Hidden hotspots of amphibian biodiversity in China.

Identifying and protecting hotspots of endemism and species richness is crucial for mitigating the global biodiversity crisis. However, our understanding of spatial diversity patterns is far from complete, which severely limits our ability to conserve biodiversity hotspots. Here, we report a comprehensive analysis of amphibian species diversity in China, one of the most species-rich countries on Earth. Our study combines 20 y of field surveys with new molecular analyses of 521 described species and also identifies 100 potential cryptic species. We identify 10 hotspots of amphibian diversity in China, each with exceptional species richness and endemism and with exceptional phylogenetic diversity and phylogenetic endemism (based on a new time-calibrated, species-level phylogeny for Chinese amphibians). These 10 hotspots encompass 59.6% of China's described amphibian species, 49.0% of cryptic species, and 55.6% of species endemic to China. Only four of these 10 hotspots correspond to previously recognized biodiversity hotspots. The six new hotspots include the Nanling Mountains and other mountain ranges in South China. Among the 186 species in the six new hotspots, only 9.7% are well covered by protected areas and most (88.2%) are exposed to high human impacts. Five of the six new hotspots are under very high human pressure and are in urgent need of protection. We also find that patterns of richness in cryptic species are significantly related to those in described species but are not identical.

Interventions to improve access to primary care for inclusion health groups in England: a scoping review.

BACKGROUND: Everyone in England has the right to primary care without financial charges. Nevertheless, evidence shows that barriers remain for inclusion health populations such as vulnerable migrants, people experiencing homelessness, Gypsy, Roma, and Traveller (GRT) communities, and people who sell sex. There is little evidence for what works to improve access. This study was a scoping review of interventions to improve access to mainstream primary care for inclusion health groups in England. METHODS: In this scoping review, we searched databases (Embase, Medline, APA PsychInfo, the Cochrane Collaboration Library, Web of Science and CINAHL) and grey literature sources, including the National Health Service and National Institute for Clinical Excellence, for articles published in English between Jan 1, 2010, and Dec 31, 2020, with no limit on study design. Data were extracted according to inclusion criteria, including interventions taking place in England and targeting people with insecure immigration status, people who sell sex, people experiencing homelessness, and GRT communities. Results were presented in a narrative synthesis. FINDINGS: 39 studies describing one or more interventions were included: four peer-reviewed articles (one randomised trial, two quality improvement projects, and one mixed-methods study protocol) and 25 grey literature items (38 interventions in total). Interventions mostly targeted people with insecure immigration status (17/38, 45%), and a majority (12/38, 32%) took place in London. The most common types of intervention were training, education, and resources (such as leaflets or websites) for patients or staff (25/38, 66%), and most interventions targeted GP registration processes (28/38, 74%). Interventions commonly involved voluntary and community sector organisations (16/38, 42%). Most interventions were not evaluated to understand their effectiveness (23/38, 61%). Sources with evaluations identified staff training, direct patient advocacy, and involvement of people with lived experience as effective elements. INTERPRETATION: Interventions to improve access to primary care for inclusion health groups in England were heterogeneous, commonly undertaken at community level, and developed to serve local inclusion health groups. Considerations for policymakers and practitioners include groups and geographical areas less commonly included in interventions, the elements of positive practice identified in evaluations, and the need for evaluation of future interventions. FUNDING: National Institute for Health and Care Research (NIHR 202050).

Perspectives on registration to primary care from inclusion health groups in England: a mixed-method study.

BACKGROUND: Although everyone living in the UK is entitled to access free primary care within the National Health Service (NHS), evidence shows that people in need of health care are wrongly being refused access. This study aimed to explore the perspectives of individuals from inclusion health groups on primary care registration and accessibility. METHODS: This was a mixed-methods study. From Oct 5, 2022, to Feb 20, 2023, we surveyed 49 people (36 [73%] men; 12 [24%] women) and interviewed 25 other (14 [56%] men; 11 [44%] women) who were service users of the University College London Hospital Find & Treat mobile service. This service included people with lived experience of homelessness, asylum seeking, addiction, selling sex, and irregular immigration. We recruited these participants through hostels for people with ongoing addiction and complex needs, initial asylum accommodation centres, and day shelters. Our research team included two peer researchers. FINDINGS: Of those surveyed, 25 (51%) perceived their access to primary health-care services as good, and 17 (35%) reported obstacles to going to the general practitioner (GP). Participants described multiple barriers to registering for GP surgeries, including a lack of understanding and poor communication with NHS services, a fear of discrimination, and a lack of digital access that prevents information seeking and access to services. Respondents also reported using emergency services instead of primary care because they were more immediately accessible without previous registration. Facilitators to GP registration included one-on-one support and outreach work that helps people navigate into services and know their rights, and the use of specialist GP services, which are perceived as more accepting, especially for people experiencing homelessness. INTERPRETATION: The barriers to registration identified are related to both individual and group level characteristics and produce both similar and divergent needs between different inclusion health groups. The need for additional support during registration was clear, and our work highlights the requirement for interventions to improve access to primary care for underserved groups, as well as coordinated policy action. One-on-one support in particular, either outreach or provided in services where inclusion health groups spend time, appears to be a key facilitator to ensuring comprehensive and fast access to GP services. FUNDING: National Institute for Health and Care Research (NIHR).

A weighted bilinear neural collaborative filtering approach for drug repositioning.

Drug repositioning is an efficient and promising strategy for traditional drug discovery and development. Many research efforts are focused on utilizing deep-learning approaches based on a heterogeneous network for modeling complex drug-disease associations. Similar to traditional latent factor models, which directly factorize drug-disease associations, they assume the neighbors are independent of each other in the network and thus tend to be ineffective to capture localized information. In this study, we propose a novel neighborhood and neighborhood interaction-based neural collaborative filtering approach (called DRWBNCF) to infer novel potential drugs for diseases. Specifically, we first construct three networks, including the known drug-disease association network, the drug-drug similarity and disease-disease similarity networks (using the nearest neighbors). To take the advantage of localized information in the three networks, we then design an integration component by proposing a new weighted bilinear graph convolution operation to integrate the information of the known drug-disease association, the drug's and disease's neighborhood and neighborhood interactions into a unified representation. Lastly, we introduce a prediction component, which utilizes the multi-layer perceptron optimized by the α-balanced focal loss function and graph regularization to model the complex drug-disease associations. Benchmarking comparisons on three datasets verified the effectiveness of DRWBNCF for drug repositioning. Importantly, the unknown drug-disease associations predicted by DRWBNCF were validated against clinical trials and three authoritative databases and we listed several new DRWBNCF-predicted potential drugs for breast cancer (e.g. valrubicin and teniposide) and small cell lung cancer (e.g. valrubicin and cytarabine).

Extreme phonon anharmonicity underpins superionic diffusion and ultralow thermal conductivity in argyrodite Ag8SnSe6.

Ultralow thermal conductivity and fast ionic diffusion endow superionic materials with excellent performance both as thermoelectric converters and as solid-state electrolytes. Yet the correlation and interdependence between these two features remain unclear owing to a limited understanding of their complex atomic dynamics. Here we investigate ionic diffusion and lattice dynamics in argyrodite Ag8SnSe6 using synchrotron X-ray and neutron scattering techniques along with machine-learned molecular dynamics. We identify a critical interplay of the vibrational dynamics of mobile Ag and a host framework that controls the overdamping of low-energy Ag-dominated phonons into a quasi-elastic response, enabling superionicity. Concomitantly, the persistence of long-wavelength transverse acoustic phonons across the superionic transition challenges a proposed 'liquid-like thermal conduction' picture. Rather, a striking thermal broadening of low-energy phonons, starting even below 50 K, reveals extreme phonon anharmonicity and weak bonding as underlying features of the potential energy surface responsible for the ultralow thermal conductivity (<0.5 W m-1 K-1) and fast diffusion. Our results provide fundamental insights into the complex atomic dynamics in superionic materials for energy conversion and storage.

Differential expression of FSTL1 and its correlation with the pathological process of periodontitis.

AIMS: This study aimed to elucidate the alterations in Follistatin-like protein 1 (FSTL1) and its association with the pathological process of periodontitis. METHODS: This study included 48 patients with periodontitis and 42 healthy controls. The expression level of FSTL1 in the gingiva was determined by RT-qPCR, validated using the dataset GSE16134, and subsequently examined by western blotting. Bioinformatics analysis revealed a single-cell distribution of FSTL1, characteristic of angiogenesis and immune cell infiltration. The expression and distribution of FSTL1, vascular endothelial marker protein CD31 and myeloperoxidase (MPO), the indicator of neutrophil activity, were determined by immunohistochemistry (IHC). A series of correlation analyses was performed to determine the associations between FSTL1 and clinical parameters, including probing depth (PD) and clinical attachment loss (CAL), and their potential role in angiogenesis (CD31) and neutrophil infiltration (MPO). RESULTS: FSTL1 was significantly upregulated in the gingiva of patients with periodontitis compared to their healthy counterparts. In addition, FSTL1 was positively correlated with the clinical parameters PD (r = .5971, p = .0005) and CAL (r = .6078, p = .0004). Bioinformatic analysis and IHC indicated that high FSTL1 expression was significantly correlated with angiogenesis and neutrophil infiltration in periodontitis. Moreover, receiver operating characteristic (ROC) analysis demonstrated that FSTL1 could serve as an independent indicator for evaluating the severity of periodontitis (area under the curve [AUC] = 0.9011, p < .0001). CONCLUSION: This study demonstrated FSTL1 upregulation in periodontitis and its potential contribution to the disease via angiogenesis and neutrophil infiltration.

Effects of immediate loading directionality on the mechanical sensing protein PIEZO1 expression and early-stage healing process of peri-implant bone.

BACKGROUND: The reduced treatment time of dental implants with immediate loading protocol is an appealing solution for dentists and patients. However, there remains a significant risk of early peri-implant bone response following the placement of immediately loaded implants, and limited information is available regarding loading directions and the associated in vivo characteristics of peri-implant bone during the early stages. This study aimed to investigate the effects of immediate loading directionality on the expression of mechanical sensing protein PIEZO1 and the healing process of peri-implant bone in the early stage. METHODS: Thirty-two implants were inserted into the goat iliac crest models with 10 N static lateral immediate loading applied, followed by histological, histomorphological, immunohistochemical, X-ray microscopy and energy dispersive X-ray spectroscopy evaluations conducted after 10 days. RESULTS: From evaluations at the cellular, tissue, and organ levels, it was observed that the expression of mechanical sensing protein PIEZO1 in peri-implant bone was significantly higher in the compressive side compared to the tensile side. This finding coincided with trends observed in interfacial bone extracellular matrix (ECM) contact percentage, bone mass, and new bone formation. CONCLUSIONS: This study provides a novel insight into the immediate loading directionality as a potential influence factor for dental implant treatments by demonstrating differential effects on the mechanical sensing protein PIEZO1 expression and related early-stage healing processes of peri-implant bone. Immediate loading directions serve as potential therapeutic influence factors for peri-implant bone during its early healing stage.

Effect of 10 Minutes of Prewarming and Prewarmed Intravenous Fluid Administration on the Core Temperature of Patients Undergoing Transurethral Surgery under General Anesthesia.

Background: Patients undergoing transurethral urologic procedures using bladder irrigation are at increased risk of perioperative hypothermia. Thirty minutes of prewarming prevents perioperative hypothermia. However, its routine application is impractical. We evaluated the effect of 10 minutes of prewarming combined with the intraoperative administration of warmed intravenous fluid on patients' core temperature. Methods: Fifty patients undergoing transurethral bladder or prostate resection under general anesthesia were included in this study and were randomly allocated to either the control group or the prewarming group. Patients in the prewarming group were warmed for 10 minutes before anesthesia induction with a forced-air warming device and received warmed intravenous fluid during operations. The patients in control group did not receive preoperative forced-air warming and were administered room-temperature fluid. Participants' core body temperature was measured on arrival at the preoperative holding area (T0), on entering the operating room, immediately after anesthesia induction, and in 10-minute intervals from then on until the end of the operation (Tend), on entering PACU, and in 10-minute intervals during the postanesthesia care unit stay. The groups' incidence of intraoperative hypothermia, change in core temperature (T0 - Tend), and postoperative thermal comfort were compared. Results: The incidence of hypothermia was 64% and 29% in the control group and prewarming group, respectively (P = 0.015). Change in core temperature was 0.93 ± 0.3 °C and 0.55 ± 0.4 °C in the control group and prewarming group, respectively (P = 0.0001). Thermal comfort was better in the prewarming group (P = 0.004). Conclusions: Ten minutes of prewarming combined with warmed intravenous fluid significantly decreased the incidence of intraoperative hypothermia and resulted in better thermal comfort in patients undergoing transurethral urologic surgery under general anesthesia.

Myositis Autoantibody Profiles and Clinical Significance in Patients with Inflammatory Myopathies in Southwest China.

BACKGROUND: The purpose of this study is to analyze the distribution of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) in patients with idiopathic inflammatory myopathies (IIMs) in southwest China and to explore the relevance between each subtype, each clinical feature, and to explore the relevance between the laboratory indexes. METHODS: For this study, 200 patients with IIMs were tested for myositis autoantibodies. Clinical manifestations and laboratory metrics were collected and the correlations between autoantibodies and clinical phenotypes were analyzed. RESULTS: MSAs were found in 73.5% of the patients. The most frequently MSAs were anti-MDA5 (26.8%), followed by anti-ARS (18.5%). Anti-Ro52 was the most prevalent in MAAs (46.2%). Interstitial lung disease (ILD) and arthralgia were more frequent in anti-MDA5 and anti-Jo-1 positive groups (each p < 0.05). Anti-TIF1-γ and anti-NXP2 were associated with dysphagia (each p < 0.05). Different antibody subtypes were associated with laboratory indicators of response to muscle damage and immune status. Logistic regression showed that anti-MDA5 and anti-Jo-1 were independent risk factors for ILD (OR = 4.542, p = 0.004; OR = 4.290, p = 0.018, respectively) and arthralgia (OR = 7.856, p = 0.000; OR = 5.731, p = 0.004, respectively), whereas anti-TIF1-γ and anti-NXP2 were independent risk factors for dysphagia (OR = 4.521, p = 0.009; OR = 6.889, p = 0.017, respectively). CONCLUSIONS: Different antibody subtypes were associated with specific clinical features. Anti-MDA5 and anti-Jo-1 were independent risk factors for ILD and arthralgia. Anti-TIF1-γ and anti-NXP2 were independent risk factors for dysphagia.

Towards a more practical analysis of Newton's rings using deep learning.

As a typical form of optical fringes with a quadratic phase, Newton's ring patterns play an important role in spherical measurements and optical interferometry. A variety of methods have been used to analyze Newton's ring patterns. However, it is still rather challenging to fulfill the analysis. We present a deep-learning-based method to estimate the parameters of Newton's ring patterns and fulfill the analysis accordingly. The experimental results indicate the excellent accuracy, noise robustness, and demodulation efficiency of our method. It provides another applicable approach to analyzing Newton's ring patterns and brings insights into fringe analysis and interferometry-based measurements.

Extracorporeal vs. conventional CPR for out-of-hospital cardiac arrest: A systematic review and meta-analysis.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) remains a significant cause of mortality and morbidity worldwide. Extracorporeal cardiopulmonary resuscitation (ECPR) is a potential intervention for OHCA, but its effectiveness compared to conventional cardiopulmonary resuscitation (CCPR) needs further evaluation. METHOD: We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, and ClinicalTrials.gov for relevant studies from January 2010 to March 2023. Pooled meta-analysis was performed to investigate any potential association between ECPR and improved survival and neurological outcomes. RESULTS: This systematic review and meta-analysis included two randomized controlled trials enrolling 162 participants and 10 observational cohort studies enrolling 4507 participants. The pooled meta-analysis demonstrated that compared to CCRP, ECPR did not improve survival and neurological outcomes at 180 days following OHCA (RR: 3.39, 95% CI: 0.79 to 14.64; RR: 2.35, 95% CI: 0.97 to 5.67). While a beneficial effect of ECPR was obtained regarding 30-day survival and neurological outcomes. Furthermore, ECPR was associated with a higher risk of bleeding complications. Subgroup analysis showed that ECPR was prominently beneficial when exclusively initiated in the emergency department. Additional post-resuscitation treatments did not significantly impact the efficacy of ECPR on 180-day survival with favorable neurological outcomes. CONCLUSIONS: There is no high-quality evidence supporting the superiority of ECPR over CCPR in terms of survival and neurological outcomes in OHCA patients. However, due to the potential for bias, heterogeneity among studies, and inconsistency in practice, the non-significant results do not preclude the potential benefits of ECPR. Further high-quality research is warranted to optimize ECPR practice and provide more generalizable evidence. Clinical trial registration PROSPERO, https://www.crd.york.ac.uk/prospero/, registry number: CRD42023402211.

Computed Tomography Scan of the Aorta to Predict Type B Aortic Dissection.

BACKGROUND: The purpose of this study is to find the high-risk morphological features in type B aortic dissection (TBAD) population and to establish an early detection model. METHODS: From June 2018 to February 2022, 234 patients came to our hospital because of chest pain. After examination and definite diagnosis, we excluded people with previous cardiovascular surgery history, connective tissue disease, aortic arch variation, valve malformation, and traumatic dissection. Finally, we included 49 patients in the TBAD group and 57 in the control group. The imaging data were retrospectively analyzed by Endosize (Therevna 3.1.40) software. The aortic morphological parameters mainly include diameter, length, direct distance, and tortuosity index. Multivariable logistic regression models were performed and systolic blood pressure (SBP), aortic diameter at the left common carotid artery (D3), and length of ascending aorta (L1) were chosen to build a model. The predictive capacity of the models was evaluated through the receiver operating characteristic (ROC) curve analysis. RESULTS: The diameters in the ascending aorta and aortic arch are larger in the TBAD group (33.9 ± 5.9 vs. 37.8 ± 4.9 mm, p < 0.001; 28.2 ± 3.9 vs. 31.7 ± 3.0 mm, p < 0.001). The ascending aorta was significantly longer in the TBAD group (80.3 ± 11.7 vs. 92.3 ± 10.6 mm, p < 0.001). Besides, the direct distance and tortuosity index of the ascending aorta in the TBAD group increased significantly (69.8 ± 9.0 vs. 78.7 ± 8.8 mm, p < 0.001; 1.15 ± 0.05 vs. 1.17 ± 0.06, p < 0.05). Multivariable models demonstrated that SBP, aortic diameter at the left common carotid artery (D3), and length of ascending aorta (L1) were independent predictors of TBAD occurrence. Based on the ROC analysis, area under the ROC curve of the risk prediction models was 0.831. CONCLUSION: Morphological characteristic including diameter of total aorta, length of ascending aorta, direct distance of ascending aorta, and tortuosity index of ascending aorta are valuable geometric risk factors. Our model shows a good performance in predicting the incidence of TBAD.

Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis.

INTRODUCTION: Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. METHODS: This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. RESULTS: Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627-1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177-0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD. CONCLUSION: This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.

Tumor-associated microbiota in colorectal cancer with vascular tumor thrombus and neural invasion and association with clinical prognosis.

Neural invasion (NI) and vascular tumor thrombus (VT) are associated with poor prognosis in patients with colorectal cancer (CRC). In this study, we apply 16S rRNA amplicon sequencing to tumor tissues and adjacent normal tissues in patients with CRC to determine the microbial differences. A discovery cohort, including 30 patients with NI, 23 with VT, and 35 with double-negative CRC tissue, is utilized. Then, we analyze the relationship between the specific bacterial taxa and indicators of different dimensions in separate cohorts. In the discovery cohort, the diversity and composition of the gut microbiome distinctly differ between the tumor and nontumor tissues in the NI and VT groups. A high abundance of Cupriavidus is found to be related to a short survival time of NI CRC, while Herbaspirillum is a potential microbial biomarker predicting the prognosis of patients with CRC with NI or VT. Moreover, the abundance of Cupriavidus or Herbaspirillum is associated with some clinical patient characteristics and prognosis, respectively. In conclusion, this study is the first to comprehensively elaborate the differences in the gut microbiota of patients with CRC with different invasion statuses and to prove the relationship between some gut microbiota and clinical patient characteristics.

Role of αENaC in root resorption of adjacent teeth due to entirely impacted mandibular third molars.

BACKGROUND: Entirely impacted mandibular third molar (EIM3M) concerns the pathological external root resorption (ERR) of the adjacent mandibular second molar (M2M) and formation of granulation tissue between two molars. The study aimed to clarify the effect of αENaC, a mechano-sensitive molecule, to explore the mechanical mechanism in this scenario. METHODS: The force EIM3M exerted on M2M was proved by finite element analysis. αENaC expressions were tested by real-time polymerase chain reaction (PCR), immunoblotting and immunofluorescence. Inflammatory and epithelial-mesenchymal transition (EMT)-related molecules expressions were also detected by real-time PCR. The correlation was analyzed by Spearman's correlation analysis, and receiver-operator characteristic (ROC) curve was further exhibited. RESULTS: The force was concentrated in the ERR area. αENaC was upregulated, positively correlated with ERR degree and localized to the fibroblasts in ERR granulation tissues. Moreover, αENaC was respectively and positively associated with elevated TNF-α and N-cadherin in ERR granulation tissues. More importantly, ROC analysis verified αENaC as a novel indication of the incidence of this disease. CONCLUSIONS: Our finding revealed the force from EIM3M causing ERR of M2M, and elucidated the expression and localization of αENaC and its positive correlation with inflammation, EMT and disease severity, suggesting a novel indication in this disease.

Expression patterns of mechanosensitive ion channel PIEZOs in irreversible pulpitis.

BACKGROUND: Mechanosensitive ion channel PIEZOs have been widely reported to involve inflammation and pain. This study aimed to clarify expression patterns of PIEZOs and their potential relations to irreversible pulpitis. MATERIALS AND METHODS: Normal pulp tissues (n = 29) from patients with impacted third molars and inflamed pulp tissues (n = 23) from patients with irreversible pulpitis were collected. Pain levels were assessed using a numerical rating scale. PIEZO expressions were measured using real-time PCR and then confirmed using GEO datasets GSE77459, immunoblot, and immunohistochemistry staining. Correlations of PIEZO mRNA expression with inflammatory markers, pain markers, or clinical pain levels were evaluated using Spearman's correlation analysis. Univariate analysis was conducted to analyze PIEZO expressions based on pain description and clinical examinations of cold test, percussion, palpation, and bite test. RESULTS: Compared with normal pulp tissues, mRNA expression levels of PIEZO1 were significantly increased in inflamed pulp tissues, while PIEZO2 was significantly decreased, which was further confirmed in GSE77459 and on a protein and histological level. The positive correlation of the mRNA expression levels between PIEZO1 and inflammatory markers, as well as between PIEZO2 and pain markers, was verified. PIEZO2 expression was also positively correlated with pain levels. Besides, irreversible pulpitis patients who reported continuous pain and who detected a positive response to cold stimulus exhibited a higher expression level of PIEZO2 in the inflamed pulp tissues. By contrast, patients reporting pain duration of more than one week showed a higher expression level of PIEZO1. CONCLUSIONS: This study demonstrated the upregulation of PIEZO1 and the downregulation of PIEZO2 in irreversible pulpitis and revealed the potential relation of PIEZO1 and PIEZO2 to inflammation and pain. These findings suggested that PIEZOs might play critical roles in the progression of irreversible pulpitis and paved the way for further investigations aimed at novel therapies of irreversible pulpitis by targeting PIEZOs.

[Clinicians' Practice and Opinions on Sedation Therapy in End-Stage Patients].

Objective To investigate clinicians' practice and opinions on sedation therapy in end-stage patients at Peking Union Medical College Hospital. Methods From August,2022 to April,2023,an online questionnaire survey was conducted among clinicians involved in end-stage patient management. Results A total of 205 questionnaires were distributed,with an effective response rate of 56.1%.Among the clinicians,55.7% of them had experience of applying sedation therapy in end-stage patients;85.2% of clinicians believed that sedation could relieve the suffering of terminal patients from physical refractory symptoms;75.7% of clinicians considered that sedation therapy could be used to relieve agony from psycho-existential distress.Most clinicians had concerns about sedation therapy due to the lack of legal support(86.1%)and the lack of understanding of patients or families(59.1%).The majority (90.4%) of clinicians were willing to receive training on palliative sedation. Conclusions A majority of clinicians agree that sedation therapy could relieve the physical distress and psycho-existential distress in end-stage patients.However,most clinicians have concerns about the application of sedation therapy due to the lack of legal support.It is necessary to enhance the training on palliative sedation.

The prognostic value of a combined immune score in tumor and immune cells assessed by immunohistochemistry in triple-negative breast cancer.

BACKGROUND: This study aimed to develop a novel combined immune score (CIS)-based model assessing prognosis in triple-negative breast cancer (TNBC). METHODS: The expression of eight immune markers (PD-1, PD-L1, PD-L2, IDO, TIM3, OX40, OX40L, and H7-H2) was assessed with immunohistochemistry on the tumor cells (TCs) and immune cells (ICs) of 227 TNBC cases, respectively, and subsequently associated with selected clinicopathological parameters and survival. Data retrieved from The Cancer Genome Atlas (TCGA) were further examined to validate our findings. RESULTS: All immune markers were often expressed in TCs and ICs, except for PD-1 which was not expressed in TCs. In ICs, the expression of all immune markers was positively correlated between one another, except between PD-L1 and OX40, also TIM3 and OX40. In ICs, PD-1, PD-L1, and OX40L positive expression was associated with a longer progression-free survival (PFS; p = 0.040, p = 0.020, and p = 0.020, respectively). In TCs, OX40 positive expression was associated with a shorter PFS (p = 0.025). Subsequently, the TNBC patients were classified into high and low combined immune score groups (CIS-H and CIS-L), based on the expression levels of a selection of biomarkers in TCs (TCIS-H or TCIS-L) and ICs (ICIS-H or ICIS-L). The TCIS-H group was significantly associated with a longer PFS (p < 0.001). Furthermore, the ICIS-H group was additionally associated with a longer PFS (p < 0.001) and overall survival (OS; p = 0.001), at significant levels. In the multivariate analysis, both TCIS-H and ICIS-H groups were identified as independent predictors of favorable PFS (p = 0.012 and p = 0.001, respectively). ICIS-H was also shown to be an independent predictor of favorable OS (p = 0.003). The analysis of the mRNA expression data from TCGA also validated our findings regarding TNBC. CONCLUSION: Our novel TCIS and ICIS exhibited a significant prognostic value in TNBC. Additional research would be needed to strengthen our findings and identify the most efficient prognostic and predictive biomarkers for TNBC patients.

Association between oxidative stress, mitochondrial function of peripheral blood mononuclear cells and gastrointestinal cancers.

BACKGROUND: The incidence and mortality rate of gastrointestinal cancers are high worldwide. Increasing studies have illustrated that the occurrence, progression, metastasis and prognosis of cancers are intimately linked to the immune system. Mitochondria, as the main source of cellular energy, play an important role in maintaining the physiological function of immune cells. However, the relationship between mitochondrial function of immune cells and tumorigenesis has not yet been systematically investigated. METHODS: A total of 150 cases, including 60 healthy donors and 90 primary gastrointestinal cancer patients without anti-tumor treatments (30 with gastric cancer, 30 with liver cancer and 30 with colorectal cancer) were involved in our study. The oxidant/antioxidant and cytokine levels in plasma, the ROS level, mitochondrial function and apoptosis ratio of peripheral blood mononuclear cells (PBMCs) were evaluated. RESULTS: The imbalance between oxidant and antioxidant in plasma was discovered in the primary gastrointestinal cancer patients. The levels of cell reactive oxygen species (ROS) and mitochondrial ROS in PBMCs of primary gastrointestinal cancers were significantly increased compared with that in healthy donors. Meanwhile, the ATP content, the mtDNA copy number and the mitochondrial membrane potential (MMP) in PBMCs of patients with primary gastrointestinal cancers were lower than those in control group. The decreased MMP also occurred in immune cells of gastrointestinal cancers, including T cell, B cell, NK cell and monocyte. Furthermore, the PBMCs apoptosis ratio of primary gastrointestinal cancer patients was significantly higher than that of control group. Importantly, an increase of IL-2 and IL-6 and a decrease of IgG in plasma were found in the patients with primary gastrointestinal cancers. These changes of mitochondrial function in immune cells were consistent among primary gastrointestinal cancers without anti-tumor treatments, such as liver cancer, gastric cancer and colorectal cancer. CONCLUSION: Our study demonstrated that the imbalance of oxidation/antioxidation in primary gastrointestinal cancer patients without anti-tumor treatments results in excessive ROS. The oxidative stress was associated to the mitochondrial dysfunction, the apoptosis of immune cells and eventually the abnormal immune function in primary gastrointestinal cancers. The application of immune cell mitochondrial dysfunction into clinical evaluation is anticipated.

KIAA1199 drives immune suppression to promote colorectal cancer liver metastasis by modulating neutrophil infiltration.

BACKGROUND AND AIMS: Metastasis is the primary cause of cancer mortality, and colorectal cancer (CRC) frequently metastasizes to the liver. Our previous studies demonstrated the critical role of KIAA1199 in tumor invasion and metastasis in CRC. In the present study, we described an immune regulatory effect of KIAA1199 that creates a permissive environment for metastasis. APPROACH AND RESULTS: Flow cytometry was used to examine the effects of KIAA1199 on the infiltration of tumor immune cells. Neutrophils and T cells were isolated, stimulated, and/or cultured for in vitro function assays. In the patients with CRC, high expression levels of KIAA1199 were associated with an increased neutrophil infiltration into the liver. This result was further validated in mouse metastasis models. The increased influx of neutrophils contributed to the KIAA1199-driven CRC liver metastasis. Mechanistically, KIAA1199 activated the TGFß signaling pathway by interacting with the TGFBR1/2 to stimulate CXCL1 and CXCL3 production, thereby driving the aggregation of immunosuppressive neutrophils. Genetic blockade or pharmacologic inhibition of KIAA1199 restored tumor immune infiltration, impeded tumor progression, and potentiated response to immune checkpoint blockade (ICB). CONCLUSIONS: These findings indicated that KIAA1199 could facilitate the liver infiltration of immunosuppressive neutrophils via the TGFß-chemokine (C-X-C motif) ligand (CXCL)3/1-CXCR2 axis, which might be clinically targeted for the treatment of hepatic metastasis.