Combined Treatment Research Articles

Bibliometric Analysis to Improve Combined Treatment Strategies for Glioblastoma in America

Introduction: Bibliometric analysis quantitatively examines scientific literature to extract insights. This article has conducted such analysis on glioblastoma multiforme (GBM) treatment articles. GBM, a prevalent brain tumor, is typically treated with surgery, radiation, and chemotherapy. Objectives: The article aimed to bibliometrically analyze articles discussing combined GBM treatment to identify impactful research areas and encourage collaboration. Materials and Methods: The study encompassed a comprehensive search in the Scopus database, spanning articles published from 1974 to 2022. Inclusion criteria encompassed research conducted in the Americas, both clinical and experimental. A total of 772 articles were collected and categorized based on their primary focus on combined treatment approaches. Results: Clinical studies constituted 52% of articles, suggesting a slight dominance. The analysis unveiled key research moments, including a 1998 focus shift and a pivotal 2005 study on temozolomide- radiation combination. Top journals, trends, and authors were identified, with the USA leading in contributions. Discussions: Despite high brain tumor incidence, research distribution discrepancy is concerning. Regional epidemiological studies have been endorsed. The dominance of US and German authors in GBM collaboration has raised equity issues due to budget and GDP disparities limiting Latin American representation. Conclusion: GBM research in the region is dominated by the USA, while contributions from Latin American countries remain limited. The absence of comprehensive epidemiological studies on GBM in Latin America is concerning, considering the evident impact of the disease in the region. This underscores the urgent need for increased research participation and collaboration to advance the understanding and treatment of GBM across Latin American nations.

Combined treatment with Aronia berry extract and oligomeric proanthocyanidins exhibit a synergistic anticancer efficacy through LMNB1-AKT signaling pathways in colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent and highly recurrent malignancies worldwide and currently ranks as the second leading cause of cancer-related deaths. The high degree of morbidity and mortality associated with CRC is primarily attributed to the limited effectiveness of current therapeutic approaches and the emergence of chemoresistance to standard treatment modalities. Recent research indicates that several natural products, including Aronia berry extracts (ABE) and oligomeric proanthocyanidins (OPCs), might offer a safe, cost-effective, and multitargeted adjunctive role to cancer treatment. Herein, we hypothesized a combined treatment with ABE and OPCs could synergistically modulate multiple oncogenic pathways in CRC, thereby enhancing their anticancer activity. We initially conducted a series of in vitro experiments to assess the synergistic anticancer effects of ABE and OPCs on CRC cell lines. We demonstrate that these two compounds exhibited a superior synergistic anticancer potential versus individual treatments in enhancing the ability to inhibit cell viability, suppress colony formation, and induce apoptosis (p < 0.05). Consistent with our in vitro findings, we validated this combinatorial anticancer effect in tumor-derived 3D organoids (PDOs; p < 0.01). Using genome-wide transcriptomic profiling, we identified that a specific gene, LMNB1, associated with the cell apoptosis pathway, was found to play a crucial role in exhibiting anticancer effects with these two products. Furthermore, the combined treatment of ABE and OPCs significantly impacted the expression of key proteins involved in apoptosis, including suppressed expression levels of LMNB1 in CRC cell lines (p < 0.05), which resulted in inhibiting downstream AKT phosphorylation. In conclusion, our study provides novel evidence of the synergistic anticancer effects of ABE and OPCs in CRC cells, partially mediated through the regulation of apoptosis and the oncogene LMNB1 within the AKT signaling pathway. These findings have the potential to better appreciate the anticancer potential of natural products in CRC and help improve treatment outcomes in this malignancy.

Five principles and protocols for the clinician based on the 2021 ERS and BTS statements for treating sarcoidosis.

The European Respiratory Society (ERS) and the British Thoracic Society (BTS) have recently published their statements on the treatment of sarcoidosis. There are five key questions in sarcoidosis treatment that need to be addressed: when to treat, how to initiate treatment, how long to treat, when and how to change treatment, and how to treat relapses. Herein, we describe the principles and protocols to answer these questions based on the ERS and BTS statements and other expert reviews. Pulmonary or extrapulmonary sarcoidosis should be treated with anti-inflammatory therapy if it significantly impairs the quality of life (QoL), causes significant organ dysfunction, or threatens to cause organ damage, disability, or death. If treatment is initiated for improving the QoL alone, low-dose (10 mg/day) prednisone is a good initial treatment that can be tapered and stopped over 3 months. Disease that causes significant organ dysfunction needs to be treated with medium-dose glucocorticoids (initial daily dose, 20 mg of prednisone equivalent) tapered over a minimum duration of 6 months. Worsening of disease while tapering treatment indicates that longer (9-24 months) treatment may be necessary. If a daily prednisone dose of >10 mg is required for >6 months to maintain remission, it is best to use a second-line drug such as methotrexate or azathioprine. Anti-tumor necrosis factor agents, such as infliximab or adalimumab, may be used to treat inflammatory disease that persists on combination treatment with glucocorticoids and a second-line agent.

Drying of avocado peels using carbonation-ultrasonication as pretreatment: energy consumption, antioxidant capacity and rheological properties

Fruit processing by-products, especially peels are underused and mostly discarded as waste. The aim of this study was to assess the effect of ultrasonication (US) combined with carbonation (CUS) on the convective drying process of avocado peels at different temperatures, adding value to this waste. For this, the avocado peels were treated with dry ice for 15 min and subjected to US (400W/10 min, 30°C) before convective air drying (50-70°C). The energy consumption, antioxidant capacity, water adsorption isotherms, rehydration rate, and dynamic rheology of dried avocado peels pretreated by CUS were compared with a control process (without pretreatment) and only US pretreatment. The combined treatment (CUS70) resulted in a 2.6-fold reduction in drying time and a 2.3-fold decrease in energy consumption, with CO2 preserving bioactive compounds and antioxidant capacity after the drying process. Differences were also observed in the rehydration capacity of the samples (CUS), with an increased water absorption capacity, along with a reduction in the viscoelastic properties of the peels. The results present new perspectives for the application of CUS in the food industry, paving the way for the development of creative, innovative, and simple approaches for the management and recycling of agri-food waste, with the potential to extend this knowledge to new food matrices.

Antioxidant anthocyanin synergistic immune enhancer nanopeptide C-I20 remarkably enhances the protective effect of largemouth bass against largemouth bass ranavirus

Largemouth bass ranavirus (LMBV) infection results in huge economic losses in largemouth bass (Micropterus salmoides) industry. Nanopeptide C-I20 and anthocyanins have a positive effect on promoting immune responses and antioxidant mechanisms in several aquatic organisms, and are therefore used to inhibit LMBV infection. In this study, we developed an LMBV immersion challenge model using three different viral concentrations (1×104 copies/mL, 1×105 copies/mL, and 1×106 copies/mL) to infect largemouth bass, and LMBV-MCP mRNA expression was detected in infected fish. Following infection, the fish exhibited severe external ulceration, redness swelling, and darkening of the skin. Histopathological examination revealed significant necrosis and inflammation in muscle tissue, epithelial cell shedding in renal tubules, macrophage aggregation centers and cellular vacuolization in spleen and head kidney, and cellular hypertrophy in liver. To mitigate LMBV infection, we explored the protective effects of a combined treatment strategy involving C-I20 and anthocyanin. Overall, the combination of anthocyanin and C-I20 demonstrated the highest protective efficacy, significantly reducing viral loads in muscle, liver, spleen, and head kidney. Moreover, this treatment regimen enhanced antioxidant enzyme activities (T-AOC, TSOD, GSH-Px, CAT) and modulated important immune genes (IL-1, IL-8, TNF-α, IL-10, Mx, and IgM) expression. In conclusion, the synergistic application of anthocyanin and C-I20 demonstrates significant efficacy in mitigating LMBV infection. This research introduces a novel and promising approach to managing infectious diseases in aquaculture settings.

Cholestatic insult triggers alcohol-associated hepatitis in mice.

Alcohol-associated hepatitis (AH) is a severe, potentially life-threatening form of alcohol-associated liver disease with limited therapeutic options. Existing evidence shows that biliary dysfunction and cholestasis are common in patients with AH and are associated with poorer prognosis. However, the role of cholestasis in the development of AH is largely unknown. We aimed to examine the hypothesis that cholestasis can be an important etiology factor for AH. To study the interaction of cholestasis and alcohol, chronically ethanol (EtOH)-fed mice were challenged with a subtoxic dose of α-naphthylisothiocyanate (ANIT), a well-studied intrahepatic cholestasis inducer. Liver injury was measured by biochemical and histological methods. RNAseq was performed to determine hepatic transcriptomic changes. The impact of inflammation was assessed using an anti-LY6G antibody to deplete the neutrophils and DNase I to degrade neutrophil extracellular traps. ANIT synergistically enhanced liver injury following a 4-week EtOH feeding with typical features of AH, including increased serum levels of ALT, AST, and total bile acids, cholestasis, necrosis, neutrophil infiltration, and accumulation of neutrophil extracellular traps. RNAseq revealed multiple genes uniquely altered in the livers of EtOH/ANIT-treated mice. Analysis of differentially expressed genes suggested an enrichment of genes related to inflammatory response. Anti-LY6G antibody or DNase I treatment significantly inhibited liver damage in EtOH/ANIT-treated mice. Our results support the hypothesis that cholestasis can be a critical contributor to the pathogenesis of AH. A combined treatment of EtOH and ANIT in mice presents biochemical, histological, and molecular features similar to those found in patients with AH, suggesting that this treatment scheme can be a useful model for studying Alcohol-associated Cholestasis and Hepatitis (AlChoHep).

Early Surgery and High Dose Steroids in Treating Patients with Indirect Traumatic Optic Neuropathy: A Meta-Analysis and Systematic Review

Introduction: Optic nerve injury is a devastating cause of permanent visual loss after blunt or penetrating injury occurring in up to 7% of head trauma cases. No single treatment strategy and timing of intervention has proved optimal. Timely and appropriate management is key to improving visual outcomes. We compared whether immediate surgical decompression or steroids would lead to improvement of visual outcomes in individuals with indirect traumatic optic neuropathy. Methods: We searched from several online databases and included studies of patients with direct Optic nerve injury, those who received combined treatment with surgery and steroids, and those with delayed initiation of treatment were excluded. Results: The final search yielded eleven eligible studies. Both interventions showed similar results in improvement of visual function (RR 2.35, 95% CI 0.87 to 6.34, p=0.09, I2 0%). Both early and late intervention also showed similar results in improvement of visual function (RR 1.72, 95% CI 0.89 to 3.35, p=0.11, I2 61%). Among patients who underwent early surgical decompression, the rate of visual acuity improvement was 73% with those who underwent transcranial surgery and 69% with those who underwent endoscopic surgery. Conclusion: This study shows that immediate surgical decompression and early high dose steroid administration are equally effective in improving visual function. Patients with no light perception (NLP) and light perception (LP) pre treatment resulted to better visual improvement with steroids while those with counting fingers (CF) and more than CF pre treatment, resulted to better visual improvement with surgical decompression.

Determination of mutagenic effectiveness and efficiency of gamma rays and EMS in Coriander

Coriander is a dual purpose vegetable used as leaf as well as a spice, along with medicinal properties. Owing to its compound umbel and difficulty in crossing programme, mutation breeding is the available source to create variability. Mutagenesis is a well-recognized tool to expand genetic variability. The present investigation involves mutagenesis in coriander cv. Sindhu with physical (gamma rays) and chemical mutagens (EMS) and their combinations. The mutation frequency, mutagenic effectiveness and mutagenic efficiency were calculated for the gamma rays, EMS and their combination doses. In gamma rays, a drop in mutagenic effectiveness was observed at 10Kr followed by increase with higher concentration. Mutagenic effectiveness due to gamma rays, ranged from 6.5 to 8.51 due to EMS ranged from 42.09 to 49.55 and due to combination treatments ranged from 12.17 to 18.80 (5kr+0.2% EMS) in coriander variety, Sindhu. The mutagenic efficiency based on survival ranged from 1.78 to 4.0, injury ranged from 3.83 to 8.2, sterility ranged from 2.37 to 5.18 indicating differential response to different mutagens. The combination of gamma rays and EMS at lower and moderate doses expressed its worth to create higher mutation frequency by manifesting higher efficiency than the individual mutagens single-handed.

Gefitinib Reverses PD-L1-Mediated Immunosuppression Induced by long-term Glutamine blockade in Bladder Cancer.

Glutamine is a major energy source for tumor cells and blocking glutamine metabolism is being investigated as a promising strategy for cancer therapy. However, the antitumor effect of glutamine blockade in bladder cancer remains unclear, necessitating further investigation. Here, we demonstrated that glutamine metabolism was involved in the malignant progression of bladder cancer. Treatment with the glutamine antagonist 6-Diazo-5-oxo-L-norleucine (DON) inhibited the growth of bladder cancer cells in vitro in several ways. In addition, we observed inhibition of tumor growth in bladder cancer-bearing mice using JHU083, a prodrug that was designed to prevent DON-induced toxicity. However, the antitumor immune effect of T cells changed from activation to inhibition as the administrated time extended. We found that both in vitro treatment with DON and in vivo prolonged administration of JHU083 led to the upregulation of PD-L1 in bladder cancer cells. Mechanistically, glutamine blockade up-regulated PD-L1 expression in bladder cancer cells by accumulating ROS, subsequently activating the EGFR/ERK/C-Jun signaling pathway. Combination treatment of JHU083 and gefitinib reversed the up-regulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade, resulting in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings show promise for glutamine metabolism targeting as a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib.

A combined debridement, antibiotics, and implant retention (DAIR) procedure with flap coverage for acute soft tissue defects following total knee arthroplasty: a retrospective study

Abstract. Acute soft tissue defects, such as persistent drainage, wound dehiscence, or necrosis, following total knee arthroplasty (TKA) can lead to the devastating complication of deep infection. Typically, when a medium-sized defect is present, a gastrocnemius flap is widely employed for soft tissue reconstruction due to its low morbidity and favourable functional outcomes. When facing this situation, we should consider associating the coverage treatment with a debridement, antibiotics, and implant retention (DAIR) surgery procedure, in order to treat a possible acute infection, even when the diagnosis of infection is not clear. We performed a retrospective study to compare TKA outcomes in patients with DAIR and flap procedures in the same surgical act against those who had received an isolated flap procedure for soft tissue reconstruction after an acute surgical wound defect. Patients had been identified from a prospectively collated TKA database. Between 2005 and 2021, 18 patients met our inclusion criteria, with a mean follow-up of approximately 8 years. A medial gastrocnemius flap procedure was performed for 15 patients (83 %). We compared the rates of infection clearance between the two groups. No differences in comorbidities or risk factors were observed between both groups. In the combination treatment group, 66.6 % of patients healed after treatment compared to 33.3 % in the isolated flap group. Although no significant statistical differences were found, the association of DAIR with the muscle flap procedure is highly recommended in the treatment of acute soft tissue defects after TKA. Further studies with larger sample sizes are necessary to extrapolate these findings to the general population.

Elraglusib induces cytotoxicity via direct microtubule destabilization independently of GSK3 inhibition.

Elraglusib (9-ING-41) is an ATP-competitive inhibitor of glycogen synthase kinase-3 (GSK3) with pre-clinical studies demonstrating broad activity against many tumour types. Promising early-phase clinical trial data led to FDA orphan drug status, and a randomized phase 2 study in combination with cytotoxic chemotherapy in pancreatic cancer has recently completed its recruitment. Similarly, single-agent responses in adult T-cell leukaemia/lymphoma and melanoma, and combination treatment data in several other tumour types have been encouraging. The elraglusib mechanism of action is unknown, but it is unlikely to act through GSK3 inhibition because cytotoxicity is observed below the IC50 for GSK3 and other small molecule GSK3 inhibitors do not produce cytotoxic effects, at least in lymphoma cells. We show here that elraglusib perturbs chromosomal alignment to cause a mitotic arrest in multiple tumour lines. This arrest is caused by direct microtubule depolymerization, which prevents the attachment of kinetochores to microtubules. At clinically relevant doses, these mitotically arrested cells eventually undergo mitotic slippage, leading to gross chromosome missegregation, DNA damage and apoptosis. These effects explain the cytotoxicity of elraglusib because temporarily pausing cell cycle progression with the CDK4/6 inhibitor palbociclib abolishes any drug-induced genotoxicity and apoptosis. In summary, elraglusib acts as a direct microtubule destabilizer both in vitro and across multiple cancer types, resulting in mitotic arrest, DNA damage and apoptosis. These effects likely account for its broad pan-cancer activity, which does not rely upon GSK3 inhibition as they are not replicated by other GSK3 inhibitors.

Multidisciplinary management of gastroesophageal reflux disease: an italian retrospective study

Abstract Background Millions of individuals are affected by gastroesophageal reflux disease (GERD) that causes significant discomfort negatively affecting patients’ overall quality of life. For a collaborative approach of continuous improvement in public health we wanted to know the real-world perspectives in the multidisciplinary and multimodal management pathway. Methods We aimed to interview a sample of gastroenterologists (GE), primary care physicians (GP), and otolaryngologists (ENT) to investigate the management of the intake and treatment of patients reporting symptoms of GERD. Symptoms were divided into typical and extraesophageal, and their severity and impact on quality of life was explored with the GERD Impact Scale (GSI) and Reflux Symptom Index (RSI). Results A total of 6211 patients were analyzed of whom with typical symptoms were 53.5%, while those with extraesophageal symptoms were 46.5%. The latter were more frequently reported by ENT patients (53.6%, p &amp;lt; 0.0001). GSI was highest in patients followed by GE (9 points) and GP (9 points) than ENT specialists (8 points), while the RSI was higher in the ENT group (14.3 ± 6.93) than in the groups of GP and GE, respectively (10.36 ± 6.36 and 10.81 ± 7.30, p &amp;lt; 0.0001). Chest pain had the greatest negative impact on quality of life (p &amp;lt; 0.0001). Of the 3,025 patients who used (proton pump inhibitors) PPIs, non-responders had a lower GSI when treated with a combination of adjunctive drug treatments and bioadhesive compounds, compared with single-component drugs. Conclusions The multidisciplinary and multimodal approach to the management pathway of GERD patients reveals variations in patient profiles by physician specialty, directing toward more appropriate and targeted treatments. In addition, the combination of adjunctive drug treatments and bioadhesive compounds appears to be effective in the management of patients refractory to PPIs. Key messages • The presentation of GERD symptoms is different in accordance with the physician’s speciality: the patients with GERD referred to a gastroenterologist had more severe disease and poorer quality of life. • The combination of adjunctive pharmacological treatments and bioadhesive compounds seems to be effective in the management of PPI refractory patients.

Cardioprotective potential of oleuropein, hydroxytyrosol, oleocanthal and their combination: unravelling complementary effects on acute myocardial infarction and metabolic syndrome

Abstract Background/Introduction Clinical studies have established the role of olive products in primary and secondary prevention of cardiovascular (CV) disease, but the single compounds or compound combinations responsible for the protective effects are still under investigation. Purpose We sought to explore and compare the cardioprotective potential of Oleuropein (OL), Hydroxytyrosol (HT), Oleocanthal (OC) and Oleanolic Acid (OA) and three combinational treatments after chronic oral administration in mice subjected to Ischemia/Reperfusion Injury (IRI) in the presence of metabolic syndrome (MS) and verify the effect of combination in a proof-of-concept clinical study in Chronic Coronary Artery Syndrome (CCAS) patients. Methods First, we explored the IRI-limiting potential of 6-weeks daily oral treatment with OL (20.6 mg/kg), HT (5.9 mg/kg), OC (11.6 mg/kg), OA (17.4 mg/kg) or vehicle (DMSO 5%) in healthy C57Bl6 mice. At week 6, myocardial ischemia/reperfusion (30 minutes/2 hours) was induced and infarct size was measured. Next, MS was established by 14 weeks of Western diet and the isolated compounds were administered for the last 6 weeks. At week 14, IRI was surgically induced, and infarct size was determined. Basic MS parameters (fasting blood glucose, plasma cholesterol, body weight and blood pressure) were recorded at baseline, weeks 8 and 14. According to the exerted benefits, three combinational treatments were designed and tested on the MS model of IRI. The underlying cardioprotective mechanism was investigated on the mixture with preponderant CV benefits (OL-HT-OC, Combo 2). ApoE-/- mice fed with Western diet for 12 weeks were treated with Combo 2 orally for the last 4 weeks and aortic atherosclerotic lesion extent was determined to detect possible antiatherosclerotic effects. After multi-organ toxicity evaluation, a Combo 2-based supplement was administered in CCAS patients for evaluation of cardiac function, inflammation and oxidative stress biomarkers. Results OL, OC and OA, but not HT, significantly reduced infarct size in vivo both in healthy and MS mice. OL was the only compound to reduce hyperglycemia, while OA significantly reduced plasma cholesterol. All mixtures (Combo 1: OL-HT-OA, Combo 2: OL-HT-OC, Combo 3: OL-HT-OC-OA) were cardioprotective, but only Combo 2 prevented MS progression by limiting hyperglycemia. Combo 2 protection against IRI was attributed to apoptosis suppression (reduced Bax/BcL-xL ratio) and increased expression of the antioxidant enzymes Superoxide Dismutase and Catalase in the ischemic myocardium. Combo 2 treatment also reduced atherosclerotic lesion extent. In our proof-of-concept clinical study, Combo 2 treatment ameliorated cardiac, vascular and endothelial function in CCAS patients. Conclusions Combinational treatment with OL-HT-OC exerts potent cardioprotective, antihyperglycemic and antiatherosclerotic properties in vivo, with remarkable and clinically translatable CV benefits in high-risk patients.

Optimizing yield and water productivity in summer mung bean (Vigna radiata L.) through crop residue management and irrigation strategies

A multi-season research trial entitled ‘crop residue management effects on yield and water productivity of summer mung bean (Vigna radiata L.) under different irrigation regimes in Indian Punjab’ was conducted at Punjab Agricultural University (PAU), Regional Research Station (RRS), Bathinda, during rabi 2020 and 2021. The field experiment was conducted in a split-plot layout with nine treatment combinations and replicated thrice. The treatments consisted of T1 (no wheat residue along with tillage), T2 (leftover wheat residue with zero tillage), and T3 (incorporated wheat residue along with tillage) in main plots and irrigation regimes viz., I1 (vegetative growth and flowering stage), I2 (vegetative growth, flowering, and pod filling stage) and I3 (vegetative growth, flowering, pod formation and pod filling stage) in sub-plots, respectively. The growth and yield attributing characters were significantly higher under T3 than T1 but statistically at par with T2 during both years. An increase of 24.1% and 19.0% in grain yield was found in residue incorporation (T3) and residue retention (T2) over residue removal (T1), respectively. Maximum crop and irrigation water productivity was observed under T3 due to reduced water use and increased yield. Among the irrigation regimes, the I3 recorded significantly higher grain yield (0.70 and 0.79 t ha− 1) than I1. It was at par with I2 during both years due to higher irrigation frequency at the pod formation and pod filling stage. Crop water productivity (CWP) was higher under I3, whereas irrigation water productivity (IWP) was higher under I1 during both years. Additional irrigation at the pod-filling stage increased the grain yield by 36.5%, and two additional irrigations at the pod-formation and pod-filling stage further increased yield by 46.2% compared to only two irrigations at the vegetative and flowering stages. The treatment combinations of T2I2 and T3I2 outperformed T1I3 in terms of growth and yield attributing characters viz. plant height, dry matter accumulation (DMA), leaf area index (LAI), pods plant− 1, seeds pod− 1, and 1000-seed weight, which resulted in higher grain yield in these treatment combinations over T1I3. Applying crop residue can help minimize water use and increase crop water productivity. So, retaining crop residue in summer mung bean resulted in saving irrigation water due to lesser evapotranspiration from the soil surface.

Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists and cancer mortality. A real-world registry

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra) reduce cardiovascular events through different mechanisms, nevertheless, their association with cancer remains unclear. Purpose We aim to compare the combined treatment (SGLT2i and GLP1ra) with monotherapy regarding hospitalization or/and death for cancer in a general population and a subgroup of patients with cardiovascular disease (CVD). Methods Retrospective observational study of patients who were prescribed SGLT2i, GLP1ra, or both drugs. Multinomial propensity score was performed in all the population and in a subgroup of patients with CVD (atrial fibrillation [AF], heart failure [HF], coronary artery disease [CAD], peripheral arterial disease [PAD], or cerebrovascular accident [CVA]). The following variables were included to adjust the three groups: Sex, Age, Obesity, diabetes mellitus (DM), high blood pressure (HBP), dyslipidemia (DLP), CAD, HF, AF, and CVA. The three primary outcomes were (i) hospitalization for any cancer, (ii) death for any cancer, and (iii) the combined event in the included population and the subgroup of patients with CVD. The multivariate Cox regression analysis determined the hazard rate (HR) of age, sex, risk factors, and treatment for each outcome. Results We included 14709 patients (11366 with SGLT2i, 1016 with GLP1ra, and 2327 with both treatments) from the treatment initiation. The subgroup with CVD included 4957 (33.7%) patients (Fig 1). After 33 months of median follow-up, the incidence of cancer events was similar between patients with and without CVD (3.4% or 3.7%, respectively). Sex (male) and age were the main risk factors for the 3 outcomes in both groups. Combined treatment and its duration had a protector role for cancer mortality regarding monotherapy with SGLT2i or GLP1ra in all population (HR [95%CI]) 0.2216 [0.106-0.459]; p&amp;lt;0.001 or 0.1928 [0.071-0.519]; p=0.001, respectively) (Fig 2a) and in the subgroup of patients with CVD (HR [95%CI]) 0.279 [0.078-0.994]; p&amp;lt;0.049 or 0.129 [0.024-0.668]; p=0.014, respectively) (Fig 2b), but these results were not found for the outcome of hospitalization for cancer. The combined therapy concerning SGLT2i and duration of treatment showed a protective role against the combined event (HR [95%CI]) 0.709 [0.521-0.967]; p=0.029) and (HR [95%CI]) 0.991 [0.983-0.999]; p=0.032) in the general population but not in the group of CVD. A higher survival rate for any cancer mortality was observed in those patients with the combined therapy respect to monotherapy (SGLT2i or GLP1ra) in the general population (Fig 2c) and the subgroup of patients with CVD (Fig 2d). Conclusions Initiation of combined therapy vs. monotherapy was associated with a lower rate of cancer mortality in the general population and patients with CVD. Future clinical trials and mechanistic studies will clarify the possible role of these drugs on carcinogenesis.Figure 1Figure 2

A Combination of Low Doses of Lithium and Valproate Improves Cognitive Outcomes after Mild Traumatic Brain Injury.

The prevalence of mild traumatic brain injury (mTBI) is high compared with moderate and severe TBI, comprising almost 80% of all brain injuries. mTBI activates a complex cascade of biochemical, molecular, structural, and pathological changes that can result in neurological and cognitive impairments. These impairments can manifest even in the absence of overt brain damage. Given the complexity of changes triggered by mTBI, a combination of drugs that target multiple TBI-activated cascades may be required to improve mTBI outcomes. It has been previously demonstrated that cotreatment with the U.S. Food and Drug Administration (FDA)-approved drugs lithium plus valproate (Li + VPA) for 3 weeks after a moderate-to-severe controlled cortical impact injury reduced cortical tissue loss and improved motor function. Since both lithium and valproate can exhibit toxicity at high doses, it would be beneficial to determine if this combination treatment is effective when administered at low doses and for a shorter duration, and if it can improve cognitive function, after a mild diffuse TBI. In the present study, we tested if the combination of low doses of lithium (1 mEq/kg or 0.5 mEq/kg) plus valproate (20 mg/kg) administered for 3 days after a mild fluid percussion injury can improve hippocampal-dependent learning and memory. Our data show that the combination of low-dose Li + VPA improved spatial learning and memory, effects not seen when either drug was administered alone. In addition, postinjury Li + VPA treatment improved recognition memory and sociability and reduced fear generalization. Postinjury Li + VPA also reduced the number of anti-ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia counted using a convolutional neural network, indicating a reduction in neuroinflammation. These findings indicate that low-dose Li + VPA administered acutely after mTBI may have translational utility to reduce pathology and improve cognitive function.

Effect of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on carotid intima-media thickness

Abstract Background/Introduction Type 2 diabetes mellitus (T2DM) is an additional factor for exacerbation of atherosclerosis increasing the risk for ischemic attacks such as coronary artery disease and ischemic stroke. Evaluation of carotid artery atherosclerosis through ultrasound techniques is a useful tool for risk stratification in type 2 diabetic patients. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on carotid intima-media thickness (cIMT) of T2DM patients. Methods A total of 320 T2DM patients were randomized to receive insulin (n = 80), liraglutide (n = 80), empagliflozin (n = 80) or their combination (GLP-1RA+SGLT-2i) (n = 80) as add-on to metformin. At baseline, at 6 and at 12 months of treatment, we measured the maximal thickness of six major points including right and left common carotid, carotid bifurcation and internal carotids. Finally, we calculated the average cIMT of all six segments (three on each side) to get mean cIMT. Results Compared to baseline, all patients had significantly reduced cIMT at 6 and at 12 months of treatment (p &amp;lt; 0.001; Table). A significant interaction of follow-up time with the type of treatment was observed regarding cIMT levels (F = 7.203, p for interaction &amp;lt; 0.001) in a model including age, sex, smoking, baseline body mass index, glucose levels, glycosylated hemoglobin, levels of blood lipids and their changes at 6 and 12 months of treatment as covariates. At 6 months, patients who were treated with GLP-1RA, SGLT-2i and those under the combination GLP-1RA+SGLT-2i showed a greater reduction of cIMT (-2.5%, -2.4% and -5.8%) compared to insulin (-0.8%; p = 0.008, p = 0.022, and p &amp;lt; 0.001, respectively). Moreover, at 12 months patients under GLP-1RA, SGLT-2i and their combination achieved remarkable reduction of cIMT (-7.4%, -4.9% and -10%) than those under insulin (-1.7%, p &amp;lt; 0.001 for all comparisons). Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cIMT in T2DM. The combined treatment was superior and additive to each regimen separately.Table

Combined administration of atorvastatin and mesenchymal stem cells synergizes to attenuate inflammation and promote efferocytosis in atherosclerotic mice

Abstract Background Atherosclerosis (AS), characterized by chronic systemic and lesional inflammation, is by far the most frequent underlying cause of cardio-cerebrovascular diseases. Recently, impaired efferocytosis, referring to defective removal of dead cells, was identified as another essential factor contributing to the development of AS, which is partly attributed to upregulation of CD47 and explain the benefits of atorvastatin (ATV). Mesenchymal stem cells (MSCs) were reported to protect against AS by inhibiting inflammation; while whether ATV and MSCs could synergize to attenuate inflammation and promote efferocytosis and consequently, reduce AS burden, remains unclear. Methods To establish the AS model, 6-week-old male ApoE-/- mice fed with Western diet for 12 weeks were used and grouped randomly (n=15 per group). The scheme of administration of ATV and human umbilical cord MSCs was shown in Figure 1A. After 6-week treatment, mice were sacrificed, and hearts and aortas were harvested. Oil Red O staining was used to evaluate the lesional burden. Immunofluorescence staining was used to assess the inflammation and efferocytosis in the plaque. A high level of CD11b+ cells (macrophages) infiltration was considered an indicator of inflammation; a high level of cleaved caspase 3 puncta unmerged with macrophages (Mac3+ area) was considered an indicator of impaired efferocytosis. Results Human umbilical cord MSCs were identified as CD73+CD90+CD105+CD45-CD14- cells. Evoked inflammation and defective clearance of apoptotic cells in the plaque were observed (Figure 1B, C). ATV and MSC treatment inhibited macrophage infiltration and activated efferocytosis. Given the mechanistic idea that upregulated CD47 blocks the Signal regulatory protein α (SIRPα) / src homology-2 (SH2)-domain-containing protein tyrosine phosphatases (SHP) signal and leads to efferocytosis impairment, we evaluated the expression levels of CD47 in plaque and phosphorylated SHP (p-SHP) in lesional macrophages (Figure 2A, B). The elevation of CD47 expression and consequent downregulation of p-SHP was reversed by both ATV and MSCs, with a lower lesion burden observed in NS+MSC, ATV+PBS and ATV+MSC groups. All benefits were more pronounced in the group received combined treatment (ATV+MSC). Conclusions The results indicated ATV and MSC administration could synergizes to attenuate inflammation and promote efferocytosis in AS plaque, and the combined treatment led to the lowest lesion burden. CD47/p-SHP signal plays an essential role in the activation of efferocytosis. The mechanisms underlying the inhibition of CD47 are currently under investigation.

Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover

Non-small cell lung cancer (NSCLC) is a prevalent and fatal malignancy with a significant global impact. Recent advancements have introduced targeted therapies like tyrosine kinase inhibitors (TKIs) such as osimertinib, which have improved patient outcomes, particularly in those with EGFR mutations. Despite these advancements, acquired resistance to TKIs remains a significant challenge. Hence, one of the current research priorities is understanding the resistance mechanisms and identifying new therapeutic targets to improve therapeutic efficacy. Herein, we identified high expression of c-Met in osimertinib-resistant NSCLC cells, and depletion of c-Met significantly inhibited the proliferation of osimertinib-resistant cells and prolonged survival in mice, suggesting c-Met as an attractive therapeutic target. To identify effective anti-tumor agents targeting c-Met, we screened a compound library containing 641 natural products and found that only xanthohumol exhibited potent inhibitory effects against osimertinib-resistant NSCLC cells. Moreover, combination treatment with xanthohumol and osimertinib sensitized osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. Mechanistically, xanthohumol disrupted the interaction between USP9X and Ets-1, and inhibited the phosphorylation of Ets-1 at Thr38, promoting its degradation, thereby targeting the Ets-1/c-Met signaling axis and inducing intrinsic apoptosis in osimertinib-resistant NSCLC cells. Overall, the research highlights the critical role of targeting c-Met to address osimertinib resistance in NSCLC. By demonstrating the efficacy of xanthohumol in overcoming resistance and enhancing therapeutic outcomes, this study provides valuable insights and potential new strategies for improving the clinical management of NSCLC.

Phase III Evaluation of Treatment Combinations in Three-Arm Trials

Phase III trials that randomly assign patients to a control treatment (C), an experimental treatment (A), or a combination treatment (AB) should be designed with the goal to recommend the best treatment: AB (if it is better than A and C), A (if it is better than C, and AB is not better than A), or C (if neither AB nor A is better than C). However, this goal can be challenging to achieve with statistical confidence. We performed a survey of cancer trials published in five journals from January 2018 to May 2024 to assess the trial designs being used in this setting and found that three quarters of them did not have a provision for a formal comparison of the AB treatment arm with the A treatment arm, a possible shortcoming. A limited simulation evaluates two analysis strategies that incorporate an AB versus A comparison and is used to formulate some recommendations for designing these types of trials.