-
BioRxiv : the Preprint Server For... Jun 2024A substantial gap persists in our comprehension of how bacterial metabolism undergoes rewiring during the transition to a persistent state. Also, it remains unclear...
A substantial gap persists in our comprehension of how bacterial metabolism undergoes rewiring during the transition to a persistent state. Also, it remains unclear which metabolic mechanisms become indispensable for persister cell survival. To address these questions, we directed our efforts towards persister cells in that emerge during the late stationary phase. These cells have been recognized for their exceptional resilience and are commonly believed to be in a dormant state. Our results demonstrate that the global metabolic regulator Crp/cAMP redirects the metabolism of these antibiotic-tolerant cells from anabolism to oxidative phosphorylation. Although our data indicates that persisters exhibit a reduced metabolic rate compared to rapidly growing exponential-phase cells, their survival still relies on energy metabolism. Extensive genomic-level analyses of metabolomics, proteomics, and single-gene deletions consistently emphasize the critical role of energy metabolism, specifically the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and ATP synthase, in sustaining the viability of persisters. Altogether, this study provides much-needed clarification regarding the role of energy metabolism in antibiotic tolerance and highlights the importance of using a multipronged approach at the genomic level to obtain a broader picture of the metabolic state of persister cells.
PubMed: 38915711
DOI: 10.1101/2024.06.10.598332 -
Frontiers in Pharmacology 2024Metastatic non-small cell lung cancer (mNSCLC) has a high incidence rate, and economic burdens to patients, healthcare systems, and societies. Durvalumab plus...
Cost-effectiveness of durvalumab plus tremelimumab in combination with chemotherapy for the treatment of metastatic non-small-cell lung cancer from the US healthcare sector's and societal perspectives.
PURPOSE
Metastatic non-small cell lung cancer (mNSCLC) has a high incidence rate, and economic burdens to patients, healthcare systems, and societies. Durvalumab plus tremelimumab and chemotherapy (T+D+CT) is a novel therapeutic strategy for mNSCLC, which demonstrated promising efficacy in a phase-3 randomized clinical trial, but its economic value remains unclear.
METHODS
This economic evaluation used a hypothetical cohort of patients with mNSCLC, with characteristics mirroring those of the participants in the POSEIDON trial. Several partitioned survival models were constructed to estimate 15-year costs and health outcomes associated with the T+D+CT, durvalumab plus chemotherapy (D+CT) and chemotherapy alone (CT) strategies, discounting costs and effectiveness at 3% annually. Costs were in 2023 US dollars. Data were derived from the POSEIDON trial and published literature. Deterministic and probabilistic sensitivity analyses were performed to assess the uncertainty of input parameters and study generalizability. The analysis was designed and conducted from September 2022 to March 2023. To evaluate the cost-effectiveness of T+D+CT, compared with CT and D+CT, for mNSCLC from the perspectives of the US healthcare sector and society.
FINDINGS
From the healthcare sector's perspective, the T+D+CT yielded an additional 0.09 QALYs at an increased cost of $7,108 compared with CT, which resulted in an ICER of $82,501/QALY. The T+D+CT strategy yielded an additional 0.02 QALYs at an increased cost of $27,779 compared with the D+CT, which resulted in an ICER of $1,243,868/QALY. The economic results of T+D+CT vs. CT were most sensitive to the annual discount rate, subsequent immunotherapy cost, tremelimumab cost, palliative care and death cost, pemetrexed cost, and durvalumab cost. The T+D+CT strategy was considered cost-effective relative to CT in 59%-82% of model iterations against willingness-to-pay. thresholds of $100,000/QALY gained to $150,000/QALY gained. From the societal perspective, the T+D+CT can be considered as cost-effective as compared with CT or D+CT, independent of histology.
IMPLICATIONS
In this cost-effectiveness analysis, the T+D+CT strategy represented good value compared with CT for patients with mNSCLC from the perspectives of the healthcare sector and the society. This treatment strategy may be prioritized for mNSCLC patients at high risks of disease progression.
PubMed: 38915475
DOI: 10.3389/fphar.2024.1256992 -
Frontiers in Immunology 2024Immune checkpoint inhibitors (ICIs) are effective for non-small cell lung cancer (NSCLC) treatment, but the response rate remains low. Programmed cell death ligand 1... (Meta-Analysis)
Meta-Analysis
Prognostic significance of programmed cell death ligand 1 blood markers in non-small cell lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis.
BACKGROUND
Immune checkpoint inhibitors (ICIs) are effective for non-small cell lung cancer (NSCLC) treatment, but the response rate remains low. Programmed cell death ligand 1 (PD-L1) in peripheral blood, including soluble form (sPD-L1), expression on circulating tumor cells (CTCs PD-L1) and exosomes (exoPD-L1), are minimally invasive and promising markers for patient selection and management, but their prognostic significance remains inconclusive. Here, we performed a meta-analysis for the prognostic value of PD-L1 blood markers in NSCLC patients treated with ICIs.
METHODS
Eligible studies were obtained by searching PubMed, EMBAS, Web of Science, and Cochrane Library prior to November 30, 2023. The associations between pre-treatment, post-treatment and dynamic changes of blood PD-L1 levels and progression-free survival (PFS)/over survival (OS) were analyzed by estimating hazard ratio (HR) and 95% confidence interval (CI).
RESULTS
A total of 26 studies comprising 1606 patients were included. High pre- or post-treatment sPD-L1 levels were significantly associated with worse PFS (pre-treatment: HR=1.49, 95%CI 1.13-1.95; post-treatment: HR=2.09, 95%CI 1.40-3.12) and OS (pre-treatment: HR=1.83, 95%CI 1.25-2.67; post-treatment: HR=2.60, 95%CI 1.09-6.20, P=0.032). High pre-treatment exoPD-L1 levels predicted a worse PFS (HR=4.24, 95%CI 2.82-6.38, P<0.001). Pre-treatment PD-L1 CTCs tended to be correlated with prolonged PFS (HR=0.63, 95%CI 0.39-1.02) and OS (HR=0.58, 95%CI 0.36-0.93). Patients with up-regulated exoPD-L1 levels, but not sPD-L1, after ICIs treatment had significantly favorable PFS (HR=0.36, 95%CI 0.23-0.55) and OS (HR=0.24, 95%CI 0.08-0.68).
CONCLUSION
PD-L1 blood markers, including sPD-L1, CTCs PD-L1 and exoPD-L1, can effectively predict prognosis, and may be potentially utilized for patient selection and treatment management for NSCLC patients receiving ICIs.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Lung Neoplasms; B7-H1 Antigen; Biomarkers, Tumor; Prognosis
PubMed: 38915398
DOI: 10.3389/fimmu.2024.1400262 -
Health Science Reports Jun 2024Marital status has been shown to be associated with mortality, but evidence in critically ill elder intensive care unit (ICU) patients with cerebrovascular diseases...
BACKGROUND AND AIMS
Marital status has been shown to be associated with mortality, but evidence in critically ill elder intensive care unit (ICU) patients with cerebrovascular diseases (CeVD) is limited. This study was to explore the correlation between marital status and the prognosis of patients with CeVD aged 65 years and over in the ICU.
METHODS
In the present study, 3564 patients were enrolled in the Medical Information Mart for Intensive Care IV database (version 2.2). Patients were divided into four groups based on marital status: married, single, divorced, and widowed. The primary outcome was all-cause mortality as patients were followed up for 3-, 6-, 9-, and 12-month. All-cause mortality risk for patients with different marital status was compared. Univariate and multivariable logistic regression analyses, survival curves and stratified analyses were performed to determine the correlation between marital status and mortality in critically ill patients with CeVD aged ≥65 years.
RESULTS
Of the patients, 51.2% (1825/3564) were married, followed by 23.8% (847/3564) were widowed, 18.2% (647/3564) were single, and 6.9% (245/3567) were divorced. Compared with the married, the unmarried had a higher proportion of female ( < 0.001), older ( < 0.001), and less proportion of mechanical ventilation ( = 0.045). Multivariate analyses showed that no differences were observed for mortality risk among different marital statuses ( > 0.05), while at late follow-up, widowed had a significance higher mortality risk than the married (9-month: odds ratio [OR]: 1.30, 95% confidence interval [CI]: 1.05-1.61, = 0.02; 12-month: OR: 1.38, 95% CI: 1.12-1.71, = 0.003). Stratified analyses indicated a stable correlation between marital status and 12-month mortality rate in sub-analysis for gender ( = 0.46) and age ( = 0.35).
CONCLUSION
Marital status is associated with long-term prognosis in older patients with CeVD admitted to ICU. Widowed people should receive more societal attention irrespective of sex or age.
PubMed: 38915359
DOI: 10.1002/hsr2.2177 -
Journal of Intensive Care Jun 2024There is no reliable indicator that can assess the treatment effect of anticoagulant therapy for sepsis-associated disseminated intravascular coagulation (DIC) in the...
BACKGROUND
There is no reliable indicator that can assess the treatment effect of anticoagulant therapy for sepsis-associated disseminated intravascular coagulation (DIC) in the short term. The aim of this study is to develop and validate a prognostic index identifying 28-day mortality in septic DIC patients treated with antithrombin concentrate after a 3-day treatment.
METHODS
The cohort for derivation was established utilizing the dataset from post-marketing surveys, while the cohort for validation was acquired from Japan's nationwide sepsis registry data. Through univariate and multivariate analyses, variables that were independently associated with 28-day mortality were identified within the derivation cohort. Risk variables were then assigned a weighted score based on the risk prediction function, leading to the development of a composite index. Subsequently, the area under the receiver operating characteristic curve (AUROC). 28-day survival was compared by Kaplan-Meier analysis.
RESULTS
In the derivation cohort, 252 (16.9%) of the 1492 patients deceased within 28 days. Multivariable analysis identified DIC resolution (hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.22-0.45, P < 0.0001) and rate of Sequential Organ Failure Assessment (SOFA) score change (HR: 0.42, 95% CI: 0.36-0.50, P < 0.0001) were identified as independent predictors of death. The composite prognostic index (CPI) was constructed as DIC resolution (yes: 1, no: 0) + rate of SOFA score change (Day 0 SOFA score-Day 3 SOFA score/Day 0 SOFA score). When the CPI is higher than 0.19, the patients are judged to survive. Concerning the derivation cohort, AUROC for survival was 0.76. As for the validation cohort, AUROC was 0.71.
CONCLUSION
CPI can predict the 28-day survival of septic patients with DIC who have undergone antithrombin treatment. It is simple and easy to calculate and will be useful in practice.
PubMed: 38915122
DOI: 10.1186/s40560-024-00739-x -
Journal of Hematology & Oncology Jun 2024It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of...
It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.
Topics: Humans; Multiple Myeloma; Aged; Prospective Studies; Male; Female; Aged, 80 and over; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols; Frailty; Lenalidomide; Bortezomib; Precision Medicine; Frail Elderly; Geriatric Assessment; Antibodies, Monoclonal
PubMed: 38915117
DOI: 10.1186/s13045-024-01569-y -
Radiation Oncology (London, England) Jun 2024Superficial soft tissue metastasis (S-STM) of malignant tumors is uncommon and often brings great pain to patients. However, current treatment options are limited. The...
Clinical efficacy and prognostic factors of CT-guided radioactive iodine-125 seed implantation for the treatment of superficial soft tissue metastasis: a 12-year retrospective analysis.
BACKGROUND
Superficial soft tissue metastasis (S-STM) of malignant tumors is uncommon and often brings great pain to patients. However, current treatment options are limited. The purpose of this study was to explore the clinical efficacy and prognostic factors of CT-guided radioactive iodine-125 (I) seed implantation (RISI) for the treatment of S-STM.
METHODS
We retrospectively evaluated 132 patients with S-STM who received RISI between June 2010 and July 2022. Local tumor progression-free survival (ltPFS), tumor response, pain control and complication were analyzed. The independent factors affecting ltPFS were screened out using a layered Cox proportional hazards model.
RESULTS
The median follow-up time was 8.3 months (interquartile range [IQR], 4.5-15.3 months). The objective response rate (ORR) was 81.8%. The median ltPFS was 9.1 (95% CI: 6.6, 11.6) months. The Cox proportional hazard regression model revealed that the independent factors influencing ltPFS included KPS score, primary tumor, metastases, boundary, density and postoperative D90 (All P < 0.05). After RISI, the rate of pain relief was 92.3%. 66 (84.6%) patients reported pain marked relief, and 6 (7.7%) experienced pain moderate relief. No severe adverse events associated with RISI were observed during follow-up.
CONCLUSIONS
CT-guided RISI was associated with high local control and pain relief without severe adverse events and should be considered as a reliable palliative treatment modality for S-STM.
TRIAL REGISTRATION
Trial registration Retrospectively registered.
Topics: Humans; Iodine Radioisotopes; Retrospective Studies; Male; Female; Middle Aged; Soft Tissue Neoplasms; Prognosis; Tomography, X-Ray Computed; Brachytherapy; Aged; Adult; Radiotherapy, Image-Guided
PubMed: 38915062
DOI: 10.1186/s13014-024-02475-w -
BMC Genomics Jun 2024Although, oocytes from prepubertal donors are known to be less developmentally competent than those from adult donors it does not restrain their ability to produce...
BACKGROUND
Although, oocytes from prepubertal donors are known to be less developmentally competent than those from adult donors it does not restrain their ability to produce full-term pregnancies. The transcriptomic profile of embryos could be used as a predictor for embryo's individual developmental competence. The aim of the study was to compare transcriptomic profile of blastocysts derived from prepubertal and pubertal heifers oocytes. Bovine cumulus-oocyte complexes (COCs) were obtained by ovum pick- up method from prepubertal and pubertal heifers. After in vitro maturation COCs were fertilized and cultured to the blastocyst stage. Total RNA was isolated from both groups of blastocysts and RNA-seq was performed. Gene ontology analysis was performed by DAVID (Database for Annotation, Visualization and Integrated Discovery).
RESULTS
A higher average blastocyst rate was obtained in the pubertal than in the pre-pubertal group. There were no differences in the quality of blastocysts between the examined groups. We identified 436 differentially expressed genes (DEGs) between blastocysts derived from researched groups, of which 247 DEGs were downregulated in blastocysts derived from pubertal compared to prepubertal heifers oocytes, and 189 DEGs were upregulated. The genes involved in mitochondrial function, including oxidative phosphorylation (OXPHOS) were found to be different in studied groups using Kyoto Encyclopedia of Genes (KEGG) pathway analysis and 8 of those DEGs were upregulated and 1 was downregulated in blastocysts derived from pubertal compared to prepubertal heifers oocytes. DEGs associated with mitochondrial function were found: ATP synthases (ATP5MF-ATP synthase membrane subunit f, ATP5PD- ATP synthase peripheral stalk subunit d, ATP12A- ATPase H+/K + transporting non-gastric alpha2 subunit), NADH dehydrogenases (NDUFS3- NADH: ubiquinone oxidoreductase subunit core subunit S3, NDUFA13- NADH: ubiquinone oxidoreductase subunit A13, NDUFA3- NADH: ubiquinone oxidoreductase subunit A3), cytochrome c oxidase (COX17), cytochrome c somatic (CYCS) and ubiquinol cytochrome c reductase core protein 1 (UQCRC1). We found lower number of apoptotic cells in blastocysts derived from oocytes collected from prepubertal than those obtained from pubertal donors.
CONCLUSIONS
Despite decreased expression of genes associated with OXPHOS pathway in blastocysts from prepubertal heifers oocytes, the increased level of ATP12A together with the lower number of apoptotic cells in these blastocysts might support their survival after transfer.
Topics: Animals; Cattle; Oxidative Phosphorylation; Female; Gene Expression Profiling; Blastocyst; Transcriptome; Sexual Maturation; Oocytes; Gene Expression Regulation, Developmental; Fertilization in Vitro
PubMed: 38914933
DOI: 10.1186/s12864-024-10532-7 -
Scientific Reports Jun 2024Medulloblastoma is a malignant neuroepithelial tumor of the central nervous system. Accurate prediction of prognosis is essential for therapeutic decisions in...
Medulloblastoma is a malignant neuroepithelial tumor of the central nervous system. Accurate prediction of prognosis is essential for therapeutic decisions in medulloblastoma patients. We analyzed data from 2,322 medulloblastoma patients using the SEER database and randomly divided the dataset into training and testing datasets in a 7:3 ratio. We chose three models to build, one based on neural networks (DeepSurv), one based on ensemble learning that Random Survival Forest (RSF), and a typical Cox Proportional-hazards (CoxPH) model. The DeepSurv model outperformed the RSF and classic CoxPH models with C-indexes of 0.751 and 0.763 for the training and test datasets. Additionally, the DeepSurv model showed better accuracy in predicting 1-, 3-, and 5-year survival rates (AUC: 0.767-0.793). Therefore, our prediction model based on deep learning algorithms can more accurately predict the survival rate and survival period of medulloblastoma compared to other models.
Topics: Medulloblastoma; Humans; Deep Learning; Female; Male; SEER Program; Child; Prognosis; Cerebellar Neoplasms; Adolescent; Child, Preschool; Proportional Hazards Models; Survival Rate; Adult; Young Adult; Middle Aged; Neural Networks, Computer; Infant
PubMed: 38914641
DOI: 10.1038/s41598-024-65367-9 -
Scientific Reports Jun 2024Aloe barbadensis is a drought-tolerant perennial medicinal plant with both nutritional and cosmetic uses. Drought is one of the main abiotic stresses limiting plant...
Evaluation of the benefits of plant growth-promoting rhizobacteria and mycorrhizal fungi on biochemical and morphophysiological traits of Aloe barbadensis Mill under water deficit stress.
Aloe barbadensis is a drought-tolerant perennial medicinal plant with both nutritional and cosmetic uses. Drought is one of the main abiotic stresses limiting plant growth and development. However, the use of drought-resistant plants combined with beneficial soil micro-organisms could improve the effectiveness of biological methods to mitigate drought damage. This research aims to evaluate the effects of Funneliformis mosseae (MF), plant growth-promoting rhizobacteria (PGPR) (including Pseudomonas putida and Pantoea agglomerans), and their co-inoculation on the macronutrient status, antioxidant enzyme activities, and other morphophysiological traits of A. barbadensis under four irrigation regimes [25%, 50%, 75% and 100% of water requirement (WR)]. Three harvests were conducted, revealing that inoculation enhanced the survival rate and shoot fresh weight (SFW) compared to the control plants. However, at 25% WR, the SFW was reduced by 43% more than the control. across all harvests, while the PGPR + MF treatment showed increases of more than 19%, 11%, and 17% compared to the control, MF, and PGPR treatments, respectively. The results also showed that A. barbadensis exhibited innate drought tolerance up to a 50% WR level by enhancing physiological defenses, such as antioxidant enzyme activity. Inoculation increased the macronutrient status of the plant at all levels of irrigation regimes especially under severe drought conditions. The highest levels of nitrogen (N) (16.24 mg g DW) and phosphorus (P) (11.29 mg g DW) were observed in the PGPR + MF treatment at 100% WR. The maximum relative water content under MF inoculation and 75% WR (98.24%) (98.24%) was reached. PGPR + MF treatment alleviated drought-induced osmotic stress, as indicated by reduced antioxidant enzyme activities and electrolyte leakage. However, P. putida and P. agglomerans strains alone or in combination with F. mosseae increased plant yield, macronutrient uptake and antioxidant enzyme activity. This study underscores the potential of these PGPR and MF strains as invaluable biological tools for the cultivation of A. barbadensis in regions with severe drought stress.
Topics: Aloe; Mycorrhizae; Droughts; Pseudomonas putida; Antioxidants; Plant Roots; Water; Stress, Physiological; Soil Microbiology; Pantoea; Dehydration; Fungi
PubMed: 38914637
DOI: 10.1038/s41598-024-64878-9