Combination Index Research Articles

Preoperative peripheral inflammatory markers are predictors of postoperative central diabetes insipidus in craniopharyngioma patients: a retrospective study

BackgroundPostoperative central diabetes insipidus (CDI) is commonly observed in craniopharyngioma (CP) patients, and the inflammatory response plays an important role in CPs. We aimed to evaluate the predictive value of preoperative peripheral inflammatory markers and their combinations regarding CDI occurrence in CPs.MethodsThe clinical data including preoperative peripheral inflammatory markers of 208 CP patients who underwent surgical treatment were retrospectively collected and analyzed. The preoperative peripheral white blood cells (WBC), neutrophils, lymphocytes, monocytes, platelet (PLT), neutrophil-to-lymphocyte ratio (NLR), derived-NLR (dNLR), monocyte-to-lymphocyte ratio (MLR) and PLT-to-lymphocyte ratio (PLR) were assessed in total 208 CP patients and different age and surgical approach CP patient subgroups. Their predictive values were evaluated by the receiver operator characteristic curve analysis.ResultsPreoperative peripheral WBC, neutrophils, NLR, dNLR, MLR, and PLR were positively correlated and lymphocyte was negatively associated with postoperative CDI occurrence in CP patients, especially when WBC ≥ 6.66 × 109/L or lymphocyte ≤ 1.86 × 109/L. Meanwhile, multiple logistic regression analysis showed that WBC > 6.39 × 109/L in the > 18 yrs age patients, WBC > 6.88 × 109/L or lymphocytes ≤ 1.85 × 109/L in the transcranial approach patients were closely associated with the elevated incidence of postoperative CDI. Furthermore, the area under the curve obtained from the receiver operator characteristic curve analysis showed that the best predictors of inflammatory markers were the NLR in total CP patients, the MLR in the ≤ 18 yrs age group and the transsphenoidal group, the NLR in the > 18 yrs age group and the dNLR in the transcranial group. Notably, the combination index NLR + dNLR demonstrated the most valuable predictor in all groups.ConclusionsPreoperative peripheral inflammatory markers, especially WBC, lymphocytes and NLR + dNLR, are promising predictors of postoperative CDI in CPs.

Molecular interactions between metformin and D-limonene inhibit proliferation and promote apoptosis in breast and liver cancer cells

BackgroundCancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative.Hypothesis/PurposeIn this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics using the human liver and breast cancer cell lines HepG2 and MCF-7.Study designAn integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene.MethodsWe applied a systems-based analysis to introduce a drug–target–pathway network that clarifies different mechanisms of treatment. The combination treatment of metformin and D-limonene induced apoptosis in both cell lines compared with single drug treatments, as indicated by flow cytometric and gene expression analysis.ResultsThe mRNA expression of Bax and P53 genes were significantly upregulated while Bcl-2, iNOS, and Cox-2 were significantly downregulated in all treatment groups compared with normal cells. The percentages of late apoptotic HepG2 and MCF-7 cells were higher in all treatment groups, particularly in the combination treatment group. Calculations for the combination index (CI) revealed a synergistic effect between both drugs for HepG2 cells (CI = 0.14) and MCF-7 cells (CI = 0.22).ConclusionOur data show that metformin, D-limonene, and their combinations exerted significant antitumor effects on the cancer cell lines by inducing apoptosis and modulating the expression of apoptotic genes.

Genetic Variability for Root and Shoot Morpho-physiological Traits Contributing to Seedling Drought Stress Tolerance in Parental Lines of Pearl Millet

Drought stress severely affects plant growth and development leading to substantial reduction in yield and biomass accumulation. Forty one Pearl millet parental lines were subjected to seedling drought stress and morpho–physiological attributes along with individual drought stress response indices were recorded. Significant genetic variability existed for all the traits and genotype ICMX 1410698-SB-11-1-1-2(B) ranked first based on combined drought stress response index. Principal component analysis indicated that first two PCs explained 86.4% of variation under drought conditions. GCV ranged from 13.84 to 23.47% under drought indicating genetic basis for variability. D2 statistics grouped the genotypes into seven clusters. The maximum inter-cluster distance was reported between the clusters III and VII while clusters III & I ranked second under drought stress. These are potential drought tolerant parental lines for hybrid breeding. Root/Shoot ratio has been the major contributor for genetic divergence under both control and drought stress.

Abstract PO1-25-03: Programmed Death-Ligand 1 and Receptor Tyrosine Kinases in Breast Cancer

Abstract Programmed death-ligand 1 (PD-L1) is an immune checkpoint expressed in a wide range of malignancies leading to immune tolerance and cancer cell immune evasion. Receptor tyrosine kinases (RTKs) are key regulators of cancer cell proliferation, survival, and invasion. The Hepatocyte Growth Factor (HGF) receptor, MET, and the Epidermal Growth Factor Receptor (EGFR) are RTKs known for their tumorigenic potential in a variety of human malignancies. This study aimed to evaluate the effect of the small-molecule tyrosine kinase inhibitors (TKIs) on the expression of PD-L1 in breast cancer cells and the effect of their combination with inflammatory cytokines. The study also assessed the association of the expression of the tumoral PD-L1 mRNA with each of MET and EGFR mRNA expression and the tumor features and treatment outcomes in breast cancer patients using the METABRIC dataset publicly available from cBioPortal for Cancer Genomics. The TKIs crizotinib [a MET inhibitor] and gefitinib [an EGFR inhibitor] were used as a single treatment and in combination with the cytokines; tumor necrosis factor-α (TNF-α) or interferon-γ (INF-γ) in MCF7 and MDA-MB-231 breast cancer cells in vitro. The cells were also treated with the mitogens HGF and EGF. The viability of cells after the different treatments was determined using the MTT viability assay. The effects of the combination treatments were analyzed using combination index (CI) analysis. The expression level of PD-L1 in cancer cells was assessed using Western blotting. The combination treatment of crizotinib with TNF-α and INF-γ produced a synergistic growth inhibition of MCF7 and MDA-MB-231 cells with CI values of 0.31 and 0.55, respectively. Alternatively, combined crizotinib and TNF-α produced an antagonist effect on the viability of MCF7 cells (CI=2.49). The combination of gefitinib with TNF-α produced a synergistic growth inhibition in both MCF7 and MDA-MB-231 cells with CI values of 0.39 and 0.78, respectively. Alternatively, gefitinib resulted in an additive effect when combined with INF-γ (CI=0.99) and an antagonistic effect when combined with TNF-α (CI=2.68) in MCF7 and MDA-MB-231 cells, respectively. Treatment with HGF (50 and 100 ng/ml) increased the protein levels of PD-L1 while EGF (50 and 100 ng/ml) reduced its levels in MDA-MB-231 cells. Treatment with the TKIs crizotinib (0.1-4 µM) and gefitinib (1-40 µM) significantly reduced PD-L1 levels in MDA-MB-231 cells compared to vehicle-treated cells. The analysis of the METABRIC dataset revealed that the mRNA expression of PD-L1 was positively correlated with the mRNA expression of the EGFR gene (r= 0.081, p< 0.001) but not the MET gene. A double-high PD-L1/MET expression was significantly associated with younger age at diagnosis, high-grade carcinoma, greater tumor size, hormone receptor-negative status, HER2-positivity, and non-luminal disease compared to patients with a double-low PD-L1/MET expression. Similar findings were reported for patients with a double-high PD-L1/EGFR expression compared to patients with a double-low PD-L1/EGFR expression. Nevertheless, the mRNA expression of the PD-L1, MET, and EGFR genes as well as the co-expression of PD-L1/MET or PD-L1/EGFR genes did not affect the overall survival of breast cancer patients. Collectively, MET and EGFR TKIs could modulate the effects of inflammatory cytokines differently based on the type of cytokine and the molecular subtype of breast cancer cells. The expression of PD-L1 in breast cancer cells was upregulated by HGF while TKIs reduced its expression. The co-expression of the PD-L1 gene with MET and EGFR genes in breast cancer was associated with advanced disease presentation and worse prognosticators in patients. Together, TKIs that target MET or EGFR could be an appealing therapeutic target in breast cancer, particularly in younger patients with the non-luminal disease. Citation Format: Nehad Ayoub, Muhsen Al-Diabat, Moath Al-Shorman, Laith Al-Eitan. Programmed Death-Ligand 1 and Receptor Tyrosine Kinases in Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-25-03.

Abstract PO4-14-12: Predicting Response to HER2 Tyrosine Kinase Inhibitors and Antibody Drug Conjugates in HER2 Mutant Invasive Lobular Carcinoma Using CRISPR/Cas9 Knock-in Cell lines and Patient-derived Organoids

Abstract Background: Activating mutations in ERBB2 (HER2) are enriched >4-fold in invasive lobular carcinoma (ILC) with a rate of up to 19% in metastatic ILC. ILC is a histologic subtype of breast cancer characterized by loss of E-cadherin (CDH1), suggesting a potential interaction between loss of CDH1 and mutations in ERBB2. Recent trials have demonstrated promising single agent efficacy using the irreversible pan-HER tyrosine kinase inhibitor (TKI), neratinib, in patients with metastatic ERBB2 mutant ILC. However, further studies on combination therapies with other anticancer agents are needed to increase response rate and progression free survival for these patients. HER2-targeted antibody drug conjugates (ADC), particularly trastuzumab deruxtecan (T-DXd), have shown great promise in HER2-low metastatic breast cancer. Yet, their efficacy as a single agent or with HER2 TKIs in HER2-low and -mutant ILC is unknown and warrants investigation. Methods: Past studies analyzing ERBB2 mutations used overexpression of ERBB2 mutant cDNA, but this approach does not faithfully recapitulate the human disease. To model ERBB2 missense mutations as found in human breast cancers, we used CRISPR-based prime editing to generate a panel of isogenic ILC cell lines and patient-derived organoids (PDO) harboring ERBB2 wild-type (WT) or ERBB2 mutations (S310F or V777L). Both of these ERBB2 mutations have been previously characterized and are known to be activating mutations. We then used them to test neratinib and other TKIs with ADCs, including T-DXd and trastuzumab emtansine (T-DM1). Results: We successfully introduced single copy, heterozygous activating ERBB2 mutations (S310F or V777L) into two ERBB2-nonamplified metastatic ILC cell lines (MDA-MB-134 and SUM44PE) and one ERBB2-nonamplified metastatic ILC PDO (IPM-BO-053). Positive clones carrying the mutations were verified by Sanger sequencing and droplet digital PCR and subsequently pooled together. We further demonstrated that these mutations hyperactivated HER2 and downstream signaling pathways. ILC cell lines harboring these mutations showed enhanced sensitivity to HER2 TKIs but not ADCs. In contrary, ERBB2 mutations did not alter responses of IPM-BO-053 PDOs to HER2 TKIs but significantly increased responses to ADCs. Interestingly, we also observed accelerated HER2 protein degradation upon heregulin stimulation in ERBB2 mutant ILC PDOs, suggesting activating ERBB2 mutations may enhance ADC/HER2 complex internalization, degradation, and release of payloads. Lastly, we explored drug synergy between HER2 TKIs and ADCs in isogenic IPM-BO-053 PDOs and found that combination of T-DXd and neratinib or afatinib showed synergy (Combination Index < 1). Conclusions: Although the reason for the discrepancies in drug response between ILC cell lines and PDOs is not clear, we hypothesize that response in 3D PDOs might be more faithfully representing response seen in patients. We will generate additional ILC PDOs with knock-in ERBB2 mutations to validate our findings. Irreversible HER2 TKIs, such as neratinib and afatinib, showed synergy with T-DXd in ERBB2 mutant ILC PDOs. This holds important therapeutic implications in light of current treatment options for ILC. In future experiments, we will test if neratinib or afatinib increases endocytic uptake of T-DXd using a fluorescently labeled endocytosis tracker. Further, an in-depth molecular characterization of our isogenic cell lines and PDOs models is ongoing to gain mechanistic insights into how activating ERBB2 mutations increase HER2 internalization and degradation. Our in vitro studies provide a strong foundation for in vivo testing of neratinib or afatinib with T-DXd for ERBB2 mutant ILC. Citation Format: Jie Bin Liu, Danielle Tseng, Jagmohan Hooda, Daniel Brown, Adrian Lee, Steffi Oesterreich. Predicting Response to HER2 Tyrosine Kinase Inhibitors and Antibody Drug Conjugates in HER2 Mutant Invasive Lobular Carcinoma Using CRISPR/Cas9 Knock-in Cell lines and Patient-derived Organoids [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-12.

Enhancing Anticancer Potential: Investigating the Synergistic Impact of Doxorubicin and Curcumin on HeLa and Vero Cells in Vitro

(1) Background: Cervical cancer ranks as the fourth most prevalent cancer globally and in Asia, standing as the second most common in Indonesia. Despite its efficacy, doxorubicin chemotherapy is associated with significant side effects. To mitigate these adverse effects, a promising approach involves combining conventional drugs with curcumin. Both curcumin and doxorubicin have demonstrated cytotoxic effects against cervical cancer (HeLa). This research aims to determine the synergistic effect of the combination of doxorubicin and curcumin on HeLa and safety in normal cells (Vero cells). (2) Methods: This study adopted an experimental design utilizing doxorubicin and curcumin samples with HeLa and Vero cells. The investigation was initiated with cytotoxic and combination tests using the MTT method. The obtained results included IC50 values and combination indices, and the analysis involved a comparative examination of outcomes between HeLa and Vero cells. (3) Results: Cytotoxic tests revealed IC50 values for doxorubicin and curcumin on HeLa cells, measured in 2,17 ± 0,06 and 26,37 ± 2,00 µg/mL, and 17,32 ± 1,99 and 181,88 ± 30,48 µg/mL on Vero cells. Combination test results were represented by combination index .(4) Conclusions: The synergistic effect is observed at the combination of curcumin at a concentration of 9 μg/mL  and doxorubicin at a concentration of 0,125 μg/mL, resulting in a combination index of 0,50.  These findings suggest a promising avenue for enhancing the therapeutic potential of doxorubicin in cervical cancer treatment while minimizing adverse effects.

Chlorin Conjugates in Photodynamic Chemotherapy for Triple-Negative Breast Cancer

Breast cancer (BC) is the most common type of cancer in women and the number of new cases in the US is still increasing each year. Triple-negative breast cancer (TNBC), which comprises 15–20% of all breast cancer, is a heterogeneous disease and is considered the most aggressive type of breast cancer due to the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expressions for treatments. Traditional chemotherapy is the standard protocol for the treatment of TNBC. Toxicity and multidrug resistance are major drawbacks to chemotherapy. The lack of molecular targets and poor prognosis for TNBC prompts an urgent need to discover novel therapeutic strategies to improve clinical outcomes and quality of life for patients. Photodynamic therapy (PDT) or light treatment is a binary anti-cancer procedure that uses a photosensitizer (PS) that, upon light activation, produces cytotoxic oxygen species, destroying tumor cells. PDT is minimally invasive and can be repeated a few times without accumulating significant toxicity in the surrounding tissues. The primary goal of this study was to investigate in vitro photodynamic chemotherapy as a ternary combination therapy using our synthesized photosensitizers (chlorin–vitamin conjugates and their corresponding indium complexes) co-treated with known chemotherapeutic agents (taxol, doxorubicin, cisplatin, fluorouracil, or methotrexate) in the presence of light and determine the optimum conditions as a pre-clinical study of an enhanced tumoricidal effect against TNBC. Our results indicated that the best combination for an effective chemophotodynamic effect involves a ternary treatment of the indium complex of the chlorin–lipoic acid conjugate (InCLA) co-treated with taxol, which exhibited strong synergism at the nanomolar concentration when combined in the presence of visible light irradiation. Other ternary combinations containing taxol with a synergistic anti-tumor effect against TNBC include chlorin–pantothenic acid (CPA) and chlorin–biotin (CBTN) conjugates. Several other ternary combinations containing InCLA, CBTN, and CPA with either cisplatin, fluorouracil, or methotrexate were identified to generate a synergistic or additive effect. The light dosage remained constant, but the dosages of photosensitizers and chemotherapy drugs were varied to obtain the lowest possible concentration for the desired effect. The synergistic, additive or antagonistic effects of the drug combinations were determined based on the Chou–Talalay method, with InCLA–taxol having the lowest combination index (CI) of 0.25. Fluorescence and transmission electron microscopy (TEM) images provided evidence of apoptosis as the preferred mode of cell death. Our study demonstrated the combination of PDT and chemotherapy as a potential treatment option for TNBC patients.

Irisin combined index to diagnose central precocious puberty in girls: a cross-sectional study

BackgroundTo investigate serum irisin levels in girls at different developmental status and explore the significance of irisin for the diagnosis of central precocious puberty (CPP) in girls.MethodsIn this cross-sectional study 111 girls were enrolled, including 43 cases of CPP, 44 cases of peripheral precocious puberty (PPP) and 24 cases of girls with normal sexual development as controls. The data on age, weight and height, measured blood levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, and irisin were collected. Pelvic Doppler ultrasound was performed to evaluate uterine length, transverse diameter, anteroposterior diameter. The girls were divided into non-CPP group and CPP group according to gonadotropin-releasing hormone (GnRH) stimulation test.ResultsSerum irisin levels were significantly higher in CPP group than in PPP group and normal control group. Serum irisin level was positively correlated with basal LH level, basal FSH level, peak LH level, peak LH /FSH ratio, uterine volume, bone age, and bone age index. The area under the curve, cut-off value, sensitivity and specificity of serum irisin were 0.958, 219.255 pg/ml, 100% and 80.6%. The combined diagnosis of CPP in girls by serum irisin and serum basal LH combined with uterine volume had an AUC, sensitivity, and specificity of 0.994, 97.6%, and 100%, superior to that of the single index.ConclusionsSerum irisin level in girls with CPP is significantly increased. An irisin combined index could help the diagnosis of CPP in girls.

Integrated anti-vascular and immune-chemotherapy for colorectal carcinoma using a pH-responsive polymeric delivery system

Colorectal carcinoma (CRC) has become one of the most prevalent malignant tumors and exploring a potential therapeutic strategy with diminished drug-associated adverse effects to combat CRC is urgent. Herein, we designed a pH-responsive polymer to efficiently encapsulate a stimulator of interferon genes (STING) agonist (5,6- dimethylxanthenone-4-acetic acid, termed ASA404) and a common clinically used chemotherapeutic agent (1-hexylcarbamoyl-5-fluorouracil, termed HCFU). Investigations in vitro demonstrated that polymer encapsulation endowed the system with a pH-dependent disassembly behavior (pHt 6.37), which preferentially selected cancerous cells with a favorable dose reduction (dose reduction index (DRI) of HCFU was 4.09). Moreover, the growth of CRC in tumor-bearing mice was effectively suppressed, with tumor suppression rates up to 94.74%, and a combination index (CI) value of less than one (CI = 0.41 for CT26 cell lines), indicating a significant synergistic therapeutic effect. Histological analysis of the tumor micro-vessel density and enzyme-linked immunosorbent assay (ELISA) tests indicated that the system increased TNF-α and IFN-β levels in serum. Therefore, this research introduces a pH-responsive polymer-based theranostic platform with great potential for immune-chemotherapeutic and anti-vascular combination therapy of CRC.

In-stent restenosis estimation following carotid artery stenting: The robust predictive value of atherogenic index of plasma and other non-traditional lipid profiles.

Atherosclerotic carotid artery stenosis is a significant contributor to ischemic strokes, and carotid artery stenting (CAS) has emerged as a pivotal treatment option. However, in-stent restenosis (ISR) remains a concern, impacting the long-term patency of CAS. This study aimed to investigate the predictive value of non-traditional lipid profiles, including the atherogenic index of plasma (AIP), in ISR development. This retrospective single-center study involved patients presenting at a tertiary healthcare facility with severe carotid artery disease between 2016 and 2020 who subsequently underwent CAS. A total of 719 patients were included in the study. The study cohort was divided into ISR and non-ISR groups based on restenosis presence, confirmed by angiography following ultrasonographic follow-up assessments. Non-traditional lipid indices, such as AIP, atherogenic index (AI), and lipoprotein combined index (LCI), were evaluated along with traditional risk factors. During a 24-month follow-up, ISR occurred in 4.03% of patients. To determine the predictors of restenosis, three different models were constructed in multivariate analysis for non-traditional lipid indices. Multivariate analysis revealed AIP as a robust independent predictor of ISR (OR: 4.83 (CI 95 % 3.05-6.63, p < .001). Notably, AIP demonstrated superior predictive accuracy compared to AI and LCI, with a higher Area Under the Curve (AUC) of 0.971. Non-traditional lipid profiles, especially AIP, were found to be associated with an increased risk of ISR and may serve as predictors of ISR in patients undergoing CAS.

Impact of ESG Disclosure Score on Firm Value: Empirical Evidence From ESG Listed Company in Indonesia Stock Exchange

The trend in ESG investment was responded to by the Indonesia Stock Exchange, which released four ESG indexes. ESG indexes consist of the companies that have a better concern in ESG. Each ESG index has its positive or negative performance compared to the combined stock index. This research aims to determine the impact of ESG Disclosure on firm value. The sample of this research covers 55 companies that have been listed in the ESG index in the 2017–2021 period. The data is collected from the Bloomberg database and processed with a panel data regression model using Stata 17. The finding of this research is that there is a positive but no significant impact between the ESG Disclosure Score and firm value. This finding will contribute to the previous study about the disclosure information of non-financial information and its impact on the firm’s value in the market.

Prognostic value of combined psoas muscle mass and controlling nutritional status in patients with pancreatic ductal adenocarcinoma: a retrospective cohort study.

Pancreatic ductal carcinoma (PDAC) is an extremely poor prognostic disease. Even though multidisciplinary treatment for PDAC has developed, supportive therapies, such as nutritional therapy or perioperative rehabilitation to sustain and complete aggressive treatment, have not yet been well-established in PDAC. The aim of this study was to elucidate the relationship between the combined index using psoas muscle mass index (PMI) values and controlling nutritional status (CONUT) score and prognosis. We included 101 patients diagnosed with PDAC who underwent radical pancreatectomy with regional lymphadenectomy. The cut-off value was set at the first quartile (male, 6.3 cm2/m2; female 4.4 cm2/m2), and patients were classified into high PMI and low PMI groups. A CONUT score of 0 to 1 was classified as the normal nutritional status group, and 2 or more points as the malnutritional status group. Patients were further divided into three groups: high PMI and normal nutrition (good general condition group), low PMI and low nutrition (poor general condition group), and none of the above (moderate general condition group). We performed a prognostic analysis of overall survival (OS), stratified according to PMI values and CONUT scores. In the poor general condition group, the proportion of elderly people over 70 years of age was significantly higher than that in the other groups (p < 0.001). The poor general condition group had a significantly worse prognosis than the good and moderate general condition groups (p = 0.012 and p = 0.037). The 5-year survival rates were 10.9%, 22.3%, and 36.1% in the poor, moderate, and good general condition groups, respectively. In multivariate analysis, poor general condition, with both low PMI and malnutrition status, was an independent poor prognostic factor for postoperative OS (hazard ratio 2.161, p = 0.031). The combination of PMI and CONUT scores may be useful for predicting the prognosis of patients with PDAC after radical surgery.

Uncertain damage identification methods based on residual force vector under the influence of measurement noise

This paper proposes probabilistic and interval methods, grounded in the residual force vector technique, to quantify measurement uncertainties and effectively integrate them into the identification process. In the probabilistic method, the measurement noise is assumed to be a zero-mean normal distribution, while the stiffness parameters of structural elements are assumed to follow a normal distribution, represented by mean values and standard deviations. In the interval method, the measurement noise is modelled as interval numbers, and the interval perturbation technique is employed to derive interval bounds for elemental stiffness parameters. A two-step model updating strategy is implemented, separately addressing pristine and damaged structures, to mitigate modeling errors. By using the results of probabilistic damage identification, a novel damage index termed damage expectation capable of capturing both the extent and probability of damage is introduced. Furthermore, an interval damage index is introduced to quantify the damage based on interval damage identification results. The impact of noise levels on the statistical properties of uncertain damage indices is also investigated. Numerical examples reveal that deterministic indexes exhibit a monotonic increase in average values with increasing noise levels. Particularly, as noise levels rise, the standard deviation of the combination index initially surpasses the deterministic damage index but eventually diminishes. Through the proposed methodology, structural damage can be identified even in the presence of uncertainties. The efficacy of the proposed damage identification technique is also validated by experimental data.

Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line.

Levofloxacin (LVX) is among the fluoroquinolones antibiotics that has also been studied in vitro and in vivo for its anticancer effects. In this study, we used LVX and novel LVX thionated derivatives; compounds 2 and 3, to evaluate their antioxidant activity, aldehyde dehydrogenase (ALDH) enzymes activity inhibition, and anticancer activity. Combination treatments with doxorubicin (DOX) were investigated as well. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the antioxidant activity. The NADH fluorescence spectrophotometric activity assay was used to determine the ALDH inhibitory effects. Resazurin dye method was applied for cell viability assays. Molecular Operating Environment software was used for the molecular docking experiments. Compared to ascorbic acid, DPPH assay showed that compound 3 had the highest antioxidant activity among the tested compounds with approximately 35% scavenging activity. On ALDH enzymes, compound 3 showed a significant ALDH activity inhibition compared to compound 2 at 200 µM. The IC50 values for the tested compounds were approximately 100 µM on A549 cell line, a non-small cell lung cancer (NSCLC) cell line. However, significant enhancement of cytotoxicity and reduction of IC50 values were observed by combining DOX and synergism was achieved with LVX with a combination index value of 0.4. The molecular docking test showed a minimum binding energy with a good affinity for compound 3 towards ALDH enzymes. Thionated LVX derivatives, may be repurposed for NSCLC therapy in combination with DOX, taking into account the antioxidant activity, ALDH activity inhibition, and the molecular docking results of compound 3.

Can ESG Stocks Be a Safe Haven during Global Crises? Evidence from the COVID-19 Pandemic and the Russia-Ukraine War with Time-Frequency Wavelet Analysis

In times of intense economic variability and social turbulence worldwide, this paper aims to examine the existence of transient correlations and interdependencies between the most important MSCI ESG indices worldwide and the most important commodities’ index, economic uncertainty, natural gas, gold, and VIX, in a geographical and social context during two recent crises: the COVID-19 pandemic and the energy crisis due to the Ukrainian war. Using daily data from 3 January 2020 and extending until 23 August 2022, this study applies a wavelet coherence approach to analyze time series co-movements, in order to emphasize all possible combinations’ correlations and achieve more accurate outcomes at any given time and frequency band simultaneously and spontaneously. The results show robust coherence between different geographical areas, time, and frequency bands, indicating both positive and negative correlations with most of the combined ESG indices and other economic indicators. The study suggests that stock indices of leading ESG companies in North America and Europe constitute a safe investment haven during major upheavals and crises, providing a way for investors to manage risk and generate positive returns while contributing to economic sustainability.

Drought stress and its characteristics in China from 2001 to 2020 considering vegetation response and drought creep effect

Study areaChina Study focusDrought is an extremely serious disaster, typically characterized by slow onset, long duration, and cumulative impacts on multifaceted aspects. Developing a combined index that integrates its various characteristics can help deepen our understanding of drought evolution and provide accurate references for farmers to take drought mitigation measures. In this study, we proposed a Modified version of the Type Response-Aided Drought Index (MTRADI), simultaneously considering the various responses of different vegetation and the slow-varying properties of drought development. New hydrological insights for the regionsThe suitability of MTRADI was evaluated through correlation analysis with Palmer Drought Severity Index (PDSI) and qualitative comparison with Meteorological Drought Composite Index (MCI) maps. The MTRADI achieved significantly higher correlation coefficients with the PDSI, outperforming other combined drought indices. Based on the run theory, Mann-Kendall (MK) test, and Sen’s slope, drought characteristics and trends in mainland China during 2001–2020 were analyzed and the results show that drought frequency and severity are relatively higher in eastern Inner Mongolia, North China Plain, and Northeast of China. Furthermore, areas with significant wetting trends are observed to be mainly distributed near the Hu line, indicating that the water conditions in China are gradually improving at the transition zone of arid and humid climate regions.

Silicon Vacancies Diamond/Silk/PVA Hierarchical Physical Unclonable Functions for Multi-Level Encryption.

Physical unclonable functions (PUFs) have emerged as a promising encryption technology, utilizing intrinsic physical identifiers that offer enhanced security and tamper resistance. Multi-level PUFs boost system complexity, thereby improving system reliability and fault tolerance. However, crosstalk-free multi-level PUFs remain a persistent challenge. In this study, a hierarchical PUF system that harnesses the spontaneous phase separation of silk fibroin /PVA blend and the random distribution of silicon-vacancy diamonds within the blend is presented. The thermodynamic instability of phase separation and inherent unpredictability of diamond dispersion gives rise to intricate random patterns at two distinct scales, enabling time-efficient hierarchical authentication for cryptographic keys. These patterns are complementary yet independent, inherently resistant to replication and damage thus affording robust security and reliability to the proposed system. Furthermore, customized authentication algorithms are constructed: visual PUFs authentication utilizes neural network combined structural similarity index measure, while spectral PUFs authentication employs Hamming distance and cross-correlation bit operation. This hierarchical PUF system attains a high recognition rate without interscale crosstalk. Additionally, the coding capacity is exponentially enhanced using M-ary encoding to reinforce multi-level encryption. Hierarchical PUFs hold significant potential for immediate application, offering unprecedented data protection and cryptographic key authentication capabilities.

Design of Logistics Sorting Algorithm Based on Deep Learning and Sampling Evaluation

The advancement of automation and Internet of Things technology has bolstered the automation process in the logistics sector. To address the challenge of localizing and generating grasping positions for intelligent robots in logistics sorting, this study developed an algorithm for item localization. The algorithm relies on enhanced YOLOv3 target detection and instance segmentation technologies to design a position generation algorithm for the robotic arm, which was further refined using sampling evaluation. The experimental results showed that the research-improved target detection model performed better on different datasets in terms of F1 value, accuracy and Area under the Curve (AUC) metrics, with the highest values of 95.77%, 94.05%, and 91.30%, respectively, which was effective in localizing document-like parcels. Meanwhile, the instance segmentation algorithm with fused features took significantly lower values than other target detection algorithms in terms of average absolute value error and root mean square error. The accuracy rate and all-class average precision value were higher than other target detection models, and the fluctuation of the value taken was smaller, which was suitable for logistics parcel localization. The position generation model, based on a sampling evaluation, yielded significantly different values compared to other algorithms. The relative position error and absolute trajectory error indexes were all below 0.4. The combined indexes of grasping accuracy and error indicate the superior performance of the research-designed algorithms. They can effectively enhance the sorting effects of real logistics scenarios. This research contributes to the improvement of the automated sorting system through the use of visual robotic arm technology. Additionally, it encourages the development of logistics automation and the establishment of intelligent logistics factories.

Synergy and Antagonism in Antimalarial Crude Extract Combinations

Background Malaria accounts for around 4.8% of all recorded fatalities in Tanzania. Medicinal plants such as Caesalpinia bonducella, Azadirachta indica, and Annickia kummeriae have demonstrated promise in treating many diseases, including malaria. However, their combined activity against malaria has not been documented. Combination therapy using some medicinal plants with antimalarial activities may enhance safety and efficacy and reduce the evolution of parasite resistance. Objectives This study aimed to investigate antiplasmodium activities of different combinations of crude extracts from selected medicinal plants. Azadirachta indica leaves, Annickia kummeriae and Caesalpinia bonducella were extracted using dichloromethane (DCM).  Methods An in vivo acute toxicity study of both individual and combined crude extracts was carried out according to Chinedu et al., 2015. The in vivo antiplasmodial activity of individual and combined crude extracts was performed in mice inoculated with Plasmodium berghei (ANKA strain) using Peters’s 4-day suppressive test.  Results Individually, Caesalpinia bonducella crude extracts exhibited the highest in vivo antiplasmodial efficacy (91% parasite suppression) than A. kummeriae (73% parasite suppression) and A. indica (60% parasite suppression) at 800 mg/kg/day. The A. indica and A. summarize combinations and A. indica and C. bonducella demonstrated higher antiplasmodial activity (synergism-combination index 0.29 and 0.97, respectively) than their constituents. However, combining A. kummeriae and C. bonducella produced the lowest antiplasmodial activity (antagonism- combination index 40.67) than its extracts. The high antiplasmodial potencies (ED50) demonstrated by AiAk and AiCb are significant and critical results for traditional, complementary and alternative medicine.  Conclusion Therefore, these preliminary findings suggest that AiAk and AiCb are potential antiplasmodium herbal therapies.  Further research should be undertaken to investigate the antiplasmodium effect of AiAk and AiCb in humans.      

Fabrication of folic acid-modified bovine serum albumin cloaked dual-drug loaded hollow mesoporous silica nanoparticles for pH-responsive and targeted delivery of gastric cancer therapy

Combination therapy is a highly successful way to address the limitations of using a single treatment method and improve therapy's overall efficacy. In this study, we developed a unique hollow mesoporous silica nanoparticle (HMSN) coated with folic acid (FA)-modified bovine serum albumin (FA-BSA). This nanoparticle, referred to as HFB, was designed to target cancer cells and release dual therapeutic drugs, Indocyanine green (ICG) and Paclitaxel (PTX), in response to specific stimuli termed as HFB@IP. The BSA protein acts as a “gatekeeper” to prevent early drug releases and cargo leakage by detaching from BSA in reaction to GSH. The FA facilitates the targeted transport of the drug into cancer cells that express folate receptors (FR), enhancing the effectiveness of chemo-photodynamic treatment (PDT). The drug nanocarrier demonstrated in vitro pH/redox-triggered drug release from HFB@IP due to breaking the imine bonds between aldehyde-functionalized HMSN (CHO-HMSN) and FA-BSA with the disulfide bond inside BSA. In addition, various biological assessments, including cell uptake experiments, demonstrated that HFB@IP effectively targets SGC-7901 cells and induces apoptosis in vitro. Further, it exhibits remarkable efficiency in synergistically killing cancer cells through chemo-photodynamic therapy, as indicated by a combination index (CI) of 0.328. The results showed that combining HMSN with biodegradable stimuli-responsive BSA molecules could offer a promising approach for precise chemo-photodynamic therapy in treating gastric cancer, allowing for the controlled release of drugs as necessary.