Combined Treatment Research Articles

Effects of dexamethasone combined with vitamin B12 on percutaneous endoscopic interlaminar discectomy early outcomes: a randomized controlled trial.

Residual low back and leg pain can occur after percutaneous endoscopic interlaminar discectomy (PEID) and compromise early surgical outcomes. This study aimed to determine the efficacy of combining dexamethasone with vitamin B12 (VB12) via epidural injection in improving the symptoms of low back and leg pain after PEID, and the underlying mechanism of action. Patients who underwent PEID for lumbar disc herniation (LDH) were enrolled and randomly assigned to the single surgery (SS) group, where disc removal was performed via PEID alone, or the combined treatment (CT) group, which received epidural injections of dexamethasone and VB12 alongside surgery. The outcome measures were the Visual Analog Scale (VAS), Japanese Orthopaedic Association (JOA) score, Oswestry Disability Index (ODI), serum inflammatory factor expression, adverse surgical events, duration of postoperative hospitalization, and modified MacNab criteria. Compared with the SS group, the CT group exhibited lower VAS scores for low back and leg pain at 1, 3, and 7 days post-surgery (P < 0.05). JOA and ODI scores were significantly improved in the CT group than in the SS group 7 days post-surgery (P < 0.05); however, no significant differences were observed at other time points. Serum inflammatory factors were lower in the CT group than in the SS group 3 days post-surgery (P < 0.05). The duration of postoperative hospitalization was shorter in the CT group (P < 0.05). Both groups had similar good outcomes (89.3% vs. 92.2%, P = 0.945). Epidural injection of dexamethasone and VB12 effectively reduces early postoperative low back and leg pain, lowers postoperative inflammatory factor expression, and improves early PEID outcomes. Its clinical adoption merits consideration. This trial was registered with the China Clinical Trial Registration Center (Identifier: ChiCTR2400088854).

Study on the Mechanism of Flavonoid Enrichment in Black Soybean Sprouts by Abscisic Acid/Melatonin Under Slight Acid Treatment

Plant hormones play a critical role in the physiological and biochemical mechanisms of plants, with functions such as regulating the metabolic pathways of secondary metabolite production and alleviating external stresses. In this study, the synthesis of flavonoids in black soybean sprouts was induced by slight acid combined with the plant hormones abscisic acid (ABA) and melatonin (MT). The results indicated that the contents of daidzin, genistin, daidzein, and genistein in black soybean sprouts treated with slight acid were increased by 10 μM ABA and 75 μM MT, and the total flavonoid content was significantly enhanced. Compared with the slight acid treatment, the H2O2 and malondialdehyde (MDA) contents in black soybean sprouts were increased after ABA treatment, and the black soybean sprouts were further stressed. However, the H2O2 and MDA contents in black soybean sprouts were significantly decreased after MT treatment, indicating that the stress of black soybean sprouts can be alleviated by MT. Under slight acid stress, the genes related to flavonoid synthesis in black soybean sprouts were induced by exogenous ABA, promoting the accumulation of flavonoids; under exogenous MT treatment, the activity of phenylpropanoid metabolism enzymes was significantly increased, the genes related to flavonoid synthesis were upregulated, and flavonoid synthesis was induced. These results suggest that the combination of slight acid and plant hormone treatments promotes the accumulation of flavonoid substances during the germination of black soybeans. This research lays the foundation for improving the growth conditions of black soybeans and promoting the enrichment of flavonoid substances in black soybeans.

Synergistic Effects of Waste Glass Powder, High-Frequency Ultrasonic Dispersion, and Liquid Glass Treatment on the Properties of Aluminum-Based Ultra-Lightweight Concrete

This research investigates the impact of waste glass powder, high-frequency ultrasonics (HFUS) dispersion, and liquid glass treatment on aluminum-based ultra-lightweight concrete. Substituting up to 80% of Portland cement with waste glass powder significantly delays hydration and reduces compressive strength by 77%. However, applying HFUS dispersion for 60 s to a mixture with 30% waste glass powder substitution restored compressive strength to the reference value of 3.1 MPa. The combined HFUS and liquid glass treatment enhanced compressive strength by 87%, increased density by 32%, and significantly reduced prosody. Scanning electron microscopy revealed a progressively denser cement matrix with each treatment, highlighting the synergistic effects of these methods in improving concrete properties.

Inhibiting ADAM17 enhances the efficacy of olaparib in ovarian cancer spheroids.

Acquired or de novo resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) is a major challenge to ovarian cancer treatment. Therefore, strategies to overcome PARPi resistance are critical to improve prognosis. The purpose of this study is to evaluate whether inhibition of ADAM17 sensitizes ovarian cancer to treatment with olaparib, a PARPi, thereby bypassing resistance mechanisms and improving treatment response. Thus, we analyzed the effect of olaparib in combination with the ADAM17 inhibitor GW280264X in ovarian cancer using a 2D monolayer and a 3D spheroid model followed by a multicontent readout (viability, caspase activation and cytotoxicity). To emphasize the translational aspect of our work, we performed corresponding experiments on primary cells derived from ovarian cancer patients initially screened for their mutation status of the breast cancer gene (BRCA 1/2). In 2D, we observed a significant reduction in cell viability and a subsequent increase in apoptosis of the combined treatment (olaparib + GW280264X) compared with olaparib mono-treatment. The combined treatment allows a substantial dose reduction of olaparib rendering a strong synergistic effect. Using a 3D spheroid model from primary cells, we confirmed the 2D monoculture results and demonstrated not only increased caspase activity under the combined treatment but also a substantial gain in cytotoxicity compared to the mono-treatment. Our study proposes ADAM17 inhibition sensitizing ovarian cancer to olaparib treatment and improving treatment response.

The radiosensitivity of niraparib tosylate to esophageal squamous cell carcinoma is stronger under hypoxia and higher-pressure conditions

Background: Radiotherapy is an effective method for esophageal squamous cell carcinoma (ESCC) treatment show reduced effectiveness in long-term due to reduced sensitivity of cancer cells to radiotherapy. Niraparib tosylate, a poly ADP-ribose polymerase (PARP) inhibitor may enhance the radiosensitivity of these cells. Hence, the present study was aimed to study the effects of niraparib tosylate on ESCC proliferation, apoptosis and cell cycle along with radiosensitivity enhancement efficiency. Materials and methods: ESCC cell lines, KYSE-30 were subjected to niraparib tosylate or irradiation treatments or combination of both. CCK8 and colony formation assays were performed to monitor cell growth status. Cell cycle and apoptosis level were investigated through flow cytometry. The expressions of targeted genes were detected at protein levels by western blot. Besides, xenografts were successfully established in immunocompromised mice. Student’s t-test was used to compare data and P &lt; 0.05 was considered statistically significant. Results: Treatment with niraparib tosylate showed G2/M cycle arrest and apoptosis in KYSE-30 cells and the rate was observed to be more significant with combination therapy. These effects were further strengthened when cells were cultured under hypoxia and high atmospheric pressure. An enhanced susceptibility to radiotherapy was observed with niraparib tosylate combination. The homologous recombination related regulator, Rad51, showed remarkable upregulation in cancer cells exposed to combination of drug-radiation treatment. The tumor burden was also relieved in xenograft mouse models with combination of drug-radiation treatment, indicating the potential of niraparib tosylate use clinical cancer therapy. Conclusion: From the results, a novel function of niraparib tosylate can be established, impairing DNA damage repair efficiency to increase the susceptibility of ESCC to radiotherapy, resulting in cell apoptosis and G2/M cycle arrest in vitro and in vivo.

Mowing and traditional grazing as a conservation strategy: Fine‐spatial scale impacts on the invasion of false indigo bush (Amorpha fruticosa L.) in marsh meadows

AbstractThis study examined the effects of conservation management strategies, including traditional grazing, on marsh vegetation invaded by false indigo bush (Amorpha fruticosa L.) Fine‐scale methods were employed to analyze vegetation in stands subjected to combined treatments (mowing and grazing) as well as in untreated invaded stands. Vegetation composition and diversity were evaluated using four key metrics: compositional diversity (CD), local distinctiveness (LD), association (AS), and realized species combinations (NRC). Results revealed that the combined treatment led to significantly increased CD (5.366 ± 0.394) and LD (6.41 ± 0.668), despite the presence of the invasive species. Conversely, untreated invaded vegetation exhibited lower CD (3.756 ± 0.755) and LD (4.079 ± 0.93). Additionally, AS and NRC values were higher in treated stands, although the differences were not statistically significant. Notably, the characteristic areas of all functions did not differ significantly between treated and untreated stands. These findings suggest that combining management strategies, such as mowing and traditional grazing, effectively limits A. fruticosa invasion and supports marsh ecosystem diversity by promoting the coexistence of native species. Continuous management, particularly grazing, is crucial, as cessation of these practices may lead to rapid reinvasion by the invasive species and a subsequent loss of native biodiversity. Overall, this study highlights the importance of proactive management strategies in combating invasive species and conserving marshland biodiversity.

Physiological and Biochemical Responses of ‘Burlat’ Sweet Cherry to Pre-Harvest Foliar Application of Calcium and Seaweed Extracts

Sweet cherry (Prunus avium L.) is a highly valued fruit, and optimal nutrient management is crucial for enhancing yield and fruit quality. However, the over-application of chemical fertilizers in cherry cultivation leads to environmental issues such as soil degradation and nutrient runoff. To address this, foliar application, a more targeted and eco-friendly fertilization method, presents a promising alternative. This study evaluates the effects of pre-harvest foliar application of calcium (Ca) (150 and 300 g hL−1) and seaweed extracts (75 and 150 mL hL−1), both individually and in combination, on the physiological and biochemical responses of ‘Burlat’ sweet cherry trees. Key physiological parameters, including plant water status, photosynthetic performance, and leaf metabolites, were analyzed. Results show that trees treated with seaweed extracts or with combined Ca and seaweed application had improved water status, higher sugar, starch, and protein content, as well as enhanced antioxidant activity and phenolic content compared to those treated solely with calcium. However, the combined treatment did not significantly enhance overall tree performance compared to individual applications. This study highlights the potential of seaweed-based biostimulants in sustainable cherry production.

Intratumoral Injectable Redox-Responsive Immune Niche Improves the Abscopal Effect in Radiotherapy.

Radiotherapy (XRT) is often utilized to improve the immune checkpoint blockade response in cancer management. Such combination treatment can enhance the abscopal effect, facilitating a prolonged and durable systemic response. However, despite intense research efforts, only a minority of patients respond to this approach, and novel strategies to increase the abscopal effect are urgently needed. Here, the development of an intratumoral (i.t.) injectable nanofiber (NF)-based tumor immune niche (TIN) that converts XRT-treated tumors into an in situ cancer vaccine, eliciting robust systemic antitumor immunity, is reported. This NF-based immune niche incorporates redox-degradable anti-CTLA-4 (α-CTLA-4) nanogels (NGs) and interleukin-2 (IL-2) NGs for controlled release in hypoxic irradiated tumors, reversing the immunosuppressive tumor microenvironment into a pro-inflammatory microenvironment, and expanding the tumor-infiltrating CD8+ T cell population. Additionally, it is functionalized with polyinosinic-polycytidylic acid (poly(I:C)) to promote antigen-presenting cell maturation and prime neoantigen-specific CD8+ T cells. In vitro studies demonstrate TIN's ability to prime antigen-specific CD8+ T cells and increase antigen-specific cell-killing efficiency under in vitro immunosuppressive conditions. In vivo studies confirm TIN's ability to elicit robust systemic anticancer activity in mouse melanoma and colorectal cancer models without inducing severe immune-related adverse events.

Effect of Spacing and Ratooning on Growth and Yield of Okra (Abelmoschus esculentus L. Moench) Var. Lal Bhendi No. 533

The experiment was laid down in Factorial Randomized Block Design (FRBD) with nine treatment combinations and four replications during year 2023. The experiment consists of two factors, factor A: Spacings (S1- 60 cm x 30 cm, S2- 90 cm x 30 cm and S3- 120 cm x 30 cm) and factor B: Stages of ratooning (R1- Ratooning at 90 DAS, R2- Ratooning at 105 DAS and R3- No ratooning). Among the three spacings, 120 cm x 30 cm (S3) revealed higher values for growth parameters such as number of leaves (33.96), nodes (17.25), branches (1.42), yield parameters like number of fruits (24.37), yield per plant (304.31 g). The highest yield per hectare (15.07 t/ha) was obtained under closer spacing S1 - 60 cm x 30 cm. Among various ratooning treatments, number of fruits (25.33), yield per plant (315.98 g) and total yield (12.51 t/ha) was significantly higher in control (R3-No ratooning), the number of fruits (22.93), yield per plant (277.54 g) and total yield (10.99 t/ha) was greater in R1 than R2. Among ratooning treatment, R1 was better than R2 in terms of growth and yield characters. In interaction, spacing of 120 cm x 30 cm without ratooning (S3R3) was found better with respect to growth and yield of okra, whereas overall yield per hectare (16.53 t/ha) was greater in (S1R3) spacing 60 cm x 30 cm without ratooning. The data recorded in present investigation revealed that spacing and ratooning influenced the growth and yield parameters of okra. Thus, considering the yield of okra, spacing of 60 cm x 30 cm without ratooning found to be beneficial for Konkan agro-climatic conditions.

Synergistic effect of the sphingosine kinase inhibitor safingol in combination with 2'-nitroflavone in breast cancer.

Sphingosine kinase-1 (SPHK1), the enzyme that catalyzes the synthesis of the pro-oncogenic molecule sphingosine-1-phosphate, is commonly upregulated in breast cancer cells and has been linked with poor prognosis and progression by promoting cell transformation, proliferation, angiogenesis, and metastasis. Therefore, SPHK1-targeting drugs have been proposed for breast cancer treatment, with better antitumor results when they are combined with chemotherapy. Previously, we demonstrated that the synthetic flavonoid 2'-nitroflavone (2'NF) exerted a potent and selective antiproliferative effect in murine HER2-positive LM3 mammary tumor cells. As we found that these cells overexpress SPHK1, we decided to explore the antitumor action of the combination of SPHK inhibitors (safingol or SKI-II) with 2'NF. In vitro assays showed that the combination induced a synergistic antiproliferative effect in LM3 cells. Similar results were obtained when human HER2-positive MDA-MB-453 breast cancer cells were treated with the combination of 2'NF/safingol. We also found that safingol potentiated the 2'NF apoptotic effect in both cell lines. The synergistic antitumor effect was confirmed in vivo in an LM3 syngeneic breast cancer model. Moreover, western blot analysis of tumor lysates revealed that combined treatment increased PARP cleavage and Bax protein levels and decreased anti-apoptotic Bcl-xL and Bcl-2 protein levels. Additionally, mice treated with both compounds showed no histopathological effects on different organ tissues. In summary, these findings suggest that the combination safingol/2'NF can be proposed as a potential therapeutic strategy for HER2-positive breast cancer treatment. KEY MESSAGES: The combination safingol/2'-nitroflavone exerts a synergic antitumor action in vitro. Safingol potentiates 2'-nitroflavone apoptotic effect in breast cancer cells. Safingol enhances the 2'-nitroflavone antitumor activity in vivo in breast cancer.

Combined Nabpaclitaxel pressurized intraPeritoneal aerosol chemotherapy with systemic Nabpaclitaxel-Gemcitabine chemotherapy for pancreatic cancer peritoneal metastases: protocol of single-arm, open-label, phase II trial (Nab-PIPAC trial)

Abstract Objectives Current therapies show limited efficacy against peritoneal metastases (PM) from pancreatic cancer. Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) has emerged as a novel intraperitoneal drug delivery method. Recently, a dose-escalation study identified the safe dose of Nabpaclitaxel for PIPAC administration, an ideal intraperitoneal chemotherapy agent against pancreatic cancer. Combining systemic NabPaclitaxel-Gemcitabine with NabPaclitaxel-PIPAC may enhance disease control in pancreatic cancer patients with PM. Methods The Nab-PIPAC trial is a single-center, prospective, open-label, phase II study (ClinicalTrials.gov identifier: NCT05371223). Its primary goal is to evaluate the antitumor activity of the combined treatment based on Disease Control Rate (DCR) using RECISTv.1.1 criteria. Secondary objectives include feasibility, safety, pathological response, progression-free and overall survival, nutritional status, quality of life, pharmacokinetics of NabPaclitaxel-PIPAC, and PM molecular evolution via translational research. The treatment protocol consists of three courses, each with two cycles of intravenous NabPaclitaxel-Gemcitabine and one cycle of NabPaclitaxel-PIPAC, with standard metastatic pancreatic cancer doses for the former and 112.5 mg/m2 for the latter. Sample size follows Simon’s two-stage design: 12 patients in stage one and 26 in stage two (80 % power, 0.1 alpha). Results Partial results will be available after first stage enrollment. Conclusions This trial aims to determine the antitumor efficacy and safety of combining NabPaclitaxel-PIPAC with systemic NabPaclitaxel-Gemcitabine in pancreatic cancer patients with PM.

KRAS inhibitors in drug resistance and potential for combination therapy.

Kirsten Rat Sarcoma (KRAS) is a potent target for cancer therapy because it acts as a signaling hub, engaging in various signaling pathways and regulating a number of cellular functions like cell differentiation, proliferation, and survival. Recently, an emergency approval from the US-FDA has been issued for KRASG12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. However, clinical studies on covalent KRASG12C inhibitors have rapidly confronted resistance in patients. Many methods are being assessed to overcome this resistance, along with various combinatorial clinical studies that are in process. Moreover, because KRASG12D and KRASG12V are more common than KRASG12C, focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors.

Cefiderocol in Combating Carbapenem-Resistant Acinetobacter baumannii: Action and Resistance

Acinetobacter baumannii (A. baumannii) has emerged as a prominent multidrug-resistant (MDR) pathogen, significantly complicating treatment strategies due to its formidable resistance mechanisms, particularly against carbapenems. Reduced membrane permeability, active antibiotic efflux, and enzymatic hydrolysis via different β-lactamases are the main resistance mechanisms displayed by A. baumannii, and they are all effective against successful treatment approaches. This means that alternate treatment approaches, such as combination therapy that incorporates beta-lactams, β-lactamase inhibitors, and novel antibiotics like cefiderocol, must be investigated immediately. Cefiderocol, a new catechol-substituted siderophore cephalosporin, improves antibacterial activity by allowing for better bacterial membrane penetration. Due to its unique structure, cefiderocol can more efficiently target and destroy resistant bacteria by using iron transport systems. Through its inhibition of peptidoglycan formation through binding to penicillin-binding proteins (PBPs), cefiderocol avoids conventional resistance pathways and induces bacterial cell lysis. The possibility of resistance development due to β-lactamase synthesis and mutations in PBPs, however, emphasizes the need for continued investigation into cefiderocol’s efficacy in combination treatment regimes. Cefiderocol’s siderophore mimic mechanism is especially important in iron-limited conditions because it can use ferric-siderophore transporters to enter cells. Additionally, its passive diffusion through bacterial porins increases its intracellular concentrations, making it a good option for treating carbapenem-resistant A. baumannii, especially in cases of severe infections and ventilator-associated diseases (IVACs). Cefiderocol may reduce MDR infection morbidity and mortality when combined with customized antimicrobial treatments, but further investigation is needed to improve patient outcomes and address A. baumannii resistance issues.

Effect of Organic Manures and Biofertilizers on Yield Attributes, Yield and Economics of Mung Bean (Vigna radiata)

Background: Pulses are significant in India's agricultural economy not only for their worth as human food, but also for animals because of their high protein content. Pulses have unique ability of maintaining and restoring soil fertility through biological nitrogen fixation as well as addition of ample amount of residues to the soil. Mung bean, also known as green gram (Vigna radiata) is a small green, and cylindrical-shaped legume that is widely cultivated in various parts of the world, including India, China, and Southeast Asia. Methods: The present study was carried out during the summer season of 2024 at Research Farm, School of Agriculture, OM Sterling Global University, Hisar. Seven treatment combinations comprising organic manures and biofertilizers were tested in randomized block design in three replications. Result: The results revealed that the yield and yield attributes viz., number of pods per plant (15.90), length of pod per plant (10.76 cm), number of seed per pod (11.05), 1000 grain weight per plant (37.00 g) and seed yield (1197 kg ha-1); Economics viz., gross returns (128212 ₹ ha-1), cultivation (43823 ₹ ha-1), net returns (86189 ₹ ha-1) and benefit-cost ratio (3.05) were maximum in the treatment of Jeevamrutha @ 3000 l ha-1 through three splits at sowing, 30 and 45 DAS + Rhizobium +PSB. Whereas, significantly minimum for all above parameters were recorded under control.

The in vitro effect riboflavin combined with or without UVA in Acanthamoeba castellanii.

The anti-Acanthamoeba properties of riboflavin and its enhanced amoebicidal effects when combined with ultraviolet A (UVA) radiation were investigated in vitro. The viability of cultured Acanthamoeba castellanii was assessed by adding varying concentrations (0 ~ 0.2% w/v) of riboflavin to the culture medium or after combined riboflavin and UVA treatment (30min, 3 mW/cm2) over 1, 3, 5, and 7 days. Intracellular reactive oxygen species (ROS) levels were measured following a 30-minute exposure to riboflavin. Additionally, the cysticidal effects of riboflavin, UVA, and their combination were evaluated. Gene transcription in Acanthamoeba was analyzed using RNA-seq.Riboflavin demonstrated dose-dependent toxicity on Acanthamoeba, accompanied by an increase in intracellular ROS. Exposure to 0.2% riboflavin reduced Acanthamoeba viability by over 50% within one day. UVA treatment alone also reduced viability by over 50%. Combined treatment with 0.2% riboflavin decreased trophozoite survival by more than 80%, and approximately 60% of cysts were killed when 0.1% riboflavin was combined with UVA. RNA-seq analysis indicated significant changes in gene expression after exposure to riboflavin, UVA, and their combination, particularly affecting oxidoreductase activity, cystathionine β synthase, and serine-threonine kinase activity. These findings indicate that riboflavin exhibits dose-dependent toxicity in Acanthamoeba, primarily through increased ROS generation. Combining riboflavin and UVA did not fully eradicate trophozoites and cysts of Acanthamoeba, but was able to partially inactivate them.

Taurine and enzymatically modified isoquercitrin synergistically protect against the methotrexate-induced cardiotoxicity in rats: antioxidant and antiapoptotic effects

This study aimed to evaluate the protective potential of taurine (Tau) and enzymatically modified isoquercitrin (EMIQ), both individually and in combination, against MTX-induced cardiotoxicity in male rats. A total of 36 rats were randomly divided into six groups (six animals each): control (vehicle), MTX alone (20 mg/kg, single dose), EMIQ+MTX (EMIQ at 26 mg/kg, p.o. for 16 days, with a single dose of MTX on the 13th day), Tau + MTX (Tau at 500 mg/kg, p.o. for 16 days, with a single dose of MTX on the 13th day), (EMIQ+Tau)+MTX, and (EMIQ+Tau)½+MTX. MTX treatment resulted in elevated levels of cardiac creatine phosphokinase-myocardial band, troponin I, nitric oxide, malondialdehyde, and serum IL-6, while decreasing levels of cardiac myeloperoxidase, catalase, and superoxide dismutase. MTX also reduced expression of BMI-1, induced DNA laddering and fragmentation, and increased cleaved caspase-3 protein expression in cardiac tissue. Both Tau and EMIQ showed equivalent effectiveness in protecting the heart against MTX-induced damage due to their antioxidant, anti-inflammatory, and antiapoptotic properties. Notably, combined treatment with half-doses of Tau and EMIQ offered superior protection compared to full doses of each agent alone. The full-dose combination showed similar efficacy to the half-dose combination, with a few exceptions. Overall, these results suggest a synergistic effect of Tau and EMIQ in mitigating MTX-induced cardiotoxicity, warranting further investigation into the underlying mechanisms.

Ultrasound‐Responsive Lipid Nanoparticles for Targeted Therapy and Controlled Drug Release in Non‐Small Cell Lung Cancer

AbstractMultifunctional drug delivery systems offer tremendous potential for improving antitumor efficacy, precise drug targeting, and controlled drug release in treating non‐small cell lung cancer (NSCLC). In this study, the study develops a novel tumor‐targeting ultrasound‐responsive lipid nanoparticle (TUSL) platform capable of responding to external stimulation, enabling precise drug delivery with controlled release at the tumor site while minimizing systemic exposure and side effects. The TUSL platform is designed to carry doxorubicin (DOX) and tetrandrine (TET), specifically for drug‐resistant NSCLC. The developed TUSL exhibits a nano sized spherical structure with a hydrodynamic size of 141.8 nm, accommodating anti‐cancer drugs with loading capacities of 3.8% and 6.2% for TET and DOX, respectively. TUSL is engineered to target the epidermal growth factor receptor (EGFR) while demonstrating an ultrasound‐triggered drug release profile. Through the generation of CO2 bubbles upon ultrasound stimulation, the TUSL enhances DOX and TET internalization into tumor cells. In tumor‐bearing mice, TUSL administration demonstrates a superior tumor accumulation with minimal off‐target toxicity. The combined treatment with DOX and TET within TUSL exhibits synergistic effects, effectively inhibiting the growth of drug‐resistant NSCLC tumors. These findings highlight the efficacy of the EGFR‐targeted TUSL formulation in overcoming drug resistance and enhancing therapeutic outcomes in NSCLC.

Tanshinone II A Facilitates Chemosensitivity of Osteosarcoma Cells to Cisplatin via Activation of p38 MAPK Pathway.

To examine the mechanism of action of tanshinone II A (Tan II A) in promoting chemosensitization of osteosarcoma cells to cisplatin (DDP). The effects of different concentrations of Tan II A (0-80 µ mol/L) and DDP (0-2 µ mol/L) on the proliferation of osteosarcoma cell lines (U2R, U2OS, 143B, and HOS) at different times were examined using the cell counting kit-8 and colony formation assays. Migration and invasion of U2R and U2OS cells were detected after 24 h treatment with 30 µ mol/L Tan II A, 0.5 µ mol/L DDP alone, and a combination of 10 µ mol/L Tan II A and 0.25 µ mol/L DDP using the transwell assay. After 48 h of treatment of U2R and U2OS cells with predetermined concentrations of each group of drugs, the cell cycle was analyzed using a cell cycle detection kit and flow cytometry. After 48 h treatment, apoptosis of U2R and U2OS cells was detected using annexin V-FITC apoptosis detection kit and flow cytometry. U2R cells were inoculated into the unilateral axilla of nude mice and then the mice were randomly divided into 4 groups of 6 nude mice each. The 4 groups were treated with equal volume of Tan II A (15 mg/kg), DDP (3 mg/kg), Tan II A (7.5 mg/kg) + DDP (1.5 mg/kg), and normal saline, respectively. The body weight of the nude mice was weighed, and the tumor volume and weight were measured. Cell-related gene and signaling pathway expression were detected by RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analysis. p38 MAPK signaling pathway proteins and apoptotic protein expressions were detected by Western blot. In vitro studies have shown that Tan II A, DDP and the combination of Tan II A and DDP inhibit the proliferation, migration and invasion of osteosarcoma cells. The inhibitory effect was more pronounced in the Tan II A and DDP combined treatment group (P<0.05 or P<0.01). Osteosarcoma cells underwent significantly cell-cycle arrest and cell apoptosis by Tan II A-DDP combination treatment (P<0.05 or P<0.01). In vivo studies demonstrated that the Tan II A-DD combination treatment group significantly inhibited tumor growth compared to the Tan II A and DDP single drug group (P<0.01). Additionally, we found that the combination of Tan II A and DDP treatment enhanced the p38 MAPK signaling pathway. Western blot assays showed higher p-p38, cleaved caspase-3, and Bax and lower caspase-3, and Bcl-2 expressions with the combination of Tan II A and DDP treatment compared to the single drug treatment (P<0.01). Tan II A synergizes with DDP by activating the p38/MAPK pathway to upregulate cleaved caspase-3 and Bax pro-apoptotic gene expressions, and downregulate caspase-3 and Bcl-2 inhibitory apoptotic gene expressions, thereby enhancing the chemosensitivity of osteosarcoma cells to DDP.

In Vitro Spermatogenesis on Human Decellularized Testicular Matrix Plates Following Exosome Treatment in a Dynamic Culture System.

Testicular tissue engineering for in vitro spermatogenesis aims to restore fertility, focusing on challenges like efficiency, ethical concerns, and the need for a deeper biological understanding. The use of decellularized scaffolds led to better cell seeding and differentiation, and exosomes led to enhanced spermatogenesis. Also, the dynamic culture systems are being explored to replicate in vivo conditions more accurately. In this study, we aimed to utilize a perfusion mini-bioreactor for the dynamic culture of mouse spermatogonial stem cells on decellularized testicular matrix plates supplemented with exosomes. Our goal was to assess the progression of the spermatogenesis process through histological, immunohistochemical, and molecular analyses over four weeks. Human testicular tissues were decellularized using 1% sodium dodecyl sulfate and were then fabricated into thin plates using a cryostat. Sertoli and spermatogonial stem cells were isolated from neonate mouse testis and seeded onto the decellularized testicular matrix plates. A mini-perfusion bioreactor was employed to create dynamic culture conditions. Also, MSCs-derived exosomes were introduced to the culture medium, alone or in combination with a spermatogenic medium containing numerous chemical factors. The histological, IHC, and molecular analyses were performed at the end of the experiment. Our decellularization procedure successfully preserved the ECM components, while eliminating native cells. The isolated cells expressed PLZF and VIMENTIN markers, confirming the presence of SSCs and Sertoli cells. The seeded scaffolds exhibited proper homing, viability, proliferation, and differentiation of the cells towards in vitro spermatogenesis. Also, exosome treatment is capable of enhancing the spermatogenic potential of SSCs. Our findings indicate that the dynamic culture system significantly promoted the proliferation and differentiation of SSCs into mature spermatozoa. The use of exosomes further enhanced these effects, as evidenced by improved cellular viability, reduced apoptosis, and advanced spermatogenesis to the elongated spermatid stage. The combined treatment of exosomes and spermatogenic medium showed a synergistic effect, yielding superior outcomes in terms of sperm cell maturity and functionality. This study underscores the potential of combining decellularized testicular matrices with exosome therapy in a dynamic culture set up to advance the field of reproductive biology and fertility restoration.

Efficacy and diabetes risk of moderate-intensity statin plus ezetimibe versus high-intensity statin after percutaneous coronary intervention

BackgroundsHigh-intensity statin is recommended for patients undergoing percutaneous coronary intervention (PCI), and ezetimibe is recommended to be added in patients not achieving low-density lipoprotein cholesterol (LDL-C) targets. Moderate-intensity statin plus ezetimibe can reduce LDL-C levels similar to high-intensity statin. The aim of this study is to examine the long-term efficacy and safety of moderate-intensity statin plus ezetimibe as the first-line strategy compared to high-intensity statin in patients undergoing PCI.MethodData was obtained from the Health Insurance Review and Assessment Service database of South Korea. Patients who underwent PCI from 2012 to 2017 were included. The primary efficacy endpoint was major adverse cardiac cerebrovascular events (MACCEs), a composite of all-cause death, revascularization, or ischemic stroke. The safety endpoint was new-onset diabetes mellitus (DM).ResultsA total of 45,501 patients received high-intensity statin (n = 38,340) or moderate-intensity statin plus ezetimibe (n = 7,161). Among propensity-score-matched 7,161 pairs, MACCEs occurred in 1,460 patients with high-intensity statin and 1,406 patients with moderate-intensity statin plus ezetimibe (33.8% vs. 31.9%, hazard ratio 0.96, 95% confidence interval 0.89–1.03, P = 0.27) at a median follow-up of 2.7 years. DM was newly diagnosed in 398 patients with high-intensity statin and 342 patients with moderate-intensity statin plus ezetimibe (12.5% vs. 10.7%; hazard ratio 0.84, 95% confidence interval 0.73–0.97, P = 0.02).ConclusionIn patients undergoing PCI, moderate-intensity statin plus ezetimibe demonstrated a similar risk of MACCEs but a lower risk of new-onset DM than high-intensity statin. Early combination treatment of moderate-intensity statin and ezetimibe may be a useful and safe lipid-lowering strategy after PCI.Graphical abstractCumulative incidence according to the first-line lipid-lowering strategy in patients undergoing percutaneous coronary intervention. Abbreviation: MACCE, major adverse cardiac cerebrovascular events; PCI, percutaneous coronary intervention.