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.

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.

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.

Machine learning-based quantitative texture analysis of CT images of small renal masses: Differentiation of angiomyolipoma without visible fat from renal cell carcinoma.

OBJECTIVE: To evaluate the diagnostic performance of machine-learning based quantitative texture analysis of CT images to differentiate small (≤ 4 cm) angiomyolipoma without visible fat (AMLwvf) from renal cell carcinoma (RCC). METHODS: This single-institutional retrospective study included 58 patients with pathologically proven small renal mass (17 in AMLwvf and 41 in RCC groups). Texture features were extracted from the largest possible tumorous regions of interest (ROIs) by manual segmentation in preoperative three-phase CT images. Interobserver reliability and the Mann-Whitney U test were applied to select features preliminarily. Then support vector machine with recursive feature elimination (SVM-RFE) and synthetic minority oversampling technique (SMOTE) were adopted to establish discriminative classifiers, and the performance of classifiers was assessed. RESULTS: Of the 42 extracted features, 16 candidate features showed significant intergroup differences (P < 0.05) and had good interobserver agreement. An optimal feature subset including 11 features was further selected by the SVM-RFE method. The SVM-RFE+SMOTE classifier achieved the best performance in discriminating between small AMLwvf and RCC, with the highest accuracy, sensitivity, specificity and AUC of 93.9 %, 87.8 %, 100 % and 0.955, respectively. CONCLUSION: Machine learning analysis of CT texture features can facilitate the accurate differentiation of small AMLwvf from RCC. KEY POINTS: • Although conventional CT is useful for diagnosis of SRMs, it has limitations. • Machine-learning based CT texture analysis facilitate differentiation of small AMLwvf from RCC. • The highest accuracy of SVM-RFE+SMOTE classifier reached 93.9 %. • Texture analysis combined with machine-learning methods might spare unnecessary surgery for AMLwvf.

Activation of Focal Adhesion Kinase and Src Mediates Acquired Sorafenib Resistance in A549 Human Lung Adenocarcinoma Xenografts.

Despite encouraging clinical results with sorafenib monotherapy in patients with KRAS-mutant non-small-cell lung cancer (NSCLC), the overall survival benefit of this drug is limited by the inevitable development of acquired resistance. The exact mechanism underlying acquired sorafenib resistance in KRAS-mutant NSCLC is unclear. In this study, the mechanism of acquired sorafenib resistance was explored using a biologically relevant xenograft model, which was established by using the A549 human lung adenocarcinoma cell line and an in vivo-derived, sorafenib-resistant A549 subline (A549/SRFres). Results from the initial study demonstrated that sorafenib treatment significantly decreased E-cadherin (P < 0.05) levels but significantly increased matrix metallopeptidase 9 (MMP9) levels (P < 0.01) in A549/SRFres tumors, whereas expression levels of phospho-protein kinase B (AKT), phospho-focal adhesion kinase (FAK), and phospho-Src were elevated in sorafenib-treated A549 and A549/SRFres tumors. We next examined whether concomitant dasatinib treatment could overcome acquired sorafenib resistance by blocking the FAK/Src escape route that mediates resistance. Despite the observed in vitro synergy between sorafenib and dasatinib, the in vivo antitumor effect of half-dose sorafenib-dasatinib combination therapy was inferior to that of the full-dose sorafenib treatment. Although the sorafenib-dasatinib combination effectively inhibited Src and AKT phosphorylation, it did not block the Y576/577-FAK phosphorylation, nor did it decrease vimentin protein expression; unexpectedly, it increased Y397-FAK phosphorylation and MMP9 protein expression in tumors. These results suggest that acquired sorafenib resistance in KRAS-mutant A549 xenografts involves the compensatory activation of FAK and Src, and Src inhibition alone is insufficient to diminish sorafenib-promoted epithelial-mesenchymal transition process and invasive potentials in tumors.

Multifaceted ability of naturally occurring polyphenols against metastatic cancer.

Although cancer metastases are known to be the main cause of cancer-related deaths, truly effective antimetastatic therapeutics remain scarce in clinical practice. Naturally occurring polyphenols are the most abundant antioxidants in human diets. Many of them possess chemopreventive and chemotherapeutic properties against various types of cancer. Recent advances in understanding the molecular pathways that mediate cancer development and progression have led to an increase of interest in preclinical investigations on the mechanisms underlying anticancer activity of polyphenols. In particular, an increasing number of preclinical studies using cultured cells and animal models have demonstrated the inhibitory effects of polyphenols on tumour cell invasion and metastasis, thereby highlighting the potential of polyphenols against metastatic cancer. This review specifically addresses growing evidence of the capability of polyphenols to impair the invasion and migration of tumour cells through a diverse set of mechanisms, including downregulation of expression of matrix metalloproteinases, modulation of regulators of epithelial-mesenchymal transition, interference with Met signalling, inhibition of nuclear factor-kappa B mediated transcription, and so on. Given that metastasis occurs through a multistep process in which each step is regulated by a complex network of signalling pathways, the multi-function and multi-target characteristics of polyphenols render those promising candidates for effective adjuvant therapy against metastatic cancer.

Subcutaneous pharmacokinetics of the cardiac hormone vessel dilator.

Vessel dilator, a hormone synthesized in the heart, eliminates 71% of human small-cell lung cancers and 67% of human breast cancers growing in mice when given subcutaneously (s.c.) via osmotic pumps. The pharmacokinetics of s.c. administered vessel dilator have not been evaluated previously. In the present study, the pharmacokinetics of vessel dilator following s.c. bolus (ScB) or 3 h s.c. infusion (ScI) were compared with those following i.v. bolus (IvB) administration in male Fischer 344 rats. The half-life (t½ ) of vessel dilator after ScI, IvB and ScB was 54, 43 and 30 min, respectively. The tmax for vessel dilator after IvB, ScB and ScI administration was 1.5, 23 and 156 min, respectively, whereas the corresponding Cmax values were 3749, 887 and 471 ng/L (normalized against the dose used for ScB and IvB). The area under the curve (AUC0-∞ ) for vessel dilator was 1166, 880 and 1652 ng h/mL (normalized) following IvB, ScB and ScI administration, respectively. The volume of distribution for vessel dilator was 2.38, 0.92 and 1.08 L following IvB, ScB and SCI administration, respectively; corresponding clearance values were 1.69, 1.50 and 0.78 L/h, respectively. Plasma concentrations of vessel dilator after each of the three methods of administration mirrored their predicted concentration-time profiles. We conclude that vessel dilator administered via ScI has a significantly greater AUC and t½ and slowed clearance compared with IvB or ScB administration (P < 0.001), suggesting that s.c. infusion is the preferred method of administration, based on pharmacokinetics, to treat cancers.

Identification of KLHL17 as a prognostic marker for prostate cancer based on single-cell sequencing and in vitro/in vivo experiments.

BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related mortality among men, characterized by significant heterogeneity that complicates diagnosis and treatment. METHODS AND RESULTS: To enhance our understanding of PCa, we utilized single-cell RNA sequencing (scRNA-seq) data to identify distinct malignant epithelial cell subpopulations and their molecular characteristics. By integrating scRNA-seq data with bulk RNA-seq data, we constructed a prognostic risk score model. The influence of key genes identified in the risk score on PCa was validated through both in vitro and in vivo experiments. Our study revealed eight unique malignant epithelial cell clusters, each exhibiting distinct molecular characteristics and biological functions. KEGG and GO enrichment analyses highlighted their involvement in various pathways. The prognostic risk score model demonstrated strong predictive power for patient outcomes, particularly in predicting progression-free survival (PFS). Notably, KLHL17, identified as a high-risk gene, was found to significantly impact PCa cell proliferation, migration, invasion, and apoptosis upon knockdown. This finding was further validated in vivo using a subcutaneous xenograft tumor model, where reduced KLHL17 expression led to decreased tumor growth. CONCLUSION: Our research provides a comprehensive analysis of PCa heterogeneity and highlights KLHL17 as a potential therapeutic target.

Evaluation of antitumor potential of an anti-glypican-1 monoclonal antibody in preclinical lung cancer models reveals a distinct mechanism of action.

Aim: The main objective of this study was to investigate the antitumor effect of a mouse anti-human glypican-1 (GPC1) monoclonal antibody (mAb) on non-small cell lung carcinoma (NSCLC) and associated molecular mechanisms. Methods: The anti-proliferative and anti-migratory activities of anti-GPC1 mAb were examined in A549 and H460 NSCLC cells and LL97A lung fibroblasts. The inhibitory effect of anti-GPC1 mAb on tumor growth was evaluated in an orthotopic lung tumor model. Results: The in vitro study showed that anti-GPC1 mAb profoundly inhibited the anchorage-independent growth of A549 and H460 NSCLC cells and exhibited relatively high cytotoxic activities towards LL97A lung fibroblasts, A549/LL97A and H460/LL97A coculture spheroids. Moreover, anti-GPC1 mAb significantly decreased the expression of phospho-Src (p-Src; Tyr416), p-Akt (Ser473) and ß-catenin in the co-cultured LL97A lung fibroblasts, and the expression of phospho-mitogen-activated protein kinase kinase (p-MEK; Ser217/221) and phospho-90 kDa ribosomal s6 kinase (p-p90RSK; Ser380) in co-cultured A549 cells. When anti-GPC1 mAb was administered to tumor-bearing mice, the inhibitory effect of anti-GPC1 mAb on the orthotopic lung tumor growth was not statistically significant. Nonetheless, results of Western blot analysis showed significant decrease in the phosphorylation of fibroblast growth factor receptor 1 (FGFR1) at Tyr766, Src at Tyr416, extracellular signal-regulated kinase (ERK) at Thr202/Tyr204, 90 kDa ribosomal S6 kinase (RSK) at Ser380, glycogen synthase kinases 3α (GSK3α) at Ser21 and GSK3ß at Ser9 in tumor tissues. These data implicate that anti-GPC1 mAb treatment impairs the interaction between tumor cells and tumor associated fibroblasts by attenuating the paracrine FGFR signal transduction. Conclusions: The relatively potent cytotoxicity of anti-GPC1 mAb in lung fibroblasts and its potential inhibitory effect on the paracrine FGFR signal transduction warrant further studies on the combined use of this mAb with targeted therapeutics to improve therapeutic outcomes in lung cancer.

[Report of 3162 cases of holmium laser enucleation of the prostate and review].

OBJECTIVE: To evaluate the safety, effectiveness, and outcomes of holmium laser enucleation of the prostate (HoLEP) for patients with symptomatic enlarged prostate after 11 years of experience. METHODS: The 3162 evaluable patients treated with holmium laser enucleation of the prostate at our institution between August 2001 and August 2011 were retrospectively analyzed. Study variables included International Prostate Symptom Score, quality of life, maximum urinary flow rate, and incidence of complications. RESULTS: HoLEP were performed successfully completed, not patients which occurs as electric cutting syndrome. The operation time was (60.8 ± 18.4) minutes; average resection of prostate quality was (45.4 ± 24.4) g. The hemoglobin reduce though surgery was (1.81 ± 0.93) g/L; percentage of red blood cell change was 1.24% ± 0.43%, and sodium blood drop was (1.14 ± 0.35) mmol/L. Postoperative patients of hospital stay (3.1 ± 1.1) days, average time of indwelling catheter time was (2.3 ± 0.8) days. Patients were followed up for 6-131 months time, an average of 32.4 months. Postoperative patients with international prostate symptom score progressive declined. The quality of life score was 2.2 ± 1.7, and it less than preoperative (5.7 ± 3.3, t = 2.447, P < 0.01). The time of follow-up droped further, and postoperative comparative differences have statistical significance (t = 2.179, 2.228, 2.306 and 2.365, P < 0.05). The maximum urinary flow rate also improved (P < 0.05). Postoperative complications included bladder neck contracture (4 cases), urinary tract infection (107 cases), urethral stricture (11 cases) and urinary incontinence (11 cases). The 11 patients reoperation. CONCLUSIONS: HoLEP treatment of benign prostatic hyperplasia could achieve the advantages of open surgery the same effect. It had fewer damage, faster recovery, fewer complications, and is a good treatment option.

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 [...].

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.

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.

Activation of alternate prosurvival pathways accounts for acquired sunitinib resistance in U87MG glioma xenografts.

Acquired drug resistance represents a major obstacle to using sunitinib for the treatment of solid tumors. Here, we examined the cellular and molecular alterations in tumors that are associated with acquired brain tumor resistance to sunitinib by using an in vivo model. U87MG tumors obtained from nude mice that received sunitinib (40 mg/kg/day) for 30 days were classified into sunitinib-sensitive and -resistant groups based on tumor volume and underwent targeted gene microarray and protein array analyses. The expression of several angiogenesis-associated genes was significantly modulated in sunitinib-treated tumors compared with those in control tumors (p<0.05), whereas no significant differences were observed between sunitinib-sensitive and -resistant tumors (p>0.05). Tumor vasculature based on microvessel density, neurogenin 2 chondroitin sulfate proteoglycan density, and α-smooth muscle actin density was also similar in sunitinib-treatment groups (p>0.05). The moderate increase in unbound sunitinib tumor-to-plasma area-under-the-curve ratio in sunitinib-resistant mice was accompanied by up-regulated ATP-binding cassette G2 expression in tumor. The most profound difference between the sunitinib-sensitive and -resistant groups was found in the expression of several phosphorylated proteins involved in intracellular signaling. In particular, phospholipase C-γ1 phosphorylation in sunitinib-resistant tumors was up-regulated by 2.6-fold compared with that in sunitinib-sensitive tumors (p<0.05). In conclusion, acquired sunitinib resistance in U87MG tumors is not associated with revascularization in tumors, but rather with the activation of alternate prosurvival pathways involved in an escape mechanism facilitating tumor growth and possibly insufficient drug uptake in tumor cells caused by an up-regulated membrane efflux transporter.

Screening candidate anticancer drugs for brain tumor chemotherapy: pharmacokinetic-driven approach for a series of (E)-N-(substituted aryl)-3-(substituted phenyl)propenamide analogues.

A pharmacokinetic [PK]-driven screening process was implemented to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON27x] that consisted of 141 compounds. The screening procedures involved a combination of in silico, in vitro and in vivo mouse studies that were cast into a pipeline of tier 1 and tier 2 failures that resulted in a final investigation of 2 analogues in brain tumor-bearing mice. Tier 1 failures included agents with a molecular weight of > 450 Da, a predicted log P (log P) of either <2 or > 3.5, and a cytotoxicity IC(50) value of > 2 uM. Next, 18 compounds underwent cassette dosing studies in normal mice that identified compounds with high systemic clearance, and low blood-brain barrier [BBB] penetration. These indices along with a derived parameter, referred to as the brain exposure index, comprised tier 2 failures that led to the administration of 2 compounds [ON27570, ON27740] as single agents [discrete dosing] to mice bearing intracerebral tumors. Comparison of ON27570's resultant PK parameters to those obtained in the cassette dosing format suggested a drug-drug interaction most likely at the level of BBB transport, and prompted the use of the in vitro MDCK-MDR1 transport model to help assess the nature of the discrepancy. Overall, the approach was able to identify candidate compounds with suitable PK characteristics yet further revisions to the method, such as the use of in vitro metabolism and transport assays, may improve the PK-directed approach to identify efficacious agents for brain tumor chemotherapy.

Preclinical pharmacokinetic and pharmacodynamic evaluation of novel anticancer agents, ON01910.Na (Rigosertib, Estybon™) and ON013105, for brain tumor chemotherapy.

PURPOSE: To evaluate a mitotic inhibitor, ON01910.Na, as a potential chemotherapeutic agent for brain tumors using a series of PK/PD studies, which led to the evaluation of its structural analog, ON013105, a prodrug of the more lipophilic product, ON013100. METHODS: Systemic PK characterization of ON01910 and ON013105 was completed in healthy mice. Using an orthotopic U87 glioma mouse model, brain and brain tumor distribution under steady-state conditions were evaluated for ON01910.Na and ON013105/ON013100; anticancer potential following a multiple-dose schedule of 250 mg/kg/day IP for 7 days was evaluated for ON01910.Na. RESULTS: ON01910 exhibited low brain and brain tumor distribution with quasi-steady-state brain/plasma (Css(brain)/Css(plasma)) and brain tumor/plasma (Css(brain tumor)/Css(plasma)) concentration ratios of 0.03 ± 0.02 and 0.14 ± 0.08, respectively. Significant antiangiogenic potential and antiproliferative capacity of ON01910 in the intracerebral model was absent. ON013100 showed high brain and brain tumor penetration with Css(brain)/Css(plasma) and Css(brain tumor)/Css(plasma) ratios of 0.92 ± 0.26 and 1.35 ± 0.40, respectively; its prodrug ON013105 showed negligible brain and brain tumor penetration. CONCLUSIONS: ON013105, not ON01910.Na, was identified as a potential anticancer drug candidate for further investigation in brain tumor chemotherapy based on the properties of ON013100.

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.

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.

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.