Combined Treatment Research Articles

Kaempferol promotes osteogenic differentiation in bone marrow mesenchymal stem cells by inhibiting CAV-1.

Our study focused on the effects and molecular mechanisms of kaempferol, a major active component of Eucommia ulmoides Oliver (EUO), on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Target molecules for EUO, osteoarthritis, and osteogenic differentiation were identified through network pharmacology analysis. BMSCs were isolated and treated with various concentrations of kaempferol. Optimal concentration was determined through MTT assays. Osteogenic differentiation was assessed using alkaline phosphatase (ALP) and Alizarin Red S staining, while osteogenic markers (Collagen I, RUNX2, and OPN) and CAV-1 expression were analyzed using RT-qPCR and Western blot. The effects of combined treatment with kaempferol and an overexpression vector for CAV-1 (oe-CAV-1) on osteogenic differentiation were also observed. Network pharmacology analysis identified kaempferol as the primary active component influencing CAV-1 targeted in subsequent experiments. It was found that 10 µM kaempferol was optimal for treating BMSCs. Post-treatment, significant increases in ALP activity and calcium deposition were observed, along with elevated expression of osteogenic markers, and decreased CAV-1. Overexpression of CAV-1 significantly reversed the promotive effects of kaempferol on BMSC osteogenic differentiation, effectively inhibiting the process. Collectively, kaempferol promotes osteogenic differentiation in BMSCs by inhibiting CAV-1 expression.

Effects of VR task-oriented training combined with rTMS on balance function and brain plasticity in stroke patients: a randomized controlled trial study protocol

BackgroundBalance dysfunction affects 70% of stroke patients. Emerging neurophysiological approaches, such as virtual reality therapy (VRT) and repetitive transcranial magnetic stimulation (rTMS), have been proven by clinical studies that the balance function of stroke patients can be improved when applied alone, but there are relatively few studies on the combined treatment of balance dysfunction after stroke. This study aimed to evaluate the impact of a 4-week intensive intervention combining VRT and rTMS on both balance function and brain plasticity among stroke patients.MethodsThis single-blind, randomized controlled trial was conducted at the Rehabilitation Medical Center of the Rehabilitation General Hospital of Ningxia Medical University. A cohort of 136 stroke patients, with durations of 2 to 24 weeks post-stroke, were enrolled in the study. Participants were randomly allocated in a 1:1:1:1 ratio to four groups: the VR group (n = 34), the rTMS group (n = 34), the combined treatment group receiving both VR and rTMS (n = 34), and the control group undergoing traditional balance training (n = 34). All patients underwent a standardized inpatient rehabilitation program over 4 weeks. The VR group received daily 30-min sessions of VR therapy for 20 days. The rTMS group underwent daily sessions of rTMS stimulation for 20 min, targeting the motor imagery region in the affected hemisphere. The combination group received VR therapy after completing their rTMS treatment. The control group received conventional balance training, with each session lasting 30 min. Additionally, all patients received an extra 60 min of standard rehabilitation therapy twice daily. Assessments were conducted at baseline, 2 weeks, and 4 weeks post-treatment, using the Berg Balance Scale (BBS) as the primary measure, and secondary measures including the Timed Up-and-Go Test (TUGT), Fugl-Meyer Assessment-Lower Extremity (FMA-LE), and 6-m walking test (6MWT), as well as assessments for brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VGEF), tyrosine receptor kinase (TrκB), motor-evoked potential latency (PL), central motor conduction time (CMCT), and amplitude.DiscussionThe widespread application of VR technology and rTMS in clinical settings is well-established. However, the potential synergistic effects of combining these modalities on balance function and neuroplasticity in stroke patients remain uncertain. Our hypothesis suggests that the integration of VR with rTMS may result in more pronounced improvements in both balance function and neuroplasticity among stroke patients, surpassing the outcomes achievable with VR alone, rTMS alone, or traditional therapy. The possible mechanism is that VR-based training combined with rTMS plays a superimposed effect, promoting better repair of damaged neurons and ultimately improving balance function in stroke patients. The positive results anticipated from this trial could provide objective evidence advocating for the concurrent use of VR and rTMS in clinical interventions.Trial registrationThe study protocol underwent review and approval by the Medical Research Ethics Committee of the General Hospital of Ningxia Medical University on January 26, 2024 (No. KYLL-2024–0162). Subsequently, it was registered in the Chinese Clinical Trial Registry on March 11, 2024 (registration number: ChiCTR2400081775). Currently, the study is still ongoing.

IL-18, a therapeutic target for immunotherapy boosting, promotes temozolomide chemoresistance via the PI3K/AKT pathway in glioma

Interleukin-18, a member of the interleukin − 1 family of cytokines, is upregulated in glioma. However, its effects on glioma remain unclear. This study aimed to explore the role and underlying mechanisms of interleukin-18 expression in glioma. Here, we demonstrated that interleukin-18 enhanced resistance to temozolomide by increasing proliferation and inhibiting apoptosis in cultured glioma cells. Further in vivo studies revealed that interleukin-18 promoted temozolomide resistance in BALB/c nude mice bearing tumor. Mechanical exploration indicated that interleukin-18 stimulation could activate the PI3K/AKT signaling pathway in glioma cells, and PI3K inhibition could reduce the temozolomide resistance promoted by interleukin-18. We found that interleukin-18 upregulated CD274 expression in glioma, revealing its potential effects on the microenvironment. Furthermore, we established a tumor xenograft model and explored the therapeutic efficacy of anti-interleukin-18 monoclonal antibody. Targeting interleukin-18 prolonged survival and attenuated CD274 expression in the mice bearing tumor. Combined treatment with anti-interleukin-18 and anti-PD-1 monoclonal antibody showed better efficacy in suppressing tumor growth than either treatment alone in mice bearing tumor. Collectively, these data present that interleukin-18 promotes temozolomide chemoresistance in glioma cells via PI3K/Akt activation and establishes an immunosuppressive milieu by modulating CD274. This study highlights the therapeutic value of interleukin-18 in glioma.

Effects of SGLT2i and Pioglitazone on FIB-4 Index in Patients with Metabolic Dysfunction Associated Steatotic Liver Disease—A Real World Retrospective Study from India

Aims: Several studies support type 2 diabetes mellitus (T2DM) as one of the risk factors of metabolic dysfunction associated steatotic liver disease (MASLD). Recently, the use of pioglitazone and sodium-glucose co-transporter 2 inhibitors (SGLT2i) has been on the rise considering its beneficial effects in reducing liver dysfunction. We aim to determine the clinical effectiveness of these drugs in improving MASLD and T2DM. Materials and methods: We conducted a retrospective study of 279 T2DM patients with MASLD who were prescribed pioglitazone and/or SGLT2i from two clinics in India. The primary endpoint was change in fibrosis (FIB-4) index and the aspartate aminotransferase to platelet ratio index (APRI) score at one year follow-up. Appropriate statistical tests were applied to assess the significance of the outcomes. Results: Of the total (276) patients, 46% of patients were at low risk of advanced fibrosis, 11% were at high risk for advanced fibrosis, and the majority (50%) were on SGLT2i treatment. At follow-up, there is a statistically significant reduction in the mean (SD) FIB-4 index (1.92 [1.22] vs. 1.68 [0.99]) and APRI score (0.42 [0.34] vs. 0.33 [0.21]); p < .001. Among treatment groups, there is a significant difference in the mean FIB-4 index both at baseline (F: 4.23; p < .05) and follow-up (F: 3.45; p < .05). These scores were highly significant in the combination treatment with SGLT2i and pioglitazone ( p < .05). Conclusions: Our results indicate a combination therapy with SGLT2i and pioglitazone might be beneficial in managing MASLD, especially in reducing the FIB-4 index and APRI score in Indian T2DM patients with MASLD.

Metabolic Response to Small Molecule Therapy in Colorectal Cancer Tracked with Raman Spectroscopy and Metabolomics.

Despite numerous screening tools for colorectal cancer (CRC), 25 % of patients are diagnosed with advanced disease. Novel diagnostic technologies that are early, accurate, and rapid are imperative to assess the therapeutic efficacy of clinical drugs and identify new biomarkers of treatment response. Here Raman spectroscopy (RS) was used to track metabolic reprogramming in KRAS-mutant HCT116 and SW837 cells, and KRAS wild-type CC cells. RS combined with multivariate analysis methods distinguished nonresponsive, partially responsive, and responsive cells treated with cetuximab, a monoclonal antibody for EGFR inhibition, sotorasib, a clinically approved KRAS inhibitor, and various doses of trametinib, an inhibitor of the MAPK pathway. Cells treated with a combination of subtoxic doses of trametinib and BKM120, an inhibitor of the PI3K pathway, showed a synergistic response between the two pathways. Using a supervised machine learning regression model, we established a scoring methodology trained to a priori predict therapeutic response to new treatment combinations. RS metabolites were verified with mass spectrometry, and enrichment pathways were identified, including amino acid, purine, and nicotinate and nicotinamide metabolism that differentiated monotherapy from combination therapy. Our approach may ultimately be applicable to patient-derived primary cells and cultures of patient tumors to predict effective drugs for individualized care.

"Hands-On" and "Hands-Off" Physiotherapy Treatments in Fibromyalgia Patients: A Systematic Review and Meta-Analysis.

Background: Physiotherapy plays a key role in managing fibromyalgia, a multifaceted disorder, through a combination of active and passive treatments. The purpose of this review is to compare the efficacy of "hands-off" treatments alone versus the combination of "hands-off" and "hands-on" therapies. Methods: MEDLINE (PubMed), CENTRAL, and Embase were searched. English-language randomized controlled trials involving adults with fibromyalgia were included. The included studies were divided into subgroups to reduce the possible heterogeneity. We calculated the standardized mean difference or mean difference with 95% confidence intervals for the continuous data according to the outcome measures. We used the risk ratio for dichotomous data of the drop-out rate of the studies. Results: We included and analyzed seven RCTs. The meta-analysis showed no significant results in the outcomes, pain, QoL, health status, and drop-out rate. We found significant results (p < 0.001) in favor of combining "hands-off" and "hands-on" treatments for the rest quality (SMD 0.72, 95% CI 0.35 to 1.09). Conclusions: This review increases the treatment options available for clinicians. Up to now, the main guidelines on managing fibromyalgia suggest only approaches based on "hands-off" treatments. These findings suggest that other approaches based on mixed interventions combining "hands-off" and "hands-on" treatments did not reduce the patient outcomes. Moreover, the mixed intervention led to better results for the patients' sleep quality than the "hands-off" treatments alone.

Simultaneous treatment with tap water-based neutral electrolyzed water and citric acid for inactivating foodborne pathogens on stainless steel and their synergistic bactericidal mechanisms

Electrolyzed water has many potential applications, the primary one being the eliminating microorganisms in the food industry. However, this application is limited by high chlorine levels. Tap water-based neutral electrolyzed water (TNEW) has the advantage of relatively low chlorine concentration (1.7–4.6 mg/L), but its sterilization effect is limited. In this study, TNEW was combined with citric acid (CA) solution, resulting in strong synergistic inactivation effect on Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes on stainless steel surfaces. Simultaneous treatment of stainless steel with TNEW [available chlorine concentration (ACC) of 4.97 mg/L] and 0.1% CA for 15 min resulted in 4.78-, 4.26-, and >5.69 log CFU/cm2 surface reduction in E. coli O157:H7, S. Typhimurium, and L. monocytogenes, respectively, which was a synergistic cell count reductions of 3.25, 2.83, and >3.84 log units, respectively. Fluorescence and RT-qPCR analyses identified synergistic production of intracellular reactive oxygen species (ROS), damage to the cell membrane resulting from lipid peroxidation, and DNA damage as the major factors contributing to the synergistic lethal effect. The results of this study suggest that the TNEW–CA combination treatment can be applied as a potential substitute for conventional electrolyzed water treatment for food contact surface disinfection.

Synergy between bio-control agents to trigger the defensive responses against Rhizoctonia root rot and enhance the growth, yield, and physiological and anatomical traits of pea plants

AbstractRhizoctonia solani (Rs) is the fungus that causes the primary and deadly disease that attacks pea plants throughout the cool growing season. It causes seed rot, damping off, and pea root rot diseases. The current study used arbuscular mycorrhizal fungi; Rhizoglomus clarum, Gigaspora margarita, Rhizophagus irregularis and Funneliformis mosseae (AMF), Pseudomonas fluorescens HE21 (Pf), and Trichoderma harzianum HL9 (TH) singly or in combination to suppress Rhizoctonia root rot of pea in a greenhouse. Using the in vitro dual culture assay, TH and Pf inhibited the radial growth of the Rs by 73.3 and 60.0%, respectively. The results of greenhouse experiments showed that all treatments significantly decreased the percentages of pre- and post-emergence damping while significantly increasing the number of surviving plants, particularly in the dual and triple combination treatments. Furthermore, all treatments improved yield and seed quality in addition to plant growth, total phenol content and antioxidant enzyme activity. There were also noted modifications to the treated plants’ anatomical, physiological, and distinctive features. The synergistic triple treatment consisting of M, TH, and Pf achieved the maximum reduction of disease severity (78.5%) compared to the untreated control treatment. As a result of the synergistic triple treatment due to their effectiveness and eco-safety, we recommend using the synergistic triple by M + Pf + TH to manage the root rot disease in peas caused by Rs and to enhance the crop’s growth, yield, and seed quality.

Marginal bone resection and immediate internal fixation in multidrug resistant chronic septic nonunions of lower limb long bones: a case series.

This study aimed to evaluate the efficacy of a combined treatment approach integrating extensive debridement, immediate internal fixation, and the Masquelet technique for the management of infected nonunion of long bones in the lower limbs caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. This retrospective case series was conducted at the Imam Khomeini Hospital Complex, Tehran, Iran, a tertiary-level academic referral centre. The study documented consecutive cases of patients presenting with infected nonunion of the tibia or femur, with a positive culture for MDR or XDR bacteria, treated between January 2019 and December 2022. Inclusion criteria were adults with a confirmed diagnosis of infected nonunion due to MDR or XDR bacteria, with exclusion criteria including patients with unrelated infections or allergies to the components of the treatment regimen. The primary outcomes measured were infection resolution and bone healing. The study cohort comprised 16 patients, predominantly male (87.5%) with an average age of 38.5 years. Methicillin-resistant Staphylococcus aureus (MRSA) was identified as the causative agent in 31.25% of the infections. Patients were followed for a period ranging from 12 to 26 months. The treatment protocol was uniformly applied across all cases. Successful bone union was observed in the majority of patients within 140 to 240 days following grafting. However, there were two instances where amputation was necessitated due to the failure to eradicate the infection. Complications arose in three cases during the follow-up period: two required re-debridement due to a recurrence of the infection, and one was subjected to bone transport owing to persistent nonunion. Notably, all cases that either failed or encountered complications were smokers. In this integrated approach, high rates of infection resolution and bone healing were achieved, suggesting this method as a viable option for these complex cases.

Combination of nusinersen and rehabilitation using hybrid assistive limb for type 3 spinal muscular atrophy

AbstractAn antisense oligonucleotide drug nusinersen can improve motor function of spinal muscular atrophy (SMA) patients. The Hybrid Assistive Limb (HAL) is a wearable robot assisting the wearers' movements in real time. Gait rehabilitation using HAL is useful for SMA. However, the efficacy of combined treatment has never been reported before. We have investigated the efficacy of combining both therapies. A 21‐year‐old man, genetically diagnosed with type 3 SMA, was treated by combining nusinersen and five sessions of gait rehabilitation using HAL over 2 years. Hammersmith Functional Motor Scale‐Expanded (HFMSE) score improved by 12 points after treatment. Electrophysiological parameters of the tibial nerves improved. Muscle volume also increased by 8% at 39 months. The combined therapy resulted in a good clinical outcome. This may be due to promotion of nerve regeneration and recovery of muscle volume by a synergy of nusinersen and motor learning correctly guided by HAL.

Intracellular Magnetic Hyperthermia Sensitizes Sorafenib to Orthotopic Hepatocellular Carcinoma Via Amplified Ferroptosis.

Sorafenib (SRF) is recognized as the primary treatment for hepatocellular carcinoma (HCC), yet the emergence of SRF resistance in many HCC patients results in unfavorable outcomes. Enhancing the efficacy of SRF in HCC remains a significant challenge. SRF works in inducing ferroptosis, a form of cell death, in cancer cells through the inhibition of glutathione peroxidase 4 (GPX4). The effectiveness of this process is limited by the low levels of cellular iron and reactive oxygen species (ROS). A promising approach to circumvent this limitation is the use of intracellular magnetic hyperthermia (MH) mediated by magnetic iron oxide nanomaterials (MIONs). When MIONs are subjected to an alternating magnetic field (AMF), they heat up, enhancing the Fenton reaction, which in turn significantly increases the production of ROS within cells. In this study, we explore the capability of MH facilitated by high-performance ferrimagnetic vortex-domain iron oxide nanoring (FVIO) to enhance the effectiveness of SRF treatment in HCC. The increased iron uptake facilitated by FVIO significantly enhances the sensitivity of HCC cells to SRF-induced ferroptosis. Moreover, the nanoheat generated by FVIO in response to an AMF further elevates ROS levels and stimulates lipid hydroperoxide (LPO) production and GPX4 inactivation, thereby intensifying ferroptosis. Both in vitro and in vivo animal studies demonstrate that combining FVIO-mediated MH with SRF significantly reduces cell viability and inhibits tumor growth, primarily through enhanced ferroptosis, with minimal side effects. The effectiveness of this combination therapy is affected by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The combination treatment of FVIO-mediated MH and SRF offers a strategy for HCC treatment by promoting accelerated ferroptosis, presenting a different perspective for the development of ferroptosis-based anticancer therapies.

Preservation with Different Smoking Techniques to Extend the Shelf Life of “Urutan” Chicken

“Urutan” chicken is one of the processed meat products processed through the manufacture of meat dough, fat and complete Balinese spices ("Basa Genep"). Extending the shelf life of “urutan” chicken can be done by smoking process either by cold smoking method or hot smoking. Smoke can preserve food ingredients due to the presence of acid, phenolic and carbonyl compounds. The method used in this study is Randomized Block Design (RBD) with a factorial pattern consisting of 2 factors, namely Factor I is Hot Smoking Technique consisting of 3 levels and Factor II is Smoking Time consisting of 4 levels so that 12 treatment combinations are obtained and 2 repetitions are carried out so that 24 experimental units are obtained. The parameters observed include phenol content, water content, ash content, fat content, protein content, Esherichia coli and Salmonella sp. Statistical analysis shows that smoking time has a significant effect (sig &lt;0.05) on the phenol content of “urutan” chicken, but does not have a significant effect (sig&gt; 0.05) on the fat and protein content of “urutan” chicken. The fat content of “urutan” chickens in the smoking duration treatment at a temperature of 100 ° C ranged from 9.798 - 11.870%. The lowest fat content was obtained in 2 hours of smoking, which was 9.798% which was not significantly different from other treatments. The protein content of “urutan” chickens in the smoking treatments of 0.5, 1, 1.5 and 2 hours ranged from 11.788 -12.197%. The smoking duration did not have a significant effect on the protein content of “urutan” chickens, which was probably because the smoking duration of 0.5 -2 hours had not denatured the protein sequence. The phenol content of “urutan” chickens in the smoking treatments of 0.5, 1, 1.5 and 2 hours ranged from 0.206 - 0.312%. The highest phenol content was obtained in 2 hours of smoking at a smoking temperature of 100 ° C, which was 0.312%. The results showed that the longer the smoking, the higher the phenol content of “urutan” chickens. The lowest pH value was obtained in the 100 °C 2-hour smoking treatment of 5.16, which was significantly different from other treatments. The highest water content was obtained in the 100 °C 2-hour temperature treatment of 63.19%, which was significantly different from other treatments

Hormopriming and duration of priming interaction on germination, emergence and subsequent growth productivity performance in pechay

This study investigated the potential of Ficus nota water (FNW) as a natural soaking agent to enhance seed germination, emergence, and subsequent growth performance in Pechay (Brassica rapa subsp. chinensis). Utilizing varying FNW concentrations (0%, 50%, and 100%) and seed soaking durations (2, 4, 6 hours), the research aimed to identify optimal treatment combinations for maximizing pre-transplant vigor and post-transplant productivity of Pechy. The results revealed a significant interaction between FNW concentration and soaking time, accelerating germination onset and promoting germination percentage. Notably, the 50% FNW treatment coupled with the 4-hour soaking duration expedited germination by 60% compared to the untreated control. This optimal priming combination also positively influenced seedling height, root proliferation, and biomass accumulation during the pre-transplant nursery stage. Post-transplantation, FNW-primed seedlings exhibited taller stems and broader leaves compared to non-primed controls. However, despite enhancing vegetative growth, priming did not translate into increased biomass yields, suggesting potential trade-offs in resource allocation patterns. The findings highlight the efficacy of FNW in expediting germination and enhancing nursery vigor, while underscoring the need for further investigations into the mechanisms governing the translation of early growth promotion into marketable yields under field conditions. This research contributes valuable insights into the application of natural plant extracts for optimizing seed priming protocols and potentially improving crop productivity.

Safety and efficacy of tisotumab vedotin with cervical cancers: A systematic review and meta-analysis.

Tisotumab vedotin (TV) holds promise for treating recurrence or metastatic cervical cancer (r/mCC), with recent FDA approval for second-line use in recurrent or metastatic cases. Our research aims to evaluate TV's efficacy and safety in these patients, focusing on overall survival (OS) and progression-free survival (PFS) outcomes. We searched five electronic databases in February 2024, retrieved articles, screened them based on inclusion and exclusion criteria, and assessed their quality. A meta-analysis of the extracted data was performed and applied a random-effects model for our analysis. The search identified 86 articles, with six meeting the inclusion criteria. Meta-analysis revealed 80.8% and 48.0% OS at 6 and 12 months, and a 29.9% PFS at 6 months. Combined treatment with carboplatin or pembrolizumab showed 33.0% PFS at 1 year and 15.1% at 2 years. The objective response rate (ORR) was 21.0%, reaching 43.3% with combined treatment. Confirmed disease control rate (CDCR) was 70.0% overall and in combination. The median duration of response (DOR) was 6.1 months, increasing to 9.5 months in combined treatment, with a consistent time to response (TTR) of 1.4 months. Adverse events included ocular issues (conjunctivitis 30.3%, dry eye 18.7%) and common side effects (nausea 38.4%, epistaxis 35.7%). This systematic review and meta-analysis highlights the potential of TV as a treatment option for r/mCC patients. However, healthcare providers must communicate safety profiles and recommend prophylactic measures for optimal patient outcomes. Further studies, particularly assessing combination treatments, are needed to clarify TV's role in treatment algorithms and improve clinical outcomes.

Cerium Oxide Nanoparticles (CeO2 NPs) Enhance Salt Tolerance in Spearmint (Mentha spicata L.) by Boosting the Antioxidant System and Increasing Essential Oil Composition

Salinity represents a considerable environmental risk, exerting deleterious effects on horticultural crops. Nanotechnology has recently emerged as a promising avenue for enhancing plant tolerance to abiotic stress. Among nanoparticles, cerium oxide nanoparticles (CeO2 NPs) have been demonstrated to mitigate certain stress effects, including salinity. In the present study, the impact of CeO2 NPs (0, 25, and 100 mg L−1) on various morphological traits, photosynthetic pigments, biochemical parameters, and the essential oil profile of spearmint plants under moderate (50 mM NaCl) and severe (100 mM NaCl) salinity stress conditions was examined. As expected, salinity reduced morphological parameters, including plant height, number of leaves, fresh and dry weight of leaves and shoots, as well as photosynthetic pigments, in comparison to control. Conversely, it led to an increase in the content of proline, total phenols, malondialdehyde (MDA), hydrogen peroxide (H2O2), and antioxidant enzyme activities. In terms of CeO2 NP applications, they improved the salinity tolerance of spearmint plants by increasing chlorophyll and carotenoid content, enhancing antioxidant enzyme activities, and lowering MDA and H2O2 levels. However, CeO2 NPs at 100 mg L−1 had adverse effects on certain physiological parameters, highlighting the need for careful consideration of the applied concentration of CeO2 NPs. Considering the response of essential oil compounds, combination of salinity stress and CeO2 treatments led to an increase in the concentrations of L-menthone, pulegone, and 1,8-cineole, which are the predominant compounds in spearmint essential oil. In summary, foliar application of CeO2 NPs strengthened the resilience of spearmint plants against salinity stress, offering new insights into the potential use of CeO2 NP treatments to enhance crop stress tolerance.

Ketamine and Esketamine in Clinical Trials: FDA-Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations.

Ketamine has a long and very eventful pharmacological history. Its enantiomer, esketamine ((S)-ketamine), was approved by the US Food and Drug Administration (FDA) and EMA for patients with treatment-resistant depression (TRD) in 2019. The number of approved indications for ketamine and esketamine continues to increase, as well as the number of clinical trials. This analysis provides a quantitative overview of the use of ketamine and its enantiomers in clinical trials during 2014-2024. A total of 363 trials were manually assessed from clinicaltrial.gov with the search term "Ketamine." The highest number of trials were found for the FDA-approved indications: anesthesia (~22%) and pain management (~28%) for ketamine and TRD for esketamine (~29%). Clinical trials on TRD for both ketamine and esketamine also comprised a large proportion of these trials, and interestingly, have reached phase III and phase IV status. Combinatorial treatment of psychiatric disorders and non-psychiatric conditions with pharmacological and non-pharmacological combinations (electroconvulsive therapy, psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation) is prevalent. Sub-anesthetic doses of ketamine may represent novel therapeutic avenues in neuropsychiatric conditions, that is, major depression, schizophrenia, and bipolar disorder, where glutamate excitotoxicity and oxidative stress are likely to be involved. The study suggests that the number of ketamine studies will continue to grow and possible ketamine variants can be approved for treatment of additional indications.

Immune marker expression and prognosis of early breast cancer expressing HER3

IntroductionThere is a strong rationale for targeting HER3, as HER3 contributes to tumorigenesis and treatment resistance. However, the prognostic role of HER3 and their association with immunoregulatory protein expression has not been established. MethodsThe main objective of this study was to investigate the prognostic role of HER3 expression and identify immunoregulatory marker expression according to HER3 status. HER3 expression and 10 immunoregulatory protein (PD-1/PD-L1/PD-L2/IDO/TIM-3/OX40/OX40L/B7-H2/B7-H3/B7-H4) expression was identified in 320 stage I-III breast cancer patients who received curative surgery at Seoul National University Hospital in 2008. The median follow-up duration was 88.8 months. Criteria for HER3 IHC was adopted from HER2 IHC score and only those with 3 + was considered positive. ResultsAmong 320 patients, 213 (67.2 %) had luminal A disease, 30 (9.5 %) had luminal B disease, 28 (8.8 %) had HER2-positive disease, and 46 (14.5 %) had triple negative disease. HER3 expression was shown in 153 patients (47.8 %). Tumors with HER3-expression had more immunogenic tumor microenvironment compared to HER3-negative tumor. In addition, patients with HER3 expression had favorable 5-year relapse free survival compared to HER3-negative patients (5-year RFS 92.5 % vs. 85.2 %, p = 0.038). However, in the multivariate analysis, HER3 expression was not a prognostic factor, but expression of immunoregulatory protein was a prognostic factor. ConclusionsThis study identified immunoregulatory protein expression according to HER3 status in breast cancer patients. As tumor with HER3 expression have more immunogenic microenvironment, investigating combination treatment of HER3 targeting agent and immunotherapy in HER3 expressing breast cancer may be promising.

Safety and efficacy of sofosbuvir/ledipasvir combination in treatment of chronic hepatitis C infection in adolescents aged 12–17 years old

BackgroundChronic hepatitis C virus (CHC) infection represents a crucial health problem, especially among children and adolescents. The ledipasvir (LDV)/sofosbuvir (SOF) regimen has been approved to treat adolescents (aged 12 to 17 years old) infected with hepatitis C virus (HCV) genotypes 1, 4, 5, and 6 and then extended to include children above or equal to 3 years old. The current study aims to evaluate the safety and efficacy of SOF/LDV combination in treating CHC-infected 12- to 17-year-old adolescents.Patients and methodsThis retrospective cohort study was performed on 147 Egyptian adolescents with CHC. The patients were treated with SOF 400 mg/LDV 90 mg combination once daily for 12 weeks. Possible side effects and laboratory data including HCV ribonucleic acid polymerase chain reaction (RNA PCR), complete blood count (CBC), and liver tests were recorded at baseline and week 12 after the end of treatment (EOT).ResultsSustained virological response 12 weeks (SVR12) after end of treatment (EOT) was observed in 146 out of 147 patients (99.3%). The treatment regimen was efficiently tolerated with no reported cases of discontinuation caused by intolerability. Moreover, the side effects were minimal; 71.4% of the patients did not report any side effects related to the treatment. However, the rest mentioned fatigue, headache, or both of them. Fatigue was the main side effect reported in 16.3% of the patients. Furthermore, ALT and AST levels were normalized after treatment. FIB-4 and APRI scores were statistically significantly decreased 2 years post-SVR, in comparison to their levels before treatment, from 0.34 and 0.36 to 0.25 and 0.17, respectively.ConclusionThe LDV/SOF regimen is one of the safe regimens used to treat adolescent patients with CHC infection.

Rhizome Propagation Methods of Lowland Bamboo (Oxytenanthera abyssinica) in Central Tigray, Northern Ethiopia

Bamboo is a plant species that has a range of economic, environmental, and sociocultural importance. Bamboo can be propagated through sexual and asexual propagation methods. Both methods have their own advantages and disadvantages. This study aims to evaluate different rhizome cutting materials that are relatively suitable for large-scale plantations. The materials for propagating bamboo by vegetative means are whole or portions of the rhizomes, each with a single culm having two to six basal nodes, preferably 1- to 2-year-old culms from the peripheral portion of the clump having 2, 4, 6 basal nodes and 1.5-2 cm, 2-4 cm, and 4-6 cm in diameter. The design of the experiment is a split plot design with three replications and nine plots. This experiment is laid in 1029 m2 (21 m x 49 m). The size of each plot is 45 m2 (15 m by 5 m), and the distance between plots and plants in plots is 2 m. The number of nodes is assigned in the main plot, and the diameter of the planting material is assigned in the subplot. There are a total of 9 treatment combinations and a total of 108 planting materials. Significantly higher (P = 0.01) mean survival rate (59%) was observed in the planting material with two basal nodes and 2-4 cm diameter and the planting material with six nodes and 2-4 cm diameter. Further research is crucial to devise effective vegetative propagation methods for large scale plantations without compromising the survival capability of the planting materials.

Efficacy and safety of a novel low-dose triple single-pill combination of telmisartan, amlodipine and indapamide, compared with dual combinations for treatment of hypertension: a randomised, double-blind, active-controlled, international clinical trial

Single-pill combinations (SPCs) of three low-dose antihypertensive drugs can improve hypertension control but are not widely available. A key issue for any combination product is the contribution of each component to efficacy and tolerability. This trial compared a new triple SPC called GMRx2, containing telmisartan, amlodipine, and indapamide, with dual combinations of components for efficacy and safety. In this international, randomised, double-blind, active-controlled trial, we enrolled adults with hypertension receiving between zero and three antihypertensive drugs, with a screening systolic blood pressure (SBP) ranging from 140-179 mm Hg (on no drugs) to 110-150 mm Hg (on three drugs). Participants were recruited from Australia, the Czech Republic, New Zealand, Poland, Sri Lanka, the UK, and the USA. In a 4-week active run-in, existing medications were switched to GMRx2 half dose (telmisartan 20 mg, amlodipine 2·5 mg, and indapamide 1·25 mg). Participants were then randomly allocated (2:1:1:1) to continued GMRx2 half dose or to each possible dual combination of components at half doses (telmisartan 20 mg with amlodipine 2·5 mg, telmisartan 20 mg with indapamide 1·25 mg, or amlodipine 2·5 mg with indapamide 1·25 mg). At week 6, doses were doubled in all groups, unless there was a clinical contraindication. The primary efficacy outcome was mean change in home SBP from baseline to week 12, and the primary safety outcome was withdrawal of treatment due to an adverse event from baseline to week 12. Secondary efficacy outcomes included differences in clinic and home blood pressure levels and control rates. This study is registered with ClinicalTrials.gov, NCT04518293, and is completed. The trial was conducted between July 9, 2021 and Sept 1, 2023. We randomly allocated 1385 participants to four groups: 551 to GMRx2, 276 to telmisartan-indapamide, 282 to telmisartan-amlodipine, and 276 to amlodipine-indapamide groups. The mean age was 59 years (SD 11), 712 (51%) participants self-reported as female and 673 (48·6%) male, and the mean clinic blood pressure at the screening visit was 142/85 mm Hg when taking an average of 1·6 blood pressure medications. Following the run-in on GMRx2 half dose, the mean clinic blood pressure level at randomisation was 133/81 mm Hg and the mean home blood pressure level was 129/78 mm Hg. At week 12, the mean home SBP was 126 mm Hg in the GMRx2 group, which was lower than for each of the dual combinations: -2·5 (95% CI -3·7 to -1·3, p<0·0001) versus telmisartan-indapamide, -5·4 (-6·8 to -4·1, p<0·0001) versus telmisartan-amlodipine, and -4·4 (-5·8 to -3·1, p<0·0001) versus amlodipine-indapamide. For the same comparisons, differences in clinic blood pressure at week 12 were 4·3/3·5 mm Hg, 5·6/3·7 mm Hg, and 6·3/4·5 mm Hg (all p<0·001). Clinic blood pressure control rate below 140/90 mm Hg at week 12 was superior with GMRx2 (74%) to with each dual combination (range 53-61%). Withdrawal of treatment due to adverse events occurred in 11 (2%) participants in the GMRx2 group, four (1%) in telmisartan-indapamide, three (1%) in telmisartan-amlodipine, and four (1%) in amlodipine-indapamide, with none of the differences being statistically significant. A novel low-dose SPC product of telmisartan, amlodipine, and indapamide provided clinically meaningful improvements in blood pressure reduction compared with dual combinations and was well tolerated. This SPC provides a new therapeutic option for the management of hypertension and its use could result in a substantial improvement in blood pressure control in clinical practice. George Medicines.