Efficient DNA walker guided by ordered cruciform-shaped DNA track for ultrasensitive and rapid electrochemical detection of lead ion.

The rational design of DNA tracks is an effective pathway to guide the autonomous movement and high-efficiency recognition in DNA walkers, showing outstanding advantages for the cascade signal amplification of electrochemical biosensors. However, the uncontrolled distance between two adjacent tracks on the electrode could increase the risk of derailment and interruption of the reaction. Hence, a novel four-way balanced cruciform-shaped DNA track (C-DNT) was designed as a structured pathway to improve the effectiveness and stability of the reaction in DNA walkers. In this work, two kinds of cruciform-shaped DNA were interconnected as a robust structure that could avoid the invalid movement of the designed DNA walker on the electrode. When hairpin H2 was introduced onto the electrode, the strand displacement reaction (SDR) effectively triggered movements of the DNA walker along the cruciform-shaped track while leaving ferrocene (Fc) on the electrode, leading to a significant enhancement of the electrochemical signal. This design enabled the walker to move in an excellent organized and controllable manner, thus enhancing the reaction speed and walking efficiency. Compared to other walkers moving on random tracks, the reaction time of the C-DNT-based DNA walker could be reduced to 20 min. Lead ion (Pb2+) was used as a model target to evaluate the analytical performance of this biosensor, which exhibited a low detection limit of 0.033 pM along with a wide detection ranging from 0.1 pM to 500 nM. This strategy presented a novel concept for designing a high-performance DNA walker-based sensing platform for the detection of contaminants.

Robust positive association between serum urate and the risk of chronic obstructive pulmonary disease: hospital-based cohort and Mendelian randomisation study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and hyperuricaemia are both characterised by systemic inflammation. Preventing chronic diseases among the population with common metabolic abnormality is an effective strategy. However, the association of hyperuricaemia with the higher incidence and risk of COPD remains controversial. Therefore, replicated researches in populations with distinct characteristics or demographics are compellingly warranted. METHODS: This cohort study adopted a design of ambispective hospital-based cohort. We used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to minimise the effects of potential confounding factors. A Cox regression model and restricted cubic spline (RCS) model were applied further to assess the effect of serum urate on the risk of developing COPD. Finally, we conducted a two-sample Mendelian randomisation (MR) analysis to explore evidence of causal association. RESULTS: There is a higher incidence in the population with hyperuricaemia compared with the population with normal serum urate (22.29/1000 person-years vs 8.89/1000 person-years, p=0.009). This result is robust after performing PSM (p=0.013) and IPTW (p<0.001). The Cox model confirms that hyperuricaemia is associated with higher risk of developing COPD (adjusted HR=3.35 and 95% CI=1.61 to 6.96). Moreover, RCS shows that the risk of developing COPD rapidly increases with the concentration of serum urate when it is higher than the reference (420 µmol/L). Finally, in MR analysis, the inverse variance weighted method evidences that a significant causal effect of serum urate on COPD (OR=1.153, 95% CI=1.034 to 1.289) is likely to be true. The finding of MR is robust in the repeated analysis using different methods and sensitivity analysis. CONCLUSIONS: Our study provides convincing evidence suggesting a robust positive association between serum urate and the risk of developing COPD, and indicates that the population with hyperuricaemia is at high risk of COPD in the Chinese population who seek medical advice or treatment in the hospital.

The Role of Hexokinases in Epigenetic Regulation: Altered Hexokinase Expression and Chromatin Stability in Yeast.

Background . Human hexokinase 2 ( HK2 ) plays an important role in regulating Warburg effect, which metabolizes glucose to lactate acid even in the presence of ample oxygen and provides intermediate metabolites to support cancer cell proliferation and tumor growth. HK2 overexpression has been observed in various types of cancers and targeting HK2 -driven Warburg effect has been suggested as a potential cancer therapeutic strategy. Given that epigenetic enzymes utilize metabolic intermediates as substrates or co-factors to carry out post-translational modification of DNA and histones in cells, we hypothesized that altering HK2 expression-mediated cellular glycolysis rates could impact the epigenome and, consequently, genome stability in yeast. To test this hypothesis, we established genetic models with different yeast hexokinase 2 ( HXK2) expression in Saccharomyces cerevisiae yeast cells and investigated the effect of HXK2 -dependent metabolism on parental nucleosome transfer, a key DNA replication-coupled epigenetic inheritance process, and chromatin stability. Results . By comparing the growth of mutant yeast cells carrying single deletion of hxk1Δ , hxk2Δ , or double-loss of hxk1Δ hxk2Δ to wild-type cells, we demonstrated that HXK2 is the dominant HXK in yeast cell growth. Surprisingly, manipulating HXK2 expression in yeast, whether through overexpression or deletion, had only a marginal impact on parental nucleosome assembly, but a noticeable trend with decrease chromatin instability. However, targeting yeast cells with 2-deoxy-D-glucose (2-DG), a HK2 inhibitor that has been proposed as an anti-cancer treatment, significantly increased chromatin instability. Conclusion . Our findings suggest that in yeast cells lacking HXK2 , alternative HXK s such as HXK1 or glucokinase 1 ( GLK1 ) play a role in supporting glycolysis at a level that adequately maintain epigenomic stability. While our study demonstrated an increase in epigenetic instability with 2-DG treatment, the observed effect seemed to occur independently of Hxk2-mediated glycolysis inhibition. Thus, additional research is needed to identify the molecular mechanism through which 2-DG influences chromatin stability.

2-Deoxyglucose and hydroxychloroquine HPLC-MS-MS analytical methods and pharmacokinetic interactions after oral co-administration in male rats.

Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2-addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) analytical methods for 2-DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples. Using a jugular vein-cannulated male rat model with serial blood collection before and after a single gavage dose of each drug alone or in combination, we examined their PK metrics for drug-drug interactions. The data demonstrated a rapid and complete separation of 2-DG from common monosaccharides by HPLC-MS-MS multi-reaction monitoring. Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of nine rats showed a peak time (Tmax ) for 2-DG of 0.5 h after 2-DG alone or with HCQ and identical post-peak half-life of approximately 1 h. With a seemingly bi-modal time course for HCQ, the Tmax for HCQ alone (1.2 h) was faster than that for the combination (2 h; p = .017). After combination dosing, the peak concentration (Cmax ) and area under the curve (AUC0-4h ) of 2-DG were decreased by 53.8% (p = .0004) and 53.7% (p = .0001), whereas AUC0-8h for HCQ was decreased by 30.8% (p = .0279) from the respective single dosing. Without changing the mean residence time (MRT0-∞ ) of each drug, the combination affected the apparent volume of distribution (Vd ) and clearance (CL) of 2-DG, and CL for HCQ without affecting its Vd . We observed significant negative PK interactions, probably at the intestinal absorption level, between 2-DG and HCQ taken simultaneously by mouth. Future optimization efforts are warranted for their combination regimen for clinical translation.

Circular RNA hsa_circ_0050386 suppresses non-small cell lung cancer progression via regulating the SRSF3/FN1 axis.

BACKGROUND: Lung cancer is the most prevalent cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all cases. Circular RNAs(circRNA) play crucial roles in regulating the progression of lung cancer. Despite the identification of a large number of circRNAs, their expression patterns, functions, and mechanisms of action in NSCLC development remain unclear.This study aims to investigate the transcriptional expressions, functions, and potential mechanisms of circRNA hsa_circ_0050386 in NSCLC. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized for the analysis of hsa_circ_0050386 expression. Cell proliferation was detected using the IncuCyte Live Cell Analysis System and clone formation assays. Migration and invasion of NSCLC cells were evaluated through Transwell assays. Flow cytometry was performed to assay cell cycle and apoptosis. Western blot was used to investigate protein expression. Protein binding analysis was conducted by employing pull-down assays, RNA immunoprecipitation (RIP), and mass spectrometry. The role of hsa_circ_0050386 in vivo was evaluated through the use of a xenograft model. RESULTS: The study discovered that hsa_circ_0050386 displayed lower expression levels in NSCLC tissues when compared to adjacent normal tissues. Patients exhibiting lower levels of hsa_circ_0050386 expression exhibited an inverse correlation with the Clinical Stage, T-stage, and M-stage of NSCLC. Functionally, hsa_circ_0050386 suppressed the proliferation and invasion of NSCLC cells both in vitro and in vivo. A comprehensive examination exposed the interaction between hsa_circ_0050386 and RNA binding protein Serine and arginine-rich splicing factor 3 (SRSF3), resulting in the down-regulation of Fibronectin 1 (FN1) expression, which inhibits the progression of NSCLC. CONCLUSIONS: Our study shows that hsa_circ_0050386 suppresses the malignant biological behavior of NSCLC cells by down-regulating the expression of FN1, and may serve as a potential biomarker and therapeutic target for NSCLC treatment.

Bibliometric and visualized analysis of cancer nanomedicine from 2013 to 2023.

Cancer nanomedicine has been an emerging field for drug development against malignant tumors during the past three decades. A bibliometric analysis was performed to characterize the current international trends and present visual representations of the evolution and emerging trends in the research and development of nanocarriers for cancer treatment. This study employed bibliometric analysis and visualization techniques to analyze the literature on antitumor nanocarriers published between 2013 and 2023. A total of 98,980 articles on antitumor nanocarriers were retrieved from the Web of Science Core Collection (WoSCC) database and analyzed using the Citespace software for specific characteristics such as publication year, countries/regions, organizations, keywords, and references. Network visualization was constructed by VOSviewer and Citespace. From 2013 to 2023, the annual global publications increased 7.39 times, from 1851 to 13,683. People's Republic of China (2588 publications) was the most productive country. Chinese Academy of Sciences (298 publications) was the most productive organization. The top 5 high-frequency keywords were "nanoparticles," "drug delivery," "nanomedicine," "cancer," and "nanocarriers." The keywords with the strongest citation bursts recently were "cancer immunotherapy," "microenvironment," "antitumor immunity," etc., which indicated the emerging frontiers of antitumor nanomedicine. The co-occurrence cluster analysis of the keywords formed 6 clusters, and most of the top 10 publications by citation counts focused on cluster #1 (nanocarriers) and cluster #2 (cancer immunotherapy). We further provided insightful discussions into the identified subtopics to help researchers gain more details of current trends and hotspots in this field. The present study processes a macro-level literature analysis of antitumor nanocarriers and provides new perspectives and research directions for future development in cancer nanomedicine.

Genetic susceptibility loci of lung cancer are associated with malignant risk of pulmonary nodules and improve malignancy diagnosis based on CEA levels.

Objective: The heightened prevalence of pulmonary nodules (PN) has escalated its significance as a public health concern. While the precise identification of high-risk PN carriers for malignancy remains an ongoing challenge, genetic variants hold potentials as determinants of disease susceptibility that can aid in diagnosis. Yet, current understanding of the genetic loci associated with malignant PN (MPN) risk is limited. Methods: A frequency-matched case-control study was performed, comprising 247 MPN cases and 412 benign NP (BNP) controls. We genotyped 11 established susceptibility loci for lung cancer in a Chinese cohort. Loci associated with MPN risk were utilized to compute a polygenic risk score (PRS). This PRS was subsequently incorporated into the diagnostic evaluation of MPNs, with emphasis on serum tumor biomarkers. Results: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G were identified as being associated with an increased risk of MPNs. The PRS, formulated from the cumulative risk effects of these loci, correlated with the malignant risk of PNs in a dose-dependent fashion. A high PRS was found to amplify the MPN risk by 156% in comparison to a low PRS [odds ratio (OR)=2.56, 95% confidence interval (95% CI), 1.40-4.67]. Notably, the PRS was observed to enhance the diagnostic accuracy of serum carcinoembryonic antigen (CEA) in distinguishing MPNs from BPNs, with diagnostic values rising from 0.716 to 0.861 across low- to high-PRS categories. Further bioinformatics investigations pinpointed rs10429489G>A as an expression quantitative trait locus. Conclusions: Loci rs10429489G>A, rs17038564A>G, and rs12265047A>G contribute to MPN risk and augment the diagnostic precision for MPNs based on serum CEA concentrations.

Long-Acting Nanohybrid Hydrogel Induces Persistent Immunogenic Chemotherapy for Suppressing Postoperative Tumor Recurrence and Metastasis.

Despite the continuous advancement of surgical resection techniques, postoperative tumor recurrence and metastasis remain a huge challenge. Here, we constructed an injectable curcumin/doxorubicin-loaded nanoparticle (NanoCD) hydrogel, which could effectively inhibit tumor regrowth and metastasis via reshaping the tumor immune microenvironment (TIME) for highly effective postsurgical cancer treatment. NanoCD was prepared by the controlled assembly of curcumin (CUR) and doxorubicin (DOX) via π-π stacking and hydrogen bonding in the presence of human serum albumin. To facilitate prolonged treatment of postsurgical tumors, NanoCD was further incorporated into the temperature-sensitive Poloxamer 407 gel (NanoCD@Gel) for intracavity administration. Mechanistically, DOX induced the generation of intracellular reactive oxygen species (ROS) and CUR reduced the ROS metabolism by inhibiting thioredoxin reductase (TrxR). The synergy of DOX and CUR amplified intracellular ROS levels and thus resulted in enhanced immunogenic cell death (ICD) of tumor cells. Upon being injected into the tumor cavity after resection, the in situ-generated NanoCD@Gel allowed the local release of CUR and DOX in a controlled manner to induce local chemotherapy and persistently activate the antitumor immune response, thereby achieving enhanced immunogenic chemotherapy with reduced systemic toxicity. Our work provides an elegant strategy for persistently stimulating effective antitumor immunity to prevent postsurgical tumor recurrence and metastasis.

The role of EPAS1 polymorphisms on COPD susceptibility in southern Chinese.

Objective: COPD is the most common chronic respiratory disease with complex environmental and genetic etiologies. It was reported that EPAS1 might participate in the occurrence and development of respiratory diseases. However, the association between EPAS1 and COPD was unclear. Methods: First, a case-control study enrolling 1130 COPD patients and 1115 healthy controls in Guangzhou was conducted to clarify the association between EPAS1 polymorphisms and COPD susceptibility. Secondly, a prevalence study recruited 882 participants in Gansu to verify the effect of positive polymorphisms on lung function. Finally, the 10-year absolute risk considering environmental factors and genetic variations was calculated by the method of Gail and Bruzzi. Results: EPAS1 rs13419896 AA genotype reduced COPD risk in southern Chinese (AA vs. GG: adjusted OR = 0.689, 95% CI = 0.498-0.955; AA vs. GG/GA: adjusted OR = 0.701, 95% CI = 0.511-0.962). Further, the rs13419896 A allele was significantly associated with higher pre-FEV1/pre-FVC in both the Guangzhou and Gansu populations (P < 0.05). Smoking status, coal as fuels, education level, and rs13419896 G > A were finally retained to develop a relative risk model for males. Smoking status, biomass as fuels, and rs13419896 G > A were retained in the female model. The population-attributable risk of the male or female model was 0.457 (0.283-0.632) and 0.421 (0.227-0.616), respectively. Conclusions: This study first revealed that EPAS1 rs13419896 G > A decreased COPD susceptibility and could be a genetic marker to predict the 10-year absolute risk for COPD.

EPO rs1617640 A>C is a Protective Factor for Chronic Obstructive Pulmonary Disease: A Case Control Study.

BACKGROUND: The occurrence and development of chronic obstructive pulmonary disease (COPD) are regulated by environmental and genetic factors. In hypoxia, Erythropoietin (EPO) satisfies the body's need for oxygen by promoting the production of red blood cells. Hypoxia was proven to be a common physiological condition in COPD progression and associated with many complications. Some studies have found that EPO is involved in the development of COPD. But the mechanism has not been fully proven. METHODS: We conducted a case-control study enrolled 1095 COPD patients and 1144 healthy controls in Guangdong Province to evaluate the association between EPO polymorphisms (rs1617640 A>C, rs507392 A>G, rs564449 G>T) and COPD susceptibility. 872 participants from southern Gansu Province were recruited to verify the effect of EPO polymorphisms on lung function. RESULTS: EPO rs1617640 C allele reduced COPD susceptibility in southern Chinese significantly (AC vs. AA: adjusted Odds ratio (OR) = 0.805, 95% CI = 0.669-0.969; AC+CC vs. AA: adjusted OR = 0.822, 95% CI = 0.689-0.980). However, there was no association between rs507392 A>G and rs564449 G>T polymorphisms and COPD susceptibility (p > 0.05). We further observed that the rs1617640 C allele was associated with higher FEV1 and FVC in Guangdong and Gansu populations significantly (both p < 0.05). In brief, the level of FEV1 and FVC increased with the C allele number. We modeled the relative risk for men and women, in which the population-attributable risks chances were 0.449 (0.258-0.641) and 0.262 (0.128-0.396) respectively. In this model, smoking status, coal as fuels, education level, and rs1617640 A>C were finally retained for males, while smoking status, biomass as fuels, and1617640 A>C were retained for females. In the end, using the method developed by Gail and Bruzzi, we fitted a 10-year absolute risk model for southern Chinese with different individual relative risks, which was presented as a table. CONCLUSIONS: In conclusion, this study found that EPO rs1617640 A>C polymorphism is associated with COPD susceptibility in southern Chinese, and the C allele was associated with better lung function. In addition, it could also be considered a genetic marker associated with environmental factors to predict the absolute 10-year risk of COPD in southern Chinese.

NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates.

Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression in vitro. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.

LncRNA-Encoded Micropeptide ACLY-BP Drives Lipid Deposition and Cell Proliferation in Clear Cell Renal Cell Carcinoma via Maintenance of ACLY Acetylation.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of lethal kidney cancer. Reprogramming of fatty acid and glucose metabolism resulting in the accumulation of lipids and glycogen in the cytoplasm is a hallmark of ccRCC. Here, we identified a micropeptide ACLY-BP encoded by the GATA3-suppressed LINC00887, which regulated lipid metabolism and promoted cell proliferation and tumor growth in ccRCC. Mechanistically, the ACLY-BP stabilizes the ATP citrate lyase (ACLY) by maintaining ACLY acetylation and preventing ACLY from ubiquitylation and degradation, thereby leading to lipid deposition in ccRCC and promoting cell proliferation. Our results may offer a new clue for the therapeutic approaches and the diagnostic assessment for ccRCC. IMPLICATIONS: This study identifies ACLY-BP encoded by LINC00887 as a lipid-related micropeptide that stabilizes ACLY to generate acetyl-CoA, driving lipid deposition and promoting cell proliferation in ccRCC.

Changes in COVID-19 vaccine hesitancy at different times among residents in Guangzhou, China.

Background: Vaccination as a fundamental pillar of promoting public health and interest is critical to limiting the COVID-19 pandemic. However, many citizens are still hesitant about this epidemic prevention measure. This article aimed to understand the COVID-19 vaccination and hesitancy rates among Guangzhou residents at different points in time as well as to explore the relevant factors that cause vaccination hesitancy. Methods: We conducted a total of nine cross-sectional surveys by enrolling 12,977 questionnaires among Guangzhou residents through the online survey software called "WenJuanXing" between April 2021 and December 2022, and residents made their choices by judging their willingness to vaccinate. These surveys collected data on the participants' sociodemographic characteristics, vaccination status, vaccine hesitancy, and factors influencing this hesitancy. The Chi-squared test was used for univariate analysis and the multivariate logistic regression model was used to further adjust the influence of the confounding factors to evaluate the main factors affecting the hesitancy of the COVID-19 vaccine at different periods. Results: Over the course of 2021-2022, a total of 12,977 residents in the study area were surveyed. The vaccine hesitancy rates fluctuated over time. From April to June 2021, the vaccine hesitancy rate decreased from 30% to 9.1% and then increased to 13.7% in November. However, from April to December 2022, the hesitancy rate continued to rise from 13.4% to 30.4%. Vaccination rates, the epidemic waves of COVID-19, and changes in policies may all be possible factors that contributed to these fluctuations in vaccine hesitancy rates. We found statistically significant correlations between factors, such as residence, education, and occupation, and vaccine hesitancy at certain points of time. The results of the surveys in April and June 2021 showed that rural residents showed higher vaccine hesitancy rate than urban residents. Their lower education level was associated with higher vaccine hesitancy. Workers and farmers are more likely to have vaccine hesitancy than people with other occupations. The univariate analysis showed that people with underlying medical conditions and lower perceived health status were more likely to experience vaccine hesitation. Logistic regression analysis revealed that the health status of individuals is the most important factor leading to vaccine hesitancy, and residents' underestimation of domestic risks and overconfidence in personal protection measures were also contributing factors. At different stages, vaccine hesitancy among residents was related to vaccine side effects, safety and efficacy, convenience fluctuation, and various factors. Conclusion: In the present study, we found that vaccine hesitancy did not display a consistent downward trend but it fluctuated over time. Higher education, residing in urban areas, lower perceived disease risk, and concerns about the vaccine's safety and side effects were risk factors for vaccine hesitancy. Implementing appropriate interventions and educational programs tailored to address these risk factors may prove to be effective in enhancing public confidence on vaccination.

The Efficacy and Safety of 5-Aminolevulinic Acid Photodynamic Therapy for Lichen Sclerosus: A Meta Analysis.

Background: Lichen sclerosus (LS) is a chronic inflammatory dermatosis that occurs mainly in the anogenital area and causes itching, soreness, atrophy and scarring, which may result in burying of the clitoris in females and phimosis in males. Photodynamic therapy (PDT) has been suggested during the past years as an alternative non-invasive treatment for LS, but there is still no meta-analysis to evaluate its efficacy and safety. Aims: To assess the efficacy and safety of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) for treatment of LS. Methods: We undertook a meta-analysis using the methodology of the Cochrane Collaboration and the guideline of PRISMA. A systematic literature search was carried out in PubMed, EMBASE, The Cochrane Library, WanFang Data, CBM and CNKI up to 30 June 2020. Randomized controlled trials (RCTs) were compared with ALA-PDT, corticosteroids or tacrolimus ointments for treating LS. The risk of bias for each trial was rated according to the Cochrane Handbook. Risk ratios (RR) with 95% confidence intervals (CI) were utilized to express the comparative outcomes. Results: We included 4 RCTs with a total of 184 participants. The meta-analysis showed ALA-PDT was better than topical ointments in treating LS (total effective rate: RR 1.38 [95% CI 1.19-1.60]). Conclusions: The current limited evidence supports the efficacy and safety of ALA-PDT in treating LS. The adverse reactions included pain, swelling, redness and exfoliation which would decrease with the continuing sessions of treatment. Further high-qualified RCTs of large samples are necessarily needed.

Nanoparticle-mediated TRPV1 channel blockade amplifies cancer thermo-immunotherapy via heat shock factor 1 modulation.

The survival of malignant tumors is highly dependent on their intrinsic self-defense pathways such as heat shock protein (HSP) during cancer therapy. However, precisely dismantling self-defenses to amplify antitumor potency remains unexplored. Herein, we demonstrate that nanoparticle-mediated transient receptor potential vanilloid member 1 (TRPV1) channel blockade potentiates thermo-immunotherapy via suppressing heat shock factor 1 (HSF1)-mediated dual self-defense pathways. TRPV1 blockade inhibits hyperthermia-induced calcium influx and subsequent nuclear translocation of HSF1, which selectively suppresses stressfully overexpressed HSP70 for enhancing thermotherapeutic efficacy against a variety of primary, metastatic and recurrent tumor models. Particularly, the suppression of HSF1 translocation further restrains the transforming growth factor ß (TGFß) pathway to degrade the tumor stroma, which improves the infiltration of antitumor therapeutics (e.g. anti-PD-L1 antibody) and immune cells into highly fibrotic and immunosuppressive pancreatic cancers. As a result, TRPV1 blockade retrieves thermo-immunotherapy with tumor-eradicable and immune memory effects. The nanoparticle-mediated TRPV1 blockade represents as an effective approach to dismantle self-defenses for potent cancer therapy.

Development and validation of nomogram including high altitude as a risk factor for COPD: A cross-sectional study based on Gansu population.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a common and harmful disease that requires an effective tool to early screen high-risk individuals. Gansu has unique environments and customs, leading to the different prevalence and etiology of COPD from other regions. The association between altitude and COPD once attracted epidemiologists' attention. However, the prevalence in Gansu and the role of altitude are still unclarified. Methods: In Gansu, a multistage stratified cluster sampling procedure was utilized to select a representative sample aged 40 years or older. The questionnaire and spirometry examination were implemented to collect participants' information. The diagnosis and assessment of COPD were identified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion, while post-bronchodilator FEV1/FVC < LLN was for sensitivity analysis. Furthermore, the effect of high altitude on COPD was evaluated by the logistic regression model after propensity score matching (PSM). Finally, the participants were randomly divided into training and validation sets. The training set was used to screen the relative factors and construct a nomogram which was further assessed by the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) in the two sets. Results: There were 2,486 eligible participants in the final analysis, of which 1,584 lived in low altitudes and 902 lived in high altitudes. Based on the GOLD criterion, the crude and standardized prevalences in Gansu were 20.4% (18.7-22.0) and 19.7% (17.9-21.6). After PSM, the logistic regression model indicated that high altitude increased COPD risk [PSM OR: 1.516 (1.162-1.978)]. Altitude, age, sex, history of tuberculosis, coal as fuel, and smoking status were reserved for developing a nomogram that demonstrated excellent discrimination, calibration, and clinical benefit in the two sets. Conclusions: COPD has become a serious public health problem in Gansu. High altitude is a risk factor for COPD. The nomogram has satisfactory efficiency in screening high-risk individuals.

2-Deoxyglucose and hydroxychloroquine HPLC-MS-MS analytical methods and pharmacokinetic interactions after oral co-administration in male rats.

Our previous work has shown a synergistic tumoricidal action of the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) on HK2-addicted prostate cancers in animal models through intraperitoneal injections. Here we developed high performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) methods for 2-DG and clinically favored drug hydroxychloroquine (HCQ) and explored PK interaction of the orally administered drugs in a jugular vein cannulated male rat model, which allowed serial blood collection before and 0.5, 1, 2, 4 and 8 h after a single gavage dose of each drug alone or simultaneously after appropriate washout periods between the drugs. The results demonstrated a rapid and satisfactory separation of 2-DG standard from common monosaccharides by HPLC-MS-MS multi-reaction monitoring (MRM) and the presence of endogenous "2-DG". Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of 9 evaluable rats showed a peak time (Tmax) of 2-DG of 0.5 h after 2-DG dosing alone or with HCQ and glucose-like PK behavior. With a seemingly bi-modal time course for HCQ, the Tmax for HCQ dosing alone (1.2 h) was faster than that for the combination (2 h; p = 0.013, 2-tailed t-test). After combination dosing, the peak concentration (Cmax) and area under the curve (AUC) of 2-DG were decreased by 54% (p < 0.0001) and 52%, whereas those for HCQ were decreased by 40% (p = 0.026) and 35%, respectively, compared to single dosing. The data suggest significant negative PK interactions between the two oral drugs taken simultaneously and warrant optimization efforts for the combination regimen.

Metabolic reprogramming and its clinical implication for liver cancer.

Cancer cells often encounter hypoxic and hypo-nutrient conditions, which force them to make adaptive changes to meet their high demands for energy and various biomaterials for biomass synthesis. As a result, enhanced catabolism (breakdown of macromolecules for energy production) and anabolism (macromolecule synthesis from bio-precursors) are induced in cancer. This phenomenon is called "metabolic reprogramming," a cancer hallmark contributing to cancer development, metastasis, and drug resistance. HCC and cholangiocarcinoma (CCA) are 2 different liver cancers with high intertumoral heterogeneity in terms of etiologies, mutational landscapes, transcriptomes, and histological representations. In agreement, metabolism in HCC or CCA is remarkably heterogeneous, although changes in the glycolytic pathways and an increase in the generation of lactate (the Warburg effect) have been frequently detected in those tumors. For example, HCC tumors with activated ß-catenin are addicted to fatty acid catabolism, whereas HCC tumors derived from fatty liver avoid using fatty acids. In this review, we describe common metabolic alterations in HCC and CCA as well as metabolic features unique for their subsets. We discuss metabolism of NAFLD as well, because NAFLD will likely become a leading etiology of liver cancer in the coming years due to the obesity epidemic in the Western world. Furthermore, we outline the clinical implication of liver cancer metabolism and highlight the computation and systems biology approaches, such as genome-wide metabolic models, as a valuable tool allowing us to identify therapeutic targets and develop personalized treatments for liver cancer patients.

Holographically Activatable Nanoprobe via Glutathione/Albumin-Mediated Exponential Signal Amplification for High-Contrast Tumor Imaging.

Glutathione (GSH)-activatable probes hold great promise for in vivo cancer imaging, but are restricted by their dependence on non-selective intracellular GSH enrichment and uncontrollable background noise. Here, a holographically activatable nanoprobe caging manganese tetraoxide is shown for tumor-selective contrast enhancement in magnetic resonance imaging (MRI) through cooperative GSH/albumin-mediated cascade signal amplification in tumors and rapid elimination in normal tissues. Once targeting tumors, the endocytosed nanoprobe effectively senses the lysosomal microenvironment to undergo instantaneous decomposition into Mn2+ with threshold GSH concentration of ≈ 0.12 mm for brightening MRI signals, thus achieving high contrast tumor imaging and flexible monitoring of GSH-relevant cisplatin resistance during chemotherapy. Upon efficient up-regulation of extracellular GSH in tumor via exogenous injection, the relaxivity-silent interstitial nanoprobe remarkably evolves into Mn2+ that are further captured/retained and re-activated into ultrahigh-relaxivity-capable complex by stromal albumin in the tumor, and simultaneously allows the renal clearance of off-targeted nanoprobe in the form of Mn2+ via lymphatic vessels for suppressing background noise to distinguish tiny liver metastasis. These findings demonstrate the concept of holographic tumor activation via both tumor GSH/albumin-mediated cascade signal amplification and simultaneous background suppression for precise tumor malignancy detection, surveillance, and surgical guidance.

A pH-Activatable Copper-Biomineralized Proenzyme for Synergistic Chemodynamic/Chemo-Immunotherapy against Aggressive Cancers.

Artificial enzymes have demonstrated therapeutic benefits against diverse malignant tumors, yet their antitumor potencies are still severely compromised by non-selective catalysis, low atomic-utilization efficiency, and undesired off-target toxicity. Herein, it is reported that peroxidase-like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH-NCs) act as a pH-activatable proenzyme to achieve tumor-selective and synergistic chemodynamic/chemo-immunotherapy against aggressive triple-negative breast cancers (TNBCs). These CuCH-NCs show pH-sensitive Cu2+ release, which spontaneously undergoes glutathione (GSH)-mediated reduction into Cu+ species for catalyzing the evolution of H2 O2 into hydroxyl radicals (·OH) in a single-atom-like manner to cause chemodynamic cell injury, and simultaneously activates non-toxic disulfiram to cytotoxic complex for yielding selective chemotherapeutic damage via blocking cell proliferation and amplifying cell apoptosis. CuCH-NCs exhibit considerable tumor-targeting capacity with deep penetration depth, thus affording preferable efficacy against orthotopic breast tumors through synergistic chemodynamic/chemotherapy, together with good in vivo safety. Moreover, CuCH-NCs arouse distinct immunogenic cell death effect and upregulate PD-L1 expression upon disulfiram combination, and thus synergize with anti-PD-L1 antibody to activate adaptive and innate immunities, together with relieving immunosuppression, finally yielding potent antitumor efficacy against both primary and metastatic TNBCs. These results provide insights into smart and high-performance proenzymes for synergistic therapy against aggressive cancers.