Prolonged Survival Time Research Articles

The triple combination DBDx alleviates cytokine storm and related lung injury

Cytokine storm is a life-threatening disorder, and therapeutic treatments are urgently needed. Here, we investigated the anti-cytokine storm efficacy of DBDx, a triple drug combination composed of dipyridamole, ubenimex and dexamethasone. Evaluated by lipopolysaccharide (LPS)-induced cytokine storm murine model, DBDx significantly improved survival rate and prolonged survival time of the model mice. Notably, the efficacy of DBDx was higher than that of dipyridamole, ubenimex and dexamethasone. Determined by ELISA, DBDx significantly reduced the LPS-stimulated serum levels of TNF-α, IL-6 and IL-1β in mice. Luminex assay showed that DBDx suppressed the serum levels of a wide variety of inflammatory cytokines and chemokines, which was more potent than dexamethasone alone. Otherwise, DBDx exerted similar inhibitory effects on cytokine profiles in bronchoalveolar lavage fluid. Histopathological observation showed that DBDx significantly reduced the LPS-induced thickening of alveolar septum, indicating its suppression of capillary congestion, edema and neutrophil infiltration in the lung. Ultra-structure analysis showed that DBDx suppressed the LPS-induced morphological changes of microvilli in type II pneumocytes. In vitro experiment showed that DBDx inhibited IL-6 and TNF-α secretion in THP-1 cells, and downregulated TLR4/NF-κB/HIF-1α signaling pathway. All of these results demonstrate that DBDx, a triple combination of clinical orally-administered drugs, can alleviate cytokine storm and related lung injury. DBDx is beneficial for treating cytokine storm disorders.

Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia.

Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy requiring novel treatment strategies. In this study, we identified phosphodiesterase 3 A (PDE3A) as a potential new target for drug repositioning in AML. PDE3A was preferentially overexpressed in AML cells than in normal cells, and high expression of PDE3A was correlated with lower event-free survival (EFS) in de novo AML patients. The PDE3A inhibitor anagrelide (ANA) profoundly suppresses the proliferation of high PDE3A-expressing AML cells while exhibiting minimal impact on those with low PDE3A expression. Moreover, synergistic effect of ANA with other chemotherapeutic drugs in high PDE3A expression AML cells was observed. The ANA-idarubicin (IDA) combination showed the most remarkable synergistic effect among all ANA-chemotherapeutic drugs commonly used in AML cell line models. Mechanistically, the synergy between ANA and IDA inhibited the survival of PDE3Ahigh AML cell lines through pyroptosis. This mechanism was initiated by GSDME cleavage triggered by caspase-3 activation. In vivo combination treatment of leukemic animals with high PDE3A expression significantly reduced leukemia burden and prolonged survival time compared with single-drug and vehicle control treatments. Our findings suggest that combined ANA and IDA treatment is an innovative and promising therapeutic strategy for AML patients with high PDE3A expression.

Sirt4 Overexpression Modulates the JAK2/STAT3 and PI3K/AKT/mTOR Axes to Alleviate Sepsis-Induced Acute Lung Injury.

Sepsis-induced acute lung injury (ALI) is a severe organ dysfunction characterized by lung inflammation and apoptosis. The mechanisms underlying sepsis-induced ALI remain poorly understood. Here, we determined the effects of sirtuin 4 (SIRT4) on sepsis-induced ALI. Lipopolysaccharide (LPS)-induced injury cell and cecal ligation and puncture (CLP) animal models were established. Overexpression vectors and lentiviral transfections were used to upregulate SIRT4 expression. Lung cell apoptosis, inflammation, and the levels of associated factors were evaluated. Changes in the PI3K/AKT/mTOR and JAK2/STAT3 pathways were measured, and their potential involvement was examined using LY294002 (PI3K inhibitor), 740 Y-P (PI3K agonist), AG490 (JAK2 inhibitor), and coumermycin A1 (JAK2 agonist). Lower SIRT4 expression was observed in LPS-exposed A549 cells and CLP rats. In LPS-induced A549 cells, Sirt4 overexpression enhanced cell viability, resisted apoptosis, restored the expression of apoptosis-associated proteins (HMB1, cleaved CASP3, BAX, and BCL), and reduced the secretion of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). In CLP rats, Sirt4 overexpression prolonged survival time, alleviated lung histopathological damage, reduced pulmonary edema, mitigated lung infection, decreased lung apoptosis, and lowered serum levels of inflammatory cytokines. Furthermore, Sirt4 overexpression blocked JAK2/STAT3/AKT/mTOR phosphorylation. 740 Y-P and coumermycin A1 reversed the protective effects of Sirt4 overexpression in LPS-treated A549 cells, resulting in decreased cell viability and increased apoptosis. LY294002 and AG490 enhanced the protective effects of Sirt4 overexpression in LPS-treated A549 cells. SIRT4 alleviates sepsis-induced ALI by inhibiting JAK2/STAT3/PI3K/AKT/mTOR signaling. Upregulating SIRT4 expression may serve as an innovative therapeutic approach for lung injury management in sepsis.

Therapeutic effects of fecal microbial transplantation on alcoholic liver injury in rat models

ObjectiveDisruption of gut microbiota is closely related to the progression of alcoholic liver disease (ALD). This study aimed to explore the therapeutic effect of fecal microbiota transplantation (FMT) in ALD rats using a combination of microbiological and metabolomic techniques. MethodsThree liver injury rat models were constructed using alcohol, CCL4, and alcohol combined with CCL4, and administered an FMT treatment comprising the fecal microbiota of healthy rats via the gastric route for 12 consecutive weeks. We measured the therapeutic effect of FMT treatment on liver inflammation, intestinal mucosal barrier, and bacterial translocation in ALD rats using 16S rRNA and UPLC-Q/TOF-MS technology to detect the effects of FMT on the intestinal microbiota and metabolic patterns of ALD rats. ResultsFMT treatment effectively improved liver function, prolonged survival time, improved the intestinal mucosal barrier, reduced bacterial translocation, alleviated liver inflammation, and delayed the progression of liver fibrosis in three types of liver injury models. The microbiome and metabolomic results showed that FMT can effectively improve gut microbiota disorder in ALD rats and improve metabolic patterns by regulating metabolic pathways such as the arachidonic acid and retinol pathways. ConclusionFMT treatment could reverse alcohol induced liver injury by improving gut microbiota and metabolic patterns in ALD rats, and oral FMT could be an effective therapeutic approach for ALD.

Developing Individualized Follow-Up Strategies Based on High-Risk Recurrence Factors and Dynamic Risk Assessment for Locally Advanced Rectal Cancer.

Locally advanced rectal cancer (LARC) is one of the most common malignant tumors worldwide, and its incidence is increasing year by year. Despite multimodal treatment, the recurrence rate of LARC patients remains high, about 20%-50%. However, the follow-up strategy according to tumor stage has certain limitations. There is no consensus on the optimal frequency and duration of follow-up. This study aims to comprehensively analyze the high-risk factors for recurrence in LARC from clinical characteristics, nutritional indicators, and imaging indexes. It intends to utilize conditional survival (CS) evaluation to assess dynamic survival and recurrence risks after comprehensive treatment of LARC and to develop individualized follow-up strategies. Logistic regression was utilized to analyze the independent recurrence factors in LARC patients. Calibration curve, decision curve, and ROC curve were employed to evaluate the model's efficacy. Kaplan-Meier curve was used to calculate CS rate and compare survival differences among different risk groups. A total of 561 patients were analyzed in our study. Our multivariable logistic regression analysis revealed that the prognostic nutritional index (PNI), extramural vascular invasion (EMVI), vascular tumor thrombus, perineural invasion, and tumor size were independent factors for recurrence. Subsequently, a nomogram model was constructed and risk stratification was performed. Calibration curves and decision curves demonstrated that the model exhibited good clinical efficacy. The area under the ROC curve for the model was 0.763, indicating good sensitivity and specificity. Kaplan-Meier curves showed significant differences in survival among different risk groups. Furthermore, we observed that the CS without local recurrence and distant metastasis increased each year, while the cumulative recurrence risk decreased annually with prolonged survival time. Tailored follow-up intensities were developed for different risk groups and clinical stages based on the cumulative recurrence risk. The personalized follow-up strategy based on risk stratification can optimize resource allocation, early detection of recurrence or metastasis, and ultimately enhance the overall care and prognosis of LARC patients.

Effects of Down-Regulation of PAK1 on Differentiation and Apoptosis of MPN Cells with MPLW515L Gene Mutation and Survival of 6133/MPL Mice

To investigate the effects of down-regulation of p21 activated kinase 1 (PAK1) on the proliferation, differentiation, and apoptosis of myeloproliferative neoplasm (MPN) cells (6133/MPL) with thrombopoietin receptor MPL mutation at codon 515 (MPLW515L) and survival of 6133/MPL mice. Interference with the protein level of PAK1 in 6133/MPL cells was assessed using lentivirus-mediated shRNA transfection technology. CCK-8 assay was used to detect the effect of down-regulation of PAK1 on the proliferation viability of 6133/MPL cells, and colony-forming ability was measured by cell counting. Flow cytometry was used to detect the PAK1 kinase activity on the ability of polyploid DNA formation and cell apoptosis in 6133/MPL cells. The expression of cyclin D1, cyclin D3 and apoptosis-related protein Bax was detected by Western blot. The infiltration of tumor cells in spleen and bone marrow of 6133/MPL mice were detected by HE staining. Down-regulation of PAK1 inhibited the proliferation and reduced the ability of cell colony formation of 6133/MPL cells. After knocking down PAK1, the content of polyploid DNA in 6133/MPL cells increased from 31.8 to 57.5% and 48.0%, and the proportion of apoptosis increased approximately to 10.8%. Down-regulation of PAK1 led to a reduction of infiltration of tumor cells in liver and bone marrow of 6133/MPL mice, thereby prolonging survival time. Down-regulation of PAK1 can significantly inhibit the growth of 6133/MPL cells, promote the formation of polyploid DNA, induce 6133/MPL cell apoptosis, and prolong the survival time of 6133/MPL mice.

Clinical characterization and founder effect analysis in Chinese amyotrophic lateral sclerosis patients with SOD1 common variants

Objective In the Asian population, SOD1 variants are the most common cause of amyotrophic lateral sclerosis (ALS). To date, more than 200 variants have been reported in SOD1. This study aimed to summarize the genotype–phenotype correlation and determine whether the patients carrying common variants derive from a common ancestor. Methods A total of 103 sporadic ALS (SALS) and 11 familial ALS (FALS) probands were included and variants were screened by whole exome sequencing. Functional analyses were performed on fibroblasts derived from patients with SOD1 p.V48A and control. Haplotype analysis was performed in the probands with p.H47R or p.V48A and their familial members. Results A total of 25 SOD1 variants were identified in 44 probands, in which p.H47R, p.V48A and p.C112Y variants were the most common variants. 94.3% and 60% of patients with p.H47R or p.V48A had lower limb onset with predominant lower motor neurons (LMNs) involvement. Patients with p.H47R had a slow progression and prolonged survival time, while patients with p.V48A exhibited a duration of 2–5 years. Patients with p.C112Y variant showed remarkable phenotypic variation in age at onset and disease course. SOD1V48A fibroblasts showed mutant SOD1 aggregate formation, enhanced intracellular reactive oxygen species level, and decreased mitochondrial membrane potential compared to the control fibroblast. Haplotype analysis showed that seven families had two different haplotypes. p.H47R and p.V48A variants did not originate from a common founder. Conclusions Our study expanded the understanding of the genotype–phenotype correlation of ALS with SOD1 variants and revealed that the common p.H47R or p.V48A variant did not have a founder effect.

RipE expression correlates with high ATP levels in Ehrlichia, which confers resistance during the extracellular stage to facilitate a new cycle of infection.

Ehrlichiosis is a potentially life-threatening disease caused by infection with the obligatory intracellular bacteria Ehrlichia species. Ehrlichia japonica infection of mice provides an animal model of ehrlichiosis as it recapitulates full-spectrum and lethal ehrlichiosis in humans. The E. japonica transposon mutant of EHF0962, which encodes a previously uncharacterized hypothetical protein, is attenuated in both infection and virulence in mice. EHF0962 was hence named here as resistance-inducing protein of Ehrlichia (RipE). Using this ΔripE mutant, we studied how RipE protein contributes to Ehrlichia pathogenesis. Ehrlichia species have an intracellular developmental cycle and a brief extracellular stage to initiate a new cycle of infection. Majority of RipE proteins were expressed on the surface of the smaller infectious dense-core stage of bacteria. Extracellular ΔripE E. japonica contained significantly less adenosine triphosphate (ATP) and lost infectivity more rapidly in culture compared with wild-type (WT) E. japonica. Genetic complementation in the ΔripE mutant or overexpression of ripE in WT E. japonica significantly increased bacterial ATP levels, and RipE-overexpressing E. japonica was more virulent in mice than WT E. japonica. RipE is conserved among Ehrlichia species. Immunization of mice with recombinant RipE induced an in vitro infection-neutralizing antibody, significantly prolonged survival time after a lethal dose of E. japonica challenge, and cross-protected mice from infection by Ehrlichia chaffeensis, the agent of human monocytic ehrlichiosis. Our findings shed light on the extracellular stage of Ehrlichia, highlighting the importance of RipE and ATP levels in Ehrlichia for extracellular resistance and the next cycle of infection. Thus, RipE is a critical Ehrlichia protein for infection as such can be a potential vaccine target for ehrlichiosis.

Does the initial treatment of primary tumor impact prognosis after recurrence in locally advanced rectal cancer? Results from a retrospective cohort analysis

IntroductionThe role of neoadjuvant therapy (NAT) in the treatment of locally advanced rectal cancer (LARC) has been well proven, but its impact on patients who relapse remains unknown. This study aims to elucidate the influence of initial treatment and MRI-defined risk factors on postrecurrent survival in patients with LARC recurrence.Patients and methodsLARC patients who underwent radical surgery and subsequently developed recurrence were retrospectively identified. Patients were stratified on the basis of MRI-defined local risk assessment and the initial treatment modality for the primary tumor (NAT or primary surgery). The patients were classified into four groups: high-risk LARC with NAT (HiN), high-risk LARC with primary surgery (HiS), low-risk LARC with NAT (LoN), and low-risk LARC with primary surgery (LoS). The primary endpoint was survival after recurrence.ResultsA total of 381 patients who experienced relapse were identified from among 2329 LARC patients. Salvage surgery was performed on 33.1% of these patients. Patients who experienced single-site recurrence or who underwent salvage surgery exhibited significantly prolonged survival times after recurrence (P < 0.001). Patients in the HiS group had poorer survival after recurrence than those in the other three groups (P = 0.034). This subset of patients, characterized by receiving less adjuvant treatment after primary surgery, had a shorter recurrence interval than those in the other groups (P = 0.001).ConclusionsOur findings reaffirm the prognostic significance of salvage surgery in patients from a LARC cohort who experienced relapse. Moreover, MRI-defined high-risk LARC patients who received upfront surgery without NAT had shorter intervals of recurrence and poorer survival outcomes after recurrence. Our results highlight the critical role of NAT in improving patient survival after recurrence.Trial registrationSupplementary registration was carried out at clinicaltrials.gov (Registration number: NCT06314737) on March 14, 2024. The study was retrospectively registered.

Gamabufotalin loaded micro-nanocomposites for multimodal therapy of metastatic TNBC by efficiently inducing ICD

Gamabufotalin (CS-6), a main active compound derived from Chinese medicine Chansu, exhibits a robust inhibitory effect on programmed death-ligand 1 (PD-L1) in triple-negative breast cancer (TNBC) cells. Despite its potential for tumor therapy, the medical application of CS-6 is constrained by its hydrophobic nature, lack of targeting capability, and weak immunogenic cell death (ICD) effect. To address these limitations and improve the therapeutic efficiency of this drug against metastatic TNBC, we designed a new kind of CS-6@CPB-S.lux that integrates carboxy-Prussian blue nanoparticles (CPB NPs), CS-6, and attenuated Salmonella typhimurium (S.lux) for TNBC therapy. In vitro and in vivo results have confirmed that CS-6@CPB NPs were efficiently delivered to neoplastic tissue by the tumor hypoxic chemotaxis property of S.lux, wherein the nanomedicine induced significant tumor cell necroptosis and apoptosis via photothermal therapy (PTT) of CPB NPs and chemotherapy of CS-6, which elicited ICD and inhibited PD-L1 expression, resulting in dendritic cells (DCs) maturation and effector T cells activation to comprehensively eliminate tumors. Additionally, the CS-6@CPB-S.lux + Laser treatment significantly transformed the immunosuppressive tumor microenvironment (TME), enhancing antitumor immunity through promoting the polarization of tumor-associated macrophages into antitumorigenic M1 and reducing Tregs recruitment. Consequently, this comprehensive therapy not only inhibited primary and abscopal tumor progression but also prevented TNBC metastasis, which significantly prolonged survival time in animal models. In summary, these findings indicated an alternative approach for metastatic TNBC therapy.

Perioperative PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer: A meta-analysis based on randomized controlled trials.

PD-1/PD-L1 inhibitors (PI) have shown promising results in both neoadjuvant and adjuvant therapies for resectable non-small cell lung cancer (NSCLC). However, substantial evidence from large-scale studies is still lacking for their use in the perioperative setting (neoadjuvant plus adjuvant). This meta-analysis aims to evaluate the integration of perioperative PI (PPI) with neoadjuvant chemotherapy for resectable NSCLC. To identify appropriate randomized controlled trials (RCTs), we thoroughly explored six different databases. The primary endpoint was survival, while the secondary measures included pathological responses and adverse events (AEs). Six RCTs involving 2941 patients were included. The PPI group significantly improved overall survival (OS) (hazard ratio [HR]: 0.62 [0.51, 0.77]), event-free survival (EFS) (HR: 0.57 [0.51, 0.64]), pathological complete response (risk ratio [RR]: 5.81 [4.47, 7.57]), and major pathological response (RR: 2.60 [1.77, 3.82]). Benefits in EFS were seen across all subgroups. OS rates at 12-48 months and EFS rates at 6-48 months were higher in the PPI cohort. Furthermore, the advantages in OS and EFS increased with prolonged survival times. The PPI group also exhibited higher rates of surgery and R0 resections. However, the PPI group experienced more grade 3-5 AEs, serious AEs, and treatment discontinuations due to AEs. The integration of perioperative PI with neoadjuvant chemotherapy can significantly improve survival and pathological responses for resectable NSCLC. However, the increased incidence of grade 3-5 AEs must be carefully evaluated.

Poly(lactic acid hydroxyacetic acid)-poly(ethylene glycol)-modified ginsenoside Rg3 nanomedicine enhances anti-tumor effect in hepatocellular carcinoma

Objective This research aims to improve the bioavailability and anti-hepatocellular carcinoma (HCC) efficacy of Ginsenoside Rg3 by modification with poly (lactic acid hydroxyacetic acid)-poly(ethylene glycol) (PLGA-PEG). Methods PLGA-PEG-Rg3 was obtained by emulsification and evaluated it physiochemical characterization by FTIR, SEM, laser particle-size analyzer and HPLC. The effect of the PLGA-PEG-Rg3 and Rg3 on HepG2 cells was compared in vitro studies, including cell proliferation, transwell and a series of apoptosis detection, and in-situ HCC model. Results The PLGA-PEG-Rg3 were 122 nm in size and 0.112 in polydispersity index with sustained release profile in vitro. Compared to Rg3, PLGA-PEG-Rg3 was more effective in suppressing HepG2 growth and inducing apoptosis by the mitochondrial apoptosis pathway in vitro. And PLGA-PEG modification enhanced the liver-targeting ability and drug circulation time of Rg3 in vivo, resulting in PLGA-PEG-Rg3 possessing superior performance in inhibiting tumor growth and prolonging the survival time of tumor-bearing mice than Rg3. Conclusions Overall, these results showed PLGA-PEG-Rg3 enhanced the anti-tumor effect of Rg3 in HCC.

Open-Source Throttling of CD8+ T Cells in Brain with Low-Intensity Focused Ultrasound-Guided Sequential Delivery of CXCL10, IL-2, and aPD-L1 for Glioblastoma Immunotherapy.

Improving clinical immunotherapy for glioblastoma (GBM) relies on addressing the immunosuppressive tumor microenvironment (TME). Enhancing CD8+ T cell infiltration and preventing its exhaustion holds promise for effective GBM immunotherapy. Here, a low-intensity focused ultrasound (LIFU)-guided sequential delivery strategy is developed to enhance CD8+ T cells infiltration and activity in the GBM region. The sequential delivery of CXC chemokine ligand 10 (CXCL10) to recruit CD8+ T cells and interleukin-2 (IL-2) to reduce their exhaustion is termed an "open-source throttling" strategy. Consequently, up to 3.39-fold of CD8+ T cells are observed with LIFU-guided sequential delivery of CXCL10, IL-2, and anti-programmed cell death 1 ligand 1 (aPD-L1), compared to the free aPD-L1 group. The immune checkpoint inhibitors (ICIs) therapeutic efficacy is substantially enhanced by the reversed immunosuppressive TME due to the expansion of CD8+ T cells, resulting in the elimination of tumor, prolonged survival time, and long-term immune memory establishment in orthotopic GBM mice. Overall, LIFU-guided sequential cytokine and ICIs delivery offers an "open-source throttling" strategy of CD8+ T cells, which may present a promising strategy for brain-tumor immunotherapy.

LTBR acts as a novel immune checkpoint of tumor-associated macrophages for cancer immunotherapy.

Tumor-associated macrophages (TAMs) greatly contribute to immune checkpoint inhibitor (ICI) resistance of cancer. However, its underlying mechanisms and whether TAMs can be promising targets to overcome ICI resistance remain to be unveiled. Through integrative analysis of immune multiomics data and single-cell RNA-seq data (iMOS) in lung adenocarcinoma (LUAD), lymphotoxin β receptor (LTBR) is identified as a potential immune checkpoint of TAMs, whose high expression, duplication, and low methylation are correlated with unfavorable prognosis. Immunofluorescence staining shows that the infiltration of LTBR+ TAMs is associated with LUAD stages, immunotherapy failure, and poor prognosis. Mechanistically, LTΒR maintains immunosuppressive activity and M2 phenotype of TAMs by noncanonical nuclear factor kappa B and Wnt/β-catenin signaling pathways. Macrophage-specific knockout of LTBR hinders tumor growth and prolongs survival time via blocking TAMimmunosuppressive activity and M2 phenotype. Moreover, TAM-targeted delivery of LTΒR small interfering RNA improves the therapeutic effect of ICI via reversing TAM-mediated immunosuppression, such as boosting cytotoxic CD8+ T cells and inhibiting granulocytic myeloid-derived suppressor cells infiltration. Taken together, we bring forth an immune checkpoint discovery pipeline iMOS, identify LTBR as a novel immune checkpoint of TAMs, and propose a new immunotherapy strategy by targeting LTBR+ TAMs.

Fei Jin Sheng formula and its effectiveness in treating advanced non-small cell lung cancer: An observational study

ObjectiveThis study involved evaluating the efficacy of the Feijinsheng formula in the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC). MethodsWe extracted the medical records of patients with advanced NSCLC undergoing treatment in the oncology department at the Second Affiliated Hospital of Zhejiang Chinese Medicine University from the medical record system. After applying inclusion and exclusion criteria, clinical data of 150 patients were collected. The patients were stratified into two groups based on their usage of the Feijinsheng formula, comprising 69 cases in the Exposed group and 81 cases in the Control group. A comparative analysis of the survival time difference between the two groups was conducted. ResultsThe data between the two groups exhibited similarity (p > 0.05). Following treatment, the Exposed group demonstrated a notably prolonged overall survival time compared to the Control group (p < 0.05). While the Exposed group displayed a higher objective remission rate than the Control group, this disparity did not reach statistical significance (p > 0.05). ConclusionThe Feijinsheng formula extended the duration of survival of patients with advanced NSCLC.

Integrating cat boost algorithm with triangulating feature importance to predict survival outcome in recurrent cervical cancer

Cervical cancer is one of the most dangerous malignancies in women. Prolonged survival times are made possible by breakthroughs in early recognition and efficient treatment of a disease.The existing methods are lagging on finding the important attributes to predict the survival outcome. The main objective of this study is to find individuals with cervical cancer who are at greater risk of death from recurrence by predicting the survival.A novel approach in a proposed technique is Triangulating feature importance to find the important risk factors through which the treatment may vary to improve the survival outcome.Five algorithms Support vector machine, Naive Bayes, supervised logistic regression, decision tree algorithm, Gradient boosting, and random forest are used to build the concept. Conventional attribute selection methods like information gain (IG), FCBF, and ReliefFare employed. The recommended classifier is evaluated for Precision, Recall, F1, Mathews Correlation Coefficient (MCC), Classification Accuracy (CA), and Area under curve (AUC) using various methods. Gradient boosting algorithm (CAT BOOST) attains the highest accuracy value of 0.99 to predict survival outcome of recurrence cervical cancer patients. The proposed outcome of the research is to identify the important risk factors through which the survival outcome of the patients improved.

Glycopolymeric Micellar Nanoparticles for Platelet-Mediated Tumor-Targeted Delivery of Docetaxel for Cancer Therapy.

The high level of accumulation of therapeutic agents in tumors is crucial for cancer treatment. Compared to the passive tumor-targeting effect, active tumor-targeting delivery systems, primarily mediated by peptides with high production costs and reduced circulation time, are highly desired. Platelet-driven technologies have opened new avenues for targeted drug delivery prevalently through a membrane coating strategy that involves intricate manufacturing procedures or the fucoidan-mediated hitchhiking method with limited platelet affinity. Here, a novel type of amphiphilic glycopolymer self-assembled micellar nanoparticle has been developed to adhere to naturally activated platelets in the blood. The simultaneous integration of fucose and sialic acid segments into glycopolymers enables closer mimicry of the structure of P-selectin glycoprotein ligand-1 (PSGL-1), thereby increasing the affinity for activated platelets. It results in the formation of glycopolymeric micelle-platelet hybrids, facilitating targeted drug delivery to tumors. The selective platelet-assisted cellular uptake of docetaxel (DTX)-loaded glycopolymeric micelles leads to lower IC50 values against 4T1 cells than that of free DTX. The directed tumor-targeting effect of activated platelets has significantly improved the tumor accumulation capacity of the glycopolymeric nanoparticles, with up to 21.0% found in tumors within the initial 0.2 h. Additionally, with acid-responsive drug release and inherent antimetastasis properties, the glycopolymeric nanoparticles ensured potent therapeutic efficacy, prolonged survival time, and reduced cardiotoxicity, presenting a new and unexplored strategy for platelet-directed drug delivery to tumors, showing promising prospects in treating localized tumors and preventing tumor metastasis.

NaCe0.7FX:Gd0.1,Tb0.2 nanoscintillator as a new sonosensitizer for potentiating cancer sonodynamic-immune therapy

Trends in sonodynamic therapy (SDT) have stimulated greater research efforts toward the development of novel sonosensitizers due to their crucial roles in increasing reactive oxygen species (ROS). Herein, a new scintillator, NaCe0.7FX:Gd0.1,Tb0.2, was explored as an ultrasmall inorganic sonosensitizer for glutathione (GSH) depletion-enhanced SDT of cancer. Specifically, fluorine vacancy-donated defective NaCe0.7FX:Gd0.1,Tb0.2 scintillating nanodots (ScNDs) were prepared via a high-temperature reaction method. PEGylated ScNDs, namely ScND-PEG, exhausted GSH at first, which further augmented the sonodynamic performance of ROS generation. In vitro studies demonstrated that US-irradiated ScND-PEG exerted significant cytotoxicity on CT26 tumor cells by triggering immunogenic cell death (ICD). In vivo studies revealed that ScND-PEG-mediated enhanced SDT substantially inhibited tumor development by activating cytotoxic T lymphocytes and secreting antitumor proinflammatory cytokines. With the assistance of immune checkpoint blockade (ICB), improved antitumor outcomes were further obtained with prolonged survival time. Notably, no significant acute or chronic toxicity occurred during our treatment schedule based on ScND-PEG. Overall, our findings paved the way for identifying a new kind of ScND-based inorganic sonosensitizer as a reserve, which might open up new opportunities for advancing sonodynamic-immune oncotherapy.

Anti-cancer effects of hyperbaric oxygen therapy in mice: a meta-analysis

Abstract Objectives Hypoxia is a ubiquitous condition in solid tumors and is associated with increased glycolysis, therapy resistance and disease progression. Hyperbaric oxygen therapy (HBOT) systemically elevates O2 tension in tissues and thus counteracts hypoxia. Here, we conducted a meta-analysis to quantify the effects of HBOT on survival in mice with cancer. Methods Studies retrieved from PubMed and Google Scholar were included if they allowed extracting restricted mean survival times in an HBOT-treated and control group. Meta-analyses were conducted using standardized mean differences (SMDs) and the log-transformed response ratio (lnRR) between the RMST of the treatment and control group with multilevel random effects models in order to account for non-independence of effect sizes. Publication bias was tested using a multilevel version of Egger’s regression. Results All studies applied HBOT with pressures between 2 and 3 atmospheres absolute (ATA). When administered without additional treatments, HBOT was associated with longer mouse survival times (pooled SMD=1.359 ± 0.624, p=0.0446; lnRR=0.065 ± 0.029, p=0.0399). Higher pressure was significantly associated with higher efficacy of hyperbaric oxygen monotherapy. When combined with chemotherapy, radiotherapy, targeted therapy or a ketogenic diet, HBOT was associated with significantly prolonged survival times compared to mice receiving these treatments without HBOT (SMD=2.696 ± 0.545, p&lt;0.0001; lnRR=0.228 ± 0.042, p&lt;0.0001). The combination of HBOT with chemotherapy was associated with lower efficacy than the combination with other treatment modalities. Conclusions We found weak evidence that HBOT prolongs survival times in cancer-bearing mice and strong evidence for synergistic effects with other therapies. The translational potential of these findings and extrapolation to lower-pressure HBOT remain to be determined.

The course of tuberculosis infection in hyper-susceptible mice carrying the &lt;i&gt;H2&lt;/i&gt;ᵛ haplotype

Genetic regulation of the host susceptibility to Mycobacterium tuberculosis (Mtb) and severity of tuberculosis (TB) infection remain incompletely investigated. Identification of particular genes and involved in TB control and immune reactions regulated by these genes is essential for our understanding of pathogenesis of the disease, discovery of drug targets and rational vaccine development. We have shown that mice of the B10.SM (H2ᵛ) strain are extremely TB susceptible; meanwhile, the general genome structure of this mouse strain and the H2ᵛ haplotype itself are poorly characterized. We selected a pool of Mit genetic markers differentiating B10.SM mice from Chr. 17-congenic mice of the B10 strain by the PCR products motility in the electrophoresis setting. TB susceptibility of B10 mice is much lower than that of B10.SM. In the model of infection triggered by two different dosed of Mtb (100 and 600 CFU per mouse) administered via respiratory tract we demonstrated that B10.SM mice have significantly shorter survival time and significantly higher lung mycobacterial multiplication compared to B10 mice. We demonstrated (intracellular staining and ELISA) that IFNγ production in the lungs of infected mice of the two strains corresponds well to their disease phenotypes. Thus, more resistant B10 mice possess significantly more lung IFNγ-positive CD4⁺ T cells and a higher level of IFNγ secretion. We have established (B10х B10.SM) F1 hybrids and demonstrated that the post-infection phenotypes of survival time, lung mycobacterial multiplication and IFNγ production in these mice are intermediate compared to parental mice. Thus, we deal with the genetic trait with incomplete dominance expression. These data were confirmed in F2 hybrids by segregation genetic analysis. To characterize the phenotype of B10.SM mice in more detail, we vaccinated these mice with the BCG vaccine before TB challenge. Vaccination significantly prolonged survival time, diminished mycobacterial multiplication in the lungs and the degree of lung tissue pathology. Thus, a high level of susceptibility to primary infection did not interfere with BCG vaccination efficacy. We intend to continue genetic and immunologic analyses of TB-hyper-susceptible B10.SM mice. Experimental data regarding the cause of extreme disturbances in protection against infection are prerequisite for our better understanding causality of the wide spectrum of TB manifestations in human populations, as well as for rational search for novel vaccines and medications against TB infection.