Combination Index Research Articles

Prediction of synergistic gemcitabine-based combination treatment through a novel tumor stemness biomarker NANOG in pancreatic cancer.

Gemcitabine remains a first-class chemotherapeutic drug for pancreatic cancer. However, due to the rapid development of gemcitabine resistance in pancreatic cancer, gemcitabine alone or in combination with other anti-cancer drugs only showed limited effect in the clinic. It is extremely challenging to effectively and efficiently determine the optimal drug regimens. Thus, identification of appropriate prediction biomarkers is critical for the rational design of gemcitabine-based therapeutic options. Herein, a pancreatic cancer stem cell (PCSC) model exhibiting chemoresistance to gemcitabine was used to test the activity of clinical cancer drugs in the presence or absence of gemcitabine. As determined by combinatorial treatment, several types of drugs resensitized gemcitabine-resistant PCSCs to gemcitabine, with sorafenib (EGFR inhibitor)/gemcitabine and sunitinib (TBK1 inhibitors)/gemcitabine drug combinations being the most preferred treatments for PCSCs. Following the validation of the PCSC model by an antibody array test of 15-gene expression of stemness biomarkers, NANOG showed markedly different expression in PCSCs compared to the parental cells. From comprehensive analysis of stem cell index versus combination index, a stemness-related correlation model was successfully constructed to demonstrate the correlation between NANOG expression and synergism. Cancer cell stemness was ascertained to be highly relevant to NANOG overexpression that can be abrogated by synergized gemcitabine-drug combinations. Therefore, NANOG works as a therapeutic biomarker for predicating efficient combinatorial treatment of gemcitabine in pancreatic cancer.

A general prediction model for compound-protein interactions based on deep learning.

The identification of compound-protein interactions (CPIs) is crucial for drug discovery and understanding mechanisms of action. Accurate CPI prediction can elucidate drug-target-disease interactions, aiding in the discovery of candidate compounds and effective synergistic drugs, particularly from traditional Chinese medicine (TCM). Existing in silico methods face challenges in prediction accuracy and generalization due to compound and target diversity and the lack of largescale interaction datasets and negative datasets for model learning. To address these issues, we developed a computational model for CPI prediction by integrating the constructed large-scale bioactivity benchmark dataset with a deep learning (DL) algorithm. To verify the accuracy of our CPI model, we applied it to predict the targets of compounds in TCM. An herb pair of Astragalus membranaceus and Hedyotis diffusaas was used as a model, and the active compounds in this herb pair were collected from various public databases and the literature. The complete targets of these active compounds were predicted by the CPI model, resulting in an expanded target dataset. This dataset was next used for the prediction of synergistic antitumor compound combinations. The predicted multi-compound combinations were subsequently examined through in vitro cellular experiments. Our CPI model demonstrated superior performance over other machine learning models, achieving an area under the Receiver Operating Characteristic curve (AUROC) of 0.98, an area under the precision-recall curve (AUPR) of 0.98, and an accuracy (ACC) of 93.31% on the test set. The model's generalization capability and applicability were further confirmed using external databases. Utilizing this model, we predicted the targets of compounds in the herb pair of Astragalus membranaceus and Hedyotis diffusaas, yielding an expanded target dataset. Then, we integrated this expanded target dataset to predict effective drug combinations using our drug synergy prediction model DeepMDS. Experimental assay on breast cancer cell line MDA-MB-231 proved the efficacy of the best predicted multi-compound combinations: Combination I (Epicatechin, Ursolic acid, Quercetin, Aesculetin and Astragaloside IV) exhibited a half-maximal inhibitory concentration (IC50) value of 19.41μM, and a combination index (CI) value of 0.682; and Combination II (Epicatechin, Ursolic acid, Quercetin, Vanillic acid and Astragaloside IV) displayed a IC50 value of 23.83μM and a CI value of 0.805. These results validated the ability of our model to make accurate predictions for novel CPI data outside the training dataset and evaluated the reliability of the predictions, showing good applicability potential in drug discovery and in the elucidation of the bioactive compounds in TCM. Our CPI prediction model can serve as a useful tool for accurately identifying potential CPI for a wide range of proteins, and is expected to facilitate drug research, repurposing and support the understanding of TCM.

Individual Identification and Assessment of Genetic Diversity Using Microsatellite Markers in Racing Pigeons Raised in Turkiye

The implementation of a swift and economical molecular genetic approach, ensuring both efficacy and cost-effectiveness and facilitating population certification, is of utmost significance for breeders and the conservation of Turkiye's native pigeon biodiversity. In this study, we aimed to examine the genetic structure of racing pigeons (Columba livia domestica) raised in Turkiye using a genetic marker panel consisting of eight short tandem repeat (STR) loci. For this purpose, DNA was isolated from the shed feathers of 216 pigeons. Genomic DNA was amplified using the multiplex allele-specific PCR and subsequent capillary electrophoresis with ABI PRISM 3130XL Genetic Analyzer. Next, PCR products were analyzed in the GeneMapper Software program (Applied Biosystems). For parent testing, paternity index (PI), combined paternity index (CPI), and cumulative probability of paternity (CPP) were calculated. Furthermore, population genetic diversity was evaluated using heterozygosity (He), polymorphism information content (PIC), and Hardy–Weinberg equilibrium (HWE) testing. Results revealed that the total number of alleles is 81 and the number of alleles per locus varies between 4 and 19. The similarity rate between parent and offspring was calculated as 99.99% and above. Since no pedigree information was given when the samples were analyzed, obtaining this similarity ratio demonstrates the reliability of the panel. He values range from 0.362 to 0.919, and the PIC values range from 0.295 to 0.909. Loci PG-1, PG-2, and PG-3 show significant genetic diversity, with moderate to high PIC values reflecting varied allele frequencies in the population. Consequently, the set of seven STR markers (+ one sex marker) can be applied to identify and confirm parentage on a regular basis, thereby facilitating efficient breeding programs and ensuring genetic diversity conservation. This panel enables efficient pedigree analysis and gender determination, optimizing cost-effectiveness. The methodology presented in this study is ideal for pedigree analysis and breed certification in the Turkish pigeon breeding industry. Consequently, we affirm that the study data carries considerable national importance.

Combination of cisplatin and ethyl acetate extract of Vernonia amygdalina Delile induces cell cycle arrest and apoptosis on PANC-1 cells via PI3K/mTOR

Context: Vernonia amygdalina Delile (VAD) is known as a potential plant with a wide variety of medicinal properties, including anticancer. Aims: To evaluate the combination effect of VAD extract with cisplatin (CIS) against PANC-1 cells, focusing on cell cycle arrest and apoptosis activities. Methods: This study is an experimental study using PANC-1 cells as objects. The phytochemical compounds were analyzed with LC-MS/MS. The cytotoxic activity of extracts and their combinations was determined using the MTT assay method in the PANC-1 cell line. Apoptosis, cell cycle arrest, and PI3K/mTOR profiles were analyzed with flow cytometry. Immunocytochemistry was used to determine Bcl-2, Cyclin D1, and p53 expression. Results: The phytochemicals found were five compounds with retention times of 8.96, 9.85, 10.52, 12.59, and 10.36. The results of the MTT assay showed that the IC50 values of extract and CIS were 21.83 ± 0.46 µg/mL and 3.02 ± 0.44 µg/mL, respectively. The combination index (CI) value of extract and CIS had a synergistic effect. Combination extract and CIS induced early and late apoptosis, inhibited cell cycle progression on the G1 phase, inhibited Bcl-2 and cyclin D1 expression, induced p53 expression, and inhibited PI3K and mTOR expression. Conclusions: The combination of extract and CIS showed anticancer activity against PANC-1 cells through induction of apoptosis and cell cycle arrest via inhibition of PI3K and mTOR expressions.

Differentiating Definite and Probable Ménière Disease: A Comprehensive Evaluation of Audio-Vestibular Function Testing Combined with Inner Ear MRI.

To evaluate the differences between audio-vestibular function testing and inner ear gadolinium magnetic resonance imaging (MRI) in distinguishing definite Ménière disease (DMD) and probable Ménière disease (PMD), and to provide a reference for early clinical diagnosis and intervention. A total of 116 patients diagnosed with DMD (n = 80) and PMD (n = 36) were enrolled. The differences in the results of pure tone audiometry, caloric test, and tympanic injection of gadolinium for contrast-enhanced MRI between the two groups were compared and analyzed. Parameters that could differentiate between the two conditions were identified, and the sensitivity and specificity and the area under the curve (AUC) of individual and combined indices in the differential diagnosis of DMD and PMD were evaluated. The hearing threshold and hearing asymmetry rate of the DMD group were significantly higher than those of the PMD group (p < 0.001), 98.8% and 30.6%, respectively. The abnormal rates of canal paresis (CP) and severity of endolymphatic hydrops in the DMD group were higher than those in the PMD group (p < 0.05). When combined with high-frequency hearing thresholds, hearing asymmetry, hearing curve type, endolymphatic hydrops, and abnormal CP, the diagnostic accuracy of DMD was improved compared to using high-frequency alone (p < 0.05). This study showed that PMD and DMD may represent two different stages in the development of MD disease. The comprehensive assessment of audio-vestibular function testing and inner ear MRI proves beneficial for early diagnosis, potentially contributing to the preservation of inner ear function.

Tomatidine, a Steroidal Alkaloid, Synergizes with Cisplatin to Inhibit Cell Viability and Induce Cell Death Selectively on FLT3-ITD+ Acute Myeloid Leukemia Cells.

Acute Myeloid Leukemia (AML) is a hematological cancer that frequently presents with a range of side effects and drug resistance during anticancer drug treatment. The current study aims to achieve increased efficacy by combining lower doses of cisplatin with increasing concentrations of tomatidine in AML cells to increase efficacy. Anti-proliferative effects of single and combination of cisplatin and tomatidine were assessed via MTT cell viability assay. The Annexin V/Propidium Iodide Double Staining method was used to measure the apoptotic effects of combined tomatidine and cisplatin treatment. Then, Western Blot analysis was performed to measure Poly (ADP-ribose) polymerase (PARP) and Caspase-3 protein expression levels. Cisplatin treatment with lower concentrations displayed high cytotoxic effects on AML cells, compared with tomatidine. The combination of the Inhibitory Concentration (IC) 20 value of cisplatin and increasing doses of tomatidine exhibited a significant decrease in cell viability relative to single treatments. The combination index analysis revealed a mild synergistic effect of cisplatin IC20 and varying tomatidine doses. The apoptosis induced when cisplatin was combined with 500 µM tomatidine by almost 20%, while the percentage of apoptosis in combination with 1 mM tomatidine was measured by 50% for both cell lines. The upregulation of proapoptotic cleaved-PARP (3.2 and 1.08-fold for THP-1 and MOLM-13, respectively) and downregulation in Caspase-3 (0.23 and 0.13-fold for THP-1 and MOLM-13, respectively) was detected. Together, the study indicated that when tomatidine combined with cisplatin on AML cell lines, a combinatorial anti-proliferative and apoptotic effect is observed. The combination of cisplatin with tomatidine may be a promising approach.

Aboveground Biomass Mapping in SemiArid Forests by Integrating Airborne LiDAR with Sentinel-1 and Sentinel-2 Time-Series Data

Aboveground biomass (AGB) is a vital indicator for studying carbon sinks in forest ecosystems. Semiarid forests harbor substantial carbon storage but received little attention due to the high spatial–temporal heterogeneity that complicates the modeling of AGB in this environment. This study assessed the performance of different data sources (annual monthly time-series radar was Sentinel-1 [S1]; annual monthly time series optical was Sentinel-2 [S2]; and single-temporal airborne light detection and ranging [LiDAR]) and seven prediction approaches to map AGB in the semiarid forests on the border between Gansu and Qinghai Provinces in China. Five experiments were conducted using different data configurations from synthetic aperture radar backscatter, multispectral reflectance, LiDAR point cloud, and their derivatives (polarimetric combination indices, texture information, vegetation indices, biophysical features, and tree height- and canopy-related indices). The results showed that S2 acquired better prediction (coefficient of determination [R2]: 0.62–0.75; root mean square error [RMSE]: 30.08–38.83 Mg/ha) than S1 (R2: 0.24–0.45; RMSE: 47.36–56.51 Mg/ha). However, their integration further improved the results (R2: 0.65–0.78; RMSE: 28.68–35.92 Mg/ha). The addition of single-temporal LiDAR highlighted its structural importance in semiarid forests. The best mapping accuracy was achieved by XGBoost, with the metrics from the S2 and S1 time series and the LiDAR-based canopy height information being combined (R2: 0.87; RMSE: 21.63 Mg/ha; relative RMSE: 14.45%). Images obtained during the dry season were effective for AGB prediction. Tree-based models generally outperformed other models in semiarid forests. Sequential variable importance analysis indicated that the most important S1 metric to estimate AGB was the polarimetric combination indices sum, and the S2 metrics were associated with red-edge spectral regions. Meanwhile, the most important LiDAR metrics were related to height percentiles. Our methodology advocates for an economical, extensive, and precise AGB retrieval tailored for semiarid forests.

Development and validation of a novel combinational index of liquid biopsy biomarker for longitudinal lung cancer patient management

ObjectivesMany cancer biomarkers such as the circulating tumor cells/microemboli (CTCs/CTM) have been reported significant associations with clinical outcomes. However, different biomarkers have different sensitivities and specificities for cancer types and cohort patients, and synergistic effects between certain biomarkers have also been observed, leading to the inaccurate, fluctuating, and even controversial results when multiple biomarkers are analyzed together. In this paper, a novel combinational index, P-score, was developed for monitoring and predicting the disease condition of lung cancer patients during follow-up visits. Materials and methodsThere were totally 13 return patients with 54 blood samples involved in this study to examine the number of CTC and CTM. Information from one group of 7 patients including 27 blood samples with published clinical data was employed to develop while those from another group of 4 patients containing 14 blood samples with unpublished clinical data were used to validate the P score in prediction. Enumerations were based on immunofluorescent staining images. Distributions of CTC/CTM and their frequencies in stratified patients were carefully examined and analyzed the ROC curve and AUC value to develop the P score and P score-based prediction model. Results and conclusionWe found that the predictive power of P-score was not only comparable to the traditional cancer marker, in comparison with individual CTC/CTM, more false positives could be corrected by using P-score, thereby to improve the accuracy of analysis. From our preliminary validation tests, the prognosis and disease progression monitored longitudinally by P-score were further confirmed by clinical outcome data from physicians and its sensitivity was even better than those from individual biomarkers. We believe that this novel combinational indicator could be a promising tool to interpret clinical outcomes more accurately from multiple factors, particularly useful for the early prognosis and longitudinal monitoring in cancer patient management.

Pharmacodynamic interaction between tamsulosin and finasteride treatment in mice induced benign prostate hyperplasia using the Chou-Talalay method

This study was conducted to evaluate the efficacy and interaction of tamsulosin with finasteride treatment on induced benign prostate hyperplasia (BPH) in mice. BPH was induced by subcutaneous injection of testosterone propionate (20 mg/kg) for 30 days. Eighty-five mice were divided into five groups. The first group (G1): twenty-five mice induced BPH treated with tamsulosin orally and divided into five equal subgroups with doses (0.017, 0.052, 0.087, 0. 123, and 0.158) mg/kg, the second group (G2): twenty-five mice induced BPH treated with finasteride orally and divided into five equal subgroups with doses (0.175, 0.527, 0.878, 1.23, and 1.580) mg/kg, the third group (G3): twenty-five mice induced BPH treated with a combination of tamsulosin with finasteride orally, and divided into five equal subgroups with doses (0.0085, 0.0875), (0.026, 0.2635), (0.0435, 0.439) , (0.0615, 0.615) and ( 0.079 , 0.790 ) mg/kg respectively. Fourth group (G4): five mice induced BPH and treated distilled water. Fifth group (G5): five mice were not inducing BPH and without any treatment. The results showed a gradual significant increase in prostate weight % and prostate index % inhibitions until reached saturation in the last two doses of tamsulosin, finasteride, and combination groups, the maximum effective doses of tamsulosin and finasteride were (0.156) and (1.495) mg/kg respectively. Moreover, the effective dose of the combination (tamsulosin and finasteride) was estimated (0.06876, 0.6876) mg/kg respectively as well as the type of interaction was synergism and the value of the combination index was 0.046. The combination of tamsulosin with finasteride showed a synergistic effect in BPH treatment by minimizing the side effect of each drug as a result of decreasing the dose of each one.

Overcoming cisplatin resistance in ovarian cancer: A novel approach via mitochondrial targeting peptide Pal-pHK-pKV

Cisplatin (DDP) resistance in advanced stages of ovarian cancer significantly reduces survival rates. Mitochondria may serve as a potential therapeutic target for ovarian cancer. Pal-pHK-pKV is a mitochondrial targeting peptide synthesized by supramolecular assembly. Our study aims to investigate whether Pal-pHK-pKV serves as a useful strategy to reverse DDP resistance in ovarian cancer. Subcutaneous tumor implantation of the DDP-resistant ovarian cancer cell line A2780CP was conducted in nude mice, and drugs were administered intraperitoneally to compare the inhibitory effects of Pal-pHK-pKV and DDP on A2780CP cells in vivo. Combination index values were calculated for various concentrations of DDP and Pal-pHK-pKV to determine the optimal combination concentration. Mitochondrial membrane potential, cytochrome C distribution and immunofluorescence were also measured. Our studies demonstrated that Pal-pHK-pKV treatment reduced the proliferation, invasion and metastasis of ovarian cancer cells and impaired mitochondrial function. Furthermore, the combination of Pal-pHK-pKV and DDP exhibited a synergistic effect. Mechanistically, Pal-pHK-pKV can impair mitochondrial function, reduce mitochondrial membrane potential and release ROS. On the other hand, Pal-pHK-pKV can affect ERK pathway activation and inhibit tumor development. In conclusion, the mitochondria-specific amphiphilic peptide Pal-pHK-pKV provides a novel approach for treating ovarian cancer and may potentially overcome DDP drug resistance.

The heterogeneity of cellular metabolism in the tumour microenvironment of hepatocellular carcinoma with portal vein tumour thrombus.

Given the growing interest in the metabolic heterogeneity of hepatocellular carcinoma (HCC) and portal vein tumour thrombus (PVTT). This study comprehensively analysed the metabolic heterogeneity of HCC, PVTT, and normal liver samples using multi-omics combinations. A single-cell RNA sequencing dataset encompassing six major cell types was obtained for integrated analysis. The optimal subtypes were identified using cluster stratification and validated using spatial transcriptomics and fluorescent multiplex immunohistochemistry. Then, a combined index based meta-cluster was calculated to verify its prognostic significance using multi-omics data from public cohorts. Our study first depicted the metabolic heterogeneity landscape of non-malignant cells in HCC and PVTT at multiomics levels. The optimal subtypes interpret the metabolic characteristics of PVTT formation and development. The combined index provided effective predictions of prognosis and immunotherapy responses. Patients with a higher combined index had a relatively poor prognosis (p <0.001). We also found metabolism of polyamines was a key metabolic pathway involved in conversion of metabolic heterogeneity in HCC and PVTT, and identified ODC1 was significantly higher expressed in PVTT compared to normal tissue (p =0.03). Our findings revealed both consistency and heterogeneity in the metabolism of non-malignant cells in HCC and PVTT. The risk stratification based on cancer-associated fibroblasts and myeloid cells conduce to predict prognosis and guide treatment. This offers new directions for understanding disease development and immunotherapy responses.

Synergistic Cytotoxicity of Histone Deacetylase and Poly-ADP Ribose Polymerase Inhibitors and Decitabine in Breast and Ovarian Cancer Cells: Implications for Novel Therapeutic Combinations.

Breast and ovarian cancers pose significant therapeutic challenges. We explored the synergistic cytotoxicity of histone deacetylase inhibitors (HDACis), poly(ADP-ribose) polymerase inhibitors (PARPis), and decitabine in breast (MDA-MB-231 and MCF-7) and ovarian (HEY-T30 and SKOV-3) cancer cell lines that were exposed to HDACi (panobinostat or vorinostat), PARPi (talazoparib or olaparib), decitabine, or their combinations. HDACi, PARPi, and decitabine combinations had synergistic cytotoxicity (assessed by MTT and clonogenic assays) in all cell lines (combination index < 1). Clonogenic assays confirmed the sensitivity of breast and ovarian cancer cell lines to the three-drug combinations (panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine; vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine). Cell proliferation was inhibited by 48-70%, and Annexin V positivity was 42-59% in all cell lines exposed to the three-drug combinations. Western blot analysis showed protein PARylation inhibition, caspase 3 and PARP1 cleavage, and c-MYC down-regulation. The three-drug combinations induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs, impaired the DNA repair pathways, and altered the epigenetic regulation of gene expression. These results indicate that HDACi, PARPi, and decitabine combinations should be further explored in these tumor types. Further clinical validation is warranted to assess their safety and efficacy.

GC-MS Analysis and Evaluation of Combination effect of Syzygium cumini L. Skeels Ethanolic Seed Extract and Vancomycin against Clinical Methicillin-Resistant Staphylococcus aureus

Syzygium cumini (L.) has been traditionally used as an antimicrobial agent and is potential to be developed. The ethanol extract of S. cumini seed was obtained through maceration and assessed for its antibacterial activity using a dilution method, with extract concentrations of 1.625; 3.125; 6.25; 12.5, and 25mg/ml. The minimum inhibitory concentration (MIC) and fractional inhibitory concentration index (FICI) of the extract-antibiotic combination against Methicillin-Resistant Staphylococcus aureus were determined. Phytochemical screening was performed using Gas Chromatography-Mass Spectrometry (GC-MS) and the result revealed the presence of 22 compounds in S. cumini ethanolic seed extract, including fatty acids (69.63%), sesquiterpenes (11.29%), monoterpenes (2.94%), steroids (6.06%), and others (8.59%). The MIC of the single extract and vancomycin against the tested bacteria was 0.78mg/ml and 2µg/ml, respectively. The lowest concentration (MIC) of the extract-vancomycin combination inhibiting the growth of MRSA was 0.39mg/ml. The FICI value was 1.5, suggesting indifferent interaction between the extract and antibiotic.

Synergistic Effects of Artesunate in Combination with Amphotericin B and Miltefosine against Leishmania infantum: Potential for Dose Reduction and Enhanced Therapeutic Strategies.

Leishmaniasis is a tropical infectious disease caused by Leishmania parasites. The disease can be spread by the bite of an infected sand fly. Currently, five chemotherapeutic drugs are available in leishmaniasis treatment. However, these drugs exhibit toxicity and serious adverse effects on infected individuals, necessitating alternative treatment strategies. One such strategy involves using combinations of existing antileishmanial drugs. In this study, we evaluated the interaction between artesunate (AS) and three antileishmanial drugs-amphotericin B (AmB), miltefosine (MF), and paromomycin (PM) against Leishmania infantum. This evaluation marks the first time such an assessment has been conducted. The Chou-Talalay combination index method was employed to analyze the drug interaction. The findings revealed that the interaction between AS and AmB ranged from antagonistic to synergistic, while the interaction between AS and MF showed moderate to strong synergism. In contrast, the interaction between AS and PM resulted in an antagonistic interaction, which differs from the combinations with AmB or MF. This study provides valuable insights for developing novel drug regimens for leishmaniasis treatment, emphasizing the potential of AS and its combination with existing antileishmanial drugs. Further research is necessary to optimize drug combinations and minimize adverse effects, leading to more effective therapeutic outcomes.

GPX4 Inhibition Enhances the Antitumor Effect of PARP Inhibitor on Homologous Recombination Proficient Ovarian Cancer Cells.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are now widely used in BRCA1/2 mutation or homologous recombination (HR) deficiency ovarian cancer but have limited efficacy in HR-proficient patients. GPX4 is a key regulator of ferroptosis and has been proven to be associated with multiple drug sensitivities. As a molecule that regulates the sensitivity of multiple drugs, the relationship between GPX4 and the efficacy of PARPi in HR-proficient ovarian cancer has not been elucidated. In this study, siRNA transfection was used to regulate the expression of GPX4. The effect of GPX4 inhibition on HR-proficient ovarian cancer was determined by CCK-8 assay and flow cytometry. Immunofluorescence and comet assays were used to reflect DNA dam-age. ROS production was measured using DCFH-DA and flow cytometry. The combination index of PARP inhibitors and RSL3 was calculated using CompuSyn software based on Chou-Talalay methodology. GPX4 inhibition confers HR-proficient ovarian cancer cells sensitive to PARPi due to ROS generation and oxidative stress caused by DNA double-strand breakage. The combina-tion of olaparib and niraparib with GPX4 inhibitor RSL3 also showed a synergistic effect. Combining GPX4 inhibition with PARP inhibitors resulted in a notable increase in DNA damage, ultimately causing the death of cancer cells with proficient HR pathways. Our findings may provide new therapeutic options for HR-proficient patients to benefit from PARP inhibitors and improve outcomes.

Association of combined body mass index and central obesity with cardiovascular disease in middle-aged and older adults: a population-based prospective cohort study

BackgroundCardiovascular diseases (CVDs) pose a significant threat to public health. Evidence indicates that the combination of central obesity and normal body mass index (BMI) is associated with an increased risk of cardiovascular disease and mortality. However, limited evidences exists in middle aged and elderly adults in China.MethodsThis was a prospective cohort study that utilized a nationally representative sample of 6,494 adults aged 45 years and above. These individuals participated in the China Health and Retirement Longitudinal Study spanning from 2011 to 2018. Height, weight and waist circumference (WC) were measured, and BMI was calculated by height and weight. Other variables were obtained through self-reported questionnaires. Association analysis was conducted using Cox proportional hazard regression models.ResultsA total of 10,186 participants were investigated, with 57,185 person-years of follow-up. During this period, 1,571 CVDs occurred, including 1,173 heart diseases and 527 strokes. After adjusting for various factors including age, gender, education, marital status, smoking status, alcohol intake, social activity, hypertension, dyslipidemia, diabetes, cancer, chronic lung diseases, liver disease, kidney disease, digestive disease, ENP(emotional, nervous, or psychiatric problems), memory related disease, arthritis or rheumatism, asthma, self-rated health and depression, the results revealed that compared to those with normal WC normal body mass index (BMI), individuals with central obesity normal BMI had a 27.9% higher risk of CVD incidence (95% confidence interval [CI]:1.074–1.524), and a 33.4% higher risk of heart disease incidence (95% CI:1.095–1.625), while no significant association was found with stroke. Additionally, those with normal WC high BMI showed a 24.6% higher risk of CVD incidence (95% CI:1.046–1.483), and a 29.1% higher risk of heart disease incidence (95% CI:1.045–1.594), again with no significant association with stroke. Finally, individuals with central obesity high BMI exhibited a 49.3% higher risk of CVD incidence (95% CI:1.273–1.751), a 61% higher risk of heart disease incidence (95% CI:1.342–1.931), and a 34.2% higher risk of stroke incidence (95% CI:1.008–1.786). Age- and sex- specific analyses further revealed varying trends in these associations.ConclusionsWe discovered that the combined association of body mass index(BMI) and central obesity with CVD incidence exhibited a significantly enhanced predictive value. Specifically, a high BMI with central obesity was notably linked to an increased risk of CVD incidence. Additionally, central obesity with a normal BMI or a normal WC coupled with a high BMI significantly augmented the risk of heart disease incidence, but not stroke. Notably, male and middle-aged adults demonstrated a greater propensity for heart disease incidence. Our study underscores the importance of maintaining an optimal BMI and preventing abdominal obesity in promoting cardiovascular health.

Antibiotic intermediates and antibiotics synergistically promote the development of multiple antibiotic resistance in antibiotic production wastewater

Antibiotic resistance (AR) is a major public health concern. Antibiotic intermediates (AIs) used in the production of semisynthetic antibiotics have the same bioactive structure as parent antibiotics and synthetic antibiotic production wastewater usually contains high concentrations of residual AIs; however, the effects of AIs and their interactive effects with antibiotics on the emergence of AR are unknown. In this study, antibiotic-sensitive E. coli K12 was exposed to five types of β-lactam AIs and their parent antibiotic ampicillin to analyze their impact on the evolution of multiple AR. The results indicated that AI 6-APA inhibits bacterial growth and stimulates the production of reactive oxygen species, as well as induces AR and antibiotic persistence like the parent antibiotic AMP. Combined exposure to 6-APA and AMP synergistically stimulated the induction of multiple AR and antibiotic persistence. The resistance mutation frequency increased up to 6.1 × 106-fold under combined exposure and the combination index reached 1326.5, indicating a strong synergy of 6-APA and AMP. Phenotypic and genotypic analyses revealed that these effects were associated with the overproduction of reactive oxygen species, enhanced stress response signatures, and activation of efflux pumps. These findings provide evidence and mechanistic insights into AR induction by AIs in antibiotic production wastewater.

Green-synthesized silver nanoparticles from peel extract of pumpkin as a potent radiosensitizer against triple-negative breast cancer (TNBC)

BackgroundTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Radiation therapy (RT) is a modality for TNBC management. Radiosensitizers can mitigate the adverse effects of RT. Applying green-synthesized silver nanoparticles (Ag-NPs) from biological sources such as plants is a potential strategy to sensitize cancer cells to radiotherapy due to the low toxicity. Therefore, identifying novel natural sources for synthesizing stable and broadly applicable green-Ag-NPs has gained more attention in cancer therapy. In the present study, we synthesized green- Ag-NPs from pumpkin peel extract and elucidated the impact of green-synthesized Ag-NPs as a radiosensitizer in MDA-MB 231 cells (a model of TNBC).ResultsThe prepared Ag-NPs had a spherical shape with an average size of 81 nm and a zeta potential of − 9.96 mV. Combination of green-synthesized Ag-NPs with RT exhibited synergistic anticancer effects with an optimum combination index (CI) of 0.49 in MDA-MB-231 cells. Green-synthesized Ag-NPs synergistically potentiated RT-induced apoptosis in MDA-MB-231 cells compared to the corresponding monotherapies. Morphological features of apoptosis were further confirmed by the DAPI–TUNEL staining assay. HIF-1α expression was decreased in cells subjected to combination therapy. Bax and p53 expression increased, whereas Bcl-2 genes decreased. Combination therapy significantly increased the protein level of PERK and CHOP while decreasing cyclin D1 and p-ERK/total ERK levels compared to monotherapies.ConclusionThese findings indicate the potential effect of green-synthesized Ag-NPs as a radiosensitizer for TNBC treatment.Graphical

Dihydroartemisinin enhances sensitivity of nasopharyngeal carcinoma HNE1/DDP cells to cisplatin-induced apoptosis by promoting ROS production

To investigate the effect of dihydroartemisinin (DHA) for enhancing the inhibitory effect of cisplatin (DDP) on DDP-resistant nasopharyngeal carcinoma cell line HNE1/DDP and explore the mechanism. CCK-8 method was used to assess the survival rate of HNE1/DDP cells treated with DHA (0, 5, 10, 20, 40, 80, and 160 μmol/L) and DDP (0, 4, 8, 16, 32, 64, 128 μmol/L) for 24 or 48 h, and the combination index of DHA and DDP was calculated using Compusyn software. HNE1/DDP cells treated with DHA, DDP, or their combination for 24 h were examined for cell viability, proliferation and colony formation ability using CCK-8, EdU and colony-forming assays. Flow cytometry was used to detect cell apoptosis and intracellular reactive oxygen species (ROS). The expression levels of apoptosis-related proteins cleaved PARP, cleaved caspase-9 and cleaved caspase-3 were detected by Western blotting. The effects of N-acetyl-cysteine (a ROS inhibitor) on proliferation and apoptosis of HNE1/DDP cells with combined treatment with DHA and DDP were analyzed. Different concentrations of DHA and DDP alone both significantly inhibited the viability of HNE1/DDP cells. The combination index of DHA (5 μmol/L) combined with DDP (8, 16, 32, 64, 128 μmol/L) were all below 1. Compared with DHA or DDP alone, their combined treatment more potently decreased the cell viability, colony-forming ability and the number of EdU-positive cells, and significantly increased the apoptotic rate, intracellular ROS level, and the expression levels of cleaved PARP, cleaved caspase-9 and cleaved caspase-3 in HNE1/DDP cells. N-acetyl-cysteine pretreatment obviously attenuated the inhibitory effect on proliferation and apoptosis-inducing effect of DHA combined with DDP in HNE1/DDP cells (P<0.01). DHA enhances the growth-inhibitory and apoptosis-inducing effect of DDP on HNE1/DDP cells possibly by promoting accumulation of intracellular ROS.

Capturing subjective cognitive decline with a new combined index in low education patients with Parkinson's disease.

Subjective Cognitive Decline (SCD) refers to self-reported cognitive decline with normal global cognition. This study aimed to capture SCD among low educated patients with Parkinson's disease (PD) using a newly established indicator. We recruited 64 PD patients with low education levels (education ≤12 years) for the study. The presence of SCD was determined based on a Unified Parkinson's Disease Rating Scale Part I (1.1) score ≥ 1. Spearman analysis and multivariate binary logistic regression analyses were conducted to investigate factors associated with the PD-SCD group. The receiver operating characteristic (ROC) curve was used to evaluate the sensitivity and specificity of the new combined index. The prevalence of SCD in PD patients was 43.75%. Low educated PD-SCD patients had higher scores on the Non-Motor Symptoms Scale (NMSS), Parkinson's Fatigue Scale (PFS), Epworth Sleepiness Scale (ESS), as well as higher scores on the UPDRS-I and UPDRS-II, compared to PD patients without SCD. They also demonstrated poorer performance on the Montreal Cognitive Assessment (MoCA), particularly in the domains of executive abilities/attention/language. Multivariate binary regression confirmed the significant association between PD-SCD and MoCA-executive abilities/attention/language. Based on these findings, a combined index was established by summing the scores of MoCA-executive abilities, MoCA-attention, and MoCA-language. ROC analysis showed that the combined index could differentiate PD-SCD patients with an area under the curve (AUC) of 0.876. A score of 12 or less on the combined index had a sensitivity of 73.9% and a specificity of 76.2% for diagnosing PD-SCD. These low education patients with PD-SCD may exhibit potential PD-related pathological changes. It is important for clinicians to identify PD-SCD patients as early as possible. The newly combined index can help capture these low educated PD-SCD patients, with an AUC of 0.867, and is expected to assist clinicians in earlier identification and better management of PD patients.