formaldehyde at 554 nm. And it exhibited fascinating advantages of good selectivity, high sensitivity, and low detection limit. In addition, the solid sensor prepared by loading the probe on the filter paper was successfully realized the visual detection of liquid and gaseous formaldehyde. More importantly, the probe possessed excellent stability in the detection of formaldehyde in real food samples and animal serum samples.

Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment.

OBJECTIVE: Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet the role of SOX9 in mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect the role of SOX9-mediated cancer stemness attributes and immunosuppressive microenvironment in advanced gastric adenocarcinoma (GAC) for novel therapeutic discoveries. METHODS: Bulk RNAseq/scRNA-seq, patient-derived cells/models and extensive functional studies were used to identify the expression and functions of SOX9 and its target genes in vitro and in vivo. Immune responses were studied in PBMCs or CD45+ immune cells cocultured with tumour cells with SOX9high or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations. RESULTS: SOX9 is one of the most upregulated SOX genes in GAC and highly expressed in primary and metastatic tissues and associated with poor prognosis. Depletion of SOX9 in patient-derived GAC cells significantly decreased cancer stemness attributes, tumour formation and metastases and consistently increased CD8+ T cell responses when cocultured with PBMCs/CD45+ cells from GAC patients. RNA sequencing identified the leukaemia inhibitory factor (LIF) as the top secreted molecule regulated by SOX9 in tumour cells and was enriched in malignant ascites and mediated SOX9-induced M2 macrophage repolarisation and inhibited T cell function. CONCLUSION: Epithelial SOX9 is critical in suppressing CD8+ T cell responses and modified macrophage function in GAC through the paracrine LIF factor. Cotargeting LIF/LIFR and CSF1R has great potential in targeting SOX9-mediated cancer stemness, T cell immunosuppression and metastases suggesting the novel combination therapy against advanced GAC.

GRK3 is a poor prognosticator and serves as a therapeutic target in advanced gastric adenocarcinoma.

BACKGROUND: G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3's functions and clinical utility in GAC progression and metastases are unknown. METHODS: We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on YAP1 and its targets was determined. RESULTS: GRK3 was overexpressed in GAC tissues compared to normal and was even higher in peritoneal metastases. Overexpression (OE) of GRK3 was significantly associated with shorter survival. Upregulation of GRK3 in GAC cells increased cell invasion, colony formation, and proportion of ALDH1+ cells, while its downregulation reduced these attributes. Further, LD2 potently and specifically inhibited GRK3, but not GRK2, a very similar kinase to GRK3. LD2 highly suppressed GAC cells' malignant phenotypes in vitro. Mechanistically, GRK3 upregulated YAP1 in GAC tissues and its transcriptional downstream targets: SOX9, Birc5, Cyr61 and CTGF. Knockdown (KD) YAP1 rescued the phenotypes of GRK3 OE in GAC cells. GRK3 OE significantly increased tumor growth but LD2 inhibited tumor growth in the PDX model and dramatically suppressed peritoneal metastases induced by GRK3 OE. CONCLUSIONS: GRK3, a poor prognosticator for survival, conferred aggressive phenotype. Genetic silencing of GRK3 or its inhibitor LD2 blunted GRK3-conferred malignant attributes, suggesting GRK3 as a novel therapeutic target in advanced GAC.

Field-Free Magnetization Switching in a Ferromagnetic Single Layer through Multiple Inversion Asymmetry Engineering.

A simple, reliable, and self-switchable spin-orbit torque (SOT)-induced magnetization switching in a ferromagnetic single layer is needed for the development of next generation fully electrical controllable spintronic devices. In this work, field-free SOT-induced magnetization switching in a CoPt single layer is realized by broken multiple inversion symmetry through simultaneously introducing both oblique sputtering and a vertical composition gradient. A quantitative analysis indicates that multiple inversion asymmetries can produce dynamical bias fields along both z- and x-axes, leading to the observed field-free deterministic magnetization switching. Our study provides a method to accomplish fully electrical manipulation of magnetization in a ferromagnetic single layer without the external magnetic field and auxiliary heavy metal layer, enabling flexible design for future spin-orbit torque-based memory and logic devices.

Outcome of the efficacy of Chinese herbal medicine for functional constipation: A systematic review and meta-analysis.

BACKGROUND: Functional constipation (FC) is a common and chronic gastrointestinal disease and its treatment remains challenging. AIM: To evaluate the efficacy and safety of Chinese herbal medicine (CHM) on efficacy rate, global symptoms, bowel movements and the Bristol Stool Scale score in patients with FC by summarizing current available randomized controlled trials (RCTs). METHODS: RCTs with CHM to treat FC were identified by a systematic search of six databases from inception to October 20, 2020. Two independent reviewers assessed the quality of the included articles and extracted data. Meta-analyses were performed to odds ratio (OR), mean differences (MD) and 95% confidence interval (CI) using random-effects models. Subgroup analyses and sensitivity analyses were used to explore and interpret the sources of heterogeneity. The funnel plot, Begg's test and Egger's test were used to detect publication bias. RESULTS: Ninety-seven studies involving 8693 patients were included in this work. CHM was significantly associated with a higher efficacy rate (OR: 3.62, 95%CI: 3.19-4.11, P < 0.00001) less severe global symptoms (OR: 4.03, 95%CI: 3.49-4.65, P < 0.00001) compared with control treatment, with the low heterogeneity between studies (I 2 = 0%, P = 0.76). CHM was also associated with more frequent bowel movements (MD 0.83, 95%CI: 0.67-0.98, P < 0.00001), a lower score on the Bristol Stool Scale (OR: 1.63, 95%CI: 1.15-2.32, P < 0.006), and a not significant recurrence rate (OR: 0.47, 95%CI: 0.22-0.99, P = 0.05). No serious adverse effects of CHM were reported. CONCLUSION: In this meta-analysis, we found that CHM may have potential benefits in increasing the number of bowel movements, improving stool characteristics and alleviating global symptoms in FC patients. However, a firm conclusion could not be reached because of the poor quality of the included trials. Further trials with higher quality are required.