Multiple Drug Combinations Research Articles

Artificial Intelligence Application for Anti-tumor Drug Synergy Prediction.

Currently, the main therapeutic methods for cancer include surgery, radiation therapy, and chemotherapy. However, chemotherapy still plays an important role in tumor therapy. Due to the variety of pathogenic factors, the development process of tumors is complex and regulated by many factors, and the treatment of a single drug is easy to cause the human body to produce a drug-resistant phenotype to specific drugs and eventually leads to treatment failure. In the process of clinical tumor treatment, the combination of multiple drugs can produce stronger anti-tumor effects by regulating multiple mechanisms and can reduce the problem of tumor drug resistance while reducing the toxic side effects of drugs. Therefore, it is still a great challenge to construct an efficient and accurate screening method that can systematically consider the synergistic anti- tumor effects of multiple drugs. However, anti-tumor drug synergy prediction is of importance in improving cancer treatment outcomes. However, identifying effective drug combinations remains a complex and challenging task. This review provides a comprehensive overview of cancer drug synergy therapy and the application of artificial intelligence (AI) techniques in cancer drug synergy prediction. In addition, we discuss the challenges and perspectives associated with deep learning approaches. In conclusion, the review of the AI techniques' application in cancer drug synergy prediction can further advance our understanding of cancer drug synergy and provide more effective treatment plans and reasonable drug use strategies for clinical guidance.

Synergistic Effect of Salinomycin With Budesonide on TNBC Regression via EMT Reversal and Autophagy Induction.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature, lack of specific therapeutic targets, and drug resistance. Chemotherapy resistance in TNBC is largely driven by the abnormal activation of epithelial-to-mesenchymal transition (EMT) and the associated cancer stem cell-like characteristics. The combination of multiple chemotherapeutic drugs has shown promise as a treatment approach for TNBC. This study evaluates the efficacy of a novel combination therapy involving the anti-inflammatory drug Budesonide and Salinomycin, which targets cancer stem cells. Co-administration of Budesonide and Salinomycin demonstrated a synergistic effect in inhibiting TNBC cell growth by activating the intrinsic apoptosis pathway. It induced a 2- to 3-fold increase in intracellular reactive oxygen species (ROS) generation and a 25%-30% rise in mitochondrial membrane depolarization. Additionally, extensive signaling studies revealed that the co-treatment specifically targeted multiple signaling nodes, limiting downstream crosstalk. The combination also enhanced autophagic activity by inhibiting the AKT/mTOR pathway and reduced cell migration and stemness by suppressing the EMT process. Therefore, the combination of Budesonide and Salinomycin offers a novel therapeutic approach for TNBC.

State of the ART (antiretroviral therapy): Long-acting HIV-1 therapeutics.

Human immunodeficiency virus (HIV) impacts millions of individuals worldwide, and well over 2/3 of those living with HIV are accessing antiviral therapies that are successfully repressing viral replication. Most often, HIV treatments and prevention are administered in the form of daily pills as combinations of multiple drugs. An emergent and effective strategy for suppressing viral replication is the application of long-acting antiretroviral therapy (LAART), or antivirals that require less-frequent, non-daily doses. Thus far, the repertoire of LAARTs includes the widely used antiviral classes of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INSTIs) and has recently expanded to include a capsid-targeting antiviral. Possible future additions are nucleoside reverse transcriptase inhibitors (NRTIs) and nucleoside reverse transcriptase translocation inhibitors (NRTTIs). Here, we discuss the different strategies of using long-acting compounds to treat or prevent HIV-1 infection by targeting reverse transcriptase, integrase, and capsid.

Antihypertensive treatment during pregnancy and maternal and fetal outcomes

Abstract Introduction Arterial hypertension affects about 5-10% of pregnancies and has detrimental effects on pregnancy outcomes in both the mother and fetus. The study aimed to analyse the outcomes of pregnancy in women treated for arterial hypertension in pregnancy in the Czech Republic. Methodology Nationwide data on all births and abortions in the period 2012-2022 in the Czech Republic were obtained from the National Registry of Reproductive Health (NRRZ) and the National Registry of Reimbursable Health Services (NRHZS). Women who had the diagnosis I10 within one year before pregnancy and were prescribed any antihypertensive drug from selected ATC groups (C02, C03, C07, C08, C09) were classified as pre-existing hypertension. Women diagnosed with O13 or I10 during pregnancy were classified as pregnancy induced hypertension. Hypoxia in the new-born was defined as pH <7.1 or Apgar score <8 present after delivery. For all factors, univariate logistic regression was used to calculate the odds ratios (OR) of adverse outcomes. Results There were total of 1,154,648 deliveries in the 11-year period. 95,215 women had hypertension in pregnancy, out of these 21,094 (22.2%) were treated with antihypertensive drugs. Odds ratios for caesarean section, pre-term delivery, low birth weight, new-born hypoxia and pre-eclampsia in women using different antihypertensive classes and drugs are shown in the Table. Risk of maternal and fetal complications was found to be higher with calcium channel blockers (mainly amlodipine) compared to methyldopa and beta blockers. Among beta blockers, bisoprolol had the most favourable safety profile. Although used in limited numbers, diuretics, verapamil, ACE-inhibitors and angiotensin receptor blockers (ARBs) appeared to be comparably safe to methyldopa. Combination of multiple antihypertensive drugs was associated with higher risk of adverse outcomes. Conclusion Bisoprolol, verapamil and diuretics seem to have the risk of adverse maternal and fetal outcomes comparable to methyldopa. Amlodipine and multiple antihypertensive drug combinations are associated with increased risk.Table

O22 MATERNAL AND FETAL OUTCOMES OF VARIOUS ANTIHYPERTENSIVE TREATMENT REGIMENS DURING PREGNANCY: INSIGHTS FROM THE CZECH NATIONAL REGISTRY 2012-2022

Introduction: Arterial hypertension affects about 5-10% of pregnancies and has detrimental effects on pregnancy outcomes in both the mother and fetus. This study aimed to analyze the outcomes of pregnancy in women treated with different antihypertensive drugs. Methodology: Nationwide data on all births and abortions in the period 2012-2022 in the Czech Republic were obtained from the National Registry of Reproductive Health (NRRZ) and the National Registry of Reimbursable Health Services (NRHZS). Women who had the diagnosis I10 within one year before pregnancy and were prescribed any antihypertensive drug from selected ATC groups (C02, C03, C07, C08, C09) were classified as pre-existing hypertension. Women diagnosed with O13 or I10 during pregnancy were classified as pregnancy-induced hypertension. Hypoxia in the newborn was defined as pH <7.1 or Apgar score <8 present after delivery. For all factors, univariate logistic regression was used to calculate the odds ratios (OR) of adverse outcomes. Results: There were a total of 1,154,648 deliveries in the 11-year period. 95,215 women (8.2%) had hypertension in pregnancy, out of these 21,094 (22.2%) were treated with antihypertensive drugs. Odds ratios for caesarean section, pre-term delivery, low birth weight, newborn hypoxia, and pre-eclampsia in women using different antihypertensive classes and drugs are shown in the Figure. The risk of maternal and fetal complications was higher with calcium channel blockers (mainly amlodipine) compared to methyldopa and beta-blockers. Among beta-blockers, bisoprolol had the most favorable safety profile. Although used in limited numbers, diuretics, verapamil, ACE-inhibitors and angiotensin receptor blockers (ARBs) appeared to be comparably safe to methyldopa. A combination of multiple antihypertensive drugs was associated with a higher risk of adverse outcomes. Conclusion: Bisoprolol, verapamil, and diuretics seem to have a risk of adverse maternal and fetal outcomes comparable to methyldopa. Amlodipine and multiple antihypertensive drug combinations are associated with increased risk.

Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer

Multidrug resistance (MDR), the major mechanism by which various cancers develop specific resistance to therapeutic agents, has set up enormous obstacles to many forms of tumor chemotherapy. Traditional cocktail therapy administration, based on the combination of multiple drugs for anti-MDR chemotherapy, often suffers from inconsistent in vivo pharmacokinetic behaviors that cannot act synchronously on the lesions, leading to limited pharmacodynamic outcomes. Despite the emergence of nanomedicines, which has improved chemotherapeutic drugs’ bioavailability and therapeutic effect on clinical application, these monotherapy-based nano-formulations still show poor progression in overcoming MDR. Herein, a “one stone and three birds” nanococktail integrated by a cocrystal@protein-anchoring strategy was purposed for triple-payload delivery, which paclitaxel-disulfiram cocrystal-like nanorods (NRs) were anchored with the basic protein drug Cytochrome c (Cyt C), followed by hyaluronic-acid modification. In particular, NRs were utilized as carrier-like particles to synchronously deliver biomacromolecule Cyt C into tumor cells and then promote cell apoptosis. Of note, on A549/Taxol drug-resistant tumor-bearing mice, the system with extraordinarily high encapsulation efficiency demonstrated prolonged in vivo circulation and increased tumor-targeting accumulation, significantly reversing tumor drug resistance and improving therapeutic efficacy. Our mechanistic study indicated that the system induced the apoptosis of Taxol-resistant tumor cells through the signal axis P-glycoprotein/Cyt C/caspase 3. Collectively, this nanococktail strategy offers a promising approach to improve the sensitivity of tumor cells to chemotherapeutic drugs and strengthen intractable drug-resistant oncotherapy.

Clofazimine inhibits innate immunity against Mycobacterium tuberculosis by NF-κB.

The complete elimination of Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, from TB patients is a complicated process that takes a long time. The excessive immune inflammatory response of the host for a long time causes irreversible organic damage to the lungs and liver. Current antibiotic-based treatment options involve multiple complex drug combinations, often targeting different physiological processes of Mtb. Given the high incidence of post-tuberculosis lung disease, we should also consider the immunomodulatory properties of other drugs when selecting drug combinations.

Potential therapeutic targets of gastric cancer explored under endogenous network modeling of clinical data

Improvement in the survival rate of gastric cancer, a prevalent global malignancy and the leading cause of cancer-related mortality calls for more avenues in molecular therapy. This work aims to comprehend drug resistance and explore multiple-drug combinations for enhanced therapeutic treatment. An endogenous network modeling clinic data with core gastric cancer molecules, functional modules, and pathways is constructed, which is then transformed into dynamics equations for in-silicon studies. Principal component analysis, hierarchical clustering, and K-means clustering are utilized to map the attractor domains of the stochastic model to the normal and pathological phenotypes identified from the clinical data. The analyses demonstrate gastric cancer as a cluster of stable states emerging within the stochastic dynamics and elucidate the cause of resistance to anti-VEGF monotherapy in cancer treatment as the limitation of the single pathway in preventing cancer progression. The feasibility of multiple objectives of therapy targeting specified molecules and/or pathways is explored. This study verifies the rationality of the platform of endogenous network modeling, which contributes to the development of cross-functional multi-target combinations in clinical trials.

Manejo de la EPOC en la era moderna

Chronic obstructive pulmonary disease (COPD) is a heterogeneous pathology that impacts more than 380 million people globally, being the third leading cause of death worldwide. Since its recognition in the 1960s, the understanding and management of COPD have significantly evolved, thanks to advances in knowledge about its etiopathogenesis and treatment. The guidelines from the Global Initiative for COPD (GOLD COPD) represent an effort to standardize diagnosis and treatment, with its review in 2023 updating the disease's definition. Proper management of COPD includes accurate diagnosis, pharmacological and non-pharmacological therapies, and prevention strategies focused especially on smoking cessation, the main cause of the disease.Diagnosis is based on the history of exposure to noxious particles or gases, with spirometry as a key exam to confirm not completely reversible bronchial obstruction. The treatment strategy has improved with the development of new drugs and administration devices, focusing on reducing symptoms and the risk of exacerbations. Pharmacological therapy is adapted according to the GOLD classification of the patient, with options ranging from bronchodilator therapies to combinations of multiple drugs for more severe cases. The importance of detecting and treating comorbidities is critical, given their high prevalence in patients with COPD and their impact on mortality.Non-pharmacological strategies include smoking cessation, long-term oxygen therapy, physical activity, and pulmonary rehabilitation, as well as ensuring adequate immunization. The management of exacerbations must be appropriate and early, as they are associated with an increase in morbidity and mortality.This review seeks to provide an evidence based integral approach to the management of COPD.

Pharmaco-Therapeutic Factors Influencing the Quality of Life in Patients on Anti-Glaucoma Medications for the Treatment of Primary Open-angle Glaucoma: A Cross-Sectional Study

Abstract Purpose: Vision significantly affects a person’s quality of life (QOL). This study aims to determine the pharmaco-therapeutic factors influencing it among patients on anti-glaucoma medications. Materials and Methods: A total of 100 patients diagnosed with primary open-angle glaucoma (POAG) on medications for six weeks were included in this cross-sectional study. QOL was assessed using a pre-validated Glaucoma Quality of Life-15 (GQOL-15) Questionnaire. Adverse drug reactions (ADRs) to the anti-glaucoma medications were determined using the pre-validated Comparison of Ophthalmic Medications for Tolerability (COMTOL) checklist. The Chi-square test, Fisher’s exact test and multiple logistic regression analysis were performed to test the statistical significance of the data. A P value of < 0.05 was considered statistically significant. Results: Out of the 100 patients, 76 had good QOL and 24 had poor QOL. Among them, 67 patients were on a single drug, 27 were on a two-drug combination and six were on a three-drug combination for the management of glaucoma. Patients receiving multiple drugs for the management of POAG were associated with poor QOL (P = 0.006). Out of the other variables tested for association, the presence of ADRs, patients having a positive family history of POAG, patients with a duration of illness of more than three years, hypertensives and diabetics had a statistically significant association with poor QOL. Conclusion: POAG patients on multiple anti-glaucoma medications had poor QOL compared to those on a single drug. Multiple drug combinations caused a greater number of ADRs compared to single drug use. Patients with ADRs had poor QOL. The presence of co-morbidities like diabetes, hypertension and positive family history were associated with poor QOL.

The Option of Chronotherapy of Hypertension.

The aim of the present paper is to explore the option of chronotherapy of hypertension and its effectiveness in blood pressure (BP) lowering compared with its standard daily treatment. The treatment of BP has gone through many different schemes over the years. From no treatment in the early 1930s, to step care, to multiple drug combinations, or to single daily drug combinations with 2-3 drugs, still BP is not well controlled in a significant number of patients. Recently, the role of the circadian rhythm in the treatment of hypertension has been tested by several studies comparing the evening versus the morning drug administration with no clear evidence of superiority of either mode of drug administration. However, in cases of morning surge of BP, nocturnal hypertension, and renal disease, the evening drug administration has been more effective than the morning drug administration, and thus, more preferable. In order to get a better perspective on this approach of hypertension treatment, a Medline search of the English literature was contacted between 2010 and 2023 using the terms BP control, circadian rhythm, morning drug administration, evening drug administration, and 38 pertinent papers were selected for analysis. Careful review of the selected papers showed that chronotherapy of hypertension is effective. However, the overall effectiveness of evening drug administration compared with the morning administration is not significantly more effective compared to the morning administration and more work is needed in this field.

Analysis of related factors for neuropsychiatric comorbidities in children with epilepsy

ObjectiveTo analyze the risk factors affecting psychiatric behavior and study the psychobehavioral conditions of children with epilepsy.MethodWe randomly selected and enrolled 294 children with epilepsy who visited and were hospitalized in the pediatric clinic of Hebei General Hospital between January 2017 and January 2022, as the study participants. We comprehensively assessed their cognitive functions using the Gesell development schedule or Wechsler Intelligence Scales. The participants were divided into the study group (n = 123) with cognitive impairment and the control group (n = 171) with normal cognitive functions, for analysis.ResultsThere were statistically significant differences between the two groups in disease course, frequency of epilepsy, status epilepticus, and the number of antiseizure medications (ASMs) used (P < 0.05), while there were no statistically significant differences in age, gender, age of onset, form of onset, interictal epileptiform discharge, history of febrile convulsion, and the time from onset to initial visit (P > 0.05). Based on multivariate logistic regression analysis, the course of disease, frequency of onset, status epilepticus and number of ASMs used were identified as high-risk factors for cognitive impairment in children with epilepsy. Similarly, early onset, long course of disease, known etiology, and combination of multiple drugs have a negative impact on behavioral problems, school education, and social adaptability.ConclusionThe course of disease, the frequency of onset, status epilepticus, and the number of ASMs used are high-risk factors for cognitive impairment in children with epilepsy, which can be prevented and controlled early. When selecting ASMs, their advantages and disadvantages should be weighed. Moreover, the availability of alternative treatment options must be considered. With the help of genomic technology, the causes of epilepsy should be identified as early as possible, and precision medicine and gene therapy for children with epilepsy should be actively developed.

Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression.

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-β1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.

Categorical Analysis of Database Consistency in Reporting Drug-Drug Interactions for Cardiovascular Diseases.

Drug-drug interactions (DDIs) can either enhance or diminish the positive or negative effects of the associated drugs. Multiple drug combinations create difficulties in identifying clinically relevant drug interactions; this is why electronic drug interaction checkers frequently report DDI results inconsistently. Our paper aims to analyze drug interactions in cardiovascular diseases by selecting drugs from pharmacotherapeutic subcategories of interest according to Level 2 of the Anatomical Therapeutic Chemical (ATC) classification system. We checked DDIs between 9316 pairs of cardiovascular drugs and 25,893 pairs of cardiovascular and other drugs. We then evaluated the overall agreement on DDI severity results between two electronic drug interaction checkers. Thus, we obtained a fair agreement for the DDIs between drugs in the cardiovascular category, as well as for the DDIs between drugs in the cardiovascular and other (i.e., non-cardiovascular) categories, as reflected by the Fleiss' kappa coefficients of κ=0.3363 and κ=0.3572, respectively. The categorical analysis of agreement between ATC-defined subcategories reveals Fleiss' kappa coefficients that indicate levels of agreement varying from poor agreement (κ<0) to perfect agreement (κ=1). The main drawback of the overall agreement assessment is that it includes DDIs between drugs in the same subcategory, a situation of therapeutic duplication seldom encountered in clinical practice. Our main conclusion is that the categorical analysis of the agreement on DDI is more insightful than the overall approach, as it allows a more thorough investigation of the disparities between DDI databases and better exposes the factors that influence the different responses of electronic drug interaction checkers. Using categorical analysis avoids potential inaccuracies caused by particularizing the results of an overall statistical analysis in a heterogeneous dataset.

Perspectives on 3D printed personalized medicines for pediatrics

In recent years, the rapid advancement of three-dimensional (3D) printing technology has yielded distinct benefits across various sectors, including pharmaceuticals. The pharmaceutical industry has particularly experienced advantages from the utilization of 3D-printed medications, which have invigorated the development of tailored drug formulations. The approval of 3D-printed drugs by the U.S. Food and Drug Administration (FDA) has significantly propelled personalized drug delivery. Additionally, 3D printing technology can accommodate the precise requirements of pediatric drug dosages and the complexities of multiple drug combinations. This review specifically concentrates on the application of 3D printing technology in pediatric preparations, encompassing a broad spectrum of uses and refined pediatric formulations. It compiles and evaluates the fundamental principles associated with the application of 3D printing technology in pediatric preparations, including its merits and demerits, and anticipates its future progression. The objective is to furnish theoretical underpinning for 3D printing technology to facilitate personalized drug delivery in pediatrics and to advocate for its implementation in clinical settings.

Optimizing the combination of chemotherapeutic drugs along with radiotherapy for extranodal NK/T-cell lymphoma

Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown. Design: Retrospective cohort study. Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations. Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens. Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p &lt; 0.001) regimens. The survival benefit of ASP/GEM-based regimens over other ASP-based regimens was substantial across risk-stratified and advanced-stage subgroups. The survival benefits of a combination of RT, ASP, and GEM were consistent after adjustment for confounding factors by IPTW. Conclusion: These results suggest that combining ASP/GEM with RT for ENKTCL is an efficacious and feasible therapeutic option and provides a rationale and strategy for developing combination therapies.

Lenalidomide in Combination with Etoposide Induced Ferroptotic Cell Death in DLBCL

Background ： Relapse/refractory(R/R) DLBCL after first-line immunochemotherapy have unfavorable outcomes, treatment of which remains challenging. The combination of multiple drugs in the second-line regimen improves efficacy but also increases toxicity, often leading to treatment-related adverse events (AEs) or dose reduction/interruption. This study aims to explore the effects of lenalidomide in combination with ibrutinib in diffuse large B-cell lymphoma and investigate its potential mechanisms. Methods: 1. From February 2019 to June 2023, patients aged 60 and above who received R 2-ICE regimen were analyzed for the efficacy and AE of the second-line therapy. 2. Human DLBCL cell lines SU-DHL-4 and U2932 were screened using the CCK-8 assay to demonstrate the synergistic cytotoxic effect of different drugs on DLBCL cells. Subsequently, various experiments were conducted to investigate whether oxidative damage occurred and explore the underlying mechanisms . These experiments included measurement of intracellular iron levels, MDA assay, detection of H 2O 2 and ·OH levels, ROS assay, assessment of mitochondrial membrane potential, and Hoechst staining. 3. SCID mouse model with subcutaneous xenografts of SU-DHL-4 cells in the right thigh was established. Different chemotherapy regimens, including PBS, R 2, R 2-ICE, and R 2-E, were administered to the mice, and the tumor-inhibitory effects and in vivo toxicity (evaluated based on body weight) of these treatments were observed. Results: 1. A total of 19 patients aged 60 years and above with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) received the R2-ICE regimen as second-line chemotherapy. They completed at least 2 treatment cycles, and the therapeutic efficacy was evaluated. Short-term efficacy: Overall Response Rate (ORR) was 81% (43.75% Complete Response [CR], 37.5% Partial Response [PR]). Long-term efficacy: Median follow-up of 30 months, with 1-year Progression-Free Survival (PFS) of 42.9% and 2-year PFS of 32.1%. One-year Overall Survival (OS) was 75%, and 2-year OS was 37.5%（Figure1A-B）. 2. Through CCK-8 cell proliferation assay, it was observed that lenalidomide，carboplatin and etoposide exerted time- and dose-dependent inhibitory effects on SU-DHL-4 and U2932 cells. Different IC50 concentrations of these drugs were chosen after 48 hours of treatment, and lenalidomide was administered in combination with etoposide or carboplatin. By calculating the CCK-8 cell survival rate and drug synergy formula, it was determined that lenalidomide in combination with etoposide had a synergistic inhibitory effect on DLBCL cell lines. Further CCK-8 experiments showed that ferroptosis inhibitor Fer-1-treated cells partially resisted the cytotoxic effect of lenalidomide in combination with etoposide on DLBCL cells (all differences were statistically significant, Figure 1. C-E). These findings indicate that lenalidomide in combination with etoposide suppresses DLBCL proliferation via the ferroptosis pathway. 3. Experiments of SU-DHL-4 cells were divided into four groups：control，len, eto，len+eto. By performing intracellular iron content detection, MDA assay, H2O2 and ·OH level detection, ROS experiment, mitochondrial membrane potential detection, and Hoechst staining, it was demonstrated that lenalidomide in combination with etoposide induces intracellular accumulation of ROS through an iron-dependent Fenton reaction, leading to cell membrane and DNA damage and DLBCL cell death(Figure 2). 4. SU-DHL-4 pretreated with Fer-1, and the experiments were divided into four groups: control, control + Fer-1, len+eto, len+eto+ Fer-1. By performing experiment mentioned above demonstrated that Fer-1 could reverse the oxidative damage induced by lenalidomide in combination with etoposide（Figure 3）. 5.In in vivo experiments, chemotherapy administered with PBS, R 2, R 2-E, and R 2-ICE regimens showed that R 2-E and R 2-ICE had similar tumor-suppressive effects and R 2-E were lower toxicity（Figure 4）. Conclusion: Lenalidomide combined with etoposide enhances intracellular reactive oxygenlevels through the ferroptosis pathway, resulting in synergistic killing of DLBCL cells through lipid and DNA oxidation damage. In vivo experiments confirmed that R 2-E showed similar antitumor effects with R 2-ICE and had lower toxicity.

Japanese nationwide questionnaire survey on delayed cerebral infarction due to vasospasm after subarachnoid hemorrhage.

Various prophylactic drugs for cerebral vasospasm and delayed cerebral infarction (DCI) after subarachnoid hemorrhage (SAH) have been used in Japan. To investigate the treatment trends for cerebral vasospasm and frequency of DCI after SAH throughout Japan in 2021. In 2021 we conducted an anonymous questionnaire survey on management for preventing cerebral vasospasm after aneurysmal SAH, and the frequency of DCI. The questionnaire was emailed to 955 certified neurosurgeons at 553 hospitals in Japan. Of them, 162 hospitals (29% response rate) responded to the questionnaire. Of these, 158 were included in this study, while four hospitals that responded insufficiently were excluded. The efficacy of treatments for reducing DCI were examined through a logistic regression analysis. Among 3,093 patients treated with aneurysmal SAH, 281 patients (9.1%) were diagnosed with DCI related to cerebral vasospasm. Coil embolization had significantly lower DCI frequency (6.9%), compared to microsurgical clipping (11.8%, odds ratio, 0.90; 95% confidential intervals, 0.84-0.96; P, 0.007). In addition, cilostazol administration was associated with significantly lower DCI frequency (0.48; 0.27-0.82; 0.026). The efficacy of cilostazol in reducing DCI remained unchanged after adjustment for covariates. The most effective combination of multiple prophylactic drugs in reducing DCI related to cerebral vasospasm was cilostazol, fasudil, and statin (0.38; 0.22-0.67; 0.005). This study elucidated the trends in prophylactic drugs to prevent cerebral vasospasm and frequency of DCI after aneurysmal SAH in Japan. Coil embolization and cilostazol administration showed effectiveness in reducing DCI related to cerebral vasospasm in 2021.

Assessing the hypolipidemic and gastro-liver protective activity of herbal combination with emphasis on PPI amid selected multiple antihypertensive drug combination in experimental animal models.

Peptic ulcer (PU) and hypertension are chronic diseases affecting up to 10% and 30% of the adult population worldwide. Most of these patients will require treatment with a combination of antihypertensive medicines, which have adverse effects on the body's different organs. This study specifically focused on antihypertensive multi-drug induced PU disease and disturbance of liver function. During a 14-day oral administration of antihypertensive drugs, Cilnidipine (1 mg/kg), Rosuvastatin (1 mg/kg), Bisoprolol (0.52 mg/kg), and Clopidogrel (7.81 mg/kg) were observed for their effects on the stomach lining and liver function in Wister albino rats. This study aimed to assess the potential of an herbal combination of (BO) + (BA) + (ZO) 0.26 mg/kg body weight (b.w.) Powder and water mixture on the ulcer, lipid profile, and liver function for 14 days in the treatment of the indomethacin-induced gastric ulcers in rats at doses of 30 mg/kg b.w. for three days. Esomeprazole (20 mg/kg b.w.) is used as a standard reference to evaluate antiulcer activity in rat models. The experiment suggests that the gastroprotective effect of the herbal combination can be attributed to its reducing effect on the peptic and the Serum Glutamic Pyruvic Transaminase (SGPT) levels and within the normal range of 34.67 ± 0.88 IU/L. The results for Total Cholesterol (TC), Triglyceride (TG), High-density lipoprotein (HDL) and Low-density lipoprotein (LDL) of the herbal combination were 52 ± 9.81495 (mg/dl), 70 ± 12.12435 (mg/dl), 23.33 ± 6.06446 (mg/dl), 14.5 ± 1.32790 (mg/dl), respectively, where the standard group (atorvastatin) 5 mg/kg TC, TG, HDL and LDL were 69.77 ± 9.92 (mg/dl), 47.7 ± 10.35 (mg/dl), 33.43 ± 5.70 (mg/dl), 26.8 ± 3.70 (mg/dl), and control group total cholesterol, triglyceride, HDL and LDL were 68.67 ± 2.20 (mg/dl), 124.07 ± 2.94 (mg/dl), 49.14 ± 1.05 (mg/dl), 54.11 ± 1.15 (mg/dl). CThis investigation reported that antihypertensive drugs did not produce gastrointestinal (GI) toxicity, and the morphological structure of the organ was not changed. So, it could be concluded that the herbal combination used in this experiment has a promising role in controlling lipid profile, liver function, and antiulcer effects. Moreover, multiple drug therapy for hypertension does not cause any harm to the stomach. Further investigations might be carried out on a larger scale to make these statements more valid.

Developing Strategies to Improve the Efficacy of CAR-T Therapy for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a fatal blood malignancy. With the development of immunotherapy, particularly chimeric antigen receptor T cells (CAR-T), the treatment of AML has undergone a significant change. Despite its advantages, CAR-T still faces a number of limitations and challenges while treating AML. Finding novel targets, altering the structure of CAR to increase efficacy while lowering side effects, and using double-target CAR and logic circuits are typical examples of key to answer these problems. With the advancement of gene editing technology, gene editing of tumor cells or normal cells to create therapeutic effects has grown in popularity. Additionally, the combination of multiple drugs is routinely used to address some of the obstacles and difficulties associated with CAR-T therapy. The review's primary goal was to summarize recent strategies and developments of CAR-T therapy for AML.