Mutual communication between radiosensitive and radioresistant esophageal cancer cells modulates their radiosensitivity.

Radiotherapy is an important treatment modality for patients with esophageal cancer; however, the response to radiation varies among different tumor subpopulations due to tumor heterogeneity. Cancer cells that survive radiotherapy (i.e., radioresistant) may proliferate, ultimately resulting in cancer relapse. However, the interaction between radiosensitive and radioresistant cancer cells remains to be elucidated. In this study, we found that the mutual communication between radiosensitive and radioresistant esophageal cancer cells modulated their radiosensitivity. Radiosensitive cells secreted more exosomal let-7a and less interleukin-6 (IL-6) than radioresistant cells. Exosomal let-7a secreted by radiosensitive cells increased the radiosensitivity of radioresistant cells, whereas IL-6 secreted by radioresistant cells decreased the radiosensitivity of radiosensitive cells. Although the serum levels of let-7a and IL-6 before radiotherapy did not vary significantly between patients with radioresistant and radiosensitive diseases, radiotherapy induced a more pronounced decrease in serum let-7a levels and a greater increase in serum IL-6 levels in patients with radioresistant cancer compared to those with radiosensitive cancer. The percentage decrease in serum let-7a and the percentage increase in serum IL-6 levels at the early stage of radiotherapy were inversely associated with tumor regression after radiotherapy. Our findings suggest that early changes in serum let-7a and IL-6 levels may be used as a biomarker to predict the response to radiotherapy in patients with esophageal cancer and provide new insights into subsequent treatments.

Hypoxia and Cancer: From Bench to Bedside.

This Special Issue of Cancers (two original articles, five reviews), presented by international experts in tumor hypoxia, focuses on the role of hypoxia, or low oxygen levels, in the development and progression of cancer [...].

Rapamycin Perfluorocarbon Nanoparticle Mitigates Cisplatin-Induced Acute Kidney Injury.

For nearly five decades, cisplatin has played an important role as a standard chemotherapeutic agent and been prescribed to 10-20% of all cancer patients. Although nephrotoxicity associated with platinum-based agents is well recognized, treatment of cisplatin-induced acute kidney injury is mainly supportive and no specific mechanism-based prophylactic approach is available to date. Here, we postulated that systemically delivered rapamycin perfluorocarbon nanoparticles (PFC NP) could reach the injured kidneys at sufficient and sustained concentrations to mitigate cisplatin-induced acute kidney injury and preserve renal function. Using fluorescence microscopic imaging and fluorine magnetic resonance imaging/spectroscopy, we illustrated that rapamycin-loaded PFC NP permeated and were retained in injured kidneys. Histologic evaluation and blood urea nitrogen (BUN) confirmed that renal structure and function were preserved 48 h after cisplatin injury. Similarly, weight loss was slowed down. Using western blotting and immunofluorescence staining, mechanistic studies revealed that rapamycin PFC NP significantly enhanced autophagy in the kidney, reduced the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), as well as decreased the expression of the apoptotic protein Bax, all of which contributed to the suppression of apoptosis that was confirmed with TUNEL staining. In summary, the delivery of an approved agent such as rapamycin in a PFC NP format enhances local delivery and offers a novel mechanism-based prophylactic therapy for cisplatin-induced acute kidney injury.

Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer's Disease.

Melatonin, insulin, and Δ9-tetrahydrocannabinol (THC) have been shown to reverse cognitive deficits and attenuate neuropathologies in transgenic mouse models of Alzheimer's disease (AD) when used individually. Here, we evaluated the therapeutic properties of long-term intranasal treatment with a novel nanoformulation containing melatonin, insulin, and THC in aged APPswe/PS1ΔE9 (APP/PS1) mice, a transgenic model of AD. Transgenic mice at the age of 12 months were intranasally administered with a new nanoformulation containing melatonin, insulin, and THC at doses of 0.04, 0.008, and 0.02 mg/kg, respectively, once daily for 3 months. The spatial memory of the mice was assessed using the radial arm water maze (RAWM) test before and after drug treatment. Brain tissues were collected at the end of the treatment period for the assessment of Aß load, tauopathy state, and markers of mitochondrial function. The RAWM test revealed that the treatment with the melatonin-insulin-THC (MIT) nasal spray improved the spatial learning memory of APP/PS1 mice significantly. Results of protein analyses of brain homogenates indicated that MIT treatment significantly decreased the tau phosphorylation implicated in tau toxicity (p < 0.05) and the expression of CKMT1 associated with mitochondrial dysfunction. Moreover, MIT significantly decreased the expression of two mitochondrial fusion-related proteins, Mfn2 and Opa1 (p < 0.01 for both), while increasing the expression of a mitophagy regulator, Parkin, suggesting a compensatory enhancement of mitophagy due to MIT-promoted mitochondrial fusion. In conclusion, this study was the first to demonstrate the ability of an MIT nanoformulation to improve spatial memory in AD mice through its multi-targeting effects on Aß production, tau phosphorylation, and mitochondrial dynamics. Thus, MIT may be a safe and effective therapeutic for AD.

The evolution of mental health related policies in China: A bibliometric analysis, 1987-2020.

Background: Since 1987, the Chinese government has promoted public mental health by continuously implementing mental health related policies. This research attempts to reveal the distribution and characteristics of mental health related policies. In addition, it can help stakeholders evaluate whether the environment for policy implementation has improved and identify key points in the development of the overall mental health system. Methods: We used a bibliometric approach to analyze the evolution of mental health related policies in China from 1987 to 2020. A total of 239 mental health related policies were collected from Beida Fabao and official Internet websites of governmental departments. Co-wording, social networks, and citation analysis were applied to explore the evolutionary features of such policies. Results: The evolution of policy development showed that the number of mental health related policies in China has been increasing and their content has been enriched. Over time, mental health related policies not only gradually expanded its focus on common mental disorders, but also included an increasing number of keywords related to service provision, organization and administration. However, most policies were implemented independently by separate agencies and the number of policies jointly implemented by different agencies only accounted for 32.64% of all the policies implemented. The Ministry of Health (MOH) is at the core of the collaborative network associated with implementing mental health related policies in China. Conclusion: The environment associated with the implementation of mental health related policies in China is gradually improving. However, cross-sector collaboration among different agencies needs to be strengthened and financial support for related resources needs more attention. A clear division of responsibilities among various agencies and a sustainable financing mechanism are essential to the development and implementation of mental health related policies.

The Memory Benefit to Aged APP/PS1 Mice from Long-Term Intranasal Treatment of Low-Dose THC.

THC has been used as a promising treatment approach for neurological disorders, but the highly psychoactive effects have largely warned off many scientists from pursuing it further. We conducted an intranasal treatment using low-dose THC on 12-month-old APP/PS1 mice daily for 3 months to overcome any potential psychoactive response induced by the systemic delivery. Our results demonstrate that the THC nasal treatment at 0.002 and 0.02 mg/kg significantly slowed the memory decline compared to that in the vehicle-treated transgenic mouse control group. An enzyme-linked immunosorbent assay showed that the Aß1-40 and 1-42 peptides decreased in the THC-treated groups. The Western blot data indicate that long-term low-dose THC intranasal administration promoted p-tau level reduction and mitochondrial function marker redistribution. The blood biochemical parameter data demonstrate some insignificant changes in cytokine, immunoglobulin, and immune cell profiles during intranasal THC treatment. Intranasal delivery is a non-invasive and convenient method that rapidly targets therapeutics to the brain, minimizing systemic exposure to avoid unwanted adverse effects. Our study provides new insights into the role of low-dose THC intranasal treatment as a pharmacological strategy to counteract alterations in Alzheimer's disease-related cognitive performance.

Impact of new health care reform on enabling environment for children's health in China: An interrupted time-series study.

Background: Creating an enabling environment (EE) can help foster the development and health of children. The Chinese government implemented a new health care reform (NHR) in 2009 in a move to promote an EE for health. The purpose of this study was to evaluate the impact of the NHR on EE for children's health. Methods: An interrupted time-series analysis was used to evaluate the changes in the EE before and after 2009 in China. This study analysed the EE through five quantitative indicators, including policy element coverage rate (PECR), service meeting with children's needs rate (SMCNR), multisector participation rate (MPR), and accountability mechanism clarity rate (AMCR), based on the content analysis of available public policy documents (updated as of 2019) from 31 provinces in mainland China, and the number of health care personnel of maternity and child care centres per 10 000 population (HP per 10 000 population), based on the 2002-2019 China Health Statistical Yearbook and China Statistical Yearbook. Results: The average values of PECR, SMCNR, and MPR increased rapidly to 90.96%, 82.46%, and 81.31%, respectively, in 2019, representing a higher value compared to the AMCR (7.38%). The NHR promoted the EE, in which HP per 10 000 population showed the fastest increase (ß1 = 0.03, P < 0.01; ß3 = 0.10, P < 0.01), followed by SMCNR (ß1 = 0.94, P < 0.01; ß3 = 1.83, P < 0.01), AMCR (ß1 = 0.13, P < 0.01; ß3 = 0.24, P = 0.14), MPR (ß1 = 1.35, P < 0.01; ß3 = 2.47, P < 0.01) and PECR (ß1 = 1.43, P < 0.01; ß3 = 1.47, P < 0.01). Conclusions: The NHR has a positive impact on the EE, especially on the human resources and service provision for children. Efforts should be intensified to improve the clarity of the accountability mechanism of the health-related sectors.

Influence of Public Health Services on the Goal of Ending Tuberculosis: Evidence From Panel Data in China.

Background: The World Health Organization has proposed an initiative to "end tuberculosis (TB)." Unfortunately, TB continues to endanger the health of people worldwide. We investigated the impact of public health services (PHS) in China on TB incidence. In this way, we provided policy ideas for preventing the TB epidemic. Methods: We used the "New Public Management Theory" to develop two indicators to quantify policy documents: multisector participation (MP) and the Assessable Public Health Service Coverage Rate (ASCR). The panel data from 31 provinces in Chinese mainland were collected from 2005 to 2019 based on 1,129 policy documents and the China Statistical Yearbook. A fixed-effect model was used to determine the impact of MP and the ASCR on TB incidence. Results: From 2005 to 2019, the average MP increased from 89.25 to 97.70%, and the average ASCR increased from 53.97 to 78.40% in Chinese mainland. However, the development of ASCR between regions was not balanced, and the average level in the western region was lower than that in the eastern coastal provinces. With an increase in MP and the ASCR, the TB incidence had been decreasing gradually in recent years. The panel analysis results showed that MP (ß = -0.76, p < 0.05). and ASCR (ß = -0.40, p < 0.01) had a negative effect on TB incidence, respectively. Even if the control variables were added, the negative effects of MP (ß = -0.86, p < 0.05) and ASCR (ß = -0.35, p < 0.01) were still statistically significant. Conclusions: Promoting the participation of multiple departments, as well as emphasizing the quality of PHS delivery, are important ways to alleviate the TB epidemic. The settings of evaluation indices for PHS provision should be strengthened in the future.

Low-Dose Delta-9-Tetrahydrocannabinol as Beneficial Treatment for Aged APP/PS1 Mice.

Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer's disease (AD) have been sparse due to the concern about THC's psychotropic activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-ß (Aß) production was examined in N2a/AßPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aß aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aß oligomers, phospho-tau and total tau, and increased the expression of Aß monomers and phospho-GSK-3ß (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.

Safety Profile of Rapamycin Perfluorocarbon Nanoparticles for Preventing Cisplatin-Induced Kidney Injury.

Cancer treatment-induced toxicities may restrict maximal effective dosing for treatment and cancer survivors' quality of life. It is critical to develop novel strategies that mitigate treatment-induced toxicity without affecting the efficacy of anti-cancer therapies. Rapamycin is a macrolide with anti-cancer properties, but its clinical application has been hindered, partly by unfavorable bioavailability, pharmacokinetics, and side effects. As a result, significant efforts have been undertaken to develop a variety of nano-delivery systems for the effective and safe administration of rapamycin. While the efficacy of nanostructures carrying rapamycin has been studied intensively, the pharmacokinetics, biodistribution, and safety remain to be investigated. In this study, we demonstrate the potential for rapamycin perfluorocarbon (PFC) nanoparticles to mitigate cisplatin-induced acute kidney injury with a single preventative dose. Evaluations of pharmacokinetics and biodistribution suggest that the PFC nanoparticle delivery system improves rapamycin pharmacokinetics. The safety of rapamycin PFC nanoparticles was shown both in vitro and in vivo. After a single dose, no disturbance was observed in blood tests or cardiac functional evaluations. Repeated dosing of rapamycin PFC nanoparticles did not affect overall spleen T cell proliferation and responses to stimulation, although it significantly decreased the number of Foxp3+CD4+ T cells and NK1.1+ cells were observed.

Evaluation of bactericidal effects of silver hydrosol nanotherapeutics against Enterococcus faecium 1449 drug resistant biofilms.

Introduction: Silver (Ag) nanoparticles (NPs) are well documented for their broad-spectrum bactericidal effects. This study aimed to test the effect of bioactive Ag-hydrosol NPs on drug-resistant E. faecium 1449 strain and explore the use of artificial intelligence (AI) for automated detection of the bacteria. Methods: The formation of E. faecium 1449 biofilms in the absence and presence of Ag-hydrosol NPs at different concentrations ranging from 12.4 mg/L to 123 mg/L was evaluated using a 3-dimentional culture system. The biofilm reduction was evaluated using the confocal microscopy in addition to the Transmission Electronic Microscopy (TEM) visualization and spectrofluorimetric quantification using a Biotek Synergy Neo2 microplate reader. The cytotoxicity of the NPs was evaluated in human nasal epithelial cells using the MTT assay. The AI technique based on Fast Regional Convolutional Neural Network architecture was used for the automated detection of the bacteria. Results: Treatment with Ag-hydrosol NPs at concentrations ranging from 12.4 mg/L to 123 mg/L resulted in 78.09% to 95.20% of biofilm reduction. No statistically significant difference in biofilm reduction was found among different batches of Ag-hydrosol NPs. Quantitative concentration-response relationship analysis indicated that Ag-hydrosol NPs exhibited a relative high anti-biofilm activity and low cytotoxicity with an average EC50 and TC50 values of 0.0333 and 6.55 mg/L, respectively, yielding an average therapeutic index value of 197. The AI-assisted TEM image analysis allowed automated detection of E. faecium 1449 with 97% ~ 99% accuracy. Discussion: Conclusively, the bioactive Ag-hydrosol NP is a promising nanotherapeutic agent against drug-resistant pathogens. The AI-assisted TEM image analysis was developed with the potential to assess its treatment effect.

Development and validation of an interpretable radiomic nomogram for severe radiation proctitis prediction in postoperative cervical cancer patients.

Background: Radiation proctitis is a common complication after radiotherapy for cervical cancer. Unlike simple radiation damage to other organs, radiation proctitis is a complex disease closely related to the microbiota. However, analysis of the gut microbiota is time-consuming and expensive. This study aims to mine rectal information using radiomics and incorporate it into a nomogram model for cheap and fast prediction of severe radiation proctitis prediction in postoperative cervical cancer patients. Methods: The severity of the patient's radiation proctitis was graded according to the RTOG/EORTC criteria. The toxicity grade of radiation proctitis over or equal to grade 2 was set as the model's target. A total of 178 patients with cervical cancer were divided into a training set (n = 124) and a validation set (n = 54). Multivariate logistic regression was used to build the radiomic and non-raidomic models. Results: The radiomics model [AUC=0.6855(0.5174-0.8535)] showed better performance and more net benefit in the validation set than the non-radiomic model [AUC=0.6641(0.4904-0.8378)]. In particular, we applied SHapley Additive exPlanation (SHAP) method for the first time to a radiomics-based logistic regression model to further interpret the radiomic features from case-based and feature-based perspectives. The integrated radiomic model enables the first accurate quantitative assessment of the probability of radiation proctitis in postoperative cervical cancer patients, addressing the limitations of the current qualitative assessment of the plan through dose-volume parameters only. Conclusion: We successfully developed and validated an integrated radiomic model containing rectal information. SHAP analysis of the model suggests that radiomic features have a supporting role in the quantitative assessment of the probability of radiation proctitis in postoperative cervical cancer patients.

Does the Direct Settlement Policy of Trans-Provincial Outpatient Expenses Aggravate the Siphoning Effect? An Empirical Study on Yangtze River Delta, China.

To solve the problem of reimbursing trans-regional medical expenses, using only cross-regional manual reimbursement but not direct medical insurance card settlement, China implemented a pilot policy of direct settlement of trans-provincial outpatient expenses (DSTOE) in the Yangtze River Delta region. Due to the differences in inter-regional medical development, patients often migrate from areas with low-level medical resources to the high-level areas, a phenomenon that we define as the "siphoning" of trans-regional patients, which can cause a variety of problems. To study whether DSTOE aggravates the siphoning effect, we analyzed the changes in the volume of trans-provincial outpatient visits and conducted a questionnaire survey and factor analysis on the willingness of trans-provincial medical treatment under DSTOE. Results showed that manual reimbursement was gradually replaced by direct settlement, while the total volume was not increased significantly, and the ratio of outpatient visits flowing into and out from Shanghai decreased. The majority of questionnaire respondents confessed that their willingness toward trans-regional medical treatment increased, while their first choice of medical location was still mainly local, with only a few indicating that they would directly choose a cross-regional, higher-level medical institution. Spatial accessibility significantly restricted the seeking of trans-regional medical treatment, whereas age, education level, and policy awareness served as significant protective factors for the choice of medical location. In conclusion, due to space accessibility constraints, insufficient policy coverage, and the rationale for choice of location, DSTOE did not aggravate the siphoning effect of trans-regional patients.

Changes of Multisectoral Collaboration and Service Delivery in Hypertension Prevention and Control before and after the 2009 New Healthcare Reform in China: An Interrupted Time-Series Study.

OBJECTIVES: There is a need to assess the 2009 new healthcare reform in China on hypertension prevention. It helps to control from the perspectives of multisectoral participation, government responsibility assignment, performance assessment, and service delivery. DESIGN: Interrupted time-series study. Setting. 31 provinces in mainland China. Primary and Secondary Outcome Measures. Based on the content analysis of publicly available policy documents from 31 provinces regarding hypertension prevention and control, we analyzed the changes brought by the 2009 new healthcare reform through four quantitative indicators, including multisector participation (MP), main department responsibility coverage (MDRC), primary department assessment indicator coverage (MDAIC), and service type coverage (STC). We compared the changing trends of four indicators before and after 2009. RESULTS: Nationally, MP, MDRC, and STC grew rapidly and increased to 88.9%, 96.4%, and 77.8%, respectively, in 2017, higher than MDAIC (36.9%). This growth was accelerated by the new healthcare reform, with the highest acceleration in MP (ß3 = 6.345, p < 0.001), followed by MDRC (ß3 = 3.829, p < 0.01), STC (ß3 = 3.799, p < 0.001), and MDAIC (ß3 = 3.585, p < 0.001). The MP and MDRC trend changes were higher in the central and western regions than in the east after the reform. CONCLUSIONS: Our research showed that the new healthcare reform had a positive effect in promoting multisectoral participation in preventing and controlling hypertension in China, improving the responsibility mechanism, and expanding the types of services provided. The government should lead the coordination and implementation of multidepartmental responsibilities and mobilize nonhealth departments to continuously participate in the prevention and control of chronic diseases by improving incentive and evaluation mechanisms.

The Impacts of Regional Regulatory Policies on the Prevention and Control of Chronic Diseases in China: A Mediation Analysis.

Regional regulatory policies (RPs) are a major factor in the prevention and control of chronic diseases (PCCDs) through the implementation of various measures. This study aimed to explore the impacts of RPs on PCCDs, with a focus on the mediating roles of community service. The soundness of the regulatory mechanism (SORM) was used to measure the soundness of RPs based on 1095 policy documents (updated as of 2015). Coverage provided by community service institutions (CSIs) and community health centres (CHCs) was used to represent community service coverage derived from the China Statistical Yearbook (2015), while the number of chronic diseases (NCDs) was used to measure the effects of PCCDs based on data taken from the 2015 China Health and Retirement Longitudinal Study survey. To assess the relationship between SORM, NCDs and community service, a negative binomial regression model and mediation analysis with bootstrapping were conducted. Results revealed that there was a negative correlation between SORM and NCDs. CSIs had a major effect on the relationship between RPs and PCCDs, while CHCs had a partial mediating effect. RPs can effectively prevent and control chronic diseases. Increased effort should also be aimed at strengthening the roles of CSIs and CHCs.

Are Essential Women's Healthcare Services Fully Covered? A Comparative Analysis of Policy Documents in Shanghai and New York City from 1978-2017.

This study aimed to analyze the changes in the 10 major categories of women's healthcare services (WHSs) in Shanghai (SH) and New York City (NYC) from 1978 to 2017, and examine the relationship between these changes and maternal mortality ratio (MMR). Content analysis of available public policy documents concerning women's health was conducted. Two indicators were designed to represent the delivery of WHSs: The essential women's healthcare service coverage rate (ESCR) and the assessable essential healthcare service coverage rate (AESCR). Spearman correlation was used to analyze the relationship between the two indicators and MMR. In SH, the ESCR increased from 10% to 90%, AESCR increased from 0% to 90%, and MMR decreased from 24.0/100,000 to 1.01/100,000. In NYC, the ESCR increased from 0% to 80%, the AESCR increased from 0% to 60%, and the MMR decreased from 24.7/100,000 to 21.4/100,000. The MMR significantly decreased as both indicators increased (p < 0.01). Major advances have been made in women's healthcare in both cities, with SH having a better improvement effect. A common shortcoming for both was the lack of menopausal health service provision. The promotion of women's health still needs to receive continuous attention from governments of SH and NYC. The experiences of the two cities showed that placing WHSs among policy priorities is effective in improving service status.

miR-20b and miR-125a promote tumorigenesis in radioresistant esophageal carcinoma cells.

Radiation therapy is an effective method in the management of esophageal cancer. MicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. However, the roles of specific miRNAs in radioresistant esophageal cancer remain to be investigated. In present study, the relative expression level of miR-20b-5p and miR-125a-5p were evaluated by quantitative Real-time polymerase chain reaction. Cell counting Kit-8 assay, wound-healing assay, transwell assay were used to assess cell proliferation, cell migration and cell invasion. TUNEL and Annexin V-FITC assays were applied to evaluate cell apoptosis. Dual-luciferase reporter gene assay was conducted to identify direct targets of miRNAs. The protein expression level was assessed by Western blot. The results indicated that miR-20b-5p was increased in radioresistant KYSE-150R cells compared with KYSE-150 cells, whereas miR-125a-5p was downregulated. MiR-20b-5p upregulation promoted cell proliferation, migration, invasion, and the EMT process, and decreased apoptosis by negatively regulating PTEN. MiR-125a-5p inhibited cell proliferation, migration, invasion, the EMT process and it induced apoptosis by negatively regulating IL6R. These data indicate that miR-20b-5p and miR-125a-5p promote tumorigenesis in radioresistant KYSE-150R cells and have the potential to be used as novel therapeutic targets for the treatment of esophageal cancer.

The Predictive Value of MLR for Radiation Pneumonia During Radiotherapy of Thoracic Tumor Patients.

PURPOSE: To evaluate the predictive value of blood lymphocyte, monocyte to lymphocyte ratio (MLR), and neutrophil to lymphocyte ratio (NLR) for radiation pneumonia (RP) in patients with thoracic tumors receiving radiotherapy. PATIENTS AND METHODS: The clinical data of 65 patients with thoracic tumor (esophageal cancer, lung cancer) treated by radiotherapy in our hospital were retrospectively analyzed. Patients were divided into the RP group and the non-RP group according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Data on blood cell counts, including lymphocytes, monocytes, and neutrophils, were collected before (0 weeks) and after 1, 2, and 4 weeks of radiotherapy. RESULTS: Of the 65 patients enrolled, 27 developed radiation pneumonia and 38 did not. Patients' clinical factors, including age, TNM stage, tumor type, underlying lung disease, and history of smoking, had no correlation with RP. ANOVA of repeated measurement data showed that the changes of MLR in the group with RP during radiotherapy were significantly different from those in the non-RP group (P<0.05). The RP prediction model based on the identified risk factors was established using receiver operator characteristic curves. The results showed that the area under the curve for the monocyte to lymphocyte ratio was 0.755 (95% CI, 0.63-0.87, P=0.000), and the best cutoff point for MLR was 0.426. CONCLUSION: MLR could predict radiation pneumonia in patients with thoracic tumor radiotherapy and achieve early monitoring, early prevention, and treatment.

Absence of HTATIP2 Expression in A549 Lung Adenocarcinoma Cells Promotes Tumor Plasticity in Response to Hypoxic Stress.

HIV-1 Tat Interactive Protein 2 (HTATIP2) is a tumor suppressor, of which reduced or absent expression is associated with increased susceptibility to tumorigenesis and enhanced tumor invasion and metastasis. However, whether the absent expression of HTATIP2 is a tumor-promoting factor that acts through improving tumor adaptation to hypoxia is unclear. Here, we established a stable HTATIP2-knockdown A549 human lung adenocarcinoma cell line (A549shHTATIP2) using lentiviral-delivered HTATIP2-targeting short hairpin RNA (shRNA), employed a double subcutaneous xenograft model and incorporated photoacoustic imaging and metabolomics approaches to elucidate the impact of the absent HTATIP2 expression on tumor response to hypoxic stress. Results from the in vivo study showed that A549shHTATIP2 tumors exhibited accelerated growth but decreased intratumoral oxygenation and angiogenesis and reduced sensitivity to sorafenib treatment as compared with their parental counterparts. Moreover, results of the immunoblot and real-time PCR analyses revealed that the HIF2α protein and mRNA levels in vehicle-treated A549shHTATIP2 tumors were significantly increased (p < 0.01 compared with the parental control tumors). Despite the strong HIF2α-c-Myc protein interaction indicated by our co-immunoprecipitation data, the increase in the c-Myc protein and mRNA levels was not significant in the A549shHTATIP2 tumors. Nonetheless, MCL-1 and ß-catenin protein levels in A549shHTATIP2 tumors were significantly increased (p < 0.05 compared with the parental control tumors), suggesting an enhanced ß-catenin/c-Myc/MCL-1 pathway in the absence of HTATIP2 expression. The finding of significantly decreased E-cadherin (p < 0.01 compared with vehicle-treated A549shHTATIP2 tumors) and increased vimentin (p < 0.05 compared with sorafenib-treated A549 tumors) protein levels in A549shHTATIP2 tumors implicates that the absence of HTATIP2 expression increases the susceptibility of A549 tumors to sorafenib-activated epithelial-mesenchymal transition (EMT) process. Comparison of the metabolomic profiles between A549 and A549shHTATIP2 tumors demonstrated that the absence of HTATIP2 expression resulted in increased tumor metabolic plasticity that enabled tumor cells to exploit alternative metabolic pathways for survival and proliferation rather than relying on glutamine and fatty acids as a carbon source to replenish TCA cycle intermediates. Our data suggest a mechanism by which the absent HTATIP2 expression modulates tumor adaptation to hypoxia and promotes an aggressive tumor phenotype by enhancing the HIF2α-regulated ß-catenin/c-Myc/MCL-1 signaling, increasing the susceptibility of tumors to sorafenib treatment-activated EMT process, and improving tumor metabolic plasticity.

Formulation and Characterization of Antithrombin Perfluorocarbon Nanoparticles.

Thrombin, a major protein involved in the clotting cascade by the conversion of inactive fibrinogen to fibrin, plays a crucial role in the development of thrombosis. Antithrombin nanoparticles enable site-specific anticoagulation without increasing bleeding risk. Here we outline the process of making and the characterization of bivalirudin and D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone (PPACK) nanoparticles. Additionally, the characterization of these nanoparticles, including particle size, zeta potential, and quantification of PPACK/bivalirudin loading, is also described.