Combined Treatment Research Articles

Poly (ADP-ribose) polymerase inhibitor sensitized DNA damage caused by an alkylating pyrrole-imidazole polyamide targeting MYCN in neuroblastoma cells

MYCN amplification (MYCN-amp) is a significant prognostic factor and early genetic marker of high-risk neuroblastoma (NB). MYCN induces the DNA damage response (DDR) and modulates the insensitivity of NB cells to Poly (ADP-ribose) polymerase (PARP) inhibitors. We previously reported that CCC-002, a DNA-alkylating agent conjugated with pyrrole-imidazole polyamide targeting MYCN, inhibits NB cell proliferation and induces DNA damage signaling. In this study, we investigated the synergistic effects of CCC-002 and PARP inhibitors on MYCN-amp NB cells. Combination treatment with PARP inhibitors significantly enhanced the sensitivity of MYCN-amp NB cells to CCC-002. DNA damage signals, such as phosphorylation of H2AX and RPA32 elicited after CCC-002 treatment, were further enhanced by PARP inhibitors, as detected through western blotting and immunofluorescence analyses. The potent cytotoxicity of this combination treatment was confirmed by the significant increase in the subG0-G1 phase. Although MYCN knockdown showed no synergistic effect with PARP inhibitors, fluorescence in situ hybridization and quantitative PCR analyses indicated that PARP inhibitors enhanced the effect of CCC-002 to reduce MYCN copy number and suppress its expression. Overall, our study provides novel insights into a therapeutic approach that combines CCC-002 and PARP inhibition to effectively induce DNA damage and apoptosis in MYCN-amp NB cells.

Stress biomarker response in Aporrectodea caliginosa earthworms exposed to single and combined pesticide treatments (Prosaro and Decis).

This study aims to assess the impact of two pesticides commonly used in Algeria (Prosaro XRT and Decis 25 EC), as well as their combinations at recommended doses, on a non-target species bioindicator of soil pollution, the earthworm Aporrectodea caliginosa, using physiological (mortality and growth) and biochemical parameters (proteins, glutathione, catalase activity and glutathione S-transferase, acetylcholine esterase, lipoxygenase). The recommended dose and its double were tested individually and in combination for this. It should be noted that the protocol used and the initial concentrations selected are the same as those used in the field. After 7 and 14 days (7D/14D) of exposure, all dosages were administered. Our findings show that the pesticides tested had no effect on earthworm survival. However, a significant decrease in their growth rates depending on the different concentrations was observed for the different treatments over the entire exposure period of 7 or 14 D. The greatest reductions (31.62%, 35.04%) are reported after 14D for the high concentrations of Decis alone (D2) as well as for the combined treatment Prosaro/Decis (P2/D2). At the same time, an increase in total protein contents (more than 50% after 14D) as well as a decrease in acetylcholine esterase activity were reported for all treatments. We were also able to identify the induction of oxidative stress after xenobiotic exposure, which is more pronounced at the end of the treatment (14D), resulting in the stimulation of the antioxidant system (gluthione, glutathione S-transférase, catalase) as well as the induction of lipoxygenase, which is responsible for the oxidation of polyunsaturated fatty acids as well as the generation of reactive oxygen species (ROS) involved in the inflammatory phenomenon. Finally, it turns out that the species Aporrectodea caliginosa is sensitive to the different concentrations applied, even those used in the open field, and that Decis (deltamethrin) seems to be more toxic than Prosaro and that the combinaison P2/D2 is as toxic as Decis alone (D2).

Concussion Health Improvement Program (CHIP): study protocol for a randomized controlled optimization trial for youth with persistent post-concussive symptoms

BackgroundUp to 1.9 million youth in the USA sustain a concussion each year, and up to 30% experience persistent post-concussive symptoms (PPCS) lasting 1 month or more. PPCS can substantially interfere with social, emotional, and academic functioning. Despite these concerns, few evidence-based treatments are available for youth with PPCS. We previously found effectiveness in treating youth with concussion using a collaborative care intervention that integrates mental health care into a medical model, with improvements in concussive symptoms and quality of life at 1 year. Using the multiphase optimization strategy (MOST) framework, we now aim to assess the contribution of each of the three components that were part of collaborative care: concussion-focused cognitive behavioral therapy (cf-CBT), parenting skills training (PST), and care management (CM).MethodsThe MOST factorial design examines all three intervention components with two levels of each (present or absent), resulting in 8 possible treatment combinations. We will recruit 368 youth with PPCS from 2 geographic locations (Seattle and Dallas), randomizing them to 1 of 8 treatment groups. Youth and/or parents will attend treatment sessions via video conferencing software over 3 months, and complete surveys regarding primary outcomes (concussive symptoms and health-related quality of life) and secondary outcomes (sleep, pain, mood, and parental distress) at 6 weeks and 3, 6, and 12 months. We will also assess potential mediators and moderators to allow for future tailoring and refinement.DiscussionThe overarching goal of this investigation is to determine which collaborative care components (delivered individually or in combination) are most effective in treating PPCS in concussion-exposed youth. The investigation will inform mental health screening, intervention, and referral procedures for youth and families following concussion. At the completion of this study, we will have an optimized and refined intervention for youth with PPCS ready for large-scale implementation and dissemination.Trial registrationClinicalTrials.gov NCT06036147. Registered on September 13, 2023.

Response of Types of Cuttings and IBA Concentration from First Sprout to Highest Sprouting and Rooting in Crossandra (Crossandra infundibuliformis L.)

The present investigation was conducted under Konkan Agro-climatic conditions at College of Horticulture, Dr. Balasaheb Sawant Konkan Krishi Vidyapeeth, Dapoli, Dist. Ratnagiri (India) during the kharif season (2023-2024). The experiment was laid out in Factorial Randomized Block Design (FRBD) with twelve treatment combinations and three replications. Present investigation found that in types of stem cuttings treatment C1 :Softwood cuttings was found best with respect to minimum days to first sprout, days to highest sprouting , maximum number of new sprouts/cuttings, girth of sprout, length of new sprout, number of leaves, leaf area, survival(%), fresh weight of shoot, dry weight of shoot, absolute growth rate, relative growth rate, number of roots, length of longest root, fresh weight of root, dry weight of root, shoot to root ratio. In different IBA concentration treatment H4 : IBA@2000ppm was found best with respect to minimum days to first sprout, days to highest sprouting , maximum number of new sprouts/cuttings, girth of sprout, length of new sprout, number of leaves, leaf area, survival(%), fresh weight of shoot, dry weight of shoot, absolute growth rate, relative growth rate, number of roots, length of longest root, fresh weight of root, dry weight of root. In interaction effect treatment C1H4 (Softwood cuttings treated with IBA@2000 ppm) is found to be most effective among all other treatment combinations in terms of most of the parameters such as Sprouting percentage, Number of new sprouts/cuttings, Length of sprout/cuttings, Girth of new sprout, Number of leaves/cuttings, Leaf area, Survival percentage, Fresh weight of shoot, Relative Growth Rate, Fresh weight to dry weight of shoot ratio, Number of roots.

Effect of heat treatment on the microstructure and mechanical properties of AZ91D magnesium alloy fabricated via GTA wire arc additive manufacturing

This study aims to address elemental segregation and poor mechanical properties in as-deposited AZ91D magnesium alloy fabricated via wire arc additive manufacturing through heat treatment. Three distinct heat treatments are investigated: solution treatment (T4), artificial aging treatment (T5), and a combination of solution and aging treatment (T6). Microstructural analysis reveals equiaxed grains in all samples. In the T4 state, the eutectic phase along grain boundaries dissolvs into the matrix, reducing elemental segregation but increasing grain size. In the T5 state, elemental segregation is further reduced; however, due to the relatively low aging temperature, the microstructural features of the as-deposited state are largely retained. In the T6 state, solution treatment increases grain sizes, and the uneven distribution of the reprecipitated β phase leads variations in mechanical properties between vertical and horizontal directions. Compared to the as-deposited state, the T6 treatment achieves a synergistic improvement in both strength and ductility. The ultimate tensile strength increases to 262.3 MPa, and the elongation rises to 13.8%, representing improvements of 12.5% and 32.7%, respectively, compared to the as-deposited values of 233.2 MPa and 10.4%.

Variation in Thickness of Embryo Covering Structures and Their Role in the Regulation of Seed Physiological Dormancy of Chenopodium hircinum (Amaranthaceae)

Chenopodium hircinum, the putative wild ancestor of quinoa, is a source of traits that could improve the tolerance of crop quinoa to high temperatures. However, seeds of C. hircinum have physiological dormancy (PD), which is an obstacle for plant propagation and use in breeding programs. We studied the intraspecific variability in morpho-anatomical traits of embryo covering structures and their association with PD. We also evaluated the effects of different dormancy-breaking treatments on PD alleviation and germination. Seeds were dispersed with a remnant perianth and a persistent pericarp that could be removed by scraping. The seed coat was formed by palisade cells impregnated with tannins, and the seed contained a thin layer of peripheral endosperm surrounding the embryo. In our investigation, the thickness of the pericarp (P) and/or seed coat (SC) varied among populations. Populations with higher P and/or SC thickness showed lower percentages of germination and water absorption. The combined dormancy-breaking treatment (bleach + perforated coverings + gibberellic acid) promoted dormancy release and increased germination. C. hircinum seeds showed non-deep physiological dormancy. Based on previous knowledge about quinoa, and our results, we conclude that embryo coverings, especially the seed coat, have an important role in dormancy control, imposing a mechanical restraint on radicle emergence.

Envafolimab plus lenvatinib and transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: a prospective, single-arm, phase II study

Evidences regarding the feasibility of transcatheter arterial chemoembolization (TACE)-based therapy for unresectable hepatocellular carcinoma (uHCC) remains limited. This study aimed to investigate the efficacy and safety of TACE combined with envafolimab and lenvatinib for uHCC. Eligible patients with uHCC received envafolimab and lenvatinib after TACE until disease progression, conversion to surgery, intolerable toxicities, or death. The primary endpoint was the objective response rate (ORR) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Between March 2022 and July 2022, 38 patients were included for safety analysis, and 36 patients were included for efficacy analysis. As of the data cutoff (13 December 2023), the median follow-up was 16.9 months. The ORR was 50%, and disease control rate (DCR) was 83.3% per RECIST 1.1 (ORR and DCR of both 83.3% per modified RECIST (mRECIST)). The median progression-free survival (PFS) was 7.58 months. Of 36 patients, 17 patients were converted to resectable HCC with a surgical conversion rate of 47.2%, and 16 patients underwent surgery with R0 resection rate of 100%, pathologic complete response (pCR) rate of 31.3%. Overall incidences of treatment-related adverse events (TRAEs) of any grade was 97.4%. Grade ≥ 3 TRAEs were observed in 52.6% patients. No treatment-related deaths occurred. Image mass cytometry (IMC) analysis revealed that combined treatment improved the immune status of the tumor microenvironment, and resident macrophages had the potential to predict efficacy of this treatment. Envafolimab plus lenvatinib and TACE yielded promising survival outcomes and conversion efficiency with a tolerable safety profile. Trial registration Clinical trials: NCT05213221.

SHR-8068 combined with adebrelimab and bevacizumab in the treatment of refractory advanced colorectal cancer: study protocol for a single-arm, phase Ib/II study

BackgroundThe third-line treatment for refractory colorectal cancer (CRC) has limited efficacy. This study aimed to evaluate the safety and efficacy of SHR-8068 (an anti-CTLA-4 antibody), combined with adebrelimab (an anti-PD-L1 antibody), and bevacizumab in refractory non-microsatellite instability-high (MSI-H) or proficient mismatch repair (pMMR) CRC.MethodThis study is a prospective, open-label, single-center phase Ib/II clinical trial. Patients with pathologically confirmed pMMR/non-MSI-H metastatic colorectal adenocarcinoma who have failed ≥2 lines prior standard systemic treatments will be enrolled (n=36). The Ib phase will evaluate two dosing regimens of SHR-8068 in combination therapy (n=9 each dosage): SHR-8068 (1 mg per kilogram, every six weeks, intravenously) or SHR-8068 (4 mg per kilogram, every twelve weeks, intravenously) combined with adebrelimab (1200 mg, every three weeks, intravenously) and bevacizumab (7.5 mg per kilogram, every three weeks, intravenously). The efficacy and adverse events (AEs) of these regimens will be assessed to determine the recommended phase II dose (RP2D) of SHR-8068. Those of RP2D group from the phase Ib will be included in the phase II. The study will go to include 18 additional patients according to the one-sample log-rank test design in the phase II. The primary endpoint of the Ib phase is safety, with secondary endpoints including the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and quality of life (QOL). The primary endpoint for phase II was PFS, with secondary endpoints including ORR, OS, DCR, safety, and QOL. Identifying biomarkers to predict the efficacy of this regimen is the exploratory study endpoint.DiscussionThis proof-of-concept study would provide safety and efficacy signals of this novel combination treatment for the MSS CRCs in the late-line setting. And it may offer new insights on the clinical application of dual immunotherapy combined with anti-angiogenic therapy in the MSS CRC.

Co-application effects of rice husk biochar and different types of nitrogen fertilizers on rice yield, yield components, and nitrogen use efficiency

The Nitrogen (N) recovery index in rice paddy soils has never been exceeded by more than 30%, regardless of using proven fertilizer management strategies and amounting to significant N being out of rice plant use. Biochar application and the newly released N biofertilizers (singly or in combination) increase the N use efficiency by increasing the soil nutrient retention capacity. Therefore, a two-year pot experiment was conducted to explore the effects of the co-application of rice husk biochar and nitrogen fertilizers on rice yield, yield components, and nitrogen use efficiency indexes. The applied treatments were rice husk biochar at three levels (0, 20, and 40 tha−1) and N fertilizers at three levels (0, chemical (Urea), and N-biofertilizer). The most effective combination treatments (200 kg N ha−1 in source of urea plus 40 tha−1 rice husk biochar) significantly (p ≤ 0.01) increased the grain yield (2.38 times), straw and biological yield (2.83 and 2.62 times, respectively), N content of soil N (59%), nitrogen uptake efficiency (2.92 times), and nitrogen internal efficiency (59%), whereas, nitrogen recovery efficiency decreased by about 52%. Moreover, the maximum increase in N content of grain and harvest index was recorded at combination application of 20 tha−1 biochar plus urea by about 48 and 15%, respectively. It can be concluded that the co-application of rice husk biochar and N fertilizers has substantial advantages over their single applications in terms of N fertilizer recovery, N uptake. Thus, it might be an effective way to enhance rice yield.

Synergistic effects of alkaline and heat treatments on structural and functional properties of mung bean protein isolate: improving physicochemical stability of plant‐based emulsions

SummaryPlant‐based meat alternatives often require fat replacers to mimic the texture of traditional products. This study aimed to develop plant‐based emulsion gels using mung bean protein isolate (MBPI) as a potential fat substitute. However, creating these gels via heat setting requires a high protein concentration, which demands modification of the MBPI structure to enhance emulsifying properties. This study investigated synergistic effects of alkaline treatment (0.3 or 3.5% Na2CO3) and heat treatments (40 or 70 °C) on the functional properties of MBPI at high protein levels, for potential application as a plant‐based emulsion. The combined treatments reduced the zeta potential of protein suspensions from −9 to −19 mV and altered the protein conformation to form smaller particles (from 426 to 166 μm) with increased β‐sheet content. These treatments improved dispersibility of 8% MBPI suspension (58 to 86%), emulsifying activity index (6.34–10.89 m2 g−1), and stability coefficient (43 to 96%). Notably, MBPI samples treated with 0.3% Na2CO3 at 40 and 70 °C exhibited excellent emulsifying properties, forming stable monolayers at the oil–water interface, likely due to the increased surface activity of MBPI. Increasing protein concentration to 11% facilitated heat‐set gel formation; however, addition of 3.5%‐Na2CO3 induced premature gelation, limiting its application in emulsions. At 0.3%‐Na2CO3, increasing the protein content from 8% to 11% and the oil content from 10% to 30% further reduced emulsion droplet size, especially for MBPI treated with 0.3% Na2CO3 at 70 °C (MB‐0.3%‐70 °C) from 5.10 to 2.61 μm, likely due to decreased coalescence. This treatment yielded superior MBPI‐stabilised emulsion gels with enhanced penetration, fluid retention, and stability by possibly reducing protein aggregation. These findings demonstrate the potential of MBPI modified by combined addition of 0.3% Na2CO3 and heat treatment, particularly MB‐0.3%‐70 °C, as a promising ingredient for producing plant‐based emulsions.

Assessing the Synergistic Effects of Deficit Irrigation and Growth Retardants on Insitu Sprouting and Quality Parameters of Groundnut VRI 8

Background: Groundnut is a crucial oilseed crop cultivated year-round, with seed dormancy controlled by genetic and environmental factors. Preventing pre-harvest sprouting is essential, as it is a common issue. To study the effect of deficit irrigation management and foliar application of growth retardant chemicals on pre-harvest sprouting control efficiency to achieve higher yield of groundnut. Methodology: In a field experiment conducted during early summer 2024 at the Agricultural College and Research Institute, Madurai, the effectiveness of different growth retardant chemicals and deficit irrigation management on reducing in-situ sprouting of groundnut kernels was investigated. The experiment included three irrigation management strategies: conventional irrigation and two deficit irrigation treatments where irrigation was withheld from 90 to 105 DAS (Days After Sowing) and 85 to 100 DAS. Additionally, foliar sprays of growth retardant chemicals were applied at 75 and 90 DAS. The chemicals tested were maleic hydrazide (MH) @ 1250 ppm, cycocel (CCC) @ 1000 ppm, abscisic acid (ABA) @ 750 ppm, and salicylic acid (SA) @ 750 ppm. Proper agronomic practices were followed throughout the crop growth cycle. Results: Among the growth retardant chemicals tested, MH @ 1250 ppm proved effective in inducing dormancy. Withdrawal of irrigation from 90 to 105 DAS also significantly contributed to dormancy induction, extending dormancy by more than 5 days post-harvest as well as reduced the pod loss which significantly increased pod yield. It was because of the reduction in soil moisture content during harvest stage and alteration in the hormonal activities. Specifically, the combined treatment of foliar application of MH @ 1250 ppm and no irrigation from 90 to 105 DAS reduced germination percentage by 12.6%, 36.8% and 60.5% immediately 5, 10 and 15 days after harvest respectively. Conclusion: The reduction in soil moisture content during the harvest stage, coupled with changes in hormonal activities, significantly impacts seed sprouting. These factors can lead to stress conditions that hinder germination, ultimately affecting crop yields. Addressing these issues is crucial for ensuring optimal seed development and enhancing agricultural productivity.

Targeting suppression of AKT activation boosts chemosensitivity of hepatocarcinoma cells via regulation of inflammation and metastasis: Functional protection of Rehmapicroside

Hepatocellular carcinoma (HCC) is the most common malignant tumors with poor prognosis and few effective therapeutic strategies. Although cisplatin (cDDP) is the first-line chemotherapy for HCC, its application has been limited due to drug resistance and side effects. Rehmapicroside (Reh) is a major active principle of the root of Radix Rehmanniae that has anti-tumor effects. In the present study, we uncovered the role of Reh in modulating chemosensitivity of cDDP in HCC. We found that combinational treatments of Reh and cDDP significantly reduced the cell proliferation of HCC cells at relatively lower concentrations for each drug. Cell cycle arrest in G2/M phase was markedly induced in HCC cells co-treated with Reh and cDDP compared with cDDP alone group. In addition, Reh dramatically enhanced the capacity of cDDP to induce apoptosis in HCC cells through increasing Caspase-3 cleavage. Co-treatment with Reh and cDDP effectively suppressed tumor growth in xenograft mouse models of HCC without adverse effects. Moreover, migration and invasion of HCC cells were significantly restrained by combinational treatments of Reh and cDDP. Mechanistically, tripartite motif protein 21-phosphatidylinositol 3-kinase/protein kinase B (TRIM21-PI3K/AKT) signaling pathway was considerably impeded in HCC cells and tumor tissues by Reh and cDDPco-treatment. Notably, we found that constitutive activation of AKT almost completely abrogated the capacity of Reh plus cDDP to inhibit cell proliferation, migration, and invasion. Collectively, our results demonstrated that combinational therapy of Reh and cDDP may be a novel and effective therapeutic strategy for HCC treatment.

Metformin in Overcoming Enzalutamide Resistance in Castration-Resistant Prostate Cancer.

Androgen deprivation is the standard treatment for prostate cancer (PCa) patients. However, the disease eventually progresses as castration-resistant PCa (CRPC). Enzalutamide, an AR inhibitor, is a typical drug to treating CRPC and due to continuous reliance on the drug, can lead to Enzalutamide-resistance (ENZ-r). This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential anti-tumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of ENZ-r CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in ENZ-r CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro Following these results, we sought to explore how combination treatment effected mitochondrial fitness utilizing mitochondrial stress test analysis and mitochondrial membrane potential (MMP) shifts due to metformin's action in inhibiting Complex I of oxidative phosphorylation. We employed 2 different strategies of in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of Ras/MAPK signaling following combination treatment. Significance Statement Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. We showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.

Silmitasertib in Combination With Cabozantinib Impairs Liver Cancer Cell Cycle Progression, Induces Apoptosis, and Delays Tumor Growth in a Preclinical Model.

The rising incidence of hepatocellular carcinoma (HCC) is a global problem. Several approved treatments, including immune therapy and multi-tyrosine kinase inhibitors, are used for treatment, although the results are not optimum. There is an unmet need to develop highly effective chemotherapies for HCC. Targeting multiple pathways to attack cancer cells is beneficial. Cabozantinib is an orally available bioactive multikinase inhibitor and has a modest effect on HCC treatment. Silmitasertib is an orally bioavailable, potent CK2 inhibitor with a direct role in DNA damage repair and is in clinical trials for other cancers. In this study, we planned to repurpose these existing drugs on HCC treatment. We observed a stronger antiproliferative effect of these two combined drugs on HCC cells generated from different etiologies as compared to the single treatment. Global RNA-seq analyses revealed a decrease in the expression of G2/M cell cycle transition genes in HCC cells following combination treatment, suggesting G2 phase cell arrest. We observed G2/M cell cycle phase arrest in HCC cells upon combination treatment compared to the single-treated or vehicle-treated control cells. The downregulation of CCNA2 and CDC25C following combination therapy further supported the observation. Subsequent analyses demonstrated that combination treatment inhibited 70 kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and increased Bim expression. Apoptosis of HCC cells were accompanied by increased poly (ADP-ribose) polymerase cleavage and caspase-9 activation. Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.

Preventing Donepezil-Induced Adverse Effects Through N-acetylcysteine Co-Administration.

Drug-induced adverse symptoms affect patients' quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer's disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL. Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and investigate the underlying mechanisms. Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes. High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2+]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2+]i levels in muscle cells. Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2+]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients.

Outcomes After Early Pregnancy Loss Management With Mifepristone Plus Misoprostol vs Misoprostol Alone

Medication management of early pregnancy loss (EPL), or miscarriage, typically involves the administration of misoprostol with or without pretreatment with mifepristone. Combination treatment with mifepristone plus misoprostol is more effective than misoprostol alone but is underutilized in the US. To describe differences in clinical outcomes after EPL management with mifepristone plus misoprostol vs misoprostol alone using commercial claims data. This retrospective cohort study used national insurance claims data from the IBM MarketScan Research Database. Participants included pregnant people (aged 15-49 years) with private insurance who presented with an initial EPL diagnosis between October 1, 2015, and December 31, 2022. The primary exposure was the medication used to manage EPL (ie, mifepristone plus misoprostol or misoprostol alone). Other exposures of interest included demographic characteristics and location of service. The primary outcome was subsequent procedural management (eg, uterine aspiration) after EPL diagnosis and medication management. Other outcomes of interest included return visits, hospitalizations, and complications occurring in the subsequent 6 weeks. Descriptive statistics and bivariate analyses were used, and a multivariable logistic regression model was created to examine factors associated with subsequent procedural management. This study included 31 977 patients (mean [SD] age, 32.7 [5.6] years) with claims for EPL who received medication management. Of these patients, 3.0% received mifepristone plus misoprostol and 97.0% received misoprostol alone. Patients who received misoprostol with pretreatment with mifepristone were less likely to have subsequent uterine aspiration (10.5% vs 14.0%; P = .002), and they were also less likely to have subsequent emergency department (ED) visits for EPL (3.5% vs 7.9%; P < .001). In multivariable analysis, use of mifepristone plus misoprostol was associated with decreased odds of subsequent procedural management (adjusted odds ratio, 0.71 [95% CI, 0.57-0.87]). The findings of this study suggest that mifepristone is underutilized for the medication management of EPL, but its use is associated with a lower need for subsequent uterine aspiration and a decrease in the number of subsequent visits to an ED. Increasing access to mifepristone for EPL management may decrease health care utilization and expenditures.

The DHODH inhibitor teriflunomide impedes cell proliferation and enhances chemosensitivity to daunorubicin (DNR) in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological tumor that requires novel treatment strategies, especially for relapsed/refractory cases. Dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, has been identified as a potential target for tumors. Besides, Teriflunomide (TRF) is a DHODH inhibitor with anticancer effects; however, its role in T-ALL remains poorly understood. Here, we investigated the potential anticancer effects of TRF on T-ALL cells, and the results showed that TRF inhibited cell proliferation, caused S-phase cell cycle arrest, and promoted apoptosis of T-ALL (MOLT4 and JURKAT) cell lines. In addition, TRF reduced the infiltration capacity of T-ALL cells in T-ALL xenograft mice while up-regulating the expression of P53 and BTG2. The BTG2 knockdown significantly attenuated the inhibitory effect of TRF on cellular growth and suppressed the TRF-mediated elevated expression of P53 in T-ALL cells. Moreover, combined treatment with TRF and daunorubicin (DNR) significantly reduced cell viability and promoted apoptosis in DNR-resistant T-ALL cells. Our study provides valuable insights into the critical role of TRF in treating T-ALL while increasing the sensitivity of DNR-resistant T-ALL cells to DNR.

Genomic characterization and clinical evaluation of prosthetic joint infections caused by Cutibacterium acnes.

Prosthetic joint infection (PJI) is a rare complication after arthroplasty surgery. The infection seldom resolves without a combination of both surgical and antibiotic treatment and can cause significant suffering among affected patients. Cutibacterium acnes is a common skin bacterium that is most often found in shoulder PJIs but can also infect other prostheses. In this study, we conducted a review of patients with previously verified PJIs involving C. acnes in hip or shoulder prostheses, along with a genomic analysis of the bacteria causing the infections. The majority of patients had successful outcomes. We did not identify any specific phylogenetic lineage or specific molecular signature of virulence factors among these PJI-associated C. acnes isolates that seemed to be associated with increased potential to cause infection among this species. This indicates that C. acnes isolated from PJIs originates from the patients' own skin microbiome and is inoculated during the arthroplasty surgery.

МОДЕЛЮВАННЯ ТА ОПТИМІЗАЦІЯ РЕЖИМУ ТЕРМООБРОБКИ ТРУБЧАСТИХ ЕЛЕМЕНТІВ ФЕРМЕННИХ КОНСТРУКЦІЙ ЛІТАЛЬНИХ АПАРАТІВ З ВУГЛЕПЛАСТИКУ

The article analyzes the current state of development of dimensionally stable tubular elements (TE) and technological problems arising during their production. It is shown that along with empirical methods of studying the influence of various technological schemes on the dimensional stability of tubular elements, it is useful to use the optimal temperature-time mode for heat treatment and, based on it, select the optimal technological scheme. Modeling and determination of the optimal mode of heat treatment of tubular elements were performed. The study of the TE heat treatment mode was carried out in two stages, first by methods of mathematical modeling and optimization, and then by empirical enumeration of various technological schemes. At the first stage, the material properties, which are parameters of the mathematical model, were studied, and the optimal curing modes were calculated. At the second stage, the calculated optimal curing modes were supplemented with various technological methods that cannot be mathematically modeled, and a study was carried out on the influence of the resulting combined heat treatment mode on the geometric characteristics and dimensional stability of carbon fiber TE. The mathematical model of the process of heat treatment and curing of TE in a heat chamber, when heated by a heating air flow, is a system of differential equations: thermal conductivity and curing kinetics. A mathematical model of the process of heat treatment of tubular elements manufactured by the winding method is proposed, the ways of optimizing the curing mode of carbon fiber TE are shown. A numerical calculation of temperature-conversion fields during curing and calculation of optimal curing modes of tubular elements are performed taking into account various process schemes. The values of heat capacity C and thermal conductivity l are calculated depending on the temperature T, the degree of curing b and the filling coefficient g, Безфітингова ферма з вуглепластику Безфітингова ферма з вуглепластику Безфітингова ферма з вуглепластику the power of heat release W and the thermal effect of the curing reaction Q of carbon fiber. Optimum curing modes for a plate made of composite polymer material are obtained, calculated from the data obtained as a result of studying material samples. Temperature-time curing modes are obtained, which are optimized for different thicknesses of the studied material. The statistical hypothesis about the significance of the influence of the process flow chart and reinforcement pattern on the wall thickness of a tubular element and its compressive strength was proved by the dispersion analysis method. The influence of process flow charts and heat treatment modes on the geometric and mechanical characteristics of carbon fiber tubular elements of aircraft truss structures was studied. The statistical hypothesis about the significance of the influence of the process flow chart and reinforcement pattern on the deviation of the wall thickness of tubular elements and their strength characteristics was tested. The significance of the influence of process flow charts with different heat treatment modes on the average wall thickness of a carbon fiber tubular element was statistically proven.

5-Fluorouracil induces apoptosis in nutritional deprived hepatocellular carcinoma through mitochondrial damage.

5-Fluorouracil (5-FU) is the leading chemotherapeutic drug used to treat hepatocellular carcinoma, one of the major cancer diseases after atherosclerosis. Because of chemo-resistance, the success rate of treatment declines with time due to continuous drug exposure. Though autophagy induction is majorly responsible for acquired resistance, the exact role of this evolutionary conserved mechanism is unknown in cancer cell survival and suppression. The usual practice involves the combinatorial use of chemotherapeutic drugs with autophagy inhibitors like Chloroquine and Bafilomycin A, while neglecting the side effects caused by autophagy impairment in healthy cells. Starvation is a well-known physiological inducer of autophagy. In this study, by caloric modulation, we tried to circumvent the resistance imposed by prolonged drug exposure and investigated the effect of 5-FU in nutrient-sufficient and deficient conditions. Our findings show a substantial correlation between autophagy and increased cancer cell death in the presence of 5-FU, with negligible effects on normal cells. Experimental data revealed that nutritional deprivation augmented cell death in the presence of 5-FU through mitochondrial membrane damage and excessive reactive oxygen species (ROS) production, initiating apoptosis. Lipidation study also unveiled that under such combinatorial treatment cellular metabolism shifts from glucose to lipid biosynthesis. Overall, our experimental findings suggest that nutritional deprivation in combination with chemotherapeutic medication can be a new effective strategy to control hepatocellular carcinoma.