Near-infrared fluorescent probe to track Cys in plant roots under heavy metal hazards and its application in cells and zebrafish.

Heavy metals, including Hg2+, Cr6+ and Cd2+, have always been a major issue in environmental pollution, leading to abnormal changes in the levels of biologically active molecules including Cys in plants, seriously affecting all aspects of the growth and development of plants. This makes it essential to develop a simple and practical method to study the potential impact of heavy metals on plants. In this paper, our research group has developed near-infrared fluorescent probe WRM-S, which has the advantages of fast response, sensitivity to Cys, and successfully applying it to cells and zebrafish. Moreover, it combined the close relationship between heavy metal stress on plants and Cys, using Cys as the detection target, monitoring the internal environment changes of two plants under Hg2+, Cr6+, and Cd2+ stress in the environment, and then conducting 3D imaging. The results indicated that the probe has strong penetration ability in plant tissues, and revealed abnormal changes in plant Cys levels caused by heavy metal stress-induced cellular oxidative stress or cytotoxicity. Thus, the in-situ imaging detection of this probe provides a direction for the physiological dynamics research of plant environmental stress.

Integrating predictive coding and a user-centric interface for enhanced auditing and quality in cancer registry data.

Data curation for a hospital-based cancer registry heavily relies on the labor-intensive manual abstraction process by cancer registrars to identify cancer-related information from free-text electronic health records. To streamline this process, a natural language processing system incorporating a hybrid of deep learning-based and rule-based approaches for identifying lung cancer registry-related concepts, along with a symbolic expert system that generates registry coding based on weighted rules, was developed. The system is integrated with the hospital information system at a medical center to provide cancer registrars with a patient journey visualization platform. The embedded system offers a comprehensive view of patient reports annotated with significant registry concepts to facilitate the manual coding process and elevate overall quality. Extensive evaluations, including comparisons with state-of-the-art methods, were conducted using a lung cancer dataset comprising 1428 patients from the medical center. The experimental results illustrate the effectiveness of the developed system, consistently achieving F1-scores of 0.85 and 1.00 across 30 coding items. Registrar feedback highlights the system's reliability as a tool for assisting and auditing the abstraction. By presenting key registry items along the timeline of a patient's reports with accurate code predictions, the system improves the quality of registrar outcomes and reduces the labor resources and time required for data abstraction. Our study highlights advancements in cancer registry coding practices, demonstrating that the proposed hybrid weighted neural-symbolic cancer registry system is reliable and efficient for assisting cancer registrars in the coding workflow and contributing to clinical outcomes.

Extracorporeal cardiopulmonary resuscitation for patients with refractory out-of-hospital cardiac arrest: a propensity score matching, observational study.

Extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly performed as an adjunct to conventional cardiopulmonary resuscitation (CCPR) for refractory out-of-hospital cardiac arrest (OHCA). However, the specific benefits of ECPR concerning survival with favorable neurological outcomes remain uncertain. This study aimed to investigate the potential advantages of ECPR in the management of refractory OHCA. We conducted a retrospective cohort study involved OHCA patients between January 2016 and May 2021. Patients were categorized into ECPR or CCPR groups. The primary endpoint assessed was survival with favorable neurological outcomes, and the secondary outcome was survival rate. Multivariate logistic regression analyses, with and without 1:2 propensity score matching, were employed to assess ECPR's effect. In total, 1193 patients were included: 85underwent ECPR, and 1108 received CCPR. Compared to the CCPR group, the ECPR group exhibited notably higher survival rate (29.4% vs. 2.4%; p < 0.001). The ECPR group also exhibited a higher proportion of survival with favorable neurological outcome than CCPR group (17.6% vs. 0.7%; p < 0.001). Multivariate logistic regression analysis demonstrated that ECPR correlated with increased odds of survival with favorable neurological outcome (adjusted odds ratio: 13.57; 95% confidence interval (CI) 4.60-40.06). Following propensity score matching, the ECPR group showed significantly elevated odds of survival with favorable neurological outcomes (adjusted odds ratio: 13.31; 95% CI 1.61-109.9). This study demonstrated that in comparison to CCPR, ECPR may provide survival benefit and increase the odds of favorable neurological outcomes in selected OHCA patients.

[Pollution Characteristics and Ecological Risk Assessment of Microplastics in the Yangtze River Basin].

The Yangtze River, the largest river in China, has not been comprehensively studied for its basin's microplastic pollution status. Therefore, a comprehensive investigation and assessment system of microplastics was developed at the river basin scale to characterize the spatial distribution and composition of microplastics in the Yangtze River Basin in order to analyze their influencing factors and assess their ecological risks. The results showed that the microplastic abundance in the study area ranged from 21 to 44 080 n·m-3, with an average abundance of 4 483 n·m-3. The spatial distribution of microplastic abundance was higher in the tributaries than in the main streams (except the Ganjiang Basin), with the Chengdu of the Minjiang Basin being the tributary area with the highest abundance of microplastics detected. The size of microplastics in the river basin was concentrated in the 0-1 mm range; the shapes were mainly fiber and fragment; and the colors were mainly colored and transparent. Further, introducing the diversity index of microplastics, it was found that both the Simpson index and the Shannon-Wiener index could quantify the diversity of microplastic characteristic composition in the river basin, but there were certain differences in the changing trends between the two. Regression analysis showed that anthropogenic activities were significantly and positively correlated with microplastic abundance (P<0.05), and among the eight anthropogenic activity factors, civilian vehicle ownership and tourism income were the most strongly correlated with microplastic abundance, indicating that transportation and tourism were the main factors influencing microplastic distribution. From the perspective of the potential ecological risk index of microplastics, microplastics in the Yangtze River Basin posed a certain ecological risk, with 68.97% of the area falling within risk zones III and IV, with the ecological risk of microplastics in Taihu Lake warranting more widespread attention.

Total Synthesis of Dynobactin A.

The first total synthesis of the potent antimicrobial agent dynobactin A is disclosed. This synthesis enlists a singular aziridine ring opening strategy to access the two disparate ß-aryl-branched amino acids present within this complex decapeptide. Featuring a number of unique maneuvers to navigate inherently sensitive and epimerizable functional groups, this convergent approach proceeds in only 16 steps (LLS) from commercial materials and should facilitate the synthesis of numerous analogues for medicinal chemistry studies.

Stimulatory effect of methylglyoxal on capsaicin-sensitive lung vagal afferents in rats: role of TRPA1.

Methylglyoxal (MG), a reactive metabolic byproduct of glycolysis, is a causative of painful diabetic neuropathy. Patients with diabetes are associated with more frequent severe asthma exacerbation. Stimulation of capsaicin-sensitive lung vagal (CSLV) afferents may contribute to the pathogenesis of hyperreactive airway diseases such as asthma. However, the possibility of the stimulatory effect of MG on CSLV afferents and the underlying mechanisms remain unknown. Our results showed that intravenous injection of MG (25 mg/kg, MG25) in anesthetized, spontaneously breathing rats elicited pulmonary chemoreflexes characterized by apnea, bradycardia, and hypotension. The MG-induced apneic response was reproducible and dose dependent. MG25 no longer evoked these reflex responses after perineural capsaicin treatment of both cervical vagi to block C-fibers' conduction, suggesting that the reflexes were mediated through the stimulation of CSLV afferents. Pretreatment with HC030031 [an antagonist of transient receptor potential ankyrin subtype 1 protein (TRPA1)] or AP18 (another TRPA1 antagonist), but not their vehicle, markedly attenuated the apneic response induced by MG25. Consistently, electrophysiological results showed that pretreatment with HC030031 largely attenuated the intense discharge in CSLV afferents induced by injection of MG25 in open-chest and artificially ventilated rats. In isolated CSLV neurons, the perfusion of MG evoked an abrupt and pronounced increase in calcium transients in a concentration-dependent manner. This stimulatory effect on CSLV neurons was also abolished by HC030031 treatment but not by its vehicle. In conclusion, these results suggest that MG exerts a stimulatory effect on CSLV afferents, inducing pulmonary chemoreflexes, and such stimulation is mediated through the TRPA1 activation.NEW & NOTEWORTHY Methylglyoxal (MG) is implicated in the development of painful diabetic neuropathy. A retrospective cohort study revealed an increased incidence of asthma exacerbations in patients with diabetes. This study demonstrated that elevated circulating MG levels stimulate capsaicin-sensitive lung vagal afferents via activation of TRPA1, which in turn triggers respiratory reflexes. These findings provide new information for understanding the pathogenic mechanism of diabetes-associated hyperreactive airway diseases and potential therapy.

Room temperature operation of germanium-silicon single-photon avalanche diode.

The ability to detect single photons has led to the advancement of numerous research fields1-11. Although various types of single-photon detector have been developed12, because of two main factors-that is, (1) the need for operating at cryogenic temperature13,14 and (2) the incompatibility with complementary metal-oxide-semiconductor (CMOS) fabrication processes15,16-so far, to our knowledge, only Si-based single-photon avalanche diode (SPAD)17,18 has gained mainstream success and has been used in consumer electronics. With the growing demand to shift the operation wavelength from near-infrared to short-wavelength infrared (SWIR) for better safety and performance19-21, an alternative solution is required because Si has negligible optical absorption for wavelengths beyond 1 µm. Here we report a CMOS-compatible, high-performing germanium-silicon SPAD operated at room temperature, featuring a noise-equivalent power improvement over the previous Ge-based SPADs22-28 by 2-3.5 orders of magnitude. Key parameters such as dark count rate, single-photon detection probability at 1,310 nm, timing jitter, after-pulsing characteristic time and after-pulsing probability are, respectively, measured as 19 kHz µm-2, 12%, 188 ps, ~90 ns and <1%, with a low breakdown voltage of 10.26 V and a small excess bias of 0.75 V. Three-dimensional point-cloud images are captured with direct time-of-flight technique as proof of concept. This work paves the way towards using single-photon-sensitive SWIR sensors, imagers and photonic integrated circuits in everyday life.

The value of CT-based radiomics in predicting hemorrhagic transformation in acute ischemic stroke patients without recanalization therapy.

Objective: The aim of this study is to investigate the clinical value of radiomics based on non-enhanced head CT in the prediction of hemorrhage transformation in acute ischemic stroke (AIS). Materials and methods: A total of 140 patients diagnosed with AIS from January 2015 to August 2022 were enrolled. Radiomic features from infarcted areas on non-enhanced CT images were extracted using ITK-SNAP. The max-relevance and min-redundancy (mRMR) and the least absolute shrinkage and selection operator (LASSO) were used to select features. The radiomics signature was then constructed by multiple logistic regressions. The clinicoradiomics nomogram was constructed by combining radiomics signature and clinical characteristics. All predictive models were constructed in the training group, and these were verified in the validation group. All models were evaluated with the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: Of the 140 patients, 59 experienced hemorrhagic transformation, while 81 remained stable. The radiomics signature was constructed by 10 radiomics features. The clinicoradiomics nomogram was constructed by combining radiomics signature and atrial fibrillation. The area under the ROC curve (AUCs) of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the training group were 0.64, 0.86, and 0.86, respectively. The AUCs of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the validation group were 0.63, 0.90, and 0.90, respectively. The DCA curves showed that the radiomics signature performed well as well as the clinicoradiomics nomogram. The DCA curve showed that the clinical application value of the radiomics signature is similar to that of the clinicoradiomics nomogram. Conclusion: The radiomics signature, constructed without incorporating clinical characteristics, can independently and effectively predict hemorrhagic transformation in AIS patients.

HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-Related HCC with Distinct Features.

Introduction: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform. Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC. Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort. Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.

S100A11 promotes focal adhesion disassembly via myosin II-driven contractility and Piezo1-mediated Ca2+ entry.

S100A11 is a small Ca2+-activatable protein known to localize along stress fibers (SFs). Analyzing S100A11 localization in HeLa and U2OS cells further revealed S100A11 enrichment at focal adhesions (FAs). Strikingly, S100A11 levels at FAs increased sharply, yet transiently, just before FA disassembly. Elevating intracellular Ca2+ levels with ionomycin stimulated both S100A11 recruitment and subsequent FA disassembly. However, pre-incubation with the non-muscle myosin II (NMII) inhibitor blebbistatin or with an inhibitor of the stretch-activatable Ca2+ channel Piezo1 suppressed S100A11 recruitment, implicating S100A11 in an actomyosin-driven FA recruitment mechanism involving Piezo1-dependent Ca2+ influx. Applying external forces on peripheral FAs likewise recruited S100A11 to FAs even if NMII activity was inhibited, corroborating the mechanosensitive recruitment mechanism of S100A11. However, extracellular Ca2+ and Piezo1 function were indispensable, indicating that NMII contraction forces act upstream of Piezo1-mediated Ca2+ influx, in turn leading to S100A11 activation and FA recruitment. S100A11-knockout cells display enlarged FAs and had delayed FA disassembly during cell membrane retraction, consistent with impaired FA turnover in these cells. Our results thus demonstrate a novel function for S100A11 in promoting actomyosin contractility-driven FA disassembly.

Field temperature performances of in-use permeable sidewalks and asphalt vehicle roads and the potential impacts on apparent temperature and land surface temperature.

Permeable pavements help reduce surface temperatures and have been widely implemented in urban areas. This study utilized an in-use permeable pavement sidewalk in front of a mass rapid transit station in the Taipei city center of Taiwan to determine the actual pavement surface temperature performance. A neighboring asphalt road and impervious pavement were also monitored. With a full year of continuous monitoring, the results showed that the temperature of permeable pavement was 3.7 °C lower than that of impervious pavement and 4.5 °C lower than that of asphalt pavement in the hot season. The frequent rainfall in spring resulted in the smallest temperature differences between the different pavement types. The cooling effects of permeable pavement differed at the different air temperatures. At air temperatures lower than 15 °C, the differences among pavement surface temperatures were noticeable. However, when the air temperature was higher than 35 °C, the surface temperature of permeable pavement was not different from that of impervious pavement and was greater than 55 °C. Field observations were carried out to determine the effects on the apparent temperature and the future surface temperature of climate change scenarios. The results showed that permeable pavement could reduce the average apparent temperature to near the air temperature, and asphalt pavement could increase the apparent temperature by 1.2 °C, assuming that the pavement temperature completely affects the air temperature. With the good prediction ability of the machine learning approach and 15 environmental factors, the preliminary prediction showed the projected surface temperature change in Taipei city in 2033. In the worst-case scenario, the average impervious pavement temperature is as high as 39.12 °C, whereas the average permeable pavement temperature is 32.50 °C.

ALDOA coordinates PDE3A through the ß-catenin/ID3 axis to stimulate cancer metastasis and M2 polarization in lung cancer with EGFR mutations.

Lung cancer has a high incidence rate and requires more effective treatment strategies and drug options for clinical patients. EGFR is a common genetic alteration event in lung cancer that affects patient survival and drug strategy. Our study discovered aberrant aldolase A (ALDOA) expression and dysfunction in lung cancer patients with EGFR mutations. In addition to investigating relevant metabolic processes like glucose uptake, lactate production, and ATPase activity, we examined multi-omics profiles (transcriptomics, proteomics, and pull-down assays). It was observed that phosphodiesterase 3A (PDE3A) enzyme and ALDOA exhibit correlation, and furthermore, they impact M2 macrophage polarization through ß-catenin and downstream ID3. In addition to demonstrating the aforementioned mechanism of action, our experiments discovered that the PDE3 inhibitor trequinsin has a substantial impact on lung cancer cell lines with EGFR mutants. The trequinsin medication was found to decrease the M2 macrophage polarization status and several cancer phenotypes, in addition to transduction. These findings have potential prognostic and therapeutic applications for clinical patients with EGFR mutation and lung cancer.

Exclusive Enteral Nutrition Alleviates Th17-Mediated Inflammation via Eliminating Mechanical Stress-Induced Th17-Polarizing Cytokines in Crohn's-like Colitis.

BACKGROUND AND AIMS: Exclusive enteral nutrition (EEN) with a liquid diet is the only established dietary treatment for Crohn's' disease (CD). However, the mechanism of action of EEN in CD is unclear. T helper 17 (Th17) immune response plays a critical role in CD. We hypothesized that EEN alleviates Th17 response by eliminating mechanical stress-induced expression of Th17-polarizing cytokines. METHODS: A rat model of Crohn's-like colitis was established by intracolonic instillation of TNBS (65 mg/kg in 250 µL of 40% ethanol). Control rats were treated with saline. We characterized immunophenotypes and molecular changes of the colon in control and colitis rats with and without EEN treatment. Th17 differentiation was determined using coculture assays. RESULTS: TNBS instillation induced transmural inflammation with stenosis in the inflammation site and a marked increase of Th17-polarizing cytokines interleukin (IL)-6 and osteopontin and the Th17 cell population in the mechanically distended preinflammation site (P-site). EEN treatment eliminated mechanical distention and the increase of IL-6, osteopontin, and Th17 response in the P-site. IL-6 and osteopontin expression was found mainly in the muscularis externa. Mechanical stretch of colonic smooth muscle cells in vitro induced a robust increase of IL-6 and osteopontin. When naïve T cells were cultured with conditioned media from the P-site tissue or stretched cells, Th17 differentiation was significantly increased. Inhibition of IL-6, but not deletion of osteopontin, blocked the increase of Th17 differentiation. CONCLUSIONS: Mechanical stress induces Th17-polarizing cytokines in the colon. EEN attenuates Th17 immune response by eliminating mechanical stress-induced IL-6 in Crohn's-like colitis.

The Design and Fabrication of Large-Area Under-Screen Fingerprint Sensors with Optimized Aperture and Microlens Structures.

In this paper, we designed and fabricated an optical filter structure applied to the FoD (Fingerprint on Display) technology of the smartphone, which contains the microlens array, black matrix, and photodetector to recognize the fingerprint on a full touchscreen. First, we used optical ray tracing software, ZEMAX, to simulate a smartphone with FoD and a touching finger. We then further discussed how the aperture and microlens influence the fingerprint image in this design. Through numerical analysis and process constraint adjustment to optimize the structural design, we determined that a modulation transfer function (MTF) of 60.8% can be obtained when the thickness of the black matrix is 4 µm, allowing successful manufacturing using photolithography process technology. Finally, we used this filter element to take fingerprint images. After image processing, a clearly visible fingerprint pattern was successfully captured.

[Photosynthetic characteristics of Leymus chinensis and Medicago sativa in artificial grassland]. / ç¾Šè‰å’Œç´«èŠ±è‹œè“¿äººå·¥è‰åœ°å ‰åˆç‰¹æ€§.

To explore the effect of monoculture and mixture sowing artificial grassland on the photosynthetic characteristics of Leymus chinensis and Medicago sativa, we determined the diurnal variation of photosynthetic properties of L. chinensis and M. sativa under different treatments. The results showed that the diurnal changes of net photosynthetic rate, blade temperature and transpiration rate of L. chinensis and M. sativa showed 'unimodal type' in monoculture, the stomatal conductance of M. sativa showed 'unimodal type', and the stomatal conductance and water use efficiency of L. chinensis showed 'bimodal type'. Under the mixed sowing treatment, the diurnal changes of net photosynthetic rate, blade temperature and transpiration rate of L. chinensis and M. sativa showed 'unimodal type', the stomatal conductance and water use efficiency of L. chinensis showed 'unimodal type', and the stomatal conductance of M. sativa showed 'bimodal type'. The peak photosynthetic rate of L. chinensis under mixture was signi-ficantly higher than that under monoculture, being 17.72 and 13.65 µmol CO2·m-2·s-1, respectively. Under monoculture and mixture sowing treatments, the chlorophyll content of L. chinensis was higher than that of M. sativa, nitrogen content of the leaves of L. chinensis was lower than that of M. sativa, and the nitrogen content in the leaves of mixture sowing L. chinensis was significantly higher than that of monoculture sowing L. chinensis, which were 27.60 and 22.55 g·kg-1, respectively. Net photosynthetic rates of L. chinensis and M. sativa were significantly positively correlated with stomatal conductance and transpiration rate, and significantly negatively correlated with intercellular CO2 concentration under different planting methods. Net photosynthetic rate of M. sativa was significantly positively correlated with blade temperature and water use efficiency. In summary, mixed sowing was beneficial to enhance nitrogen content of L. chinensis. Our results provided a theoretical basis for the response of the photosynthetic characteristics of forage to planting mode of artificial grassland.

Haematopoietic cell-derived exosomes in cancer development and therapeutics: From basic science to clinical practice.

BACKGROUND: The tumour microenvironment (TME) is a specialised niche involving intercellular communication among cancer cells and various host cells. Among the host cells, the quantity and quality of immune cells within the TME play essential roles in cancer development and management. The immunologically suppressive, so-called 'cold' TME established by a series of tumour-host interactions, including generating immunosuppressive cytokines and recruiting regulatory host immune cells, is associated with resistance to therapies and worse clinical outcomes. MAIN BODY: Various therapeutic approaches have been used to target the cold TME, including immune checkpoint blockade therapy and adoptive T-cell transfer. A promising, less explored therapeutic strategy involves targeting TME-associated exosomes. Exosomes are nanometer-sized, extracellular vesicles that transfer material from donor to recipient cells. These particles can reprogram the recipient cells and modulate the TME. In particular, exosomes from haematopoietic cells are known to promote or suppress cancer progression under specific conditions. Understanding the effects of haematopoietic cell-secreted exosomes may foster the development of therapeutic exosomes (tExos) for personalised cancer treatment. However, the development of exosome-based therapies has unique challenges, including scalable production, purification, storage and delivery of exosomes and controlling batch variations. Clinical trials are being conducted to verify the safety, feasibility, availability and efficacy of tExos. CONCLUSION: This review summarises our understanding of how haematopoietic cell-secreted exosomes regulate the TME and antitumour immunity and highlights present challenges and solutions for haematopoietic cell-derived exosome-based therapies.

Measurement of Thermal Stress by X-ray Nano-Diffraction in (111)-Oriented Nanotwinned Cu Bumps for Cu/SiO2 Hybrid Joints.

X-ray nanodiffraction was used to measure the thermal stress of 10 µm nanotwinned Cu bumps in Cu/SiO2 hybrid structures at -55 °C, 27 °C, 100 °C, 150 °C, and 200 °C. Bonding can be achieved without externally applied compression. The X-ray beam size is about 100 nm in diameter. The Cu bump is dominated by (111) oriented nano-twins. Before the hybrid bonding, the thermal stress in Cu bumps is compressive and remains compressive after bonding. The average stress in the bonded Cu joint at 200 °C is as large as -169.1 MPa. In addition, using the strain data measured at various temperatures, one can calculate the effective thermal expansion coefficient (CTE) for the 10 µm Cu bumps confined by the SiO2 dielectrics. This study reports a useful approach on measuring the strain and stress in oriented metal bumps confined by SiO2 dielectrics. The results also provide a deeper understanding on the mechanism of hybrid bonding without externally applied compression.

CAN008 prolongs overall survival in patients with newly diagnosed GBM characterized by high tumor mutational burden.

BACKGROUND: A previous phase 1 dose-escalation study in Taiwan indicated CAN008 (asunercept) with standard concurrent chemoradiotherapy (CCRT) improved progression-free survival (PFS) in newly diagnosed glioblastoma (GBM) patients. This study evaluates the efficacy of CAN008 in promoting overall survival (OS) and identifies genetic alterations associated with treatment responses. METHODS: We compared OS of 5-year follow-ups from 9 evaluable CAN008 cohort patients (6 received high-dose and 3 received low-dose) to a historical Taiwanese GBM cohort with 164 newly diagnosed patients. CAN008 treatment response-associated genetic alterations were identified by whole-exome sequencing and comparing variant differences between response groups. Associations among patient survival, tumor mutational burden (TMB), and genetic alterations were analyzed using CAN008 cohort and TCGA-GBM dataset. RESULTS: OS for high-dose CAN008 patients at 2 and 5 years was 83% and 67%, respectively, and 40.1% and 8.8% for the historical GBM cohort, respectively. Better OS was observed in the high-dose CAN008 cohort (without reaching the median survival) than the historical GBM cohort (median OS: 20 months; p=0.0103). Five high-dose CAN008 patients were divided into good and poor response groups based on their PFS. A higher variant count and TMB were observed in good response patients, whereas no significant association was observed between TMB and patient survival in the newly diagnosed TCGA-GBM dataset, suggesting TMB may modulate patient CAN008 response. CONCLUSION: CAN008 combined with standard CCRT treatment prolonged the PFS and OS of newly diagnosed GBM patients compared to standard therapy alone. Higher treatment efficacy was associated with higher TMB.

Identification of immune microenvironment changes, immune-related pathways and genes in male androgenetic alopecia.

BACKGROUND: Although androgenetic alopecia (AGA) is classified as a non-inflammatory alopecia, histological evidence of microinflammation has long been recognized. However, changes in the immune microenvironment, immune-related pathways and the expression of immune-related genes (IRGs) involved in AGA remain unclear. METHODS: The microarray gene expression data (GSE36169) from patients with male AGA were analyzed. gene set enrichment analysis (GSEA) among statistically changed genes was done. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses among differentially expressed genes were performed. differentially expressed genes were screened to identify IRGs based on the ImmPort database. The cytohubba-MCC plugin of Cytoscape was applied to screen hub immune genes. The infiltration levels of 28 immune cells were quantified adopting single-sample GSEA (ssGSEA) algorithm. The microarray gene expression data (GSE90594) of male AGA was analyzed to validate hub IRGs genes and differential infiltrated immune cells. RESULTS: The ssGSEA revealed γδT cell, central memory CD8+ T cell, mast cell, immature B cell, activated CD8+ T cell, effector memory CD4+ T cell, eosinophil and neutrophil were significantly increased infiltration in the bald scalp. GSEA showed statistically changed genes were most enriched in immune related pathways, including innate immune system, adaptive immune system, cytokine signaling, interferon-γ signaling, interferon signaling and interleukins signaling. The 4 hub IRGs, including matrix metallopeptidase 9, protein tyrosine phosphatase receptor type C, bone morphogenetic protein 2, and thrombospondin 1, were enriched in the pathways of allograft rejection, coagulation and interferon-γ response. CONCLUSION: In summary, we proposed that the increase in γδ T cells, central memory CD8+ T cells, activated CD8+ T cell as well as the infiltration of mast cells contributed to immune microenvironment changes in male AGA. The 4 hub IRGs may be involved in the development and progression of hair loss in male AGA through interferon-γ signal pathways.