Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis.

Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.

Lipidomics revealed alterations in glycerophospholipid metabolism in skin squamous cell carcinoma.

Background: Skin squamous cell carcinoma (SCC) is a prevalent malignancy, and dysregulated lipid metabolism has been implicated in its pathogenesis. However, detailed characterization of lipid alterations in SCC remains limited. Methods: We analyzed lipid metabolic variations in tissue samples from 34 SCC patients and adjacent healthy tissues (located more than 1 cm from the tumor margin) using liquid chromatography-mass spectrometry (LC-MS). Data visualization and discriminatory lipid profiles were identified using principal component analysis (PCA) and sparse partial least squares discriminant analysis (sPLS-DA). Key lipids involved in the SCC metabolism were identified and further validated using an external data set (from a previous study, which similarly explored lipid profiles in oral SCC using lipidomics approaches). Pathway enrichment analysis was conducted to elucidate the metabolic pathways associated with these key lipids. Results: Eight lipids were identified by comparing SCC and healthy tissues including PI(16:0/22:4), PI(18:1/20:4), PE(16:0/20:4), PE(16:0/22:5), PE(16:0/22:6), PE(18:1/20:3), PC(18:1/20:2), and PC(18:2/20:2), as confirmed by independent datasets. All of these lipids were upregulated in SCC tumor tissues. Pathway enrichment analysis revealed significant alterations in glycerophospholipid metabolic pathways, particularly affecting the metabolism of diacylglycerophosphocholines, glycerophosphoethanolamines, and glycerophosphoinositols. Conclusion: Our findings reveal that dysregulated glycerophospholipid metabolism plays a pivotal role in the development of SCC.

Association Between the Copper-to-Zinc Ratio and Cardiovascular Disease Among Chinese Adults: A China Multi-ethnic Cohort (CMEC) Study.

The impact of metal exposure on cardiovascular diseases has become an increasingly concerning topic. To date, few studies have investigated the relationship between the copper-to-zinc ratio and CVD (Cardiovascular disease). This China multi-ethnic cohort study explored the association between the copper-to-zinc ratio and CVD in Chinese adults. The study included a sample size of 9878 people. Logistic regression analysis was used to examine the correlation between urinary copper, urinary zinc, and the copper-to-zinc ratio and CVD prevalence. Restricted cubic spline (RCS) analysis was used to investigate the potential dose-response relationships among copper-to-zinc ratio, urinary copper, urinary zinc, and CVD prevalence. In addition, the least absolute shrinkage and selection operator (LASSO) regression method was used to identify significant risk factors associated with CVD, leading to the development of a nomogram. The predictive performance of the nomogram model for CVD was assessed using the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Compared with the copper-to-zinc ratio in Q1, the copper-to-zinc ratio in Q4 was associated with CVD after adjusting for all potential confounders (Model 3) (Q4, odds ratio [OR] 0.608, 95% confidence interval [CI] 0.416-0.889, P = 0.010). After adjusting for all potential confounders (Model 3), urinary copper levels in Q4 were associated with CVD (Q4, odds ratio [OR] 0.627, 95% confidence interval [CI] 0.436-0.902, P = 0.012). No significant difference was found between urinary zinc levels and CVD. The RCS showed a linear dose-response relationship between the copper-to-zinc ratio and CVD (P for overall = 0.01). The nomogram based on the influencing factors examined with LASSO showed good predictive power, and the AUC was 76.3% (95% CI 73.7-78.9%). Our results suggest that there is a significant linear negative correlation between the copper-to-zinc ratio and CVD in Chinese adults and that it has good predictive value for CVD.

Aucubin suppresses TLR4/NF-κB signalling to shift macrophages toward M2 phenotype in glucocorticoid-associated osteonecrosis of the femoral head.

In this study, we investigated whether the ability of aucubin to mitigate the pathology of GONFH involves suppression of TLR4/NF-κB signalling and promotion of macrophage polarization to an M2 phenotype. In necrotic bone tissues from GONFH patients, we compared levels of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages as well as levels of TLR4/NF-κB signalling. In a rat model of GONFH, we examined the effects of aucubin on these parameters. We further explored its mechanism of action in a cell culture model of M1 macrophages. Necrotic bone tissues from GONFH patients contained a significantly increased macrophage M1/M2 ratio, and higher levels of TLR4, MYD88 and NF-κB p65 than bone tissues from patients with hip osteoarthritis. Treating GONFH rats with aucubin mitigated bone necrosis and demineralization as well as destruction of trabecular bone and marrow in a dose-dependent manner, based on micro-computed tomography. These therapeutic effects were associated with a decrease in the overall number of macrophages, decrease in the proportion of M1 macrophages, increase in the proportion of M2 macrophages, and downregulation of TLR4, MYD88 and NF-κB p65. These effects in vivo were confirmed by treating cultures of M1 macrophage-like cells with aucubin. Aucubin mitigates bone pathology in GONFH by suppressing TLR4/NF-κB signalling to shift macrophages from a pro- to anti-inflammatory phenotype.

Granulomatous lobular mastitis treated by a combined internal and external treatment of traditional Chinese medicine: A case report.

BACKGROUND: Granulomatous lobular mastitis (GLM) is a rare benign inflammatory disease of the breast and is classified under comedo mastitis in traditional Chinese medicine (TCM). The etiology of this disease is unknown, and it mainly occurs in women of childbearing age. The diagnosis depends on histopathological biopsy. At present, there is no systematic and standardized treatment plan for GLM. In the absence of evidence supporting an infectious etiology, affected patients might continue to receive multiple courses of antibiotics and unnecessary surgery. CASE SUMMARY: A 37-year-old Chinese woman with a history of coronavirus disease 2019 infection presented with swelling and pain in the left breast. She also had erythema, nodules in the lower extremities, arthritis in both knees, cough, and headache. In the early stage of GLM, the mass was not significantly reduced by conservative treatment with internal application of TCM; hence, surgical treatment was carried out. The aim of postoperative treatment was to drain the pus, eliminate the necrosed tissue, and expand the muscles; fumigation and washing using TCM was applied. CONCLUSION: Combined internal and external treatment with TCM, following the principle of "Prioritize internal treatment before ulceration and emphasize external treatment after ulceration" was effective in our patient with GLM. The prognosis was good. We believe that TCM offered valuable therapeutic benefits in this disease.

Omics-Based Investigation on Mechanisms Controlling Cellular Internalization of Keratin Monomers during Biodegradation by Stenotrophomonas maltophilia DHHJ.

INTRODUCTION: The global poultry industry produces millions of tons of waste feathers every year, which can be bio-degraded to make feed, fertilizer, and daily chemicals. However, feather bio-degradation is a complex process that is not yet fully understood. This results in low degradation efficiency and difficulty in industrial applications. Omics-driven system biology research offers an effective solution to quickly and comprehensively understand the molecularmechanisms involved in a metabolic pathway. METHODS: In the early stage of this process, feathers are hydrolyzed into water-soluble keratin monomers. In this study, we used high-throughput RNA-seq technology to analyze the genes involved in the internalization and degradation of keratin monomers in Stenotrophomonas maltophilia DHHJ strain cells. Moreover, we used Co-IP with LC-MS/MS technology to search for proteins that interact with recombinant keratin monomers. RESULTS: We discovered TonB transports and molecular chaperones associating with the keratin monomer, which may play a crucial role in the transmembrane transport of keratin. Meanwhile, multiple proteases belonging to distinct families were identified as binding partners of keratin monomers, among which ATPases associated with diverse cellular activity (AAA+) family proteases are overrepresented. Four genes, including JJL50_15620, JJL50_17955 (TonB-dependent receptors), JJL50_03260 (ABC transporter ATP-binding protein), and JJL50_20035 (ABC transporter substrate-binding protein), were selected as representatives for determining their expressions under different culture conditions using qRT-PCR, and they were found to be upregulated in response to keratin degradation consistent with the data from RNA-seq and Co-IP. CONCLUSION: This study highlights the complexity of keratin biodegradation in S. maltophilia DHHJ, in which multiple pathways are involved such as protein folding, protein transport, and several protease systems. Our findings provide new insights into the mechanism of feather degradation.

[Discussion on reference sample research of traditional Chinese medicine compound preparations developed from catalogued ancient classical prescriptions].

The concept of reference sample was put forward in the Guidance on CMC of Traditional Chinese Medicine Compound Preparations Developed from Catalogued Ancient Classical Prescriptions(Interim). The research on reference sample is a key link in the research and development of traditional Chinese medicine(TCM) compound prescriptions from catalogued ancient classical prescriptions(known as Category 3.1 TCM). This paper discusses the content of research on reference sample by analyzing the characteristics of Category 3.1 TCM and the purpose of research on reference sample. Furthermore, suggestions on the research of reference sample are proposed according to the development and evaluation practice of Category 3.1 TCM and research achievements of TCM regulatory science, aiming to provide reference for colleagues in this industry.

Analysis of therapeutic monoclonal antibodies by imaged capillary isoelectric focusing (icIEF).

Imaged capillary isoelectric focusing (icIEF) is a preferred analytical method for determining isoelectric points (pIs) and charge heterogeneity profiles in biotherapeutic proteins. In this study, we optimized the icIEF method for an in-house IgG1κ monoclonal antibody (mAb-1) and assessed its reproducibility, robustness, and autosampler stability. The optimized method was used to evaluate batch-to-batch consistency in pIs for multiple lots of mAb-1 and determine the relative percentages of charge variants. We also tested the method's performance using multiple lots of another IgG1 mAb, commercially available as Herceptin (trastuzumab). Additionally, we designed and assessed native and denaturing platform icIEF methods for 11 other marketed mAbs, with pIs ranging from 6.0 (eculizumab) to 9.22 (tocilizumab).

Associations between individual and mixed urinary metal exposure and dyslipidemia among Chinese adults: Data from the China Multi-Ethnic Cohort Study.

The prevalence of dyslipidemia is increasing, and it has become a significant global public health concern. Some studies have demonstrated contradictory relationships between urinary metals and dyslipidemia, and the combined effects of mixed urinary metal exposure on dyslipidemia remain ambiguous. In this study, we examined how individual and combined urinary metal exposure are associated with the occurrence of dyslipidemia. According to the data from the 2018-2019 baseline survey database of the China Multi-Ethnic Cohort (CMEC) Study, a population of 9348 individuals was studied. Inductively coupled plasmamass spectrometry (ICP-MS) was used to measure 21 urinary metal concentrations in the collected adult urinary samples. The associations between urinary metals and dyslipidemia were analyzed by logistic regression, weighted quantile sum regression (WQS), and quantile-based g-computation (qgcomp), controlled for potential confounders to examine single and combined effects. Dyslipidemia was detected in 3231 individuals, which represented approximately 34.6 % of the total population. According to the single-exposure model, Al and Na were inversely associated with the risk of dyslipidemia (OR = 0.95, 95 % CI: 0.93, 0.98; OR = 0.89, 95 % CI: 0.83, 0.95, respectively), whereas Zn, Ca, and P were positively associated (OR = 1.69, 95 % CI: 1.42, 2.01; OR = 1.12, 95 % CI: 1.06, 1.18; OR = 1.21, 95 % CI: 1.09, 1.34, respectively). Moreover, Zn and P were significantly positively associated even after adjusting for these metals, whereas Al and Cr were negatively associated with the risk of dyslipidemia. The results of the WQS and qgcomp analyses showed that urinary metal mixtures were positively associated with the risk of dyslipidemia (OR = 1.26, 95 % CI: 1.15, 1.38; OR = 1.09, 95 % CI: 1.01, 1.19). This positive association was primarily driven by Zn, P, and Ca. In the sensitivity analyses with collinearity diagnosis, interaction, and stratified analysis, the results remained, confirming the reliability of the study findings. In this study, the individual and combined effects of urinary Zn, P, and Ca on dyslipidemia were determined, which provided novel insights into the link between exposure to metals and dyslipidemia.

Interaction between visual working memory and upright postural control in young adults: an event-related potential study based on the n-back paradigm.

As a part of the overall information-processing system of the brain, postural control is related to the cognitive processes of working memory. Previous studies have suggested that cognitive tasks and postural control processes can compete for resources in common brain areas, although there is an "inverted U" relationship between arousal level and behavioral control - the arousal level of individuals changes when performing cognitive tasks. However, the exact neural connections between the two are unclear. This may be related to the nature of cognitive tasks. Some studies believe that posture occupies not only spatial information processing resources but also visual non-spatial information processing resources. Other studies believe that posture control only occupies spatial information processing resources in the central system, but does not occupy non-spatial information processing resources. Previous studies used different cognitive task materials and reached different conclusions. In this study, we used the same visuospatial and non-spatial materials, the n-back visual working memory paradigm, the event-related potential technique to investigate the effects of visuospatial and non-spatial working memory tasks on adolescents' postural control under different cognitive loads. The results of this study showed that in both visuospatial and non-spatial conditions, the N1 effect of the parieto-occipital lobe was larger during upright posture than in the sitting position (160-180 ms), the P300 effect of the central parieto-occipital region (280-460 ms) was induced by working memory in different postures, and the P300 wave amplitude was higher in the sitting position than in the upright position. We demonstrated that upright postural control enhances early selective attention but interferes with central memory encoding, thus confirming that postural control and visuospatial and non-spatial working memory share brain regions and compete with each other.

Pulmonary embolism in patients with chronic coronary syndrome masquerading as acute coronary syndrome: a case report and literature review.

BACKGROUND: Pulmonary embolisms (PEs) exhibit clinical features similar to those of acute coronary syndrome (ACS), including electrocardiographic abnormalities and elevated troponin levels, which frequently lead to misdiagnoses in emergency situations. CASE PRESENTATION: Here, we report a case of PE coinciding with chronic coronary syndrome in which the patient's condition was obscured by symptoms mimicking ACS. A 68-year-old female with syncope presented to the hospital. Upon admission, she was found to have elevated troponin levels and an electrocardiogram showing ST-segment changes across multiple leads, which initially led to a diagnosis of ACS. Emergency coronary arteriography revealed occlusion of the posterior branches of the left ventricle of the right coronary artery, but based on the complexity of the intervention, the occlusion was considered chronic rather than acute. On the 3rd day after admission, the patient experienced recurrent chest tightness and shortness of breath, which was confirmed as acute PE by emergency computed tomography pulmonary angiography. Following standardized anticoagulation treatment, the patient improved and was subsequently discharged. CONCLUSIONS: This case report highlights the importance of recognizing the nonspecific features of PE. Clinicians should be vigilant when identifying other clinical features that are difficult to explain accompanying the expected disease, and it is necessary to carefully identify the causes to prevent missed diagnoses or misdiagnoses.

Thoracoscopic pulmonary resection combined with real-time image-guided percutaneous ablation for multiple pulmonary nodules: a novel surgical approach and literature review.

Background: Due to the widespread use of computed tomography (CT) screening and advances in diagnostic techniques, an increasing number of patients with multiple pulmonary nodules are being detected and pathologically diagnosed as synchronous multiple primary lung cancers (sMPLC). It has become a new challenge to treat multiple pulmonary nodules and obtain a favorable prognosis while minimizing the perioperative risk for patients. The purpose of this study was to summarize the preliminary experience with a hybrid surgery combining pulmonary resection and ablation for the treatment of sMPLC and to discuss the feasibility of this novel procedure with a literature review. Methods: This is a retrospective non-randomized controlled study. From January 1, 2022 to July 1, 2023, four patients underwent hybrid surgery combining thoracoscopic pulmonary resection and percutaneous pulmonary ablation for multiple pulmonary nodules. Patients were followed up at 3, 6 and 12 months postoperatively and the last follow-up was on November 30, 2023. Clinical characteristics, perioperative outcomes, pulmonary function recovery and oncologic prognosis were recorded. Meanwhile we did a literature review of studies on hybridized pulmonary surgery for the treatment of multiple pulmonary nodules. Results: All the four patients were female, aged 52 to 70 years, and had no severe cardiopulmonary dysfunction on preoperative examination. Hybrid surgery of simultaneous pulmonary resection and ablation were performed in these patients to treat 2 to 4 pulmonary nodules, assisted by intraoperative real-time guide of C-arm X-ray machine. The operation time was from 155 to 240 minutes, and intraoperative blood loss was from 50 to 200 mL. Postoperative hospital stay was 2 to 7 days, thoracic drainage duration was 2 to 6 days, and pleural drainage volume was 300-1,770 mL. One patient presented with a bronchopleural fistula due to pulmonary ablation; the fistula was identified and sutured during thoracoscopic surgery and the patient recovered well. No postoperative 90-day complications occurred. After 3 months postoperatively, performance status scores for these patients recovered to 80 to 100. No tumor recurrence or metastasis was detected during the follow-up period. Conclusions: Hybrid procedures combining minimally invasive pulmonary resection with ablation are particularly suitable for the simultaneous treatment of sMPLC. Patients had less loss of pulmonary function, fewer perioperative complications, and favorable oncologic prognosis. Hybrid surgery is expected to be a better treatment option for patients with sMPLC.

Proteomics and its application in the research of acupuncture: An updated review.

As a complementary and alternative therapy, acupuncture is widely used in the prevention and treatment of various diseases. However, the understanding of the mechanism of acupuncture effects is still limited due to the lack of systematic biological validation. Notably, proteomics technologies in the field of acupuncture are rapidly evolving, and these advances are greatly contributing to the research of acupuncture. In this study, we review the progress of proteomics research in analyzing the molecular mechanisms of acupuncture for neurological disorders, pain, circulatory disorders, digestive disorders, and other diseases, with an in-depth discussion around acupoint prescription and acupuncture manipulation modalities. The study found that proteomics has great potential in understanding the mechanisms of acupuncture. This study will help explore the mechanisms of acupuncture from a proteomic perspective and provide information to support future clinical decisions.

Opportunistic use of chest low-dose computed tomography (LDCT) imaging for low bone mineral density and osteoporosis screening: cutoff thresholds for the attenuation values of the lower thoracic and upper lumbar vertebrae.

Background: Osteoporosis remains substantially underdiagnosed and undertreated worldwide. Chest low-dose computed tomography (LDCT) may provide a valuable and popular opportunity for osteoporosis screening. This study sought to evaluate the feasibility of the screening of low bone mineral density (BMD) and osteoporosis with mean attenuation values of the lower thoracic compared to upper lumbar vertebrae. The cutoff thresholds of the mean attenuation values in Hounsfield units (HU) were derived to facilitate implementation of opportunistic screening using chest LDCT. Methods: The participants aged 30 years or older who underwent chest LDCT and quantitative computed tomography (QCT) examinations from August 2018 to October 2020 in our hospital were consecutively included in this retrospective study. A region of interest (ROI) was placed in the trabecular bone of each vertebral body to measure the HU values. The correlations of mean HU values of lower thoracic (T11-T12) and upper lumbar (L1-L2) vertebrae with age and lumbar BMD obtained with QCT were performed using the Pearson correlation coefficient, respectively. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve was generated to determine the cutoff thresholds for distinguishing low BMD from normal and osteoporosis from non-osteoporosis. Results: A total of 1,112 participants were included in the final study cohort (743 men and 369 women, mean age 58.2±8.9 years; range, 32-88 years). The mean HU values of T11-T12 and L1-L2 were significantly different among 3 QCT-defined BMD categories of osteoporosis, osteopenia, and normal (P<0.001). The differences in HU values between T11-T12 and L1-L2 in each category of bone status were statistically significant (P<0.001). The mean HU values of T11-T12 (r=-0.453, P<0.001) and L1-L2 (r=-0.498, P<0.001) had negative correlations with age. Positive correlations were observed between the mean HU values of T11-T12 (r=0.872, P<0.001) and L1-L2 (r=0.899, P<0.001) with BMD. The optimal cutoff thresholds for distinguishing low BMD from normal were average T11-T12 ≤157 HU [AUC =0.941, 95% confidence interval (CI): 0.925-0.954, P<0.001] and L1-L2 ≤138 HU (AUC =0.950, 95% CI: 0.935-0.962, P<0.001), as well as distinguishing osteoporosis from non-osteoporosis were average T11-T12 ≤125 HU (AUC =0.960, 95% CI: 0.947-0.971, P<0.001) and L1-L2 ≤107 HU (AUC =0.961, 95% CI: 0.948-0.972, P<0.001). There was no significant difference between the AUC values of T11-T12 and L1-L2 for low BMD (P=0.07) and osteoporosis (P=0.92) screening. Conclusions: We have conducted a study on low BMD and osteoporosis screening using mean attenuation values of lower thoracic and upper lumbar vertebrae. Assessment of mean attenuation values of T11-T12 and L1-L2 can be used interchangeably for low BMD and osteoporosis screening using chest LDCT, and their cutoff thresholds were established.

Highly Stable Cesium Molybdenum Chloride Perovskite Nanocrystals for Photothermal Semihydrogenation Applications.

Metal halide perovskite materials with excellent carrier transport properties have been regarded as a new class of catalysts with great application potential. However, their development is hampered by their instability in polar solvents and high temperatures. Herein, we report a solution-processed Cs2MoCl6 perovskite nanocrystals (NCs) capped with the Mo6+, showing high thermostability in polar solvents. Furthermore, the Pd single atoms (PdSA) can be anchored on the surface of Cs2MoCl6 NCs through the unique coordination structure of Pd-Cl sites, which exhibit excellent semihydrogenation of different alkyne derivatives with high selectivity at full conversion at room temperature. Moreover, the activity could be improved greatly under Xe lamp irradiation. Detailed experimental characterization and DFT calculations indicate the improved activity under light illumination is due to the synergistic effect of photo-to-heat conversion and photoinduced electron transfer from Cs2MoCl6 to PdSA, which facilitates the activation of the C≡C group. This work not only provides a new catalyst for high selective semihydrogenation of alkyne derivatives but also opens a new avenue for metal halides as photothermal catalysts.

Towards long-tailed, multi-label disease classification from chest X-ray: Overview of the CXR-LT challenge.

Many real-world image recognition problems, such as diagnostic medical imaging exams, are "long-tailed" - there are a few common findings followed by many more relatively rare conditions. In chest radiography, diagnosis is both a long-tailed and multi-label problem, as patients often present with multiple findings simultaneously. While researchers have begun to study the problem of long-tailed learning in medical image recognition, few have studied the interaction of label imbalance and label co-occurrence posed by long-tailed, multi-label disease classification. To engage with the research community on this emerging topic, we conducted an open challenge, CXR-LT, on long-tailed, multi-label thorax disease classification from chest X-rays (CXRs). We publicly release a large-scale benchmark dataset of over 350,000 CXRs, each labeled with at least one of 26 clinical findings following a long-tailed distribution. We synthesize common themes of top-performing solutions, providing practical recommendations for long-tailed, multi-label medical image classification. Finally, we use these insights to propose a path forward involving vision-language foundation models for few- and zero-shot disease classification.

Spatial and functional targeting of intratumoral Tregs reverses CD8+ T cell exhaustion and promotes cancer immunotherapy.

Intratumoral Tregs are key mediators of cancer immunotherapy resistance, including anti-programmed cell death (ligand) 1 [anti-PD-(L)1] immune checkpoint blockade (ICB). The mechanisms driving Treg infiltration into the tumor microenvironment (TME) and the consequence on CD8+ T cell exhaustion remain elusive. Here, we report that heat shock protein gp96 (also known as GRP94) was indispensable for Treg tumor infiltration, primarily through the roles of gp96 in chaperoning integrins. Among various gp96-dependent integrins, we found that only LFA-1 (αL integrin), and not αV, CD103 (αE), or ß7 integrin, was required for Treg tumor homing. Loss of Treg infiltration into the TME by genetic deletion of gp96/LFA-1 potently induced rejection of tumors in multiple ICB-resistant murine cancer models in a CD8+ T cell-dependent manner, without loss of self-tolerance. Moreover, gp96 deletion impeded Treg activation primarily by suppressing IL-2/STAT5 signaling, which also contributed to tumor regression. By competing for intratumoral IL-2, Tregs prevented the activation of CD8+ tumor-infiltrating lymphocytes, drove thymocyte selection-associated high mobility group box protein (TOX) induction, and induced bona fide CD8+ T cell exhaustion. By contrast, Treg ablation led to striking CD8+ T cell activation without TOX induction, demonstrating clear uncoupling of the 2 processes. Our study reveals that the gp96/LFA-1 axis plays a fundamental role in Treg biology and suggests that Treg-specific gp96/LFA-1 targeting represents a valuable strategy for cancer immunotherapy without inflicting autoinflammatory conditions.

Prognostic Significance of Preoperative and Postoperative Evaluation of Combined Tumor Markers for Patients With Colon Cancer.

BACKGROUND: The combined value of the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in patients with colon cancer (CC) is unclear. This study aimed to investigate the role of composite tumor markers in the prognosis of CC. METHODS: Patients who underwent curative resection of colon adenocarcinoma were enrolled. The tumor marker status before and after the operation was used to divide the patients into groups according to the number of tumor markers with abnormal expression, and recurrence-free survival (RFS) and overall survival (OS) of different groups were compared. The impact of changes in composite tumor markers in the perioperative period on outcomes was further explored. RESULTS: Ultimately, 531 patients were enrolled in the study. As the number of preoperative and postoperative elevated tumor markers increased, both RFS and OS rates became lower (both P <0.05). Further analysis revealed that the number of elevated tumor markers after resection can significantly affect the outcomes (both P <0.05). In patients with abnormal preoperative tumor markers, normalization of markers after surgery was a protective factor for prognosis (both P <0.05), and patients with postoperative elevated levels of both tumor markers had a 5.5-fold and 6-fold increase in the risk of recurrence and death. In addition, patients with elevated markers after surgery had a high risk of recurrence within 5 years after colectomy. CONCLUSIONS: Postoperative tumor markers had a better ability to differentiate postoperative outcomes in patients with CC than preoperative tumor markers. Patients whose tumor markers normalized after surgery had a better prognosis.

Objectivization study of acupuncture Deqi and brain modulation mechanisms: a review.

Deqi is an important prerequisite for acupuncture to achieve optimal efficacy. Chinese medicine has long been concerned with the relationship between Deqi and the clinical efficacy of acupuncture. However, the underlying mechanisms of Deqi are complex and there is a lack of systematic summaries of objective quantitative studies of Deqi. Acupuncture Deqi can achieve the purpose of treating diseases by regulating the interaction of local and neighboring acupoints, brain centers, and target organs. At local and neighboring acupoints, Deqi can change their tissue structure, temperature, blood perfusion, energy metabolism, and electrophysiological indicators. At the central brain level, Deqi can activate the brain regions of the thalamus, parahippocampal gyrus, postcentral gyrus, insular, middle temporal gyrus, cingulate gyrus, etc. It also has extensive effects on the limbic-paralimbic-neocortical-network and default mode network. The brain mechanisms of Deqi vary depending on the acupuncture techniques and points chosen. In addition, Deqi 's mechanism of action involves correcting abnormalities in target organs. The mechanisms of acupuncture Deqi are multi-targeted and multi-layered. The biological mechanisms of Deqi are closely related to brain centers. This study will help to explore the mechanism of Deqi from a local-central-target-organ perspective and provide information for future clinical decision-making.

Carexqingyuanensis (Cyperaceae), a new species from Guangdong, China.

Carexqingyuanensis, a new species of Cyperaceae from Guangdong Province, China, is described and illustrated. The new species is morphologically similar to Carexpeliosanthifolia F. T. Wang & Tang ex P. C. Li, but it can be distinguished by the racemose inflorescence branches appearing single (rarely binate or ternate) (vs. binate or ternate), one (rarely two or three) (vs. 1-3) spiked, male part of linear-cylindrical spikes much longer than the female part (vs. just male part short-cylindrical and slightly longer than female part), style base thickened (vs. not thickened) and perigynium horizontally patent with a short (vs. long and excurved) beak. Phylogenetic analysis, based on the two nuclear DNA regions (ETS 1f and ITS) and three chloroplast DNA regions (matK, ndhF and rps16), suggests that the new species belongs to sect. Siderostictaes.s. of subg. Siderosticta and shows a closer phylogenetic relationship to Carexscaposa C. B. Clarke.