Combination Index Research Articles

Malleatin A and B: New Premyrsine-Type Diterpenes from Euphorbia malleata with Cytotoxic Effects Against A2780 Wild and A2780 R-CIS Ovarian Cancer Cell Lines in Mono or Combination Treatment with Cisplatin

Background: This study focused on macrocyclic diterpenes derived from Euphorbia, particularly myrsinanes, and their potential in cytotoxic and combination treatments for resistant cancer cells. We examine premyrsinanes isolated from Euphorbia malleata and explore their cytotoxic properties. Methods: Euphorbia malleata was collected from Taragh-Roud, Natanz, Iran. The semi-polar chloroform/acetone extract was chromatographed and fractionated using a large silica column. Fractions containing diterpene resonances were selected based on 1H-NMR spectra and were further subjected to smaller silica or Sephadex columns, followed by a recycling HPLC system. The isolated compounds were identified through 1D and 2D-NMR experiments and mass spectrometry. The cytotoxicity of the isolated compounds was assessed using the MTT assay against A2780 wild and A2780 cisplatin-resistant (R-CIS) cells, both in mono and combination treatments with cisplatin. Results: Using a Waters 616 HPLC pump and a YMC prep silica column, we successfully isolated two new premyrsinane diterpenes (Malleatin A and Malleatin B) alongside two known compounds (beta-sitosterol and loliolide). Malleatin A exhibited cytotoxicity against A2780 wild and A2780 R-CIS cells, with an IC50 range of 50 - 65 μM in the MTT assay. While cisplatin demonstrated significant cytotoxic effects on the A2780 wild cell line, it was ineffective against the A2780 R-CIS cells due to their resistance. However, the combination therapy of Malleatin A and cisplatin exhibited a synergistic effect, significantly increasing the mortality rate of the resistant cells compared to monotherapy. The Combination Index (CI) of 0.58 indicates effective synergy, and the Dose Reduction Index (DRI) of 3.65 suggests a favorable reduction in the dosage of cisplatin needed, potentially reducing its associated side effects.

Triglyceride-glucose index and hsCRP-to-albumin ratio as predictors of major adverse cardiovascular events in STEMI patients with hypertension.

This study aimed to evaluate the association between the triglyceride-glucose (TyG) index and high-sensitivity C-reactive protein-to-albumin ratio (hsCAR) and the prognosis of patients with STEMI and hypertension. A total of 699 patients diagnosed with STEMI and hypertension were included in this study database. Compared to the low TyG index group (< 7.8), the high TyG index group (≥ 7.8) was associated with an increased risk of MACE (HR 2.09, 95% CI = 1.58-2.77; P < 0.001). Similarly, a higher hsCAR (≥ 0.15) was linked to an increased risk of MACE (HR 1.46, 95% CI = 1.12-1.90; P = 0.005). Subsequently, we categorized the population into four groups based on the defined cutoff points. Compared to the low TyG-low hsCAR subgroup, the other three subgroups demonstrated an elevated risk of MACE. Among patients treated with PCSK9 and SGLT2 inhibitors, the combined effect of the TyG index and hsCAR on MACE was attenuated. Finally, The combined TyG index and hsCAR model exhibited optimal performance (AUC = 0.71, 95% CI = 0.67-0.75; P < 0.001). This study demonstrates that the TyG index and hsCAR provide strong combined predictive power. The synergistic utilization offers a comprehensive approach to cardiovascular risk assessment.

Unlocking the mysteries of drought: integrating snowmelt dynamics into drought analysis at the Narayani River Basin, Nepal

AbstractDrought is among the most impactful natural hazards, undermining water security, agriculture, and livelihoods worldwide. Analysing droughts in large catchments presents several unique challenges, primarily related to the complexity of land surface characteristics and data availability limitations. Conducting drought analysis in the Narayani River Basin, which encompasses a vast area within the Himalayan region of Nepal, is extremely challenging but crucial for maintaining the river basin's social, economic, and environmental balance. In response, this study develops a new combined drought index (CDI), integrating satellite-based reanalysis parameters [i.e., Land Surface Temperature (LST), Snow Cover (SC), and Normalised Difference Vegetation Index (NDVI)] with a meteorological parameter [i.e., Standardised Precipitation (std_prec)]. The novel CDI was applied at the Narayani Basin to assess the droughts over the 2004–2013 period, and the results were independently evaluated using streamflow observations to validate the accuracy of the novel drought index. The principal component analysis (PCA) technique was used to determine the contribution of input parameters to the multivariate drought index. The PCA results show a strong positive correlation (0.78) between the CDI and standardised streamflow, indicating the effectiveness of the novel index in monitoring drought conditions. Accordingly, it can be concluded that surface water availability is interdependent on landscape characteristics, such as LST, SC, and NDVI, in addition to the effects of precipitation. Also, the novel CDI can identify the specific drought-affected areas in the Narayani River Basin, offering insights into its drought characteristics beyond traditional drought assessment techniques.

Molecular Interactions of the Plant Steroid Hormone Epibrassinolide on Human Drug-Sensitive and Drug-Resistant Small-Cell Lung Carcinoma Cells

Background: Small-cell lung cancer (SCLC) has a poor prognosis because it is often diagnosed after it has spread and develops multi-drug resistance. Epibrassinolide (EB) is a plant steroid hormone with widespread distribution and physiological effects. In plants, EB-activated gene expression occurs via a GSK-mediated signaling pathway, similar to Wnt-β-catenin signaling in animal cells that is elevated in cancer cells. Methods: This mechanistic parallel prompted investigations of the molecular interactions of EB on drug-sensitive (H69) and multi-drug-resistant (VPA) SCLC cells. Cellular and molecular investigations were performed. Results: Pharmacologic interactions between EB and the Wnt signaling inhibitors IGC-011 and PRI-724 were determined by the combination index method and showed antagonism, indicating that EB acts on the same pathway as these inhibitors. Following incubation of drug-sensitive and drug-resistant SCLC cells with EB, there was a reduction in β-catenin (e.g., 3.8 to 0.7 pg/µg protein), accompanied by a reduction in β-catenin promoter activity, measured by firefly luciferase-coupled promoter element transfection. Cellular β-catenin concentration is regulated by the active form of GSK3β. In Wnt signaling, active GSK3β is converted to inactive pGSK3β, thereby increasing the concentration of β-catenin. After incubation of SCLC cells with EB, there was a reduction in the inactive form (pGSK3β) and a relative increase in the active form (GSK3β). In vitro enzyme assays showed that EB did not inhibit purified GSK3β, but there was non-competitive inhibition when SCLC cell extracts were used as the source of enzyme. This indirect inhibition by EB indicates that it may act on the Wnt pathway by blocking the phosphorylation of GSK3β. The protein levels of three SCLC tumor markers, namely, NSE, CAV1, and MYCL1, were elevated in drug-resistant SCLC cells. EB incubation led to a significant reduction in the levels of the three markers. Two major effects of EB on SCLC cells are the promotion of apoptosis and the reversal of drug resistance. Transcriptional analyses showed that after exposure of SCLC cells to EB, there were increases in the expression of genes encoding apoptotic inducers (e.g., BAX and FAS) and effectors (e.g., CASP3) and reductions in the expression of genes encoding apoptosis inhibitors (e.g., survivin). PGP1 and MRP1, two membrane efflux pumps expressed in SCLC cells, were elevated in drug-resistant cells, but EB incubation did not affect these protein levels. Cellular assays of drug efflux by PGP1 showed an increase in drug-resistant cells, but EB did not alter efflux activity. Following exposure to human liver microsomes, EB was metabolized by NADPH-dependent oxidation and UDPG-dependent glucuronidation, as evidenced by the elimination of EB cytotoxicity against SCLC cells. Conclusions: Taken together, these data indicate that EB, a steroid hormone in plants consumed in the human diet, is pharmacologically active in drug-sensitive and drug-resistant SCLC cells in the Wnt signaling pathway, alters apoptotic gene expression, and is a substrate for microsomal modifications.

Repositioning of aripiprazole, an anti‑psychotic drug, to sensitize the chemotherapy of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited therapeutic options. Cisplatin is a primary chemotherapeutic agent utilized in combination with other drugs or radiotherapy for PDAC treatment. However, the severe side effects of cisplatin often necessitate discontinuation of therapy and drug resistance in tumor cells poses significant clinical challenges. Therefore, the development of effective therapeutic strategies is imperative. The present study investigated whether repositioning of the antipsychotic drug aripiprazole could sensitize the anticancer activity of cisplatin in pancreatic cancer at doses calculated by the combination index. The findings indicated that aripiprazole combined with cisplatin to suppress pancreatic cancer cell growth. Notably, the combination notably increased the expression of apoptosis markers, including cleaved caspase‑3, compared with cisplatin alone. Additionally, this combination effectively decreased XIAP and MCL‑1 expression via mitochondrial membrane potential change as revealed by JC‑1 assay, thereby inducing apoptosis. Furthermore, in fluid shear stress assay, the combination of aripiprazole and cisplatin notably inhibited cell adhesion and tumor spheroid formation. Mechanistically, phospho‑kinase array profiles showed that the enhanced anticancer efficacy of the combination treatment could be attributed to the inhibition of STAT3 signaling, which led to a significant reduction in tumor growth in a pancreatic cancer animal model. The results showed that the repositioning of aripiprazole inhibits cancer cell growth by blocking the STAT3 signaling pathway and effectively enhancing cisplatin‑induced apoptosis, thereby suggesting that the combination of aripiprazole and cisplatin may be a potent chemotherapeutic strategy for the treatment of pancreatic cancer.

Betulinic Acid Acts in Synergism with Imatinib Mesylate, Triggering Apoptosis in MDR Leukemia Cells.

Chronic myeloid leukemia (CML) is a myeloproliferative disease, characterized by the presence of the oncogene BCR-ABL. Imatinib mesylate (IMA) is the first-line treatment for CML, and some treatment resistance has been reported. Natural products are rich sources of bioactive compounds with biological effects, opening a possibility to alter cell susceptibility to drugs such as imatinib. Herein, we evaluated the interference of betulinic acid and ursolic acid in glycoprotein P (P-gp) activity and the possible synergistic effect when associated with IMA by the Chou-Talalay method. Ursolic acid presented an IC50 of 14.0 µM and 19.6 µM for K562 and Lucena 1, respectively, whilst betulinic acid presented an IC50 of 8.6 µM and 12.5 µM for these cell lines. Evaluation of the combination of terpenoids and imatinib mesylate revealed that ursolic acid or betulinic acid acts in synergism with IMA, as indicated by the combination indexes (CI<1). Analysis of annexin V labeling demonstrated that a combination of IMA with betulinic acid enhances the inhibition on cell proliferation via the apoptosis pathway, with caspases 3/7 activation after 24 hours of treatment and inhibition of the STAT5/survivin pathway, decreasing cell viability. The combination of natural products and IMA on a multidrug-resistant leukemia cell line is a promising strategy for CML treatment.

Hedgehog Pathway Is a Regulator of Stemness in HER2-Positive Trastuzumab-Resistant Breast Cancer

HER2 overexpression occurs in 20–30% of breast cancers and is associated with poor prognosis. Trastuzumab is a standard treatment for HER2-positive breast cancer; however, resistance develops in approximately 50% of patients within a year. The Hedgehog (Hh) signalling pathway, known for its role in maintaining stemness in various cancers, may contribute to trastuzumab resistance in HER2-positive breast cancer. This study aimed to investigate the role of Hedgehog signalling in maintaining stemness and contributing to trastuzumab resistance in HER2-positive breast cancer cell lines. Trastuzumab-resistant HER2-positive breast cancer cell lines, SKBR3 and HCC1954, were developed through continuous trastuzumab exposure. Cells were treated with GANT61 (Hh inhibitor, IC50:10 µM) or SAG21K (Hh activator, IC50:100 nM) for 24 h to evaluate the Hedgehog signalling response. Stemness marker expression (Nanog, Sox2, Bmi1, Oct4) was measured using qRT-PCR. The combination index (CI) of GANT61 with trastuzumab was calculated using CompuSyn software(version 1.0) to identify synergistic doses (CI &lt; 1). The synergistic concentrations’ impact on stemness markers was assessed. Data were analysed using two-way ANOVA and Tukey’s post hoc test (p &lt; 0.05). Trastuzumab-resistant cells exhibited increased Hedgehog signalling activity. Treatment with GANT61 significantly downregulated stemness marker expression, while SAG21K treatment led to their upregulation in both SKBR3-R and HCC1954-R cells. The combination of GANT61 and trastuzumab demonstrated a synergistic effect, markedly reducing the expression of stemness markers. These findings indicate that Hedgehog signalling plays a pivotal role in maintaining stemness in trastuzumab-resistant cells, and that the inhibition of this pathway may prevent tumour progression. Hedgehog signalling is crucial in regulating stemness in trastuzumab-resistant HER2-positive breast cancer. Targeting this pathway could overcome resistance and enhance trastuzumab efficacy. Further studies should explore the clinical potential of Hedgehog inhibitors in combination therapies.

Repurposing of sericin combined with dactolisib or vitamin D to combat non-small lung cancer cells through computational and biological investigations

This study aims to repurpose sericin in combating non-small lung cancer cells (A549 and H460) by combining it with dactolisib or vitamin D to reduce the dose of dactolisib and boost the anticancer effectiveness of dactolisib and vitamin D. Therefore, the binding affinities of individual and combined drugs were examined using in silico and protein-protein interaction studies, targeting NF-κB, Cyclin D1, p-AKT, and VEGF1 proteins. The findings manifested remarkable affinities for combinatorial drugs compared to individual compounds. To substantiate these findings, the combined IC50 for each combination (sericin + dactolisib and sericin + vitamin D) were determined, reporting 31.9 and 41.8 µg/ml, respectively, against A549 cells and 47.9 and 55.3 µg/ml, respectively, against H460 cells. Furthermore, combination indices were assessed to lower the doses of each drug. Interestingly, in vitro results exhibited marked diminutions in NF-κB, Cyclin D1, p-AKT, and VEGF1 after treatment with sericin + dactolisib and sericin + vitamin D compared to control lung cancer cells and those treated with a single drug. Moreover, A549 and H460 cells treated with both combinations demonstrated augmented caspase-3 levels, implying substantial apoptotic activity. Altogether, these results accentuated the prospective implementation of sericin in combination with dactolisib and vitamin D at low doses to preclude lung cancer cell proliferation.

Prediction of malnutrition using combined index of different nutritional parameters in elderly home care patients

&lt;b&gt;Aim: &lt;/b&gt;This descriptive and cross-sectional study was conducted to assess nutritional status in elderly home care patients using a combined index.&lt;br /&gt; &lt;b&gt;Methods: &lt;/b&gt;The combined index was calculated as a reference tool based on the results of five nutritional parameters (Mini Nutritional Assessment-Short Form [MNA-SF], Short Nutritional Assessment Questionnaire [SNAQ], body mass index, dietary energy, and dietary protein). If a patient was assessed as malnourished or undernourished in at least three of these five parameters, he/she was considered as “any stage of malnutrition” according to the combined index.&lt;br /&gt; &lt;b&gt;Results: &lt;/b&gt;The prevalence of malnutrition was 48.6%, 28.3%, and 47.4% according to the MNA-SF, SNAQ, and combined index, respectively. Dietary energy had the best sensitivity (92.7%) and negative predictive value (91.3%), while SNAQ had the highest specificity (100.0%) and positive predictive value (100.0%) according to the combined index. MNA-SF had the highest inter-rater agreement (kappa [κ]) with the combined index (κ =0.792).&lt;br /&gt; &lt;b&gt;Conclusions:&lt;/b&gt; The use of combined index based on both screening tools and other nutritional parameters could be effective in the diagnosis of malnutrition in elderly home care patients.

Study on Single and Combination of Galangal, Turmeric, and Ginger Ethanol Extracts as Anthelmintic

Soil-Transmitted Helminth infection (STH) such as ascariasis, has become one of the most persistent parasitic diseases in most developing countries, including Indonesia. Galangal, turmeric, and ginger plants are known to provide various of pharmacologically active substances which commonly used as antibacterial, aphrodisiac, and antiparasitic. This research was aimed to study the anthelmintic activity of ethanol extract of ginger, turmeric, galangal in single extract as well as their combination against Ascaris suum Goeze as a model. The anthelmintic activity was analyzed by determining the profile of time of paralysis (TOP), time of death (TOD), and the IC50­ of the inhibition activity from single extracts and extract combinations as well as the combination index (CI). The results showed that galangal, turmeric, and ginger ethanol extract have anthelmintic activity with IC50 7.66, 22, and 13,14 mg/mL, respectively. Meanwhile, the IC50 values for the extract combination of galangal with turmeric (KL), galangal with ginger (JL), and turmeric with ginger (JK) were 10.22; 3.92; and 34.93 mg/mL, respectively. The synergistic combination properties were shown by combination of galangal with turmeric extracts and galangal with ginger extracts with the combination index (CI) 0,67 and 0,38, respectively.

Associations between various anthropometric indices and hypertension and hyperlipidaemia: a cross-sectional study in China

BackgroundThis study aims to explore the association and determine the distinguished potential of anthropometric adiposity indices in screening for hypertension and hyperlipidaemia in the Chinese population.MethodsA recent nationwide cross-sectional study, called the Thyroid Disorders, Iodine State, and Diabetes Epidemiological Survey (TIDE 2015–2017), provided the newest data on the relationships between anthropometric adiposity indices and hypertension and hyperlipidaemia and included 65,231 subjects. The area under the curve (AUC) was used to assess the feasibility of using these indices to distinguish hypertension and hyperlipidaemia. After age stratification, a restricted cubic spline (RCS) fitted for generalized linear regression was used to visualize the relationships of the body mass index (BMI), waist circumference (WC), the waist-to-height ratio (WHtR), the body roundness index (BRI), and the “a body shape index” (ABSI) with hypertension and hyperlipidaemia.ResultsThe results showed that there were significant differences in the BMI, WC, the WHtR, the BRI, and the ABSI among the different age groups (P < 0.0001). After adjusting for sex, age, education, income, smoking status, urban or rural residence, and ethnicity in model, The WHtR and BRI had greater discriminatory power in identifying hypertension (AUC = 0.665, 95% confidence interval (CI) 0.660–0.671 for both), hypercholesterolaemia (AUC = 0.629, 95% CI 0.624–0.634 for both), and high low-density lipoprotein cholesterol (LDL-C; AUC = 0.659, 95% CI 0.653–0.664 for both) status in the overall population. When distinguishing hypertriglyceridaemia among the general population, the BMI (AUC = 0.711, 95% CI 0.706–0.716) and WC (AUC = 0.715, 95% CI 0.710–0.720) had greater discriminatory ability than the other anthropometric indices did. The BMI (AUC = 0.631, 95% CI 0.625–0.637) had the highest power for low high-density lipoprotein cholesterol (HDL-C) status in the general population.ConclusionsSeveral anthropometric indices show significant correlation with hypertension and hyperlipidaemia. The WHtR and BRI were better in distinguishing hypertension, hypercholesterolaemia and high LDL-C status, while the BMI was better in hypertriglyceridaemia and low HDL-C status. The use of combined indices, such as the BMI, WC, the WHtR and the BRI, can be included in an individual’s medical history and can be used as tools for cardiovascular health screening, which may yield superior results for public health.

Synergistic anticancer efficacy of polydatin and sorafenib against the MCF-7 breast cancer cell line via inhibiting of PI3K/AKT/mTOR pathway and reducing resistance to treatment

Polydatin (PD), a glucoside derivative of resveratrol, has been investigated for its potential to mitigate sorafenib (SOF) side effects and combat multidrug resistance in cancer treatment. The study evaluated its mechanism of action for inhibiting the protein kinase B/mTOR pathway in promoting breast cancer proliferation. The combined PD and SOF have synergistic effects with a combination index (CI) < 1 in the liver (HepG2) and breast (MCF-7) cancer cell lines. Molecular docking studies were conducted to analyze interactions of PD& SOF with protein kinases as well as apoptotic and multidrug resistance proteins, including AKT1, PI3K, mTOR, Apaf-1, and ABCB1 in MCF-7 cells. Experimental validation through real-time PCR confirmed. PD has a strong binding affinity, particularly with AKT1 (-56 kcal/mol) and ABCB1 (-27.16 kcal/mol), a gene associated with multidrug resistance. These interactions were linked to anti-proliferative anti-angiogenic effects and reduced resistance to treatment, demonstrating PD has potential therapeutic benefits. Furthermore, PD combined with SOF induced apoptosis, inhibited cell growth, and arrested MCF-7 cells in the sub-G1 phase with increased intracellular ROS. This was accompanied by reduced expression of AKT1 and ABCB1 genes, reinforcing the anticancer efficacy of PD/SOF combination therapy. In conclusion, the findings suggest that PD/SOF could serve as a promising anticancer treatment strategy, warranting further investigation for potential clinical applications and mechanistic studies in vivo.

The synergistic protective effects of paeoniflorin and β-ecdysterone against cardiac hypertrophy through suppressing oxidative stress and ferroptosis.

Exploring feasible drugs for the treatment of pathological cardiac hypertrophy has always been a focus of cardiovascular disease research. Paeoniflorin (PF) and β-Ecdysterone (β-Ecd) are the main active components of Paeonia lactiflora and Achyranthes bidentata, which can be used for the treatment of cardiovascular diseases, but their mechanism of action remains unclear. This study focused on oxidative stress and ferroptosis to investigate the protective effects of PF and β-Ecd on cardiac hypertrophy in primary cardiomyocytes and C57BL/6 mice, utilizing the integration of CCK8 assays, ros detection, molecular docking, real-time quantitative PCR, western blot, immunofluorescence, etc. The result of combination indices demonstrated a significant synergistic protective effect of PF and β-Ecd on cardiac hypertrophy. Furthermore, in vitro and in vivo studies further showed that the combination of PF and β-Ecd could improve the abnormalities of cell surface area, ANP, β-MHC, MDA, SOD, calcium ion, mitochondrial membrane potential and so on induced by cardiac hypertrophy through the inhibition effects of oxidative stress and iron metabolism, which might be closely related to the impact on the Nrf2/HO-1 and SLC7A11/GPX4 pathways. Altogether, this work revealed the mechanism of the combination of PF and β-Ecd in the treatment of cardiac hypertrophy from the aspects of suppressing oxidative stress and ferroptosis, aiming to promote effective treatment of the disease and the clinical application of PF and β-Ecd.

Anatomical Significance of the Patent Foramen Ovale by Real-Time 3D TEE in Cryptogenic Stroke and Migraine.

The transesophageal echocardiogram (TEE) is the standard imaging modality for confirming the presence or absence of patent foramen ovale. PFO is a flap valve depending on the pressure change between the left and right atrium, which can help determine whether to open. 3D-TEE was shown to optimize the visualization of PFO. There is a causal association between PFO and unexplained stroke. It seems that 3D-TEE can present a high-risk PFO morphological feature, which seems to show more than just being easier to open. In total, 134 consecutive patients with cryptogenic stroke or migraine who had suspected PFO and underwent c-TCD, TTE, and c-TEE were included in this study. TEE confirmed the PFO. The right-to-left shunt (RLS) grade of PFO at rest and abdominal compression Valsalva maneuver was detected by c-TEE. The long diameter of FO (1.74 ± 0.3vs. 1.60 ± 0.4, p = 0.039), the short diameter of FO (1.12 ± 0.3vs. 1.00 ± 0.3, p = 0.036), perimeter of FO (4.62 ± 0.7vs. 4.22 ± 1.0, p = 0.026), and area (1.80 ± 0.8vs. 1.35 ± 0.8, p = 0.05) of the FO were significantly larger in the larger RLS group. In group of CS, a larger proportion of Eustachian valve or a Chiari's network (14.3%vs. 3.5%, p = 0.036), a larger proportion of in the left funnelform (55.1%vs. 16.3%, p < 0.001), a longer length of the PFO tunnel (13.4 ± 4.4vs. 7.8 ± 2.5, p < 0.001), a lower IVC-PFO angle (16.4 ± 3.4vs. 20.3 ± 7.7, p = 0.001), a higher proportion of LA multiple exits of the tunnel (46.9%vs. 14.3%, p < 0.001). Multivariate regression analysis showed that male gender (HR: 4.026, 95% CI: 0.883-18.361, p = 0.072), age (HR: 1.076, 95% CI: 1.002-1.155, p = 0.045), the left funnelform (HR: 7.299, 95% CI: 1.585-33.618, p = 0.011), a longer length of the PFO tunnel (HR: 1.843, 95% CI: 1.404-2.418, p < 0.001) and multiple exits of the tunnel of LA (HR: 8.544, 95% CI: 1.595-45.754, p = 0.012) increased the risk of cerebral infarction. The cut-off value calculated by ROC for the diagnosis of high-risk PFO was that the length of the PFO tunnel was 12mm and the left funnelform combined with multiple exits of the left atrial (sensitivity was 92%, specificity was 90%). The area under the curve of the combined index versus PoPE score (0.932 vs. 0.736) relative to the RoPE score was statistically significant. TEE has shown outstanding advantages in displaying the specific morphological characteristics of PFO. The left funnelform, a longer length of the PFO tunnel, and multiple exits of the tunnel of LA are associated with an increasing risk of CS in anatomical PFO respect.

Pharmacological Interactions of Jadomycin B with Topoisomerase Poisons in MDA-MB-231 Human Breast Cancer Cells.

Jadomycin B, a natural product isolated from Streptomyces venezuelae, exerts an anti-cancer effect on human triple negative breast cancer cells in vitro and has anti-tumoral effects in vivo in animal models of breast cancer. One proposed mechanism for this anti-cancer effect is through interaction with topoisomerase 2 (TOP2). Based on the previously described interactions between jadomycin B and TOP2 we hypothesized that jadomycin B will act additively with TOP2 poisons and produce a similar functional outcome in eliciting cell cycle arrest. Combined treatments of jadomycin B and the TOP2 poisons doxorubicin or mitoxantrone produced moderately synergistic to additive cytotoxicity (combination index values ranging from 0.72-0.94) in MDA-MB-231 cells. In comparison, combined mitoxantrone and doxorubicin produced additive cytotoxicity (combination index values 0.96-1.11). Jadomycin B combined with the proteosome inhibitor MG132 had additive cytotoxicity (combination index values 0.76-1.18). In contrast, mitoxantrone or doxorubicin cytotoxicity was antagonized by MG132 (combination index values 1.21-2.31). Jadomycin B treatment arrested cells in S-phase (P = 0.0024) as opposed to mitoxantrone which caused G2/M-phase arrest (P < 0.0001). In conclusion, jadomycin B interacts differently than known TOP2 poisons in combination, supporting a novel pharmacological mechanism(s) of action for jadomycin B cytotoxicity.

Synergistic Combination of Quercetin and Mafosfamide in Treatment of Bladder Cancer Cells.

Bladder cancer, which has a rising incidence, is the 10th most common cancer. The transitional cell carcinoma histotype is aggressive and often current therapies are ineffective. We investigated the anti-proliferative effect of quercetin, a natural flavonoid, in combination with the alkylating agent mafosfamide (MFA) on two human bladder cancer cell lines, namely RT112 and J82, representing the progression from low-grade to high-grade tumors, respectively. In both cell types, the combined treatment led to a synergic reduction in cell viability confirmed by a combination index of less than one, though different biological responses were noted. In J82 cells, MFA alone and, to a lesser extent, with quercetin caused cell cycle arrest in the G2/M phase, but only the combined treatment triggered apoptotic cell death. In contrast, in RT112 cells, quercetin induced autophagy, evidenced by the autophagosome formation and the increase in LC-3 lipidation. Interestingly, the synergistic effect was observed only when cells were pre-treated with MFA for 24 h before adding quercetin, not in the reverse order. This suggests that quercetin may help overcome MFA resistance to apoptosis. Although further studies are needed, investigating the combined effects of quercetin and MFA could help elucidate the mechanisms of drug resistance in bladder cancer treatment.

Agricultural drought monitoring and early warning at the regional scale using a remote sensing-based combined index.

Early detection of agricultural drought can alert farmers and authorities, enhancing the resilience of the food sector. A framework is proposed for developing a novel regional agricultural drought index (RegCDI) by combining remotely sensed vegetation health, soil moisture and crop water stress via a transparent Shannon's entropy weighting method. The framework consists of the selection of suitable datasets based on their regional performance, the aggregation of selected drought indicators, the validation of the combined index against crop yield, and the testing of predictive capabilities. The creation and performance of RegCDI are demonstrated for the drought prone Indian state of Odisha. MODIS surface reflectance is selected for crop water stress and GLDAS-2 for assessing soil moisture deficits and vegetation health. Three selected indicators (SMCI, TCI, and SIWSI-1) are combined into RegCDI for Odisha. The performance of RegCDI is evaluated (a) against other popular drought indices and (b) by comparing with seasonal crop yields. RegCDI is used to identify drought hotspots based on drought severity, duration, and propensity over the study area. A reforecast evaluation of RegCDI (up to three months ahead) showed that the indicators based on soil moisture deficit and crop water stress could predict drought conditions up to two months ahead with no less than 80% accuracy. This demonstrated the potential of the RegCDI framework and its component indicators for early warning of drought in Odisha.

Human-forest proximity and the risk infectious diseases in a changing world

Abstract Background Emerging Infectious Diseases (EIDs) pose a significant threat to global human health; they can lead to epidemics and pandemics with severe repercussions on human life, economic performance, and societal well-being. Despite the recognized negative impact of the EIDs, current research lacks a comprehensive global framework to assess the significance and interaction of various environmental and anthropogenic factors driving emergence of these diseases. Methods In this study, we examine both environmental and anthropogenic factors and their relation to the emergence of EIDs, focusing on historical trends from 1975 to 2020. We focus on 10 diseases with pandemic and epidemic potential. Spatial data on outbreaks in humans and animals from 1975 to 2020 were retrieved from the GIDEON database. Using Bayesian statistical models, we pinpoint regions at increased risk, and we focus on a new indicator based on the human-forest proximity. Conclusions Our results show that human-forest proximity together with biodiversity loss, and high population density increase the likelihood of diseases being transmitted from animals to humans, influencing where outbreaks occur among human populations. Lastly, we introduce a country vulnerability index that combines our risk assessment with the IHRC3 indicator from the WHO, which gauges a country’s capability to handle zoonotic diseases. These combined indices help us to assess each country’s ability to respond to an outbreak. The study also addresses data limitations and proposes directions for future research, emphasizing the importance of our findings in shaping public health policies and decision-making. Key messages • Anthropogenic drivers shape the distribution of outbreaks in human populations. • Human-forest proximity exacerbates the likelihood of Emerging Infectious Disease.

Prognostic value of combined myocardial performance index in patients with acute ST-elevation myocardial infarction

Abstract Background Myocardial performance index (MPI) also known as Tei index is a unique echocardiographic parameter which can estimate both systolic and diastolic performances of left and right ventricles. We previously suggested the echocardiographic parameter combined MPI (CMPI) as a new predictor of the prognosis of acute ST-elevation myocardial infarction (STEMI). The CMPI is the sum of left ventricular (LV) MPI and right ventricular (RV) MPI (CMPI = LV MPI + RV MPI). We supposed that CMPI might be a better predictor in STEMI, because it reflects both ventricular systolic and diastolic functions. Objectives The purpose of this study is to assess the prognostic value of a new echocardiographic parameter CMPI in STEMI patients calculated in acute phase. Methods 240 STEMI patients who underwent primary PCI have been included in the study. Echocardiography (EchoCG) was performed, and LV MPI and RV MPI were assessed within 24 hours after the symptom onset, prior to primary PCI. The MPI was calculated as the sum of isovolumic contraction time (ICT) and isovolumic relaxation time (IRT), divided by the ejection time (ET): MPI = (ICT + IRP) / ET. 50 % of the patients had anterior STEMI. 30 patients (12.5%) had concomitant RV myocardial infarction (MI). Patients were divided into two groups: Group 1 – CMPI &amp;gt; 0.9 (110 patients), Group 2 – CMPI ≤ 0.9 (130 patients). Baseline demographic and clinical characteristics were similar in both groups. Also, there were no differences in LV MI localization and concomitant RV MI between the groups. Primary endpoints were in-hospital and the one-year cardiovascular mortality rates. The secondary endpoint was the one-year heart failure hospitalization rate. Results In Group 1 the in-hospital mortality rate was 9.1%, and 3.1% in Group 2 (p = 0.0489). One-year cardiovascular mortality rate was 12.7% in and 5.4%, respectively (p = 0.0465). One-year heart failure hospitalization was also significantly lower in Group 2 (22.7% vs. 12.3%, p = 0.0332). Conclusion CMPI can be offered as a new predictor for the in-hospital and one-year cardiovascular mortality and one-year heart failure hospitalization rate in patients with acute STEMI.

Three dimensional biatrial expansion index as an independent predictor of outcome in dilated cardiomyopathy

Abstract Background Left atrial expansion index (LAEI) is a marker of left ventricular (LV) diastolic dysfunction and an outcome predictor in heart failure (HF). However, the role of the right atrial expansion index (RAEI) in the setting of left-sided HF is incompletely understood. Purpose We sought to evaluate the left, right and combined bi-atrial expansion index (BAEI) with three-dimensional (3D) echocardiography in a cohort of patients with dilated cardiomyopathy (DCM) and to assess their prognostic role. Methods We enrolled 121 consecutive patients (mean age 59±14 years, 74% men) with DCM in sinus rhythm, who underwent 3D echocardiography and were prospectively followed for 19±11 months for an endpoint of death, nonfatal cardiac arrest and HF hospitalization. As previously described, for the left atrium (LA), LAEI was measured as (3D LA Vmax – 3D LA Vmin) x 100/3D LA Vmin, where Vmax was the maximal end-systolic atrial volume and Vmin was the minimal end-diastolic atrial volume. For the right atrium (RA), RAEI was calculated as (3D RA Vmax – 3D RA Vmin) x 100/3D RA Vmin. BAEI was defined as the sum of LAEI and RAEI. Results 55 patients (46%) reached the endpoint: there were 27 deaths, 5 nonfatal cardiac arrests and 23 readmissions for HF. Patients with adverse outcome had lower LAEI (52±25 vs. 63±36, p=0.047), lower RAEI (57±29 vs. 70±32, p=0.02), lower BAEI (108±46 vs. 133±55, p=0.008). In univariate Cox regression, all three expansion indices were predictors of adverse events: HR=3.23 [95% CI, 1.45-7.20], p=0.004 for LAEI, HR=2.12 [95% CI, 1.24-3.61], p=0.006 for RAEI, HR=3.99 [95% CI, 1.70-9.36], p=0.001 for BAEI. We constructed a multivariable model with well-established event predictors in DCM and one expansion index at a time. After adjustment for age, left ventricular ejection fraction, mitral regurgitation severity and pulmonary artery systolic pressure, all three expansion indices remained independent predictors of the composite endpoint: HR=2.75 [95% CI, 1.18-6.38], p=0.02 for LAEI, HR=1.86 [95% CI, 1.04-3.31], p=0.04 for RAEI, HR=3.53 [95% CI, 1.46-8.51], p=0.005 for BAEI. BAEI yielded the highest incremental prognostic power (likelihood ratio chi2 test=14, p=0.03) on top of the baseline model consisting of age, left ventricular ejection fraction, mitral regurgitation severity and pulmonary artery systolic pressure (likelihood ratio chi2 test=9). Conclusion In DCM, 3D atrial expansion indices are significantly lower in patients with major adverse events, reflecting a more impaired atrial reservoir dysfunction. Both LAEI, RAEI and BAEI were independent outcome predictors in patients with DCM. Combining the left and right atrial expansion indices might improve risk stratification, since BAEI had the highest predictive value after adjustment for confounders.