A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair-Proficient Colorectal or Pancreatic Cancer.

BACKGROUND: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib). METHODS: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. RESULTS: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. CONCLUSIONS: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.

Low-Friction Soft Robots for Targeted Bacterial Infection Treatment in Gastrointestinal Tract.

Untethered and self-transformable miniature robots are capable of performing reconfigurable deformation and on-demand locomotion, which aid the traversal toward various lumens, and bring revolutionary changes for targeted delivery in gastrointestinal (GI) tract. However, the viscous non-Newtonian liquid environment and plicae gastricae obstacles severely hamper high-precision actuation and payload delivery. Here, we developed a low-friction soft robot by assembly of densely arranged cone structures and grafting of hydrophobic monolayers. The magnetic orientation encoded robot can move in multiple modes, with a substantially reduced drag, terrain adaptability, and improved motion velocity across the non-Newtonian liquids. Notably, the robot stiffness can be reversibly controlled with magnetically induced hardening, enabling on-site scratching and destruction of antibiotic-ineradicable polymeric matrix in biofilms with a low-frequency magnetic field. Furthermore, the magnetocaloric effect can be utilized to eradicate the bacteria by magnetocaloric effect under high-frequency alternating field. To verify the potential applications inside the body, the clinical imaging-guided actuation platforms were developed for vision-based control and delivery of the robots. The developed low-friction robots and clinical imaging-guided actuation platforms show their high potential to perform bacterial infection therapy in various lumens inside the body.

A Mitochondria-Targeted Photosensitizer for Combined Pyroptosis and Apoptosis with NIR-II Fluorescence/Photoacoustic Imaging-Guided Phototherapy.

Overcoming tumor apoptosis resistance is a major challenge in enhancing cancer therapy. Pyroptosis, a lytic form of programmed cell death (PCD) involving inflammasomes, Gasdermin family proteins, and cysteine proteases, offers potential in cancer treatment. While photodynamic therapy (PDT) can induce pyroptosis by generating reactive oxygen species (ROS) through the activation of photosensitizers (PSs), many PSs lack specific subcellular targets and are limited to the first near-infrared window, potentially reducing treatment effectiveness. Therefore, developing effective, deep-penetrating, organelle-targeted pyroptosis-mediated phototherapy is essential for cancer treatment strategies. Here, we synthesized four molecules with varying benzene ring numbers in thiopyrylium structures to preliminarily explore their photodynamic properties. The near-infrared-II (NIR-II) PS Z1, with a higher benzene ring count, exhibited superior ROS generation and mitochondria-targeting abilities, and a large Stokes shift. Through nano-precipitation method, Z1 nanoparticles (NPs) also demonstrated high ROS generation (especially type-I ROS) upon 808 nm laser irradiation, leading to efficient mitochondria dysfunction and combined pyroptosis and apoptosis. Moreover, they exhibited exceptional tumor-targeting ability via NIR-II fluorescence imaging (NIR-II FI) and photoacoustic imaging (PAI). Furthermore, Z1 NPs-mediated phototherapy effectively inhibited tumor growth with minimal adverse effects. Our findings offer a promising strategy for cancer therapy, warranting further preclinical investigations in PDT.

Relationship between Indel Variants within the JAK2 Gene and Growth Traits in Goats.

Janus kinase 2 (JAK2) plays a critical role in myoblast proliferation and fat deposition in animals. Our previous RNA-Seq analyses identified a close association between the JAK2 gene and muscle development. To date, research delving into the relationship between the JAK2 gene and growth traits has been sparse. In this study, we sought to investigate the relationship between novel mutations within the JAK2 gene and goat growth traits. Herein, two novel InDel (Insertion/Deletion) polymorphisms within the JAK2 gene were detected in 548 goats, and only two genotypes were designated as ID (Insertion/Deletion) and DD (Deletion/Deletion). The results indicate that the two InDels, the del19008 locus in intron 2 and del72416 InDel in intron 6, showed significant associations with growth traits (p < 0.05). Compared to Nubian and Jianzhou Daer goats, the del72416 locus displayed a more pronounced effect in the Fuqing breed group. In the Nubian breed (NB) group, both InDels showed a marked influence on body height (BH). There were strong linkages observed for these two InDels between the Fuqing (FQ) and Jianzhou (JZ) populations. The DD-ID diplotype was associated with inferior growth traits in chest width (ChW) and cannon circumference (CaC) in the FQ goats compared to the other diplotypes. In the NB population, the DD-DD diplotype exhibited a marked negative impact on BH and HuWI (hucklebone width index), in contrast to the other diplotypes. In summary, our findings suggest that the two InDel polymorphisms within the JAK2 gene could serve as valuable molecular markers for enhancing goat growth traits in breeding programs.

Prediction of Residual Compressive Strength after Impact Based on Acoustic Emission Characteristic Parameters.

This study proposes a prediction method for residual compressive strength after impact based on the extreme gradient boosting model, focusing on composite laminates as the studied material system. Acoustic emission tests were conducted under controlled temperature and humidity conditions to collect characteristic parameters, establishing a mapping relationship between these parameters and residual compressive strength under small sample conditions. The model accurately predicted the residual compressive strength of the laminates after impact, with the coefficient of determination and root mean square error for the test set being 0.9910 and 2.9174, respectively. A comparison of the performance of the artificial neural network model and the extreme gradient boosting model shows that, in the case of small data volumes, the extreme gradient boosting model exhibits superior accuracy and robustness compared to the artificial neural network. Furthermore, the sensitivity of acoustic emission characteristic parameters is analyzed using the SHAP method, revealing that indicators such as peak amplitude, ring count, energy, and peak frequency significantly impact the prediction results of residual compressive strength. The machine-learning-based method for assessing the damage tolerance of composite laminates proposed in this paper utilizes the global monitoring advantages of acoustic emission technology to rapidly predict the residual compressive strength after the impact of composite laminates, providing a theoretical approach for online structural health monitoring of composite laminates. This method is applicable to various composite laminate structures under different impact conditions, demonstrating its broad applicability and reliability.

Comparison of Postoperative Pain and Surgical Outcomes Between Three Types of Modified Muscle-Sparing Laminoplasty and Conventional Laminoplasty for Multilevel Degenerative Cervical Myelopathy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: This study aimed to compare postoperative pain and surgical outcomes of open-door laminoplasty (LP) and three types of muscle-sparing laminoplasties, namely unilateral muscle-preservation laminoplasty (UL), spinous process splitting double-door laminoplasty (DL) and intermuscular "raising roof" laminoplasty (RL) for multilevel degenerative cervical myelopathy (MDCM). METHODS: Consecutive MDCM patients underwent LP or modified laminoplasties (UL, DL, RL) in 2022 were enrolled. Patients' preoperative baseline data and surgical characteristics were collected. Postoperative transient pain (TP), the axial pain and Japanese Orthopedic Association (JOA) score and neck disability index (NDI) at 6-month and 12-month follow-up were documented. RESULTS: A total of 154 MDCM patients were included and a 12-month follow-up was completed for 148 patients (LP: 36, UL:39, DL: 37, RL:36). No significant difference was observed in the baseline data. Four groups presented favorable and comparable surgical outcome. The RL group reported significantly the least severe TP on the first three days following surgery. However, no significant difference was found in the axial pain and axial symptoms at both follow-ups. After regression analysis, RL group exhibited significantly better efficacy in alleviating Day-1 TP (P = 0.047) and 6-month axial pain (P = 0.040). However, this superiority was not observed at 12-month follow-up. CONCLUSION: All the three muscle-sparing laminoplasty procedures showed similar short-term surgical outcomes compared to LP. The RL procedure demonstrated superiority in alleviating TP and 6-month axial pain compared to LP. The RL and DL groups showed less C5 palsy compared to LP.

Identifying significant structural factors associated with knee pain severity in patients with osteoarthritis using machine learning.

Our main objective was to use machine learning methods to identify significant structural factors associated with pain severity in knee osteoarthritis patients. Additionally, we assessed the potential of various classes of imaging data using machine learning techniques to gauge knee pain severity. The data of semi-quantitative assessments of knee radiographs, semi-quantitative assessments of knee magnetic resonance imaging (MRI), and MRI images from 567 individuals in the Osteoarthritis Initiative (OAI) were utilized to train a series of machine learning models. Models were constructed using five machine learning methods: random forests (RF), support vector machines (SVM), logistic regression (LR), decision tree (DT), and Bayesian (Bayes). Employing tenfold cross-validation, we selected the best-performing models based on the area under the curve (AUC). The study results indicate no significant difference in performance among models using different imaging data. Subsequently, we employed a convolutional neural network (CNN) to extract features from magnetic resonance imaging (MRI), and class activation mapping (CAM) was utilized to generate saliency maps, highlighting regions associated with knee pain severity. A radiologist reviewed the images, identifying specific lesions colocalized with the CAM. The review of 421 knees revealed that effusion/synovitis (30.9%) and cartilage loss (30.6%) were the most frequent abnormalities associated with pain severity. Our study suggests cartilage loss and synovitis/effusion lesions as significant structural factors affecting pain severity in patients with knee osteoarthritis. Furthermore, our study highlights the potential of machine learning for assessing knee pain severity using radiographs.

Would the one-stage combined approach lead to better long-term neurological outcomes than the posterior approach alone in multilevel degenerative cervical myelopathy patients with T2-Weighted increased signal intensity? An 8-year follow-up results and propensity score matching analysis.

BACKGROUND: T2-weighted increased signal intensity (ISI) is commonly recognized as a sign of more severe spinal cord lesions, usually accompanied by worse neurological deficits and possibly worse postoperative neurological recovery. The combined approach could achieve better decompression and better neurological recovery for multilevel degenerative cervical myelopathy (MDCM). The choice of surgical approach for MDCM with intramedullary T2-weighted ISI remains disputed. This study aimed to compare the neurological outcomes of posterior and one-stage combined posteroanterior approaches for MDCM with T2-weighted ISI. METHODS: A total of 83 consecutive MDCM patients with confirmed ISI with at least three intervertebral segments operated between 2012 and 2014 were retrospectively enrolled. Preoperative demographic, radiological and clinical condition variables were collected, and neurological conditions were evaluated by the Japanese Orthopedic Assessment score (JOA) and Neck Disability Index (NDI). Propensity score matching analysis was conducted to produce pairs of patients with comparable preoperative conditions from the posterior-alone and combined groups. Both short-term and mid-term surgical outcomes were evaluated, including the JOA recovery rate (JOARR), NDI improvements, complications, and reoperations. RESULTS: A total of 83 patients were enrolled, of which 38 and 45 patients underwent posterior surgery alone and one-stage posteroanterior surgery, respectively. After propensity score matching, 38 pairs of comparable patients from the posterior and combined groups were matched. The matched groups presented similar preoperative clinical and radiological features and the mean follow-up duration were 111.6 ± 8.9 months. The preoperative JOA scores of the posterior and combined groups were 11.5 ± 2.2 and 11.1 ± 2.3, respectively (p = 0.613). The combined group presented with prolonged surgery duration(108.8 ± 28.0 and 186.1 ± 47.3 min, p = 0.028) and greater blood loss(276.3 ± 139.1 and 382.1 ± 283.1 ml, p<0.001). At short-term follow-up, the combined group presented a higher JOARR than the posterior group (posterior group: 50.7%±46.6%, combined group: 70.4%±20.3%, p = 0.024), while no significant difference in JOARR was observed between the groups at long-term follow-up (posterior group: 49.2%±48.5%, combined group: 59.6%±47.6%, p = 0.136). No significant difference was found in the overall complication and reoperation rates. CONCLUSIONS: For MDCM patients with ISI, both posterior and one-stage posteroanterior approaches could achieve considerable neurological alleviations in short-term and long-term follow-up. With greater surgical trauma, the combined group presented better short-term JOARR but did not show higher efficacy in long-term neurological function preservation in patients with comparable preoperative conditions.

Targeting the STAT3/IL-36G signaling pathway can be a promising approach to treat rosacea.

BACKGROUND: Rosacea is an inflammatory skin disorder characterized by the release of inflammatory mediators from keratinocytes, which are thought to play a crucial role in its pathogenesis. Despite an incidence of approximately 5.5%, rosacea is associated with a poor quality of life. However, as the pathogenesis of rosacea remains enigmatic, treatment options are limited. OBJECTIVES: To investigate the pathogenesis of rosacea and explore new therapeutic strategies. METHODS: Transcriptome data from rosacea patients combined with immunohistochemical staining were used to investigate the activation of STAT3 in rosacea. The role of STAT3 activation in rosacea was subsequently explored by inhibiting STAT3 activation both in vivo and in vitro. The key molecules downstream of STAT3 activation were identified through data analysis and experiments. Dual-luciferase assay and ChIP-qPCR analysis were used to validate the direct binding of STAT3 to the IL-36G promoter. DARTS, in combination with experimental screening, was employed to identify effective drugs targeting STAT3 for rosacea treatment. RESULTS: STAT3 signaling was hyperactivated in rosacea and served as a promoter of the keratinocyte-driven inflammatory response. Mechanistically, activated STAT3 directly bind to the IL-36G promoter region to amplify downstream inflammatory signals by promoting IL-36G transcription, and treatment with a neutralizing antibody (α-IL36γ) could mitigate rosacea-like inflammation. Notably, a natural plant extract (pogostone), which can interact with STAT3 directly to inhibit its activation and affect the STAT3/IL36G signaling pathway, was screened as a promising topical medication for rosacea treatment. CONCLUSIONS: Our study revealed a pivotal role for STAT3/IL36G signaling in the development of rosacea, suggesting that targeting this pathway might be a potential strategy for rosacea treatment.

A Mendelian randomization study between metabolic syndrome and its components with prostate cancer.

Previous research has produced inconsistent findings concerning the connection between metabolic syndrome and prostate cancer. It is challenging for observational studies to establish a conclusive causal relationship between the two. However, Mendelian randomization can provide stronger evidence of causality in this context. To examine the causal link between a metabolic composite and its components with prostate cancer, we performed a two-sample Mendelian randomization (MR) study utilizing aggregated data from genome-wide association studies, followed by meta-analyses. In our study, we employed inverse variance weighting as the primary method for MR analysis. Additionally, we assessed potential sources of heterogeneity and horizontal pleiotropy through the Cochran's Q test and MR-Egger regression. Moreover, we used multivariate MR to determine whether smoking versus alcohol consumption had an effect on the outcomes. We found no causal relationship between metabolic syndrome and its components and prostate cancer(MetS, odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.738-1.223, p = 0.691; TG, [OR] = 1.02, 95%[CI] = 0.96-1.08, p = 0.59); HDL, [OR] = 1.02, 95% [CI] = 0.97-1.07, p = 0.47; DBP, [OR] = 1.00, 95%[CI] = 0.99-1.01, p = 0.87; SBP, [OR] = 1.00, 95%[CI] = 0.99-1.00, p = 0.26; FBG [OR] = 0.92, 95%[CI] = 0.81-1.05, p = 0.23; WC, [OR] = 0.93, 95%[CI] = 0.84-1.03, p = 0.16). Finally, the MVMR confirms that the metabolic syndrome and its components are independent of smoking and alcohol consumption in prostate cancer. We didn't find significant evidence to determine a causal relationship between the metabolic syndrome and its components and prostate cancer through MR analysis. Further research is necessary to explore the potential pathogenesis between the two diseases.

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Shanxi Province holds an important strategic position in the overall ecological pattern of the Yellow River Basin. To investigate the changes of the ecological environment in the Shanxi section of the Yellow River Basin from 2000 to 2020, we selected MODIS remote sensing image data to determine the remote sensing ecological index (RSEI) based on the principal component analysis of greenness, humidity, dryness, and heat. Then, we analyzed the spatial and temporal variations of ecological quality in this region to explore the influencing factors. We further used the CA-Markov model to simulate and predict the ecological environment under different development scenarios in the Shanxi section of the Yellow River Basin in 2030. The results showed that RSEI had good applicability in the Shanxi section of the Yellow River Basin which could be used to monitor and evaluate the spatiotemporal variations in its ecological environment. From 2000 to 2020, the Shanxi section of the Yellow River Basin was dominated by low quality habitat areas, in which the ecological environment quality continued to improve from 2000 to 2010 and decreased from 2010 to 2020. The high quality habitat areas mainly located on the mountainous areas with superior natural conditions and rich biodiversity, while the low ecological quality areas were mainly in the Taiyuan Basin and the northern part of the study area, where the mining industry developed well. Climate factors were negatively correlated with ecological environment quality in the northern and central parts of the study area, and positively correlated with that in the mountainous area. Under all three development scenarios, the area of cultivated land, forest, water and construction land increased in 2030 compared to that in 2020. Compared to the natural development scenario and the cultivated land protection scenario, the ecological constraint scenario with RSEI as the limiting factor had the highest area of new forest and the lowest expansion rate of cultivated land and construction land. The results would provide a reference for land space planning and ecological environment protection in the Shanxi section of the Yellow River Basin.

Repair spinal cord injury with a versatile anti-oxidant and neural regenerative nanoplatform.

Spinal cord injury (SCI) often results in motor and sensory deficits, or even paralysis. Due to the role of the cascade reaction, the effect of excessive reactive oxygen species (ROS) in the early and middle stages of SCI severely damage neurons, and most antioxidants cannot consistently eliminate ROS at non-toxic doses, which leads to a huge compromise in antioxidant treatment of SCI. Selenium nanoparticles (SeNPs) have excellent ROS scavenging bioactivity, but the toxicity control problem limits the therapeutic window. Here, we propose a synergistic therapeutic strategy of SeNPs encapsulated by ZIF-8 (SeNPs@ZIF-8) to obtain synergistic ROS scavenging activity. Three different spatial structures of SeNPs@ZIF-8 were synthesized and coated with ferrostatin-1, a ferroptosis inhibitor (FSZ NPs), to achieve enhanced anti-oxidant and anti-ferroptosis activity without toxicity. FSZ NPs promoted the maintenance of mitochondrial homeostasis, thereby regulating the expression of inflammatory factors and promoting the polarization of macrophages into M2 phenotype. In addition, the FSZ NPs presented strong abilities to promote neuronal maturation and axon growth through activating the WNT4-dependent pathways, while prevented glial scar formation. The current study demonstrates the powerful and versatile bioactive functions of FSZ NPs for SCI treatment and offers inspiration for other neural injury diseases.

Advancing autologous CAR T-cell therapy through real-time patient health data integration: a simulation-based approach.

Autologous chimeric antigen receptor T-cell therapy presents promising treatment outcomes for various cancers. However, its potential is restrained by unique supply chain challenges, including dynamic patient health conditions and extended turnaround time. These challenges often lead to missed optimal treatment windows, impeding the effective delivery of life-saving treatments. This article presents SimPAC (simulation-based decision support for Patient-centric manufacturing of autologous cell therapies). SimPAC is designed to model and incorporate real-time patient health conditions into the supply chain decisions of autologous chimeric antigen receptor T-cell therapy. SimPAC integrates system dynamics and agent-based simulation techniques, facilitating the adaptation of manufacturing processes and production schedules based on real-time patient health conditions. SimPAC can model various patient disease progressions using parametric functions, nonparametric functions, or tabular data. Additionally, SimPAC offers easy configuration options to model various cell therapy supply chains. We provide two case studies to demonstrate the capabilities of SimPAC and highlight the benefits of patient-centric manufacturing, including improved survival rates and potential economic advantages. However, while the benefits are significant, our study also emphasizes the importance of balancing improved patient outcomes, economic viability and ethical considerations in the context of personalized medicine. SimPAC can be used to explore applications of this approach to diverse therapeutic contexts and supply chain configurations.

Grooving and Absorption on Substrates to Reduce the Bulk Acoustic Wave for Surface Acoustic Wave Micro-Force Sensors.

Improving measurement accuracy is the core issue with surface acoustic wave (SAW) micro-force sensors. An electrode transducer can stimulate not only the SAW but also the bulk acoustic wave (BAW). A portion of the BAW can be picked up by the receiving transducer, leading to an unwanted or spurious signal. This can harm the device's frequency response characteristics, thereby potentially reducing the precision of the micro-force sensor's measurements. This paper examines the influence of anisotropy on wave propagation, and it also performs a phase-matching analysis between interdigital transducers (IDTs) and bulk waves. Two solutions are shown to reduce the influence of BAW for SAW micro sensors, which are arranged with acoustic absorbers at the ends of the substrate and in grooving in the piezoelectric substrate. Three different types of sensors were manufactured, and the test results showed that the sidelobes of the SAW micro-force sensor could be effectively inhibited (3.32 dB), thereby enhancing the sensitivity and performance of sensor detection. The SAW micro-force sensor manufactured using the new process was tested and the following results were obtained: the center frequency was 59.83 MHz, the fractional bandwidth was 1.33%, the range was 0-1000 mN, the linearity was 1.02%, the hysteresis was 0.59%, the repeatability was 1.11%, and the accuracy was 1.34%.

Minimally Invasive Costal Cartilage Harvesting Incision for Chest Deformity in Microtia Reconstruction.

BACKGROUND: Chest deformity is a potential complication associated with auricular reconstruction using autologous costal cartilage. The impact of the incision size employed for costal cartilage harvesting on chest deformities remains unclear. This study aimed to investigate the correlation between the incision size used for harvesting costal cartilage and the occurrence of chest deformities. METHODS: We retrospectively analyzed patients who underwent ear reconstruction using autologous costal cartilage between June 2021 and September 2022. The patients were categorized into two groups based on the size of the costal cartilage incision: large and small. Chest computed tomography (CT) was performed 18-24 months postoperatively, followed by three-dimensional color map quantification to assess the degree of asymmetry of the chest surface. Subsequently, quantitative data analysis was performed to compare the extent of chest asymmetry between the large- and small-incision groups. The Visual Analog Scale (VAS) was used to assess patient satisfaction with chest morphology. RESULTS: This study included 62 patients, with an equal distribution of 31 in each group. The mean asymmetry value of the small and large incision groups was -3.15 ± 1.88 and -5.27 ± 3.63, respectively. Moreover, the mean VAS score for the small and large incision groups was 7.48 ± 0.72 and 5.09 ± 0.94, respectively. Statistically significant differences were observed between the two groups. CONCLUSIONS: Small incision costal cartilage harvesting can effectively alleviate the severity of chest deformities and significantly enhance patient satisfaction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A GAD1 inhibitor suppresses osteosarcoma growth through the Wnt/ß-catenin signaling pathway.

Background: As a marker of the GABAergic system, the expression of glutamate decarboxylase 1 (GAD1) is mainly restricted to the central nervous system. Emerging studies have shown that aberrant expression of GAD1 in tumor tissues may promote tumor cell growth. The role of GAD1 in the development of osteosarcoma (OS) remains unclear, so this study sought to investigate the expression status of GAD1 and the effect of its specific inhibitor 3-mercaptopropionic acid (3-MPA) on OS. Methods: The R2 database was used to analyze the relationship between the expression of GAD1 and clinical prognosis in OS patients. Immunohistochemistry was used to compare the expression profile of GAD1 between OS and matched neighboring tissues. The potential antitumor effects of 3-MPA on cell viability, colony formation and the cell cycle were examined. Moreover, the in vivo effect of 3-MPA on tumor growth was investigated using tumor-bearing nude mice. Results: The expression level of GAD1 was aberrantly upregulated in OS tissues, but almost no expression of GAD1 was found in matched neighboring tissues. Western blotting analyses showed upregulation of GAD1 in OS cells compared to human osteoblast cells. In vitro and in vivo, 3-MPA significantly suppressed the growth of OS. Regarding the mechanism, 3-MPA inhibited ß-catenin and cyclin D1 in OS cells, thereby inactivating the Wnt/ß-catenin pathway. Conclusions: OS displays increased expression of the GABAergic neuronal marker GAD1, and 3-MPA significantly reduces OS growth by inhibiting the Wnt/ß-catenin pathway.

A robust web-based tool to predict viral shedding in patients with Omicron SARS-CoV-2 variants.

Background: Data on viral kinetics and variants affecting the duration of viral shedding were limited. Our objective was to determine viral shedding in distinct severe acute respiratory syndrome coronavirus 2 variants, including Omicron BA.4/5 and BF.7, and to identify the relevant influencing factors. Methods: We carried out a longitudinal cohort study at Beijing Xiaotangshan Fangcang shelter hospital from May to June 2022 (Omicron BA.4/5) and from November to December 2022 (Omicron BF.7). Nucleocapsid protein (N) and open reading frame (ORF) genes were considered as the target genes of the reverse transcription PCR. The daily results of cycle threshold (CT), including lowest ORF1ab-CT values for days 1-3 post-hospitalisation and lowest N-CT values for days 1-3 post-hospitalisation (CT3minN) and demographic and clinical characteristics were collected. Results: 1433 patients with coronavirus disease 2019 (COVID-19) were recruited from the Fangcang shelter hospital, in which 278 patients were diagnosed with Omicron BA.4/5 and 1155 patients with Omicron BF.7. Patients with BF.7 infection showed a longer duration of viral shedding. The duration of viral shedding was associated with the variants age, alcohol use, the severity of COVID-19 and CT3minN. Moreover, the nomogram had excellent accuracy in predicting viral shedding. Conclusions: Our results indicated that patients with Omicron BF.7 had a longer period of contagiousness than those with BA.4/5. The duration of viral shedding was affected by a variety of factors and the nomogram may become an applicable clinical instrument to predict viral shedding. Furthermore, we developed a new COVID-19 viral shedding predicting model that can accurately predict the duration of viral shedding for COVID-19, and created a user-friendly website to apply this prediction model (https://puh3.shinyapps.io/CVSP_Model/).

Serum klotho associated with thyroid hormone in adults: A population-based cross-sectional research.

BACKGROUND AND STUDY AIM: The klotho protein, a multifunctional protein, has been shown to be associated with a wide range of endocrine diseases and has been linked to thyroid tumourigenesis. However, the relationship between serum klotho levels and thyroid hormones remains poorly understood. This study aimed to explore the correlation between serum klotho levels and thyroid hormones. METHODS: Data was obtained from the NHANES cycles 2007-2008, 2009-2010, and 2011-2012. A total of 4674 participants were recruited for this study. Statistical analysis was using multiple linear regression analyses, and restricted cubic spline plots (RCS) to investigate the association between serum klotho levels and serum levels of thyroid hormones. RESULTS: In the unadjusted covariate model, ln(klotho) significantly positively correlated with tT3, tT4, fT3, tT4/fT4, and tT3/fT3 (all P<0.01) and negatively correlated with TSH, tT4/tT3, and fT4/fT3 (all P<0.05). Furthermore, tT3, tT4, fT3and tT3/fT3 (P < 0.05) were still significant in the adjusted model. And it is worth noting that there is an approximately L-shaped nonlinear relationship between ln(klotho) and fT3,tT3 with a cut-off point of 6.697 (P-non-linear < 0.05). The stratification analysis showed gender and iodine level differences in the relationship between serum Klotho levels and thyroid hormones. CONCLUSION: There is an L-shaped nonlinear relationship between ln(klotho) and fT3, tT3, suggesting that klotho could be involved in the physiological regulation of thyroid function.

Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.

The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46+ILC3 in tumors positively correlates with monocytic cells and conventional type 2 dendritic cells, revealing potentially new interconnected immune cell subsets in the tumor microenvironment. Consequently, these observations may have direct relevance to tumor microenvironment composition and how ILC subset may influence anti-tumor immunity.

The role of Interleukin-22 in severe acute pancreatitis.

Severe acute pancreatitis (SAP) begins with premature activation of enzymes, promoted by the immune system, triggering a potential systemic inflammatory response that leads to organ failure with increased mortality and a bleak prognosis. Interleukin-22 (IL-22) is a cytokine that may have a significant role in SAP. IL-22, a member of the IL-10 cytokine family, has garnered growing interest owing to its potential tissue-protective properties. Recently, emerging research has revealed its specific effects on pancreatic diseases, particularly SAP. This paper provides a review of the latest knowledge on the role of IL-22 and its viability as a therapeutic target in SAP.