Prevalence and contributing factors of anemia in patients with gynecological cancer: a retrospective cohort study.

This retrospective cohort study aimed to determine the prevalence of anemia among patients with gynecological cancer prior to any treatment and to identify contributing factors associated with anemia in this group. We retrospectively analyzed data from female patients aged 18 and above, diagnosed with various forms of gynecological cancer at The Affiliated Hospital of Southwest Medical University between February 2016 and March 2021. Anemia was assessed based on the most recent CBC results before any cancer treatment. Eligibility was based on a definitive histopathological diagnosis. Key variables included demographic details, clinical characteristics, and blood counts, focusing on hemoglobin levels. Statistical analysis was conducted using logistic regression models, and anemia was defined as hemoglobin levels below 12 g/dL for women, according to WHO criteria. Of the 320 participants, a significant prevalence of anemia was found. Correlations between anemia and factors like age, educational level, and biological markers (iron, folic acid, and vitamin B12 levels) were identified. In our study, we found that the prevalence of anemia among patients with gynecological cancer prior to any treatment was 59.06%, indicating a significant health concern within this population. The study highlights a significant prevalence of anemia in patients with gynecological cancer, emphasizing the need for regular hemoglobin screening and individualized management. These findings suggest the importance of considering various characteristics and clinical variables in anemia management among this patient group. Further studies are needed to explore the long-term effects of these factors on patient outcomes and to develop targeted interventions.

Establishment of human hematopoietic organoids for evaluation of hematopoietic injury and regeneration effect.

BACKGROUND: Human hematopoietic organoids have a wide application value for modeling human bone marrow diseases, such as acute hematopoietic radiation injury. However, the manufacturing of human hematopoietic organoids is an unaddressed challenge because of the complexity of hematopoietic tissues. METHODS: To manufacture hematopoietic organoids, we obtained CD34+ hematopoietic stem and progenitor cells (HSPCs) from human embryonic stem cells (hESCs) using stepwise induction and immunomagnetic bead-sorting. We then mixed these CD34+ HSPCs with niche-related cells in Gelatin-methacryloyl (GelMA) to form a three-dimensional (3D) hematopoietic organoid. Additionally, we investigated the effects of radiation damage and response to granulocyte colony-stimulating factor (G-CSF) in hematopoietic organoids. RESULTS: The GelMA hydrogel maintained the undifferentiated state of hESCs-derived HSPCs by reducing intracellular reactive oxygen species (ROS) levels. The established hematopoietic organoids in GelMA with niche-related cells were composed of HSPCs and multilineage blood cells and demonstrated the adherence of hematopoietic cells to niche cells. Notably, these hematopoietic organoids exhibited radiation-induced hematopoietic cell injury effect, including increased intracellular ROS levels, γ-H2AX positive cell percentages, and hematopoietic cell apoptosis percentages. Moreover, G-CSF supplementation in the culture medium significantly improved the survival of HSPCs and enhanced myeloid cell regeneration in these hematopoietic organoids after radiation. CONCLUSIONS: These findings substantiate the successful manufacture of a preliminary 3D hematopoietic organoid from hESCs-derived HSPCs, which was utilized for modeling hematopoietic radiation injury and assessing the radiation-mitigating effects of G-CSF in vitro. Our study provides opportunities to further aid in the standard and scalable production of hematopoietic organoids for disease modeling and drug testing.

Physical exercise and hypertension: A retrospective study in southern Sichuan.

This study aimed to scrutinize the relationship between physical exercise and hypertension, taking into account multiple variables such as age, body mass index (BMI), family history, smoking, and alcohol consumption in the Southern Sichuan population, China, using a retrospective approach based on hospital record data. This retrospective study analyzed data from 946 participants obtained from a hospital electronic medical record system. The data included information regarding participants' lifestyle factors, family history, and a clinical diagnosis of hypertension. Univariate and multivariate logistic regression models were employed to identify the association between lifestyle factors and hypertension. The study found a hypertension prevalence of 38.5% in the analyzed population. Multivariate analyses identified significant factors associated with hypertension as age (odds ratio [OR]: 1.045, 95% confidence interval [CI]: 1.036-1.054), BMI (OR: 1.107, 95% CI: 1.084-1.132), smoking (OR: 2.299, 95% CI: 1.674-3.157), alcohol consumption (OR: 0.644, 95% CI: 0.478-0.867), and physical exercise (OR: 0.682, 95% CI: 0.506-0.920). Findings from this hospital record-based retrospective study reinforce the multifactorial nature of hypertension. They highlight the significance of physical exercise, along with maintaining optimal BMI and encouraging healthy habits like nonsmoking and moderate alcohol consumption in hypertension prevention. Our findings also underscore the need for future prospective studies to establish causality and explore the generalizability of these results beyond the Southern Sichuan population.

Low Initial Cell Density Promotes the Differentiation and Maturation of Human Pluripotent Stem Cells into Erythrocytes.

Human pluripotent stem cell (hPSC)-derived red blood cells (RBCs) possess great potential for compensating shortages in transfusion medicine. For better RBC generation from hPSCs, we compared the cell seeding density in the embryoid body formation-based hPSC induction protocol. In the selection of low- and high-density inoculation conditions, we found that low-density culture performed better in the final RBC product with more cell output and increased average cellular hemoglobin content. An elaborate study using flow cytometry demonstrated that low inoculation density promoted endothelial-to-hematopoietic transition, followed by improved hematopoietic progenitor formation and erythrocyte generation. The improved transformation from glycolysis to mitochondrial oxidation and reduced apoptosis might be responsible for this effect. Hints from RNA sequencing suggested that molecules involved in microenvironment interaction and metabolic regulation might respond for the different developmental potential. The possible mediators between outer message and intracellular response could be the nutrition sensors FOXO, PRKAA1 (AMPK), and MTOR genes. It is possible that low inoculation density triggered metabolic regulation signals, promoted mitochondrial oxidation, and resulted in enhanced cell amplification and hematopoietic differentiation. The low cell culture density will improve RBC generation from hPSCs.

Complete remission in a pretreated, microsatellite-stable, KRAS-mutated colon cancer patient after treatment with sintilimab and bevacizumab and platinum-based chemotherapy: a case report and literature review.

Metastatic colon cancer remains an incurable disease, and it is difficult for existing treatments to achieve the desired clinical outcome, especially for colon cancer patients who have received first-line treatment. Although immune checkpoint inhibitors (ICIs) have demonstrated durable clinical efficacy in a variety of solid tumors, their response requires an inflammatory tumor microenvironment. However, microsatellite-stable (MSS) colon cancer, which accounts for the majority of colorectal cancers, is a cold tumor that does not respond well to ICIs. Combination regimens open the door to the utility of ICIs in cold tumors. Although combination therapies have shown their advantage even for MSS colon cancer, it remains unclear whether combination therapies show their advantage in patients with pretreated metastatic colon cancer. We report a patient who has achieved complete remission and good tolerance with sintilimab plus bevacizumab and platinum-based chemotherapy after postoperative recurrence. The patient had KRAS mutation and MSS-type colon cancer, and his PD-1+CD8+ and CD3-CD19-CD14+CD16-HLA-DR were both positive. He has achieved a progression-free survival of 43 months and is still being followed up at our center. The above results suggest that this therapeutic regimen is a promising treatment modality for the management of pretreated, MSS-type and KRAS-mutated metastatic colorectal cancer although its application to the general public still needs to be validated in clinical trials.

The critical role of tumor microbiome in cancer immunotherapy.

In recent years, the microbiome has shown an integral role in cancer immunotherapy and has become a prominent and widely studied topic. A full understanding of the interactions between the tumor microbiome and various immunotherapies offers opportunities for immunotherapy of cancer. This review scrutinizes the composition of the tumor microbiome, the mechanism of microbial immune regulation, the influence of tumor microorganisms on tumor metastasis, and the interaction between tumor microorganisms and immunotherapy. In addition, this review also summarizes the challenges and opportunities of immunotherapy through tumor microbes, as well as the prospects and directions for future related research. In conclusion, the potential of microbial immunotherapy to enhance treatment outcomes for cancer patients should not be underestimated. Through this review, it is hoped that more research on tumor microbial immunotherapy will be done to better solve the treatment problems of cancer patients.

Predicting online information seeking on Douyin, Baidu, and other Chinese search engines among gynecologic oncology patients: a cross-sectional study.

Objective: The rise of online platforms like Douyin, Baidu, and other Chinese search engines has changed how gynecologic oncology patients seek information about their diagnosis or condition. This study aimed to investigate the factors associated with information seeking among these patients and to evaluate their predictive performance. Methods: A cross-sectional study was conducted among 199 gynecologic oncology patients at a single hospital in China. The patients' demographic characteristics and scores on the State-Trait Anxiety Inventory (STAI-S and STAI-T) and the Hospital Anxiety and Depression Scale (HADS-A and HADS-D) were compared between those who sought information online and those who did not. Logistic regression analyses and receiver operating characteristic (ROC) curve analyses were performed. Results: The patients' age, marital status, STAI-S scores, and HADS-A scores were significantly associated with online information seeking. The combined model that included these factors showed good predictive performance with an area under the ROC curve of 0.841. Conclusion: The combination of demographic and psychological factors can be used to predict the likelihood of gynecologic oncology patients seeking information online. These findings can help healthcare providers understand their patients' information-seeking behaviors and tailor their communication strategies accordingly.

Predictive modeling of postoperative gastrointestinal dysfunction: the role of serum bilirubin, sodium levels, and surgical duration in gynecological cancer care.

OBJECTIVE: To elucidate the role of preoperative serum bilirubin and sodium levels, along with the duration of surgery, in predicting postoperative gastrointestinal dysfunction (POGD) following gynecological cancer surgery, informing tailored perioperative strategies. METHODS: We conducted a retrospective analysis of 281 patients undergoing gynecological cancer surgery between 2018 and 2023. This analysis focused on preoperative serum bilirubin and sodium levels and intraoperative factors (surgical duration) as potential predictors of POGD. Logistic regression models were utilized for analysis, controlling for relevant confounders. RESULTS: Elevated preoperative serum bilirubin was associated with a reduced risk of POGD (mean level in non-POGD cases: 14.172 ± 4.0701, vs. POGD cases: 9.6429 ± 3.5351; p <  0.001), suggesting a protective role. Lower preoperative sodium levels were identified in the POGD group (136.26 mEq/L [IQR: 135.2-137.63]) compared to the non-POGD group (139.32 mEq/L [IQR: 137.7-140.75]; p <  0.001), highlighting its predictive value. Additionally, longer surgical duration was associated with increased POGD incidence, with POGD cases experiencing surgeries lasting 6.1547 ± 1.9426 hours compared to 4.5959 ± 1.5475 hours in non-POGD cases (p <  0.001). CONCLUSION: Our findings underscore the importance of serum bilirubin, sodium levels, and surgical duration as significant predictors of POGD in patients undergoing gynecological cancer surgery. These indicators should be integrated into a predictive model, aiding clinicians in identifying high-risk patients, allowing for personalized perioperative care adjustments, potentially mitigating POGD risks.

Nutritional risk index predicts the prognosis of gastric cancer patients with pyloric stenosis who received preoperative parenteral nutrition.

Patients with gastric cancer with pyloric stenosis frequently have poor nutritional status and preoperative parenteral nutrition has been a common treatment strategy. The present study aimed to explore the predictive ability of the nutritional risk index (NRI) regarding the prognosis of patients with gastric cancer and pyloric stenosis who received preoperative parenteral nutrition. A total of 194 patients with gastric cancer with pyloric stenosis who received preoperative parenteral nutrition at Tthe Second People's Hospital of Neijiang (Neijiang, China) between January 2016 and December 2021 were included. At the same time, 221 patients with gastric cancer without pyloric stenosis who received surgery during the same period were also collected and the clinicopathological characteristics of the patients were compared. The optimal cut-off value of the NRI was determined from the receiver operating characteristic curve and prognostic factors were identified by survival analysis. Finally, a nomogram was constructed to predict the survival probability of patients with gastric cancer. The results indicated that patients with pyloric stenosis exhibited a wide range of unfavorable pathological characteristics and blood parameters. In addition, their overall survival (OS) was significantly worse (P<0.001). Among the patients with pyloric stenosis, there were 120 patients (61.9%) with an NRI <93.42 and 74 patients (38.1%) with NRI ≥93.42. Furthermore, patients with an NRI <93.42 had poorer OS (34.37 months vs. not reached, P=0.004). Of note, age, tumor size, radical resection, NRI and TNM stage were determined to be independent prognostic factors for OS. The C-index of the nomogram was 0.760 (95%CI: 0.688-0.832). In conclusion, the NRI was indicated to be an accurate score reflecting the nutritional status of patients, which was able to predict the clinical outcomes of patients with gastric cancer with pyloric stricture who received preoperative parenteral nutrition. Patients with a low NRI had shorter survival times.

A torus source and its application for non-primary radiation evaluation.

Objective. Non-primary radiation doses to normal tissues from proton therapy may be associated with an increased risk of secondary malignancies, particularly in long-term survivors. Thus, a systematic method to evaluate if the dose level of non-primary radiation meets the IEC standard requirements is needed.Approach. Different from the traditional photon radiation therapy system, proton therapy systems are composed of several subsystems in a thick bunker. These subsystems are all possible sources of non-primary radiation threatening the patient. As a case study, 7 sources in the P-Cure synchrotron-based proton therapy system are modeled in Monte Carlo (MC) code: tandem injector, injection, synchrotron ring, extraction, beam transport line, scanning nozzle and concrete reflection/scattering. To accurately evaluate the synchrotron beam loss and non-primary dose, a new model called the torus source model is developed. Its parametric equations define the position and direction of the off-orbit particle bombardment on the torus pipe shell in the Cartesian coordinate system. Non-primary doses are finally calculated by several FLUKA simulations.Main results. The ratios of summarized non-primary doses from different sources to the planned dose of 2 Gy are all much smaller than the IEC requirements in both the 15-50 cm and 50-200 cm regions. Thus, the P-Cure synchrotron-based proton therapy system is clean and patient-friendly, and there is no need an inner shielding concrete between the accelerator and patient.Significance. Non-primary radiation dose level is a very important indicator to evaluate the quality of a PT system. This manuscript provides a feasible MC procedure for synchrotron-based proton therapy with new beam loss model. Which could help people figure out precisely whether this level complies with the IEC standard before the system put into clinical treatment. What' more, the torus source model could be widely used for bending magnets in gantries and synchrotrons to evaluate non-primary doses or other radiation doses.

Shift work is associated with an increased risk of type 2 diabetes and elevated RBP4 level: cross sectional analysis from the OHSPIW cohort study.

BACKGROUND: Shift work, with its growing prevalence globally, disrupts the body's inherent circadian rhythm. This disruption may escalate the risk of chronic diseasesxacerbate chronic disease risk by dysregulating physiological, behavioral, and psychosocial pathways. This study aimed to evaluate the effect of shift work on type 2 diabetes (T2DM) and Retinol binding protein 4 (RBP4) level. METHODS: The current study employed a multi-stage stratified cluster sampling technique, examining 1499 oilfield workers from the OHSPIW cohort who participated in occupational health assessments between March 2017 and June 2018.The evaluation involved shift work, sleep quality, T2DM status with questionnaires and plasma RBP4 levels in blood samples. Statistical analysis includes, Chi-square tests, t-tests, multivariate logistic regression analyses, and multivariate linear mixed models. RESULTS: The prevalence rate of T2DM in shift workers (6.56%) was significantly higher than in day workers (4.21%) (OR = 1.60, 95% CI: 1.01-2.53), with no significant difference found in the family history of diabetes, hypertension, or other chronic heart diseases (P = 0.378). The shift worker (6.89 ± 3.35) also exhibited distinctly higher PSQI scores than day workers (5.99 ± 2.87) (P < 0.001). Adjusting the age, gender, BMI, family income, tobacco smoking, alcohol drinking and PSQI, hailed shift work as a risk factor for T2DM (OR = 1.91, 95% CI: 1.17-3.14). The pairwise comparison revealed significant differences in RBP4 levels across different groups: shift and non-shift workers both with and without T2DM (P < 0.001). The RBP4 level of the shift group without T2DM was higher than the non-shift group without T2DM (P < 0.05). The levels of RBP4 level in shift and non-shift groups with T2DM was higher than those without T2DM (P < 0.05). The multivariate linear mixed model showed that when age, gender, BMI, diabetes, PSQI, family income, smoking and drinking remained unchanged, the RBP4 level of the shift workers increased by an average of 9.51 µg/mL compared with the day workers. CONCLUSIONS: Shift work is associated with an increased risk of T2DM and high levels of RBP4. Follow-up of RBP4 could facilitateearly detection of T2DM among shift workers.

Clinical-grade human umbilical cord-derived mesenchymal stem cells improved skeletal muscle dysfunction in age-associated sarcopenia mice.

With the expansion of the aging population, age-associated sarcopenia (AAS) has become a severe clinical disease of the elderly and a key challenge for healthy aging. Regrettably, no approved therapies currently exist for treating AAS. In this study, clinical-grade human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were administrated to two classic mouse models (SAMP8 mice and D-galactose-induced aging mice), and their effects on skeletal muscle mass and function were investigated by behavioral tests, immunostaining, and western blotting. Core data results showed that hUC-MSCs significantly restored skeletal muscle strength and performance in both mouse models via mechanisms including raising the expression of crucial extracellular matrix proteins, activating satellite cells, enhancing autophagy, and impeding cellular aging. For the first time, the study comprehensively evaluates and demonstrates the preclinical efficacy of clinical-grade hUC-MSCs for AAS in two mouse models, which not only provides a novel model for AAS, but also highlights a promising strategy to improve and treat AAS and other age-associated muscle diseases. This study comprehensively evaluates the preclinical efficacy of clinical-grade hUC-MSCs in treating age-associated sarcopenia (AAS), and demonstrates that hUC-MSCs restore skeletal muscle strength and performance in two AAS mouse models via raising the expression of extracellular matrix proteins, activating satellite cells, enhancing autophagy, and impeding cellular aging, which highlights a promising strategy for AAS and other age-associated muscle diseases.

Murine Cytomegalovirus Infection Induced miR-1929-3p Down-Regulation Promotes the Proliferation and Apoptosis of Vascular Smooth Muscle Cells in Mice by Targeting Endothelin A Receptor and Downstream NLRP3 Activation Pathway.

Our previous study demonstrated in vivo that mouse cytomegalovirus (MCMV) infection promoted vascular remodeling after downregulation of miR-1929-3p. This study aimed to investigate the role of miR-1929-3p/ETAR/NLRP3 pathway in mouse vascular smooth muscle cells (MOVAS) after MCMV infection. First, PCR was used to detect the success of the infection. Second, MOVAS were transfected with the miR-1929-3p mimic, inhibitor, and ETAR overexpressed adenovirus vector. Cell proliferation was detected using EdU, whereas apoptosis was detected using flow cytometry. The expression of miR-1929-3p and ETAR were detected using qRT-PCR. Western blot detected proteins of cell proliferation, apoptosis, and the NLRP3 inflammasome. Interleukin-1ß and interleukin-18 were determined using ELISA. The results revealed that after 48 h, MCMV infection promoted the proliferation of MOVAS when the MOI was 0.01. MCMV infection increased ETAR by downregulating miR-1929-3p. The miR-1929-3p mimic reversed the proliferation and apoptosis, whereas the miR-1929-3p inhibitor promoted this effect. ETAR overexpression further promoted MCMV infection by downregulating miR-1929-3p-mediated proliferation and apoptosis. MCMV infection mediates the downregulation of miR-1929-3p and the upregulation of ETAR, which activates NLRP3 inflammasome. In conclusion, MCMV infection promoted the proliferation of MOVAS, possibly by downregulating miR-1929-3p, promoting the upregulation of the target gene ETAR and activating NLRP3 inflammasome.

Preferential Hematopoietic Differentiation in Induced Pluripotent Stem Cells Derived From Human Umbilical Cord Arterial Endothelial Cells.

BACKGROUND: The major obstacle for applications of human induced pluripotent stem cells (hiPSCs) is efficient and controlled lineage-specific differentiation. Hence, a deeper understanding of the initial populations of hiPSCs is required to instruct proficient lineage commitment. METHODS: hiPSCs were generated from somatic cells by transduction of 4 human transcription factors (OCT4, SOX2, KLF4, and C-MYC) using Sendai virus vectors. Genome-wide DNA methylation analysis and transcriptional analysis were performed to evaluate the pluripotent capacity and somatic memory state of hiPSCs. Flow cytometric analysis and colony assays were performed to assess the hematopoietic differentiation capacity of hiPSCs. RESULTS: Here, we reveal human umbilical arterial endothelial cell-derived induced pluripotent stem cells (HuA-iPSCs) exhibit indistinguishable pluripotency in comparison with human embryonic stem cells and hiPSCs derived from other tissues of origin (umbilical vein endothelial cells, cord blood, foreskin fibroblasts, and fetal skin fibroblasts). However, HuA-iPSCs retain a transcriptional memory typical of the parental human umbilical cord arterial endothelial cells, together with a strikingly similar DNA methylation signature to umbilical cord blood-derived induced pluripotent stem cells that distinguishes them from other human pluripotent stem cells. Ultimately, HuA-iPSCs are most efficient in targeted differentiation toward hematopoietic lineage among all human pluripotent stem cells based on the functional and quantitative evaluation of both flow cytometric analysis and colony assays. Application of the Rho-kinase activator significantly reduces the effects of preferential hematopoietic differentiation in HuA-iPSCs, reflected in CD34+ cell percentage of day 7, hematopoietic/endothelial-associated gene expression, and even colony-forming unit numbers. CONCLUSIONS: Collectively, our data suggest that somatic cell memory may predispose HuA-iPSCs to differentiate more amenably into hematopoietic fate, bringing us closer to generating hematopoietic cell types in vitro from nonhematopoietic tissue for therapeutic applications.

To explore the regulatory effect of Buyang Huanwu Decoction on cerebral infarction based on quantitative proteomics.

Buyang Huanwu Decoction (BYHW) contains chemical components such as ligustrazine, oxypaeoniflora, chlorogenic acid, and others. To explore the neuroprotective effect and potential target protein of BYHW in cerebral infarction (CI). A double-blind, randomized controlled trial was established and patients with CI were divided into the BYHW group (n = 35) and the control group (n = 30). To evaluate the efficacy by TCM syndrome score and clinical indicators, and to explore the changes of serum proteins by proteomics technology, so as to explore the mechanism of BYHW and potential target proteins. The study found that compared with the control group, the TCM syndrome score, including Deficiency of Vital Energy (DVE), Blood Stasis (BS), and NIHSS in the BYHW group decreased significantly (p < 0.05), and the Barthel Index (BI) score was significantly higher. A total of 99 differential regulatory proteins were identified by proteomics, which act on lipids and atherosclerosis, complement and coagulation cascade, and TNF-α signaling pathway. In addition, Elisa verified the results of proteomics and found that BYHW can reduce the neurological impairments focus on IL-1ß, IL-6, TNF-α, MCP-1, MMP-9, and PAI-1. Significance: In this study, quantitative proteomics was used in combination with liquid chromatography-mass spectrometry (LC-MS/MS) to study the therapeutic effect of BYHW on cerebral infarction (CI) and potential changes in serum proteomics. In addition, the public proteomics database was used for bioinformatics analysis, and Elisa experiment verified the results of proteomics, further clarifying the potential protection mechanism of BYHW on CI.

Glutamine metabolism targeting liposomes for synergistic chemosensitization and starvation therapy in ovarian cancer.

Platinum-based chemotherapy is a first-line therapeutic regimen against ovarian cancer (OC); however, the therapeutic potential is always reduced by glutamine metabolism. Herein, a valid strategy of inhibiting glutamine metabolism was proposed to cause tumor starvation and chemosensitization. Specifically, reactive oxygen species-responsive liposomes were developed to co-deliver cisplatin (CDDP) and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to CDDP by reducing glutathione generation to prevent CDDP detoxification, suppressing ATP production to avoid CDDP efflux, hindering nucleotide synthesis to aggravate DNA damage induced by CDDP, and blocking mammalian target of rapamycin (mTOR) signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs. STATEMENT OF SIGNIFICANCE: This work proposed a valid strategy of inhibiting glutamine metabolism to cause tumor starvation and chemosensitization. Specifically, ROS-responsive liposomes were developed to co-deliver cisplatin CDDP and BPTES [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to cisplatin by reducing glutathione generation to prevent cisplatin detoxification, suppressing ATP production to avoid cisplatin efflux, hindering nucleotide synthesis to aggravate DNA damage induced by cisplatin, and blocking mTOR signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs.

Biomimetic Prussian blue nanozymes with enhanced bone marrow-targeting for treatment of radiation-induced hematopoietic injury.

There is an urgent medical need to develop effective therapies that can ameliorate damage to the radiation-exposed hematopoietic system. Nanozymes with robust antioxidant properties have a therapeutic potential for mitigating radiation-induced hematopoietic injury. However, enhancing nanozyme recruitment to injured tissues in vivo while maintaining their catalytic activity remains a great challenge. Herein, we present the design and preparation of a biomimetic nanoparticle, a mesenchymal stem cell membrane camouflaged Prussian blue nanozyme (PB@MSCM), which exhibits biocompatible surface properties and demonstrates enhanced injury site-targeting towards the irradiated murine bone marrow niche. Notably, the constructed PB@MSCM possessed redox enzyme-mimic catalytic activity and could scavenge overproduced reactive oxygen species in the irradiated bone marrow cells, both in vitro and ex vivo. More importantly, the administration of PB@MSCM significantly mitigated hematopoietic cell apoptosis and accelerated the regeneration of hematopoietic stem and progenitor cells. Our findings provide a new targeted strategy to improve nanozyme therapy in vivo and mitigate radiation-induced hematopoietic injury.

A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy.

Ovarian cancer (OC) is one of the most common and recurring malignancies in gynecology. Patients with relapsed OC always develop "cascade drug resistance" (CDR) under repeated chemotherapy, leading to subsequent failure of chemotherapy. To overcome this challenge, amphiphiles (P1) carrying a nitric oxide (NO) donor (Isosorbide 5-mononitrate, ISMN) and high-density disulfide are synthesized for encapsulating mitochondria-targeted tetravalent platinum prodrug (TPt) to construct a nanocomposite (INP@TPt). Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum, depleting glutathione, and preventing apoptosis escape through generating highly toxic peroxynitrite anion (ONOO-). To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor, an OC patient-derived tumor xenograft (PDXOC) model in BALB/c nude mice was established. INP@TPt showed the best therapeutic effects in the PDXOC model. The corresponding tumor tissues contained high ONOO- levels, which were attributed to the simultaneous release of O2•- and NO in tumor tissues. Taken together, INP@TPt-based systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR, providing practical applications for ovarian therapy.

Synergetic delivery of artesunate and isosorbide 5-mononitrate with reduction-sensitive polymer nanoparticles for ovarian cancer chemotherapy.

Ovarian cancer is a highly fatal gynecologic malignancy worldwide. Chemotherapy remains the primary modality both for primary and maintenance treatments of ovarian cancer. However, the progress in developing chemotherapeutic agents for ovarian cancer has been slow in the past 20 years. Thus, new and effective chemotherapeutic drugs are urgently needed for ovarian cancer treatment. A reduction-responsive synergetic delivery strategy (PSSP@ART-ISMN) with co-delivery of artesunate and isosorbide 5-mononitrate was investigated in this research study. PSSP@ART-ISMN had various effects on tumor cells, such as (i) inducing the production of reactive oxygen species (ROS), which contributes to mitochondrial damage; (ii) providing nitric oxide and ROS for the tumor cells, which further react to generate highly toxic reactive nitrogen species (RNS) and cause DNA damage; and (iii) arresting cell cycle at the G0/G1 phase and inducing apoptosis. PSSP@ART-ISMN also demonstrated excellent antitumor activity with good biocompatibility in vivo. Taken together, the results of this work provide a potential delivery strategy for chemotherapy in ovarian cancer.

The accumulation of miR-125b-5p is indispensable for efficient erythroblast enucleation.

Erythroblast enucleation is a precisely regulated but not clearly understood process. Polycythemia shows pathological erythroblast enucleation, and we discovered a low miR-125b-5p level in terminal erythroblasts of patients with polycythemia vera (PV) compared to those of healthy controls. Exogenous upregulation of miR-125b-5p levels restored the enucleation rate to normal levels. Direct downregulation of miR-125b-5p in mouse erythroblasts simulated the enucleation issue found in patients with PV, and miR-125b-5p accumulation was found in enucleating erythroblasts, collectively suggesting the importance of miR-125b-5p accumulation for erythroblast enucleation. To elucidate the role of miR-125b-5p in enucleation, gain- and loss-of-function studies were performed. Overexpression of miR-125b-5p improved the enucleation of erythroleukemia cells and primary erythroblasts. Infused erythroblasts with higher levels of miR-125b-5p also exhibited accelerated enucleation. In contrast, miR-125b-5p inhibitors significantly suppressed erythrocyte enucleation. Intracellular imaging revealed that in addition to cytoskeletal assembly and nuclear condensation, miR-125b-5p overexpression resulted in mitochondrial reduction and depolarization. Real-time PCR, western blot analysis, luciferase reporter assays, small molecule inhibitor supplementation and gene rescue assays revealed that Bcl-2, as a direct target of miR-125b-5p, was one of the key mediators of miR-125b-5p during enucleation. Following suppression of Bcl-2, the activation of caspase-3 and subsequent activation of ROCK-1 resulted in cytoskeletal rearrangement and enucleation. In conclusion, this study is the first to reveal the pivotal role of miR-125b-5p in erythroblast enucleation.