GRP94 promotes anoikis resistance and peritoneal metastasis through YAP/TEAD1 pathway in gastric cancer.

Anoikis resistance allows cancer cells to avoid death caused by detachment from the extracellular matrix's adhesion, enabling these cells to infiltrate and migrate to regions such as the peritoneum. This study emphasizes GRP94's involvement in anoikis resistance and peritoneal metastasis in gastric cancer (GC). It's found that GRP94 overexpression, linked to poor prognosis, was potentially due to SP1 and GRP94 promoter interactions, confirmed through dual luciferase reporter (DLR), chromatin immunoprecipitation (ChIP), and quantitative real-time PCR (real-time qPCR). Increased GRP94 enhanced GC cells' anoikis resistance and metastasis. Decreasing GRP94 had opposite effects, potentially through yes-associated protein (YAP)/TEAD1 axis inhibition, with raised YAP phosphorylation and decreased TEAD1 levels detected by western blotting (WB). Inhibiting YAP counteracted GRP94's effects on anoikis resistance and metastasis, while activating YAP reversed the effects of GRP94 reduction. Animal experiments verified GRP94's contribution to GC's peritoneal metastasis. In conclusion, our work highlights the effect of GRP94 on anoikis resistance, showing potential value in treating peritoneal metastasis of GC.

A special coupling strategy: Cu2MoS4 as a large-sized co-catalyst for promoting photocatalytic hydrogen production performance.

The photocatalytic hydrogen production performance of semiconductor materials can be improved by co-catalyst modification. In most of the studies, the size of the co-catalyst is relatively small compared to the primary catalyst. However, in this study, we employed a novel strategy by synthesizing a relatively large-sized Cu2MoS4 as the co-catalyst and in situ loading smaller-sized Zn0.5Cd0.5S onto Cu2MoS4, verifying that Cu2MoS4 enhances the photocatalytic hydrogen production efficiency of Zn0.5Cd0.5S. It can be observed by scanning electron microscopy (SEM) that the lateral size of 2D Cu2MoS4 is at least 50 times larger than the Zn0.5Cd0.5S nanoparticle particle size. In addition, Density Functional Theory (DFT) calculations have demonstrated that the active site for hydrogen production in the composite is located in Cu2MoS4. The large-sized of Cu2MoS4 not only provides more active sites but also broadens the electron transport channel, which is conducive to promoting the transfer of photogenerated electrons from Zn0.5Cd0.5S. This work enriches the study of large-sized materials as co-catalyst and provides a strategy for the construction of composite catalysts.

How local electric field regulates C-C coupling at a single nanocavity in electrocatalytic CO2 reduction.

C-C coupling is of utmost importance in the electrocatalytic reduction of CO2, as it governs the selectivity of diverse product formation. Nevertheless, the difficulties to directly observe C-C coupling pathways at a specific nanocavity hinder the advances in catalysts and electrolyzer design for efficient high-value hydrocarbon production. Here we develop a nano-confined Raman technology to elucidate the influence of the local electric field on the evolution of C-C coupling intermediates. Through precise adjustments to the Debye length in nanocavities of a copper catalyst, the overlapping of electrical double layers drives a transition in the C-C coupling pathway at a specific nanocavity from *CHO-*CO coupling to the direct dimerization of *CO species. Experimental evidence and simulations validate that a reduced potential drop across the compact layer promotes a higher yield of CO and promotes the direct dimerization of *CO species. Our findings provide insights for the development of highly selective catalyst materials tailored to promote specific products.

Paired organoids from primary gastric cancer and lymphatic metastasis are useful for personalized medicine.

BACKGROUND: Organoids are approved by the US FDA as an alternative to animal experiments to guide drug development and for sensitivity screening. Stable organoids models of gastric cancer are desirable for personalized medicine and drug screening. METHODS: Tumor tissues from a primary cancer of the stomach and metastatic cancer of the lymph node were collected for 3D culture. By long-term culture for over 50 generations in vitro, we obtained stably growing organoid lines. We analyzed short tandem repeats (STRs) and karyotypes of cancer cells, and tumorigenesis of the organoids in nude mice, as well as multi-omics profiles of the organoids. A CCK8 method was used to determine the drugs sensitivity to fluorouracil (5-Fu), platinum and paclitaxel. RESULTS: Paired organoid lines from primary cancer (SPDO1P) and metastatic lymph node (SPDO1LM) were established with unique STRs and karyotypes. The organoid lines resulted in tumorigenesis in vivo and had clear genetic profiles. Compared to SPDO1P from primary cancer, upregulated genes of SPDO1LM from the metastatic lymph node were enriched in pathways of epithelial-mesenchymal transition and angiogenesis with stronger abilities of cell migration, invasion, and pro-angiogenesis. Based on drug sensitivity analysis, the SOX regimen (5-Fu plus oxaliplatin) was used for chemotherapy with an optimal clinical outcome. CONCLUSIONS: The organoid lines recapitulate the drug sensitivity of the parental tissues. The paired organoid lines present a step-change toward living biobanks for further translational usage.

Drug-induced senescence by aurora kinase inhibitors attenuates innate immune response of macrophages on gastric cancer organoids.

Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with aggressiveness and poor prognosis. It is of great significance to find sensitive drugs for DGC. In the current study, a total of 20 patient-derived organoids (PDOs) were analyzed for screening the therapeutic efficacy of small molecule kinases inhibitors on gastric cancers, especially the therapeutic difference between intestinal-type gastric cancer (IGCs) and DGCs. The IGCs are sensitive to multiple kinases inhibitors, while DGCs are resistant to most of these kinases inhibitors. It was found that DGCs showed drug-induced senescent phenotype after treatment by aurora kinases inhibitors (AURKi) Barasertib-HQPA and Danusertib. The cell diameter of cancer cells are increased with stronger staining of senescence-associated ß-galactosidase (SA-ß-GAL), and characteristic appearance of multinucleated giant cells. The senescent cancer cells secrete large amounts of chemokine MCP-1/CCL2, which recruit and induce macrophage to M2-type polarization in PDOs of DGC (DPDOs)-macrophage co-culture system. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2) expressed on macrophages and suppress their innate immunity to cancer cells. Overall, the special response of DGC to AURKi suggests that clinicians should select a sequential therapy with senescent cell clearance after AURKi treatment for DGC.

The efficacy and safety of using a combination of rocuronium and sugammadex for awake craniotomy anesthesia: A randomized clinical trial.

BACKGROUND: Awake craniotomy (AC) is a neurosurgical method for the resection of brain lesions located in eloquent areas to achieve maximal and safe resection. A patient's arousal quality is essential for the success of the operation. This study compared the arousal time and quality after AC achieved by 2 different drug combinations: rocuronium with sugammadex and propofol with remifentanil. METHODS: This prospective, randomized, controlled trial included 42 adult patients undergoing AC with a laryngeal mask, who were randomly assigned to either a rocuronium-sugammadex group (RS; n = 21) or a propofol-remifentanil without muscle relaxant group (nRS; n = 21). The primary outcomes were the arousal time and arousal quality. The secondary outcomes included the number of laryngeal mask airway (LMA) adjustments and diaphragmatic excursion length. RESULTS: This study included 42 participants. The median (IQR) arousal time was 13.5 minutes (7-20) in the RS group and 21 minutes (16.5-26.5) in the nRS group (P = .005). There was no significant difference in arousal quality between the 2 groups (P = .229). LMA adjustments were significantly less frequent in the nRS group than in the RS group [0.25 times (±0.62) vs 1.26 times (±1.17), P = .001]. Adverse events, such as spontaneous movements and brain swelling, were more frequent in the nRS group than in the RS group. CONCLUSIONS: Using a combination of rocuronium and sugammadex with propofol and remifentanil may shorten the awakening time, reduce the duration of laryngeal mask adjustment, and do not affect the arousal quality and postoperative outcomes for patients undergoing awake craniotomy, compared to propofol and remifentanil alone.

Mining the Micro-Trajectory of Two-Wheeled Non-Motorized Vehicles Based on the Improved YOLOx.

Two-wheeled non-motorized vehicles (TNVs) have become the primary mode of transportation for short-distance travel among residents in many underdeveloped cities in China due to their convenience and low cost. However, this trend also brings corresponding risks of traffic accidents. Therefore, it is necessary to analyze the driving behavior characteristics of TNVs through their trajectory data in order to provide guidance for traffic safety. Nevertheless, the compact size, agile steering, and high maneuverability of these TNVs pose substantial challenges in acquiring high-precision trajectories. These characteristics complicate the tracking and analysis processes essential for understanding their movement patterns. To tackle this challenge, we propose an enhanced You Only Look Once Version X (YOLOx) model, which incorporates a median pooling-Convolutional Block Attention Mechanism (M-CBAM). This model is specifically designed for the detection of TNVs, and aims to improve accuracy and efficiency in trajectory tracking. Furthermore, based on this enhanced YOLOx model, we have developed a micro-trajectory data mining framework specifically for TNVs. Initially, the paper establishes an aerial dataset dedicated to the detection of TNVs, which then serves as a foundational resource for training the detection model. Subsequently, an augmentation of the Convolutional Block Attention Mechanism (CBAM) is introduced, integrating median pooling to amplify the model's feature extraction capabilities. Subsequently, additional detection heads are integrated into the YOLOx model to elevate the detection rate of small-scale targets, particularly focusing on TNVs. Concurrently, the Deep Sort algorithm is utilized for the precise tracking of vehicle targets. The process culminates with the reconstruction of trajectories, which is achieved through a combination of video stabilization, coordinate mapping, and filtering denoising techniques. The experimental results derived from our self-constructed dataset reveal that the enhanced YOLOx model demonstrates superior detection performance in comparison to other analogous methods. The comprehensive framework accomplishes an average trajectory recall rate of 85% across three test videos. This significant achievement provides a reliable method for data acquisition, which is essential for investigating the micro-level operational mechanisms of TNVs. The results of this study can further contribute to the understanding and improvement of traffic safety on mixed-use roads.

Brainstem anesthesia during awake craniotomy: illustrative case.

BACKGROUND: Awake craniotomy (AC) is performed to remove the lesions near or in eloquent areas, during which the patients are alert and without any airway instrument. Apnea is a severe complication in AC. Here, the authors describe a case of sudden apnea induced by unexpected local anesthesia of the brainstem during AC. OBSERVATIONS: A 42-year-old male underwent AC for a large, recurrent, bilateral frontal lobe mass and experienced transient apnea and loss of brainstem reflexes during the surgery. The patient recovered spontaneous breath rhythm just a few minutes after the removal of a lidocaine cotton pledget, which was found near the patient's midbrain. Then the patient awoke and cooperated to finish the surgery. LESSONS: The administration of a local anesthetic subdurally in AC is common but risky. The scouring action of cerebral spinal fluid can spread those agents and cause unexpected brainstem anesthesia. A lower concentration of the anesthetic and keeping away from the cistern can make it safer.

Intellectualized Visualization of Single-Particle Raman Spectra for Sensitive Detection and Simultaneous Multianalysis of Heavy Metal Ions.

Easy-to-use, reliable, and real-time methods for detecting heavy metal ion contamination are urgently required, which is a primary concern for water pollution control and human health. However, present methods for this aim are still unable to achieve simultaneous multianalysis for complex real sample detection. Herein, an intellectualized vision-based single-nanoparticle Raman imaging strategy combined with ion-responsive functional nucleic acids (FNAs) was proposed to address these issues. We reported a correspondence between the concentration of the analytes and the density of particles (DOP) of specifically captured nanoparticles to achieve sensitive detection and simultaneous multianalysis of heavy metal ions. The specific detection of Pb2+ (Hg2+) was obtained with a detection linear range from 100 pM to 100 nM (from 500 fM to 100 nM) and limit of detections low to 1 pM (100 fM), with the advantages of good specificity, excellent homogeneity, and reproducibility. Furthermore, the differentiation of different heavy metal ions (Pb2+/Hg2+) was achieved, i.e., the simultaneous multianalysis, based on Raman imaging of the single particle and intelligent machine vision method. Finally, the Raman imaging assay was utilized for real sample analysis, and it provided a powerful and reliable tool for detecting trace Pb2+/Hg2+ in real water samples and facilitated the portable on-site monitoring of heavy metal ions.

Ferroptosis and mitochondrial dysfunction in acute central nervous system injury.

Acute central nervous system injuries (ACNSI), encompassing traumatic brain injury (TBI), non-traumatic brain injury like stroke and encephalomeningitis, as well as spinal cord injuries, are linked to significant rates of disability and mortality globally. Nevertheless, effective and feasible treatment plans are still to be formulated. There are primary and secondary injuries occurred after ACNSI. Most ACNSIs exhibit comparable secondary injuries, which offer numerous potential therapeutic targets for enhancing clinical outcomes. Ferroptosis, a newly discovered form of cell death, is characterized as a lipid peroxidation process that is dependent on iron and oxidative conditions, which is also indispensable to mitochondria. Ferroptosis play a vital role in many neuropathological pathways, and ACNSIs may induce mitochondrial dysfunction, thereby indicating the essentiality of the mitochondrial connection to ferroptosis in ACNSIs. Nevertheless, there remains a lack of clarity regarding the involvement of mitochondria in the occurrence of ferroptosis as a secondary injuries of ACNSIs. In recent studies, anti-ferroptosis agents such as the ferroptosis inhibitor Ferrostain-1 and iron chelation therapy have shown potential in ameliorating the deleterious effects of ferroptosis in cases of traumatic ACNSI. The importance of this evidence is extremely significant in relation to the research and control of ACNSIs. Therefore, our review aims to provide researchers focusing on enhancing the therapeutic outcomes of ACNSIs with valuable insights by summarizing the physiopathological mechanisms of ACNSIs and exploring the correlation between ferroptosis, mitochondrial dysfunction, and ACNSIs.

A quick and reliable image-based AI algorithm for evaluating cellular senescence of gastric organoids.

OBJECTIVE: Organoids are a powerful tool with broad application prospects in biomedicine. Notably, they provide alternatives to animal models for testing potential drugs before clinical trials. However, the number of passages for which organoids maintain cellular vitality ex vivo remains unclear. METHODS: Herein, we constructed 55 gastric organoids from 35 individuals, serially passaged the organoids, and captured microscopic images for phenotypic evaluation. Senescence-associated ß-galactosidase (SA-ß-Gal), cell diameter in suspension, and gene expression reflecting cell cycle regulation were examined. The YOLOv3 object detection algorithm integrated with a convolutional block attention module (CBAM) was used to evaluate organoid vitality. RESULTS: SA-ß-Gal staining intensity; single-cell diameter; and expression of p15, p16, p21, CCNA2, CCNE2, and LMNB1 reflected the progression of aging in organoids during passaging. The CBAM-YOLOv3 algorithm precisely evaluated aging organoids on the basis of organoid average diameter, organoid number, and number × diameter, and the findings positively correlated with SA-ß-Gal staining and single-cell diameter. Organoids derived from normal gastric mucosa had limited passaging ability (passages 1-5), before aging, whereas tumor organoids showed unlimited passaging potential for more than 45 passages (511 days) without showing clear senescence. CONCLUSIONS: Given the lack of indicators for evaluating organoid growth status, we established a reliable approach for integrated analysis of phenotypic parameters that uses an artificial intelligence algorithm to indicate organoid vitality. This method enables precise evaluation of organoid status in biomedical studies and monitoring of living biobanks.

Exposure to Agent Orange and Risk of Bladder Cancer Among US Veterans.

Importance: To date, limited data exist regarding the association between Agent Orange and bladder cancer, and the Institute of Medicine concluded that the association between exposure to Agent Orange and bladder cancer outcomes is an area of needed research. Objective: To examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans. Design, Setting, and Participants: This nationwide Veterans Affairs (VA) retrospective cohort study assesses the association between exposure to Agent Orange and bladder cancer risk among 2 517 926 male Vietnam veterans treated in the VA Health System nationwide from January 1, 2001, to December 31, 2019. Statistical analysis was performed from December 14, 2021, to May 3, 2023. Exposure: Agent Orange. Main Outcomes and Measures: Veterans exposed to Agent Orange were matched in a 1:3 ratio to unexposed veterans on age, race and ethnicity, military branch, and year of service entry. Risk of bladder cancer was measured by incidence. Aggressiveness of bladder cancer was measured by muscle-invasion status using natural language processing. Results: Among the 2 517 926 male veterans (median age at VA entry, 60.0 years [IQR, 56.0-64.0 years]) who met inclusion criteria, there were 629 907 veterans (25.0%) with Agent Orange exposure and 1 888 019 matched veterans (75.0%) without Agent Orange exposure. Agent Orange exposure was associated with a significantly increased risk of bladder cancer, although the association was very slight (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). When stratified by median age at VA entry, Agent Orange was not associated with bladder cancer risk among veterans older than the median age but was associated with increased bladder cancer risk among veterans younger than the median age (HR, 1.07; 95% CI, 1.04-1.10). Among veterans with a diagnosis of bladder cancer, Agent Orange was associated with lower odds of muscle-invasive bladder cancer (odds ratio [OR], 0.91; 95% CI, 0.85-0.98). Conclusions and Relevance: In this cohort study among male Vietnam veterans, there was a modestly increased risk of bladder cancer-but not aggressiveness of bladder cancer-among those exposed to Agent Orange. These findings suggest an association between Agent Orange exposure and bladder cancer, although the clinical relevance of this was unclear.

Patient-derived organoids in translational oncology and drug screening.

Patient-derived organoids (PDO) are a new biomedical research model that can reconstruct phenotypic and genetic characteristics of the original tissue and are useful for research on pathogenesis and drug screening. To introduce the progression in this field, we review the key factors of constructing organoids derived from epithelial tissues and cancers, covering culture medium and matrix, morphological characteristics, genetic profiles, high-throughput drug screening, and application potential. We also discuss the co-culture system of cancer organoids with tumor microenvironment (TME) associated cells. The co-culture system is widely used in evaluating crosstalk of cancer cells with TME components, such as fibroblasts, endothelial cells, immune cells, and microorganisms. The article provides a prospective for standardized cultivation mode, automatic morphological evaluation, and drug sensitivity screening using high-throughput methods.

Maximal safe resection of diffuse lower grade gliomas primarily within central lobe using cortical/subcortical direct electrical stimulation under awake craniotomy.

Background: Diffuse lower-grade glioma (DLGG) in the central lobe is a challenge for safe resection procedures. To improve the extent of resection and reduce the risk of postoperative neurological deficits, we performed an awake craniotomy with cortical-subcortical direct electrical stimulation (DES) mapping for patients with DLGG located primarily within the central lobe. We investigated the outcomes of cortical-subcortical brain mapping using DES in an awake craniotomy for central lobe DLGG resection. Methods: We performed a retrospective analysis of clinical data of a cohort of consecutively treated patients from February 2017 to August 2021 with diffuse lower-grade gliomas located primarily within the central lobe. All patients underwent awake craniotomy with DES for cortical and subcortical mapping of eloquent brain areas, neuronavigation, and/or ultrasound to identify tumor location. Tumors were removed according to functional boundaries. Maximum safe tumor resection was the surgical objective for all patients. Results: Thirteen patients underwent 15 awake craniotomies with intraoperative mapping of eloquent cortices and subcortical fibers using DES. Maximum safe tumor resection was achieved according to functional boundaries in all patients. The pre-operative tumor volumes ranged from 4.3 cm3 to 137.3 cm3 (median 19.2 cm3). The mean extent of tumor resection was 94.6%, with eight cases (53.3%) achieving total resection, four (26.7%) subtotal and three (20.0%) partial. The mean tumor residue was 1.2 cm3. All patients experienced early postoperative neurological deficits or worsening conditions. Three patients (20.0%) experienced late postoperative neurological deficits at the 3-month follow-up, including one moderate and two mild neurological deficits. None of the patients experienced late onset severe neurological impairments post-operatively. Ten patients with 12 tumor resections (80.0%) had resumed activities of daily living at the 3-month follow-up. Among 14 patients with pre-operative epilepsy, 12 (85.7%) were seizure-free after treatment with antiepileptic drugs 7 days after surgery up to the last follow-up. Conclusions: DLGG located primarily in the central lobe deemed inoperable can be safely resected using awake craniotomy with intraoperative DES without severe permanent neurological sequelae. Patients experienced an improved quality of life in terms of seizure control.

The potato StMKK5-StSIPK module enhances resistance to Phytophthora pathogens through activating the salicylic acid and ethylene signalling pathways.

Mitogen-activated protein kinase (MAPK) cascades play pivotal roles in plant responses to both biotic and abiotic stress. A screen of a Nicotiana benthamiana cDNA virus-induced gene silencing (VIGS) library for altered plant responses to inoculation with Phytophthora infestans previously identified an NbMKK gene, encoding a clade D MAPKK that we renamed as NbMKK5, which is involved in immunity to P. infestans. To study the role of the potato orthologous gene, referred to as StMKK5, in the response to P. infestans, we transiently overexpressed StMKK5 in N. benthamiana and observed that cell death occurred at 2 days postinfiltration. Silencing of the highly conserved eukaryotic protein SGT1 delayed the StMKK5-induced cell death, whereas silencing of the MAPK-encoding gene NbSIPK completely abolished the cell death response. Further investigations showed that StMKK5 interacts with, and directly phosphorylates, StSIPK. Furthermore, both StMKK5 and StSIPK trigger salicylic acid (SA)- and ethylene (Eth)-related gene expression, and co-expression of the salicylate hydroxylase NahG with the negative regulator of Eth signalling CTR1 hampers StSIPK-triggered cell death. This observation indicates that the cell death triggered by StMKK5-StSIPK is dependent on the combination of SA- and Eth-signalling. By introducing point mutations, we showed that the kinase activity of both StMKK5 and StSIPK is required for triggering cell death. Genetic analysis showed that StMKK5 depends on StSIPK to trigger plant resistance. Thus, our results define a potato StMKK5-SIPK module that positively regulates immunity to P. infestans via activation of both the SA and Eth signalling pathways.

The Association Between Tobacco Retailer Outlet Density and Prevalence of Cigarette Smoking in Virginia.

OBJECTIVE: We examine the association between tobacco retail outlet density and adult smoking prevalence at the county level in Virginia, controlling for spatial autocorrelations. AIMS AND METHODS: Pooling data from 2020 County Health Rankings (compiled data from various sources including, but not limited to, the National Center for Health Statistics-Mortality Files, the Behavioral Risk Factor Surveillance System (BRFSS), and the American Community Survey) and Counter Tools, we conducted regression analyses that accounted for spatial autocorrelation (spatial lag models, LMlag) and adjusted for county-level access to healthcare, demographics, SES, environmental factors, risk conditions or behaviors, and population health measures. RESULTS: Our estimates provide evidence that every increase of one tobacco retail outlet per 1000 persons was associated with 1.16 percentage points (95% CI: 0.80-1.52) higher smoking prevalence at the county level in Virginia after controlling for spatial autocorrelation. The effect of outlet density was largely explained by social determinants of health such as SES, risky conditions or behaviors, and environmental factors. We further noticed that the impact of social determinants of health were closely related and can be explained by indicators of population health (rates of mental distress (ß = 1.49, 95% CI: 1.31-1.67) and physical inactivity (ß = 0.07, 95% CI: 0.04-0.10). CONCLUSIONS: Although higher tobacco outlet density was associated with an increase in county-level smoking prevalence, the impact of outlet density was largely explained by social determinants of health and mental illness. Improving well-being at the community level could be a promising strategy in future tobacco control policies. IMPLICATION: The influence of tobacco outlet density seems to be explained by other social determinants of health and population level of mental or physical health. Thus, efforts to reduce tobacco use and consequent negative health effects should explore the impact of improving regional living standards. However, a sole focus on economic growth may not be sufficient, whereas a focus on such things as promoting work-life balance and improving overall well-being at the community level may be more.

Potato protein tyrosine phosphatase StPTP1a is activated by StMKK1 to negatively regulate plant immunity.

Phytophthora infestans causes severe losses in potato production. The MAPK kinase StMKK1 was previously found to negatively regulate potato immunity to P. infestans. Our results showed that StMKK1 interacts with a protein tyrosine phosphatase, referred to as StPTP1a, and StMKK1 directly phosphorylates StPTP1a at residues Ser-99, Tyr-223 and Thr-290. StPTP1a is a functional phosphatase and the phosphorylation of StPTP1a at these three residues enhances its stability and catalytic activity. StPTP1a negatively regulates potato immunity and represses SA-related gene expression. Furthermore, StPTP1a interacts with, and dephosphorylates, the StMKK1 downstream signalling targets StMPK4 and -7 at their Tyr-203 residue resulting in the repression of salicylic acid (SA)-related immunity. Silencing of NbPTP1a + NbMPK4 or NbPTP1a + NbMPK7 abolished the plant immunity to P. infestans caused by NbPTP1a silencing, indicating that PTP1a functions upstream of NbMPK4 and NbMPK7. StMKK1 requires StPTP1a to negatively regulate SA-related immunity and StPTP1a is phosphorylated and stabilized during immune activation to promote the de-phosphorylation of StMPK4 and -7. Our results reveal that potato StMKK1 activates and stabilizes the tyrosine phosphatase StPTP1a that in its turn de-phosphorylates StMPK4 and -7, thereby repressing plant SA-related immunity.

Benchmark for establishment of organoids from gastrointestinal epithelium and cancer based on available consumables and reagents.

Gastrointestinal cancers are a public health problem that threatens the lives of human being. A good experimental model is a powerful tool to promote the uncovering pathogenesis and establish novel treatment methods. High-quality biomedical research requires experimental models to recapitulate the physiological and pathological states of their parental tissues as much as possible. Organoids are such experimental models. Organoids refer to small organ-like cellular clusters formed by the expansion and passaging of living tissues in 3D culture medium in vitro. Organoids are highly similar to the original tissues in terms of cellular composition, cell functions, and genomic profiling. Organoids have many advantages, such as short preparation cycles, long-term storage based on cryopreservation, and reusability. In recent years, researchers carried out the establishment of organoids from gastrointestinal mucosa and cancer tissues, and accumulated valuable experiences. In order to promote effective usage and further development of organoid-related technologies in the research of gastrointestinal diseases, this study proposes a benchmark based on utilization of available experimental consumables and reagents, which are involved in the key steps such as collection and pretreatment of biospecimen, organoid construction, organoid cryopreservation and recovery, growth status evaluation, and organoid quality control. We believe that the standard for the construction and preservation of organoids derived from human gastrointestinal epithelium and cancer tissues can provide an important reference for the majority of scientific researchers.

Identification of Patients With Metastatic Prostate Cancer With Natural Language Processing and Machine Learning.

PURPOSE: Understanding treatment patterns and effectiveness for patients with metastatic prostate cancer (mPCa) is dependent on accurate assessment of metastatic status. The objective was to develop a natural language processing (NLP) model for identifying patients with mPCa and evaluate the model's performance against chart-reviewed data and an International Classification of Diseases (ICD) 9/10 code-based method. METHODS: In total, 139,057 radiology reports on 6,211 unique patients from the Department of Veterans Affairs were used. The gold standard was metastases by detailed chart review of radiology reports. NLP performance was assessed by sensitivity, specificity, positive predictive value, negative predictive value, and date of metastases detection. Receiver operating characteristic curves was used to assess model performance. RESULTS: When compared with chart review, the NLP model had high sensitivity and specificity (85% and 96%, respectively). The NLP model was able to predict patient-level metastasis status with a sensitivity of 91% and specificity of 81%, whereas sensitivity and specificity using ICD9/10 billing codes were 73% and 86%, respectively. For the NLP model, date of metastases detection was exactly concordant and within < 1 week in 55% and 58% of patients, compared with 8% and 17%, respectively, using the ICD9/10 billing codes method. The area under the curve for the NLP model was 0.911. A limitation is the NLP model was developed on the basis of a subset of patients with mPCa and may not be generalizable to all patients with mPCa. CONCLUSION: This population-level NLP model for identifying patients with mPCa was more accurate than using ICD9/10 billing codes when compared with chart-reviewed data. Upon further validation, this model may allow for efficient population-level identification of patients with mPCa.