Transcriptome and single-cell analysis reveal disulfidptosis-related modification patterns of tumor microenvironment and prognosis in osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor with high pathological heterogeneity. Our study aimed to investigate disulfidptosis-related modification patterns in OS and their relationship with survival outcomes in patients with OS. We analyzed the single-cell-level expression profiles of disulfidptosis-related genes (DSRGs) in both OS microenvironment and OS subclusters, and HMGB1 was found to be crucial for intercellular regulation of OS disulfidptosis. Next, we explored the molecular clusters of OS based on DSRGs and related immune cell infiltration using transcriptome data. Subsequently, the hub genes of disulfidptosis in OS were screened by applying multiple machine models. In vitro and patient experiments validated our results. Three main disulfidptosis-related molecular clusters were defined in OS, and immune infiltration analysis suggested high immune heterogeneity between distinct clusters. The in vitro experiment confirmed decreased cell viability of OS after ACTB silencing and higher expression of ACTB in patients with lower immune scores. Our study systematically revealed the underlying relationship between disulfidptosis and OS at the single-cell level, identified disulfidptosis-related subtypes, and revealed the potential role of ACTB expression in OS disulfidptosis.

Application of TCM Nursing in Post-anesthesia Recovery Room Under Integrated Management Mode.

Objective: To explore the effect of traditional Chinese medicine (TCM) nursing under the integrated management mode during anesthesia recovery. Methods: The researchers' hospital admitted 114 patients who underwent general anesthesia between August 2022 and April 2023. Based on the admission order, these patients were divided into a control group (N=57) and an observation group (N=57). The control group received routine nursing intervention, while the observation group received comprehensive TCM nursing management, which included therapies such as cupping, acupressure, massage, herbal decoction, and mirabilite application. The study evaluated the psychological status, recovery indexes after anesthesia, comfort level, incidence of complications, and patient satisfaction with nursing care. Results: Compared to the control group, the observation group showed significant improvement in their psychological well-being (P < .05) and better recovery outcomes after anesthesia (P < .05). Additionally, the observation group reported higher levels of comfort (P < .05), a lower incidence of complications (8.77% vs 29.82%, P < .05), and greater satisfaction with nursing care (98.25% vs 84.21%, P < .05) compared to the control group. Conclusion: Integrated management of traditional Chinese medicine effectively reduces postoperative adverse events, improves treatment outcomes, and facilitates patient recovery. Its benefits are evident, and its feasibility is well-established.

An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.

Targeting cancer cell mitochondria holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we introduce mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. We synthesize a blue light-gated channelrhodopsin (CoChR) in the IMM and co-express a blue bioluminescence-emitting Nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes are selectively delivered to cancer cells in vivo by using adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV. Induction with NLuc luciferin elicits robust endogenous bioluminescence, which activates mitochondrial CoChR, triggering cancer cell IMM permeability disruption, mitochondrial damage, and subsequent cell death. Importantly, mLumiOpto demonstrates remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma or triple-negative breast cancer xenografted mouse models. These findings establish mLumiOpto as a novel and promising therapeutic strategy by targeting cancer cell mitochondria in vivo.

DePARylation is critical for S phase progression and cell survival.

Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S-phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.

Proteomic analysis of ferroptosis pathways reveals a role of CEPT1 in suppressing ferroptosis.

Ferroptosis has been recognized as a unique cell death modality driven by excessive lipid peroxidation and unbalanced cellular metabolism. In this study, we established a protein interaction landscape for ferroptosis pathways through proteomic analyses, and identified choline/ethanolamine phosphotransferase 1 (CEPT1) as a lysophosphatidylcholine acyltransferase 3 (LPCAT3)-interacting protein that regulates LPCAT3 protein stability. In contrast to its known role in promoting phospholipid synthesis, we showed that CEPT1 suppresses ferroptosis potentially by interacting with phospholipases and breaking down certain pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing phospholipids. Together, our study reveals a previously unrecognized role of CEPT1 in suppressing ferroptosis.

Osteogenesis or Apoptosis-Twofold Effects of Zn2+ on Bone Marrow Mesenchymal Stem Cells: An In Vitro and In Vivo Study.

Zinc (Zn) is a bioabsorbable metal that shows great potential as an implant material for orthopedic applications. Suitable concentrations of zinc ions promote osteogenesis, while excess zinc ions cause apoptosis. As a result, the conflicting impacts of Zn2+ concentration on osteogenesis could prove to be significant problems for the creation of novel materials. This study thoroughly examined the cell viability, proliferation, and osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) cultured in various concentrations of Zn2+ in vitro and validated the osteogenesis effects of zinc implantation in vivo. The effective promotion of cell survival, proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cell (BMSCs) may be achieved at a low concentration of Zn2+ (125 µM). The excessively high concentration of zinc ions (>250 µM) not only reduces BMSCs' viability and proliferation but also causes them to suffer apoptosis due to the disturbed zinc homeostasis and excessive Zn2+. Moreover, transcriptome sequencing was used to examine the underlying mechanisms of zinc-induced osteogenic differentiation with particular attention paid to the PI3K-AKT and TGF-ß pathways. The present investigation elucidated the dual impacts of Zn2+ microenvironments on the osteogenic characteristics of rBMSCs and the associated processes and might offer significant insights for refining the blueprint for zinc-based biomaterials.

BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers.

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from BRCA1-mutant breast cancer patients with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers.

A pig model of symptomatic spinal epidural hematoma.

PURPOSE: The purpose of this study was to establish an animal model capable of simulating the development and decompression process of symptomatic spinal epidural hematoma (SSEH). METHODS: A total of 16 male Bama miniature pigs were included in this study and randomly allocated into four groups: Group A (4 h 20 mmHg hematoma compression), Group B (4 h 24 mmHg hematoma compression), Group C (4 h 28 mmHg hematoma compression), and Group Sham (control). Real-time intra-wound hematoma compression values were obtained using the principle of connectors. Electrophysiological analyses, including the latency and amplitude of somatosensory evoked potentials (SSEP) and motor evoked potentials (MEP), along with behavioral observations (Tarlov score), were performed to assess this model. RESULTS: ANOVA tests demonstrated significant differences in the latency and relative amplitude of SSEP and MEP between Groups C and Sham after 4 h of hematoma compression and one month after surgery (P < 0.01). Behavioral assessments 8 h after surgery indicated that animals subjected to 28 mmHg hematoma compression suffered the most severe spinal cord injury. Pearson correlation coefficient test suggested a negative correlation between the epidural pressure and Tarlov score (r = -0.700, p < 0.001). With the progression of compression and the escalation of epidural pressure, the latency of SSEP and MEP gradually increased, while the relative amplitude gradually decreased. CONCLUSIONS: When the epidural pressure reaches approximately 24 mmHg, the spinal cord function occurs progressive dysfunction. Monitoring epidural pressure would be an effective approach to assist to identify the occurrence of postoperative SSEH.

Advanced biomanufacturing and evaluation of adeno-associated virus.

Recombinant adeno-associated virus (rAAV) has been developed as a safe and effective gene delivery vehicle to treat rare genetic diseases. This study aimed to establish a novel biomanufacturing process to achieve high production and purification of various AAV serotypes (AAV2, 5, DJ, DJ8). First, a robust suspensive production process was developed and optimized using Gibco Viral Production Cell 2.0 in 30-60 mL shaker flask cultures by evaluating host cells, cell density at the time of transfection and plasmid amount, adapted to 60-100 mL spinner flask production, and scaled up to 1.2-2.0-L stirred-tank bioreactor production at 37 °C, pH 7.0, 210 rpm and DO 40%. The optimal process generated AAV titer of 7.52-8.14 × 1010 vg/mL. Second, a new AAV purification using liquid chromatography was developed and optimized to reach recovery rate of 85-95% of all four serotypes. Post-purification desalting and concentration procedures were also investigated. Then the generated AAVs were evaluated in vitro using Western blotting, transmission electron microscope, confocal microscope and bioluminescence detection. Finally, the in vivo infection and functional gene expression of AAV were confirmed in tumor xenografted mouse model. In conclusion, this study reported a robust, scalable, and universal biomanufacturing platform of AAV production, clarification and purification.

Thermal stability and quantum efficiency improvement of Cr3+-activated garnet phosphors via regulating A/B sites for near-infrared LED applications.

The discovery of phosphors with highly efficient broadband near-infrared emission is urgent for constructing NIR sources for various applications. Herein, we synthesized a series of near-infrared emitting garnet-type (A3B2C3O12) Lu2-xCaAl3.99Cr0.01SiO12:xGd/La and Lu2CaAl3.99-yCr0.01SiO12:ySc/Ga phosphors and systematically investigated the effect of A/B-site substitution on the crystal structure and luminescence properties. Structural and optical analyses revealed that the A/B-site substitution weakened the crystal field strength, further enhancing the broadband emission of the allowed 4T2 → 4A2transition and diminishing the narrow-peak emission of the forbidden 2E → 4A2 transition. As expected, NIR phosphors, exemplified by Lu1.7CaAl3.99Cr0.01SiO12:0.3Gd and Lu2CaAl3.49Cr0.01SiO12:0.5Sc, showed outstanding thermal stabilities at 423 K (150 °C) registering values of 103.02% and 94.91%, with high quantum efficiencies of 80.48% and 85.01%, respectively. In addition, pc-LEDs with broadband NIR output and good optoelectronic properties have been realized, demonstrating the great potential of broadband NIR pc-LEDs for applications. This work not only provides a series of high-efficiency phosphors for NIR pc-LED applications, but also provides a systematic idea and an efficient method to improve the luminescence performance of garnet-type phosphors.

Metabolic Landscape of Osteosarcoma: Reprogramming of Lactic Acid Metabolism and Metabolic Communication.

BACKGROUND: Lactic acid, previously regarded only as an endpoint of glycolysis, has emerged as a major regulator of tumor invasion, growth, and the tumor microenvironment. In this study, we aimed to explore the reprogramming of lactic acid metabolism relevant to osteosarcoma (OS) microenvironment by decoding the underlying lactic acid metabolic landscape of OS cells and intercellular signaling alterations. METHODS: The landscape of OS metabolism was evaluated using single-cell gene expression data, lactic acid metabolism clustering, and screening of the hub genes in lactic acid metabolism of OS samples using transcriptome data. The role of the hub gene NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 6 (NDUFAF6) was validated with in vitro studies and patient experiments. RESULTS: Single-cell RNA sequencing data validated a lactic acid metabolismhigh subcluster in OS. Further investigation of intercellular communications revealed a unique metabolic communication pattern between the lactic acid metabolismhigh subcluster and other subclusters. Next, two lactic acid metabolic reprogramming phenotypes were defined, and six lactic acid metabolism-related genes (LRGs), including the biomarker NDUFAF6, were screened in OS. In vitro studies and patient experiments confirmed that NDUFAF6 is a crucial lactic acid metabolism-associated gene in OS. CONCLUSIONS: The patterns of lactic acid metabolism in OS suggested metabolic reprogramming phenotypes relevant to the tumor microenvironment (TME) and identified NDUFAF6 as an LRG prognostic biomarker.

Comparison of En Bloc Resection and Intralesional Excision for Re-resection of Giant Cell Tumors of the Spine.

OBJECTIVE: Re-resection of spinal giant cell tumors is an exceedingly difficult procedure. Moreover, the prognosis of patients with en bloc resection or intralesional excision for re-resection has rarely been reported. This study aimed to compare the prognostic value of en bloc resection with that of intralesional excision in patients undergoing re-resection for giant cell tumors of the spine. METHODS: This retrospective analysis evaluated patients who underwent revision surgeries for relapse of giant cell tumors of the spine at our center between January 2005 and January 2021. Local progression-free survival represents the duration between en bloc resection or intralesional excision and tumor recurrence. Neurological recovery, survival rates, local control, and complications were evaluated. The Kaplan-Meier estimator was used for survival analysis. RESULTS: A total of 22 patients (nine men and 13 women) with a mean age of 34.1 (range 19-63) years were included. Significant statistical differences were found in the local tumor recurrence rate between patients treated with en bloc resection and those treated with intralesional excision (p < 0.05). The 5- and 10-year local progression-free survival rates were both 90% in the en bloc resection group, while in the intralesional excision group, the 5-year local progression-free survival rate was 80% with a 10-year rate of 45.7%. The en bloc resection group had a lower local tumor recurrence rate than that of the intralesional excision group (p < 0.05), but the former had a higher rate of complications (p = 0.015). CONCLUSIONS: This study revealed a low local recurrence rate in patients who underwent en bloc resection for giant cell tumors, while the perioperative complication rate was high.

Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.

How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.

A novel process based on powder carriers demonstrates robustness in nitrogen and phosphorus removal from real municipal wastewater.

The development of efficient and low-consumption wastewater upgrading process is currently at the forefront of the wastewater treatment field. In this study, a novel wastewater treatment process based on powder carriers was proposed. Three systems, namely the activated sludge (AS) system, powder carrier (PC) system, and moving bed biofilm reactor (MBBR) system, were established and operated for over 140 days to treat real municipal wastewater. The characteristics and differences between the three systems were comprehensively investigated. The results suggested that the PC system exhibited notable advantages in nitrogen and phosphorus removal, especially under high influent load and low aeration conditions. The PC system, characterized by a higher nitrification rate compared to the MBBR system and a higher denitrification rate compared to the AS system, contributed to the stable nitrogen removal performance. The particle size of the zoogloea increased under the linkage of the powder carriers, and the mean size of micro-granules reached 170.88 µm. Large number of hydrophobic functional groups on sludge surface, coupled with increased protein content in EPS, further promoted sludge aggregation. Micro-granules formation improved settling performance and enhanced the abundance and activity of functional microbes. A significant enrichment in denitrifying bacteria and denitrifying phosphorus accumulating bacteria was observed in PC system. Up-regulation of the napA, narG, and nosZ genes was responsible for efficient nitrogen removal of the PC system. Moreover, a higher abundance in polyphosphate phosphotransferase (2.11 %) was found in PC system compared with AS and MBBR systems. The increase in the enzymes associated with poly-ß-hydroxybutyrate (PHB) synthesis metabolism in PC system provided the energy for denitrification and phosphorus removal processes.

Thermal hydrolysis prior to hydrothermal carbonization resulted in high quality sludge hydrochar with low nitrogen and sulfur content.

Hydrothermal carbonization of waste activated sludge suffers from a low degree of carbonization caused by limited hydrolysis of carbohydrates and proteins, resulting in a high nitrogen content in hydrochar. Thus, it is hypothesized that thermal hydrolysis could destroy the stable floc structure of waste activated sludge, leading to higher degree of carbonization and high quality hydrochar with low nitrogen content by improving the solubilization and hydrolysis of organic matter. In the current study, thermal hydrolysis at 90 °C, 125 °C, and 155 °C was performed prior to hydrothermal carbonization to obtain low-nitrogen-content hydrochar. Thermal hydrolysis greatly improved the hydrolysis of sewage sludge. The nitrogen and sulfur content in hydrochars obtained after thermal hydrolysis decreased to 1.5-1.6 % from 1.7 %, and to 0.4 % from 0.5 %, respectively, depending on the hydrolysis conditions. Thermal decomposition stability of hydrochars obtained after thermal hydrolysis were also improved. Thermal hydrolysis at 90 °C and 125 °C promoted hydrolysis, dehydration, and the Diels-Alder reaction during hydrothermal carbonization, resulting in lower hydrochar yield but higher H/C and O/C atomic ratio. The Maillard reaction occurred during thermal hydrolysis at 155 °C, leading to the formation of large molecular refractory compounds that were retained in the hydrochar and increased the hydrochar yield. Furthermore, thermal hydrolysis can accelerate pyrolysis reaction of hydrochars, resulting in reduced energy consumption. The newly established thermal hydrolysis-hydrothermal carbonization process using sewage sludge as the feedstock has the potential to contribute to the development of the hydrothermal carbonization industry.

Formation of autotrophic nitrogen removal granular sludge driven by the dual-partition airlift internal circulation: Insights from performance assessment, community succession, and metabolic mechanism.

Granular sludge has been recognized as an effective method for the application and industrialization of the anammox-based process due to its good biomass retention capacity and environmental tolerance. In this study, a one-stage autotrophic nitrogen removal (ANR) dual-partition system with airlift internal circulation was implemented for 320 days. A high nitrogen removal efficiency of 84.6% was obtained, while the nitrogen removal rate reached 1.28 g-N/L/d. ANR granular sludge dominated by Nitrosomonas and Candidatus Brocadia was successfully cultivated. Results showed that activity and abundance of functional flora first increased with granulation process, but eventually declined slightly when particle size exceeded the optimal range. Total anammox activity was observed to be significantly correlated with protein content (R2 = 0.9623) and nitrogen removal performance (R2 = 0.8796). Correlation network revealed that AnAOB had complex interactions with other bacteria, both synergy for nitrogen removal and competition for substrate. Changes in abundances of genes encoding the Carbohydrate Metabolism, Energy Metabolism, and Membrane Transport suggested energy production and material transfer were possibly blocked with further sludge granulation. Formation of ANR granular sludge promoted the interactions and metabolism of functional microorganisms, and the complex nitrogen metabolic pathways improved the performance stability. These results validated the feasibility of granule formation in the airlift dual-partition system and revealed the response of the ANR system to sludge granulation.

Hypoxia-Inducible Factor-1α (HIF-1α) as a Factor to Predict the Prognosis of Spinal Chordoma.

STUDY DESIGN: Retrospective study. OBJECTIVE: In this study, the authors explore the potential relationship between hypoxia inducible factor-1α (HIF-1α) and the prognosis of patients with spinal chordoma. SUMMARY OF BACKGROUND DATA: Currently, prognostic factors related to the clinical course in the setting of spinal chordoma are poorly understood. Although the close relationship between HIF-1α and tumor angiogenesis, metastasis, and recurrence have been widely reported, it has not been investigated in the context of spinal chordoma. MATERIALS AND METHODS: In this study, 32 samples of chordoma patients were compared with 14 nucleus pulposus tissues as controls. The specific expression of HIF-1α was detected by immunohistochemistry. Continuous disease-free survival (CDFS) was defined as the interval from tumor resection to confirmation of the first local recurrence or distant metastasis. Overall survival (OS) was defined as the interval from the date of surgery to death related to any cause. The relationship between HIF-1α expression and the clinicopathologic characteristics of patients with chordoma was analyzed using the Pearson χ 2 test. Multivariate Cox analysis was used to evaluate whether HIF-1α expression was associated with the prognosis of patients after controlling for confounders. RESULTS: HIF-1α was mainly expressed in the cytoplasm or nucleus in all of the chordoma samples, which showed significantly higher than that in the normal nucleus pulposus tissue ( P =0.004). Multivariate Cox regression analyses showed that high HIF-1α expression and location of HIF-1α expression were significantly associated with poor CDFS (hazard ratio (HR)=3.374; P =0.021) and OS (HR=4.511; P =0.012). In addition, we further found that high HIF-1α expression both in the cytoplasm and nucleus indicated a stronger prognostic factor for poor CDFS (HR=3.885; P =0.011) and OS (HR=4.014; P =0.011) in spinal chordoma patients. CONCLUSION: High HIF-1α expression may become a potential new biological indicator to predict a poor prognosis in patients with spinal chordoma. HIF-1α may also represent a novel therapeutic target for the treatment of spinal chordoma.

Iron-Catalyzed Gamma-Gamma Dimerization of Siloxydienes.

We report the oxidative dimerization reaction of siloxydienes derived from simple enones that creates a new gamma-gamma (γ-γ) C-C bond using catalytic iron and benzoyl peroxide as the terminal oxidant in acetonitrile solvent at ambient temperature. The reaction shows a broad substrate scope including cyclic and acyclic siloxydienes derived from ketones, aldehydes, and esters, which are converted to 1,8-dicarbonyl compounds under mild catalytic reaction conditions in 19-89 % yield across 30 examples. The method is suitable for the coupling of sterically demanding carbon centers, including the formation of vicinal quaternary centers. Conceptually, the dienol ether serves as a precursor to a conjugated radical cation, which undergoes highly site selective γ-dimerization reactions. The γ-γ dimerization strategy is applied to the synthesis of a bioactive analogue of honokiol.

Engineering extracellular vesicles mimetics for targeted chemotherapy of drug-resistant ovary cancer.

Aim: To develop nanocarriers for targeting the delivery of chemotherapeutics to overcome multidrug-resistant ovarian cancer. Materials & methods: Doxorubicin-loaded nanovesicles were obtained through serial extrusion, followed by loading of P-glycoprotein siRNA and folic acid. The targeting ability and anticancer efficacy of the nanovesicles were evaluated. Results: The doxorubicin-loaded nanovesicles showed a high production yield. The presence of P-glycoprotein siRNA and folic acid resulted in reversed drug resistance and tumor targeting. This nanoplatform tremendously inhibited the viability of multidrug-resistant ovarian cancer cells, which was able to target tumor tissue and suppress tumor growth without adverse effects. Conclusion: These bioengineered nanovesicles could serve as novel extracellular vesicles mimetics for chemotherapeutics delivery to overcome multidrug resistance.

When treating cancer affecting the ovaries, which is an organ in the female reproductive system, two challenges that arise are the inefficient delivery of chemotherapeutic drugs and the development of drug resistance inside the tumor. In this study, very small nano-scale particles called nanovesicles, which contain a chemotherapeutic drug called doxorubicin, were developed in an attempt to overcome both of these concerns. These nanovesicles were secreted by a healthy cell from an ovary, isolated and loaded with doxorubicin. These nanovesicles were also loaded with siRNA, which, in this case, prevents the synthesis of a protein in ovarian tumor cells called P-glycoprotein. This protein is responsible for pumping chemotherapy drugs back out of tumor cells, so preventing its synthesis was intended to counter chemotherapeutic resistance. The targeting ability of the nanovesicle was also enhanced with folic acid, as folic acid receptors are present on the surface of these tumor cells in higher numbers. These nanovesicles were readily and specifically taken up by ovarian tumor cells in mice with induced ovarian cancer. This reversed drug resistance and enhanced the toxic effects of doxorubicin on the tumor cells, which, in turn, increased tumor cell death and prevented tumor cell migration. No obvious adverse effect was found in mice treated with the nanovesicle system compared with the free chemotherapy drug with critical systematic toxicity. This research provides new avenues for ovarian cancer treatment, with combined therapies of siRNAs and chemotherapeutic drugs, targeted to tumor cells specifically, within nanovesicles.

Development and application of a nomogram model for the prediction of carbapenem-resistant Klebsiella pneumoniae infection in neuro-ICU patients.

IMPORTANCE: Patients in neuro-ICU are at a high risk of developing nosocomial CRKP infection owing to complex conditions, critical illness, and frequent invasive procedures. However, studies focused on constructing prediction models for assessing the risk of CRKP infection in neurocritically ill patients are lacking at present. Therefore, this study aims to establish a simple-to-use nomogram for predicting the risk of CRKP infection in patients admitted to the neuro-ICU. Three easily accessed variables were included in the model, including the number of antibiotics used, surgery, and the length of neuro-ICU stay. This nomogram might serve as a useful tool to facilitate early detection and reduction of the CRKP infection risk of neurocritically ill patients.