Combined Treatment Group Research Articles

Treatment of active ulcerative colitis with Yinmei Kuijie decoction combined with 5-aminosalicylic acid: A non-randomized multicenter prospective observational protocol based on real-world conditions

ObjectiveTo determine the efficacy and safety of the Yinmei Kuijie decoction combined with 5-aminosalicylic acid (5-ASA) in treating mildly to moderately active ulcerative colitis (UC) under real-world conditions. MethodsThis multicenter, prospective, non-randomized, observational study will be conducted in real-world settings. A total of 204 eligible patients will be consecutively enrolled in the study. Patients in the combination treatment group will receive Yinmei Kuijie decoction in combination with 5-ASA, whereas those in the control group will be treated with 5-ASA alone. The primary endpoint will be a clinical response at week 12, defined as a ≥3 point and ≥30% reduction from baseline in the Mayo total score with ≥1 reduction in rectal bleeding or rectal bleeding score = 0 or 1. Secondary efficacy endpoints at week 12 will include health-related quality of life, mucosal healing, and inflammation indicators. ConclusionThe results of this study may provide evidence of the efficacy and safety of Yinmei Kuijie decoction combined with 5-ASA in treating patients with mildly to moderately active UC under real-world principles. The results will provide a basis for further confirmatory studies on the efficacy of Yinmei Kuijie decoction.

TLR7 agonist, DSP-0509, with radiation combination therapy enhances anti-tumor activity and modulates T cell dependent immune activation

BackgroundTLR7 is a key player in the antiviral immunity. TLR7 signaling activates antigen-presenting cells including DCs and macrophages. This activation results in the adaptive immunity including T cells and B cells. Therefore, TLR7 is an important molecule of the immune system. Based on these observations, TLR7 agonists considered to become a therapy weaponize the immune system against cancer. Radiation therapy (RT) is one of the standard cancer therapies and is reported to modulate the tumor immune response. In this study, we aimed to investigate the anti-tumor activity in combination of TLR7 agonist, DSP-0509, with RT and underlying mechanism.ResultWe showed that anti-tumor activity is enhanced by combining RT with the TLR7 agonist DSP-0509 in the CT26, LM8, and 4T1 inoculated mice models. We found that once- weekly (q1w) dosing of DSP-0509 rather than biweekly (q2w) dosing is needed to achieve superior anti-tumor activities in CT26 model. Spleen cells from the mice in RT/DSP-0509 combination treatment group showed increased tumor lytic activity, inversely correlated with tumor volume, as measured by the chromium-release cytotoxicity assay. We also found the level of cytotoxic T lymphocytes (CTLs) increased in the spleens of completely cured mice. When the mice completely cured by combination therapy were re-challenged with CT26 cells, all mice rejected CT26 cells but accepted Renca cells. This rejection was not observed with CD8 depletion. Furthermore, levels of splenic effector memory CD8 T cells were increased in the combination therapy group. To explore the factors responsible for complete cure by combination therapy, we analyzed peripheral blood leukocytes (PBLs) mRNA from completely cured mice. We found that Havcr2low, Cd274low, Cd80high, and Il6low were a predictive signature for the complete response to combination therapy. An analysis of tumor-derived mRNA showed that combination of RT and DSP-0509 strongly increased the expression of anti-tumor effector molecules including Gzmb and Il12.ConclusionThese data suggest that TLR7 agonist, DSP-0509, can be a promising concomitant when used in combination with RT by upregulating CTLs activity and gene expression of effector molecules. This combination can be an expecting new radio-immunotherapeutic strategy in clinical trials.

Combining [177Lu]Lu-DOTA-TOC PRRT with PARP inhibitors to enhance treatment efficacy in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive tumor with neuroendocrine origin. Although SCLC frequently express somatostatin receptor type 2 (SSTR2), a significant clinical benefit of SSTR2-targeted radionuclide therapies of SCLC was not observed so far. We hypothesize that combination treatment with a PARP inhibitor (PARPi) could lead to radiosensitization and increase the effectiveness of SSTR2-targeted therapy in SCLC. SSTR2-ligand uptake of the SCLC cell lines H69 and H446 was evaluated in vitro using flow cytometry, and in vivo using SPECT imaging and cut-and-count biodistribution. Single-agent (Olaparib, Rucaparib, [177Lu]Lu-DOTA-TOC) and combination treatment responses were determined in vitro via cell viability, clonogenic survival and γH2AX DNA damage assays. In vivo, we treated athymic nude mice bearing H69 or H446 xenografts with Olaparib, Rucaparib, or [177Lu]Lu-DOTA-TOC alone or with combination treatment regimens to assess the impact on tumor growth and survival of the treated mice. H446 and H69 cells exhibited low SSTR2 expression, i.e. 60 to 90% lower uptake of SSTR2-ligands compared to AR42J cells. In vitro, combination treatment of [177Lu]Lu-DOTA-TOC with PARPi resulted in 2.9- to 67-fold increased potency relative to [177Lu]Lu-DOTA-TOC alone. We observed decreased clonogenic survival and higher amounts of persistent DNA damage compared to single-agent treatment for both Olaparib and Rucaparib. In vivo, tumor doubling times increased to 1.6-fold (H446) and 2.2-fold (H69) under combination treatment, and 1.0 to 1.1-fold (H446) and 1.1 to 1.7-fold (H69) in monotherapies compared to untreated animals. Concurrently, median survival was higher in the combination treatment groups in both models compared to monotherapy and untreated mice. Fractionating the PRRT dose did not lead to further improvement of therapeutic outcome. The addition of PARPi can markedly improve the potency of SSTR2-targeted PRRT in SCLC models in SSTR2 low-expressing tumors. Further evaluation in humans seems justified based on the results as novel treatment options for SCLC are urgently needed.

Exploring the combined therapeutic efficacy of bexarotene and icariin in type 2 diabetic rats.

The aim of this study was to determine the single and combined antidiabetic activity and side effects of the retinoid X receptor agonist bexarotene and the thioredoxin-interacting protein inhibitor and peroxisome proliferator-activated receptor γ and AMP-activated protein kinase activator icariin. The rats were grouped as healthy (control), diabetes, diabetes + bexarotene (20mg/kg), diabetes + icariin (60mg/kg), diabetes + bexarotene (10mg/kg) + icariin (30mg/kg) low-dose combination and diabetes + bexarotene (20mg/kg) + icariin (60mg/kg) high-dose combination groups. Icariin treatment led to a significant reduction in glucose levels compared with the diabetes control group, a remarkable outcome observed 45 days after the initial application. HbA1c levels of the icariin and low-dose combination treatment groups were significantly lower than in the diabetes group. Notably, icariin treatment also significantly elevated HOMA-β levels, which is indicative of improved β-cell function. Icariin significantly decreased glucose levels at 30 and 120min in the oral glucose tolerance test. Moreover, it ameliorated hepatocyte degeneration, hepatic cord dissociation, congestion, mononuclear cell infiltration in the liver, and degeneration in the pancreas. Icariin treatment exhibited robust antidiabetic effects with fewer side effects than other treatment options in this study. In future studies, long-term and varying doses of icariin will contribute to the development of novel antidiabetic drugs.

Magnetic-guided nanocarriers for ionizing/non-ionizing radiation synergistic treatment against triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is a subtype of breast cancer with the worst prognosis. Radiotherapy (RT) is one of the core modalities for the disease; however, the ionizing radiation of RT has severe side effects. The consistent development direction of RT is to achieve better therapeutic effect with lower radiation dose. Studies have demonstrated that synergistic effects can be achieved by combining RT with non-ionizing radiation therapies such as light and magnetic therapy, thereby achieving the goal of dose reduction and efficacy enhancement.MethodsIn this study, we applied FeCo NPs with magneto thermal function and phototherapeutic agent IR-780 to construct an ionizing and non-ionizing radiation synergistic nanoparticle (INS NPs). INS NPs are first subjected to morphology, size, colloidal stability, loading capacity, and photothermal conversion tests. Subsequently, the cell inhibitory and cellular internalization were evaluated using cell lines in vitro. Following comprehensive assessment of the NPs’ in vivo biocompatibility, tumor-bearing mouse model was established to evaluate their distribution, targeted delivery, and anti-tumor effects in vivo.ResultsINS NPs have a saturation magnetization exceeding 72 emu/g, a hydrodynamic particle size of approximately 40 nm, a negatively charged surface, and good colloidal stability and encapsulation properties. INS NPs maintain the spectral characteristics of IR-780 at 808 nm. Under laser irradiation, the maximum temperature was 92 °C, INS NPs also achieved the effective heat temperature in vivo. Both in vivo and in vitro tests have proven that INS NPs have good biocompatibility. INS NPs remained effective for more than a week after one injection in vivo, and can also be guided and accumulated in tumors through permanent magnets. Later, the results exhibited that under low-dose RT and laser irradiation, the combined intervention group showed significant synergetic effects, and the ROS production rate was much higher than that of the RT and phototherapy-treated groups. In the mice model, 60% of the tumors were completely eradicated.ConclusionsINS NPs effectively overcome many shortcomings of RT for TNBC and provide experimental basis for the development of novel clinical treatment methods for TNBC.

Efficacy and safety of gemcitabine/nab-paclitaxel combined with anlotinib and PD-1 inhibitors as a first-line treatment for advanced pancreatic cancer

ObjectiveTo investigate the clinical efficacy and adverse reactions of gemcitabine/nab-paclitaxel (AG regimen) combined with anlotinib and PD-1 inhibitors as a first-line treatment for advanced pancreatic cancer (PC). MethodsData of 52 patients with advanced PC who were treated in the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China) between August 2019 and March 2023 were retrospectively analyzed. According to the treatment regimen, patients were divided into two groups, including 27 patients in the chemotherapy group (AG regimen) and 25 patients in the combined treatment group (AG regimen combined with anlotinib and PD-1 inhibitors). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse reactions were compared between the two groups. The survival curves of the two groups were drawn using the Kaplan-Meier method, and the differences in PFS and OS between the two groups were compared by the log-rank test. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors influencing prognosis. ResultsThe median OS and PFS in the combined treatment group were significantly longer than those in the chemotherapy group (OS, 12.8 vs. 7.9 months, P = 0.005; PFS, 5.6 vs. 4.4 months, P = 0.003). There was no significant difference in ORR between the two groups (32.0 % vs. 25.9 %, P = 0.629), and DCR in the combined treatment group was significantly better than that in the chemotherapy group (84.0 % vs. 59.3 %, P = 0.049). Grade 1–2 adverse reactions were predominant in both groups, and no adverse reaction-related deaths occurred. ConclusionCompared with chemotherapy alone, AG regimen combined with anlotinib and PD-1 inhibitors exhibited to have a higher efficacy for the first-line treatment of advanced PC, and the adverse reactions were also controllable.

Combined neurokinin-1 receptor antagonist and sorafenib is a promising approach for hepatocellular carcinoma therapy

BackgroundHCC (Hepatocellular carcinoma) is the most common primary malignant cancer in the liver. Treatment options to incurable HCC such as sorafenib, an oral multikinase inhibitor, had numerous side effects and questionable effectiveness. Neurokinin-1 receptor (NK1R) have a major role in inflammation and tumour environment including the resistance to cell death, the induction of angiogenesis and the promotion of cell migration and proliferation. Additionally, NK-1R is over-expressed in human tumour cells including HCC. Moreover, Aprepitant, one of the NK-1R antagonists exerts multiple antitumor activities (antiproliferative, apoptotic, antimigration, and antiangiogenesis) in vivo and in vitro.Study aimTo analyze the effectiveness of combining sorafenib with aprepitant in the management of HCC (experimental).Patients and methodsIn this retrospective experimental study, the human HCC cell line, HepG2, cells were exposed to increasing concentrations of sorafenib alone, aprepitant alone and combination of both sorafenib and aprepitant evaluation of cytotoxicity, apoptosis, MMP-9, VEGF, NF-kB p-65, p-AKT and p-ERK were done. Moreover, The extent of the NK-1 receptor expression was assessed by immunocytochemistry on 50 HCC paraffin blocks of Egyptian HCC patients and another 50 paraffin blocks of liver cirrhosis only as a control.ResultsDecreased levels of MMP-9, VEGF, NF-kB p-65, p-AKT and p-ERK was more substantial in the combination therapy compared to sorafenib alone and aprepitant alone. Moreover, the rate of apoptosis and cytotoxicity were significantly higher in the combination treatment group than the monotherapy groups with more anti inflammatory, anti angiogentic and anti metastatic effects. Also, among the 50 HCC paraffin blocks, the majority (60%) showed a strong NK-1 expression; which significantly (p < 0.05) correlated with the progression free survival (PFS) but not the overall survival (OS) of the patients when applying multivariate analysis.ConclusionHCC had strong expression and immunostaining for NK1R.Therefore, combined aprepitant and sorafenib may be a promising approach in HCC treatment compared to each one alone.

Innovative approaches for coronary heart disease management: integrating biomedical sensors, deep learning, and stellate ganglion modulation

Coronary heart disease (CHD) is a significant global health concern, necessitating continuous advancements in treatment modalities to improve patient outcomes. Traditional Chinese medicine (TCM) offers alternative therapeutic approaches, but integration with modern biomedical technologies remains relatively unexplored. This study aimed to assess the efficacy of a combined treatment approach for CHD, integrating traditional Chinese medicinal interventions with modern biomedical sensors and stellate ganglion modulation. The objective was to evaluate the impact of this combined treatment on symptom relief, clinical outcomes, hemorheological indicators, and inflammatory biomarkers. A randomized controlled trial was conducted on 117 CHD patients with phlegm-turbidity congestion and excessiveness type. Patients were divided into a combined treatment group (CTG) and a traditional Chinese medicinal group (CMG). The CTG group received a combination of herbal decoctions, thread-embedding therapy, and stellate ganglion modulation, while the CMG group only received traditional herbal decoctions. The CTG demonstrated superior outcomes compared to the CMG across multiple parameters. Significant reductions in TCM symptom scores, improved clinical effects, reduced angina manifestation, favorable changes in hemorheological indicators, and decreased serum inflammatory biomarkers were observed in the CTG post-intervention. The combination of traditional Chinese medicinal interventions with modern biomedical sensors and stellate ganglion modulation has shown promising results in improving symptoms, clinical outcomes, and inflammatory markers in CHD patients. This holistic approach enhances treatment efficacy and patient outcomes. Further research and advancements in sensor technology are needed to optimize this approach.

Ecotoxicological Research on the Toxic Impact of Zinc Oxide and Silver Nanoparticles on Oreochromis mossambicus.

Silver nanoparticles (AgNPs) and Zinc oxide nanoparticles (ZnONPs) have been widely used and are eventually been discharged into the natural aquatic ecosystem. The current study examined and correlated the toxicity of AgNPs and ZnONPs on the Mozambique tilapia, Oreochromis mossambicus. Lethal concentration (LC50) was determined with four different concentrations (0.05, 0.10, 0.15, and 0.20 mg/L) of AgNPs and ZnONPs; subsequently, the fishes were exposed to sublethal concentrations for a period of 21 days, and the oxidative stress and antioxidant and nonantioxidant parameters were studied. Results revealed oxidative stress evinced by increased lipid peroxidation (LPO) protein carbonyl activity (PCA), glutathione-S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) activity, metallothionein (MT) activity, and reduced glutathione in chronic exposure compared with acute exposure. Nonspecific immunological characteristics such as lysozyme (LYZ), myeloperoxidase (MPO), and respiratory burst activity (RBA) were also noticed in the serum. Furthermore, severe histological damages including damages in telangiectasia and epithelial cell hyperplasia were found in the combined treated group with Ag and ZnONPs than in individual treatments. When Ag and ZnONPs were combined, a reduction in the accumulation of Ag was observed in the liver, which increased drastically in individual exposure. The current findings highlight the importance of taking into account the combined exposure and correlation of NPs, their bioavailability, and toxicity in the aquatic ecosystem.

Efficacy of hip abductors exercise training combined with repetitive transcranial magnetic stimulation on knee osteoarthritis: A randomized controlled trial.

Knee osteoarthritis is a common degenerative joint disease where a single treatment method often fails to fully alleviate symptoms. Hence, finding effective non-invasive combined treatment approaches is particularly crucial. The efficacy of treating knee osteoarthritis with hip abductors exercise training combined with repetitive transcranial magnetic stimulation was assessed through functional scales and objective evaluation methods. In this four-week randomized clinical trial, 160 patients meeting inclusion criteria were randomly assigned 1:1 to group A to receive oral celecoxib and group B to receive a combination of hip abductors exercise training and repeated transcranial magnetic stimulation. The primary outcome was the western Ontario and McMaster universities osteoarthritis index. The secondary outcomes include Visual Analogue Scale, knee outcome survey activities of daily living scale, Active Range of Motion, and the Quadriceps Angle, the tibiofemoral angle, peak adductor moment, the integrated electromyography and root mean square of the surface electromyography of the lower extremity muscles. Paired sample t test was used for Within-Group comparison of outcome indicators, and independent sample t test was used for Between-Group comparison. Of the 160 randomly assigned patients, 150 completed the study. After 4 weeks, the WOMAC index decreased from 61 ± 10.83 to 40.55 ± 7.58 in the combined treatment group and from 60.97 ± 10.18 to 47.7 ± 10.13 in the celecoxib group. The effect of the combined treatment group was significantly higher than that in the celecoxib group (P< 0.001). In the combined treatment group, the score of knee joint daily living scale increased (P< 0.001), the active range of motion increased (P< 0.001), the quadriceps angle decreased (P< 0.001), the tibiofemoral angle increased (P< 0.001), and the peak adduction moment decreased (P< 0.001), integrated electromyography and root mean square increased (P< 0.001), and the effect was better than that of celecoxib group (P< 0.001). The visual analog scale score in celecoxib group was lower (P< 0.001) and knee outcome survey activities of daily living scale was higher (P< 0.001). The incidence of treatment-related adverse events was 10% in the celecoxib group and 2.5% in the combined treatment group, all of which were mild. Hip abductors exercise training combined with repetitive transcranial magnetic stimulation can enhance abduction muscle strength, improve mobility, reduce joint pain, and enhance quality of life. This combined approach shows superior clinical effectiveness compared to oral celecoxib.

Gentamicin combination treatment is associated with lower mortality in patients with invasive listeriosis: a retrospective analysis.

Listeria monocytogenes causes severe bacterial infections with the highest mortality rate among foodborne pathogens in Europe. Combination treatment with ampicillin and gentamicin is recommended for invasive manifestations. However, evidence to support this treatment approach remains limited due to a lack of randomised controlled trials. To explore this critical issue further, we conducted this retrospective, single-center study. We identified all patients hospitalized with invasive listeriosis at the University Medical Center Hamburg-Eppendorf between 2009 and 2020 and analyzed the effect of gentamicin combination treatment versus monotherapy on 90-day mortality. In total, 36 patients with invasive listeriosis were included, of which 21 patients received gentamicin combination treatment and 15 received monotherapy. The mean age-adjusted Charlson Comorbidity Index (aaCCI) value was lower in the gentamicin combination treatment group (5.4 vs. 7.4). Neurolisteriosis was more common in the gentamicin group (81% vs. 20%). The 90-day mortality was with significantly lower in the gentamicin combination treatment group (10%) compared to the monotherapy group (60%). Multivariable cox regression analysis, adjusted for a propensity score computed based on neurolisteriosis, aaCCI and sex, revealed a significantly reduced hazard ratio of 0.07 (95% CI: 0.01-0.53, p = 0.01) for 90-day mortality for the gentamicin combination treatment. This retrospective study highlights the benefit of gentamicin combination treatment in reducing the 90-day mortality rate among patients with invasive listeriosis. The high prevalence of monotherapy in this study cohort raises concerns about the adequacy of antibiotic therapy in clinical practice.

Efficacy of Aphrodisiac Drugs Combination with Phosphodiesterase-5 (PDE5) Inhibitors in Patients with Erectile Dysfunction (Pilot Study)

Abstract Background Erectile dysfunction is a common medical disorder that primarily affects men older than 40 years of age. Many lines of treatments are used. An aphrodisiac is defined as any food or drug that arouses the sexual instinct, induces sexual desire and increases pleasure and performance. Aim of the Work The aim of this study to assess the efficacy of aphrodisiac drugs (Cavigen), in combination with Phosphodiesterase-5 (PDE5)”Sildenafil” Inhibitors in management of erectile dysfunction in men responding to Phosphodiesterase-5 (PDE5) inhibitors in patients with (IIEF) score: Mild (22-25), mild to moderate (17-21). Patients and Methods This study was a prospective, double-blind, case control placebo (pilot study) performed at the outpatient clinic of the Department of Urology and Andrology, Ain Shams University hospitals. The number of patients after the dropouts and exclusion were 40 patients, twenty in each group one group was administrated gingko biloba capsules(Cavigen) twice daily combined with phosphodiesterase 5 inhibitor (Viagra) on demand and the other one administrated placebo capsules similar to the ginkgo biloba twice daily combined with phosphodiesterase 5 inhibitor (Viagra) on demand. The study protocol was approved by our institutional review board. This study was performed in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement and all participants provided written informed consent before nrolment. Patients were recruited from February 2020 to August 2020 and the final results were obtained in August 2020. Results The present study enrolled two well matched groups, twenty patients in each group as regard base line characteristics including demographic data, pretreatment IIEF total score and pretreatment type of ED. The present study enrolled two well matched groups and both groups showed improvement but there was no significant difference between the studied groups as regard IIEF total score and type of ED at one- and three- months posttreatment. After 6 months posttreatment there was significant difference between the studied groups as regard IIEF total score and type of ED with superiority of combined treatment group. The amount of increase in total score of IIEF after 6 months was found significantly higher in study group (6.35±3.38) than control group (2.15 ± 2.13) with p-value &amp;lt;0.001. In both of studied groups, we found that there was statistically significant increase in the total score of IIEF after 1 month, 3 months and 6 months than pre study and also increase in the percentage of no ED cases after 1 month, 3 months and 6 months than pre study. Conclusion Our findings demonstrate that two Ginkgo Biloba capsules oral intake per day combined with PDE-5 inhibitors on demand were safe and effective for the improvement of erectile function in patients with mild and mild to moderate ED. Overall, Aphrodisiacs drugs seem to be a promising cure for ED and improvement of sexual health.

Analysis of Therapeutic Options for Noise-Induced Hearing Loss: Retroauricular Injection of Methylprednisolone Sodium Succinate Combined with Hyperbaric Oxygenation.

To evaluate the clinical effect of retroaural injection of methylprednisolone sodium succinate combined with hyperbaric oxygen (HBO) on the treatment of noise-induced hearing loss. Case data of 220 patients with hearing loss treated at the Zhongda Hospital Southeast University from January 1, 2019 to August 1, 2023 were obtained. As per the treatment plan, the recruited patients were divided into two cohorts: 158 cases in the combined-treatment group (retroaural injection of methylprednisolone sodium succinate combined with HBO) and 62 cases in the single-hormone group (retroaural injection of methylprednisolone sodium succinate). Comparison of the clinical efficacies and postoperative complication rates of the two groups was performed after treatment. MS-Excel was used to build a database for all data, and SPSS26.0 was utilized in the statistical analysis of recorded data. For patients with low-frequency, high-frequency, and flat descending type, the combined-treatment group showed significantly higher clinical effective rate than the single-hormone group (P < 0.05). For patients with disease duration ≤7 days, the combined-treatment group attained a significantly higher clinical effective rate was than the single-hormone group (P < 0.05). The safety of patients in both groups was evaluated mainly through their adverse reactions. The total incidence of adverse reactions in the single-hormone group reached 9.68%, and that in the combined-treatment group was 8.23%. The two groups revealed no significant difference in terms of incidence of adverse reactions (P > 0.05). HBO combined with retroaural injection of methylprednisolone sodium succinate has good clinical efficacy and safety in the treatment of hearing loss.

Action observation therapy impact on mirror neurons combined with acupuncture for upper limb motor impairment rehabilitation in stroke patients

Abstract: OBJECTIVE: Upper limb (UL) dysfunction rehabilitation in stroke patients is complicated in the clinic. Action observation therapy’s (AOT) impact on mirror neurons (MNs) has been observed and made applications in related brain disease treatment. Acupuncture mentioned in the present study mainly stimulates peripheral nerves for neuronal plasticity. However, the clinical effect of AOT impact on MNs and acupuncture irritate afferent nerve fibers in combination for UL motor impairment rehabilitation after stroke is still unclear. In the present study, we investigate the central and peripheral neural stimulation meanwhile for UL recovery with stroke patients. METHODS: In this clinical study, 82 stroke patients recruited with impaired UL were randomly assigned to three groups. Twenty-four cases were in the AOT group, 28 cases were in the AOT combined acupuncture treatment group, and 30 cases were in the acupuncture treatment group. All volunteers were scored for limb function through the Fugl–Meyer Assessment of the Upper Extremity (FMA-UE), the Action Research Arm Test, and the modified Barthel Index (BI) before and after a systematic treatment according to the groups. Meanwhile, conventional physical therapy was also implemented for all cases. RESULTS: Before the specific intervention, the scores of FMA-UE, FMA-UE, and BI with all stroke patients have no significant statistical difference (P &gt; 0.05). After the corresponding treatment, we assessed UL function again at 4 and 8 weeks. At 4 weeks, the patients with AOT showed a significant increase in BI scores compared to the acupuncture group (P &lt; 0.05). At 8 weeks, the FMA-UE scores of the patients with AOT combined with acupuncture were significantly increased than acupuncture alone (P &lt; 0.05). We also observed that the BI scores of the combination and the AOT group both were improved compared to the acupuncture group with significant statistical analysis (P &lt; 0.05). CONCLUSIONS: Based on the MNs theory, we adopted AOT impact on MNs which would be a promising rehabilitation technique, especially combined with acupuncture treatment in UL recovery of stroke. Mirror therapy seems to be effective for central neuronal plasticity, but for action or AOT, there is still insufficient evidence to recommend its optimal strategy and neuromodulation mechanism. Here, research on the MNs-based AOT technique with acupuncture in UL dysfunction with stroke patients is recommended. TRIAL REGISTRATION: http://www.chictr.org.cn (identifier: ChiCTR2300077010).

Efficacy and safety of regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study.

The RESORCE-III trial demonstrated that advanced hepatocellular carcinoma (HCC) patients who progressed on sorafenib and had second-line therapy with regorafenib improved overall survival compared with placebo. Later, immunotherapy with immune checkpoint inhibitors (ICIs) combined with antiangiogenetic antibodies has evolved as the preferred first-line treatment for fit patients. We aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with ICIs in patients with advanced HCC. We identified 50 patients with advanced HCC treated with regorafenib as a first-line agent. Two patients were lost to follow-up and excluded. Baseline factors, dosing, concomitant use of ICIs, toxicity and outcome of treatment were recorded from electronic medical records. Twenty-six patients received regorafenib as monotherapy and twenty-two received regorafenib + ICI in combination. In the total cohort, the median progression-free survival (mPFS) was 7.7 months and the median overall survival (mOS) was 16.7 months (P=0.02). Objective response rate (ORR) and disease control rate (DCR) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were 21% and 73%. In the regorafenib monotherapy group, mPFS was 5.9 months, and mOS was 13.9 months; in the combination group, mPFS was 7.8 months, and mOS was 23.6 months. ORR and DCR were 15% and 65% in the monotherapy group, and 27% and 82% in the combined treatment group, respectively. Regorafenib used in combination with ICIs had a mild safety profile and resulted in improved response and an almost doubling of mOS compared to monotherapy, warranting further prospective evaluation in a randomized study.

Anti-Inflammation Effectiveness of Ginger (Kaemferia galanga l.) and Shallots (Allium ascalonicum l.) Extract Combination on Sprague-Dawley Male Rat

Inflammation can be caused by various stimuli which include physical injury, infection, heat and antigen antibody interactions. Ginger (Kaempferia galanga L.) and Shallots (Allium ascalonicum L.) are medicinal plants that are often used by Indonesians as an alternative to natural medicine and have been studied to have good anti-inflammatory properties because they contain quercetin. This study aims to determine the effective dose of the combination of Ginger ethanol extract and Shallots as anti-inflammatory with a smaller dose. This study was carried out using male rats in 5 treatment groups, consisting of negative control (CMC-Na 0.5 %), control positive (diclofenac Na tablets 0,1 mg/kg body weight rat), and 3 combination doses of Ginger extract: Shallots extract, dose combination I (3 mg/kg body weight Rat: 2 mg / kg body weight Rat), dose combination II (6 mg / kg body weight Rat : 1 mg/kg body weight Rat), and the dose combination III (6 mg/kg body weight Rat: 2 mg kg body weight Rat) using Carrageenan Method on Rat's Feet. The results of the anti-inflammatory activity test showed that all the dose combination treatment groups had anti-inflammatory. The dose combination III was significantly different from the negative control group and showed the most effective dose of combination. The formulated combination shows a synergistic effect between ginger and shallots as an anti-inflammatory. Average percentage (%) of edema inhibition combination III is 71,08 %.

Effects of Combined Low-Dose Spironolactone Plus Vitamin E versus Vitamin E Monotherapy on Lipidomic Profile in Non-Alcoholic Fatty Liver Disease: A Post Hoc Analysis of a Randomized Controlled Trial.

Background/Objectives: Lipid dysmetabolism seems to contribute to the development and progression of nonalcoholic fatty liver disease (NAFLD). Our aim was to compare serum lipidomic profile between patients with NAFLD having received monotherapy with vitamin E (400 IU/d) and those having received combination therapy with vitamin E (400 IU/d) and low-dose spironolactone (25 mg/d) for 52 weeks. Methods: This was a post hoc study of a randomized controlled trial (NCT01147523). Serum lipidomic analysis was performed in vitamin E monotherapy group (n = 15) and spironolactone plus vitamin E combination therapy group (n = 12). We employed an untargeted liquid chromatography-mass spectrometry lipid profiling approach in positive and negative ionization mode. Results: Univariate analysis revealed 36 lipid molecules statistically different between groups in positive mode and seven molecules in negative mode. Multivariate analysis in negative mode identified six lipid molecules that remained robustly different between groups. After adjustment for potential confounders, including gender, omega-3 supplementation, leptin concentration and homeostasis model assessment-insulin resistance (HOMA-IR), four lipid molecules remained significant between groups: FA 20:5, SM 34:2;O2, SM 42:3;O2 and CE 22:6, all being higher in the combination treatment group. Conclusions: The combination of spironolactone with vitamin E led to higher circulating levels of four lipid molecules than vitamin E monotherapy, after adjustment for potential confounders. Owing to very limited relevant data, we could not support that these changes in lipid molecules may be beneficial or not for the progression of NAFLD. Thus, mechanistic studies are warranted to clarify the potential clinical significance of these findings.

The effects of the combination of temozolomide and Eribulin on T98G human glioblastoma cell line: an ultrastructural study

ABSTRACT Glioblastoma tumors are the most aggressive primary brain tumors that develop resistance to temozolomide (TMZ). Eribulin (ERB) exhibits a unique mechanism of action by inhibiting microtubule dynamics during the G2/M cell cycle phase. We utilized the T98G human glioma cell line to investigate the effects of ERB and TMZ, both individually and in combination. The experimental groups were established as follows: control, E5 (5 nM ERB), T0.75 (0.75 mM TMZ), T1 (1.0 mM TMZ), and combination groups (E5+T0.75 and E5+T1). All groups showed a significant decrease in cell proliferation. Apoptotic markers revealed a time-dependent increase in annexin-V expression, across all treatment groups at the 48-hour time point. Caspase-3, exhibited an increase in the combination treatment groups at the 48-hour mark. Transmission electron microscopy (TEM) revealed normal ultrastructural features in the glioma cells of the control group. However, treatments induced ultrastructural changes within the spheroid glioblastoma model, particularly in the combination groups. These changes included a dose-dependent increase in autophagic vacuoles and apoptotic morphology of the cells. In conclusion, the similarity in the mechanism of action between ERB and TMZ suggests the potential for synergistic effects when combined. Our results highlight that this combination induced severe damage and autophagy in glioma spheroids after 48 hours.

The Liver Circadian Metabolic Homeostasis Influence by Combining Ketogenic Diet with Exercise.

The ketogenic diet (KD) and regular exercise (EX) are both capable of orchestrating circadian metabolism homeostasis during losing weight. However, the combined effects of these two factors on circadian metabolism remain poorly understood. To determine if the combined treatment yields a superimposed physiological phenotype, we measured weight loss, white adipose, the respiratory exchange ratio (RER), heat production, and activity parameters in individual and combined treatment groups. Surprisingly, none of these metrics displayed a cumulative effect when administered in the combined treatment approach. Additionally, we investigated the impact of combination therapy on molecular homeostasis through using high-throughput liver transcriptomic approaches. The results revealed that individual and combined treatments can reprogram the circadian rhythm; yet, the combined group exhibited a minimum quantity of cyclic transcript genes. Noteworthy, the amplitude of 24 h circadian expression genes was not significantly increased in the combination treatment, indicating that the combined approach has non-overlapping effects on maintenance peripheral metabolism homeostasis. This may be due to the liver requiring less ketogenic and gluconeogenic potential during metabolic processes. This research suggests that combined treatment may have adverse effects on the body's homeostasis and provide crucial insights for the homeostatic health of athletes or individuals who wish to lose weight.

Tumor-targeted nano-assemblies for energy-blocking cocktail therapy in cancer

Starvation therapy aims to “starve” tumor cells by cutting off their nutritional supply. However, due to the complex and varied energy metabolism of tumors, targeting a single nutrient supply often fails to yield significant therapeutic benefits. This study proposes a tumor energy cocktail therapy that combines metformin, an oxidative phosphorylation inhibitor, with 2-deoxy-d-glucose (2-DG), a glycolysis inhibitor, to target tumor cells. To minimize the dosage of both drugs, we have developed a drug delivery strategy that prepared metformin as a nanoderivative, denoted as MA-dots. These MA-dots not only preserve the antitumor properties of metformin but also serve as a targeted delivery platform for 2-DG, ensuring its direct reach to the tumor site. Upon reaching the acidic tumor environment, the composite disintegrates, releasing 2-DG to inhibit glycolysis by targeting hexokinase 2 (HK2), the key enzyme in glycolysis, while MA-dots inhibit mitochondrial OXPHOS. This dual action significantly reduces ATP production in tumor cells, leading to apoptosis. In human lung tumor cells, the half-maximal inhibitory concentration (IC50) of 2-DG@MA-dots was significantly lower than that of either metformin or 2-DG alone, showing a nearly 100-fold and 30-fold reduction in IC50 values to 11.78 µg mL−1, from 1159 µg mL−1 and 351.20 µg mL−1, respectively. In studies with A549 tumor-bearing mice, the combination of low-dose 2-DG and metformin did not impede tumor growth, whereas 2-DG@MA-dots markedly decreased tumor volume, with the mean final tumor volume in the combination treatment group being approximately 89 times greater than that in the 2-DG@MA-dot group. Statement of significanceMetformin is a promising antitumor agent capable of modulating mitochondrial oxidative phosphorylation to inhibit cancer growth. However, its antitumor efficacy is limited when used alone due to compensatory energy mechanisms. Hence, we introduced glycolysis inhibitor 2-deoxy-d-glucose (2-DG) to inhibit an alternative tumor energy pathway. In our study, we developed a drug delivery strategy using metformin-derived nanomedicine (MA-dots) to load 2-DG. This approach enables the co-delivery of both drugs and their synergistic effect at the tumor site, disrupting both energy pathways and introducing an innovative “energy cocktail therapy”.