Combined Treatment Research Articles

Immune checkpoint reprogramming via sequential nucleic acid delivery strategy optimizes systemic immune responses for gastrointestinal cancer immunotherapy

Monoclonal antibodies targeting immune checkpoints have been widely applied in gastrointestinal cancer immunotherapy. However, systemic administration of various monoclonal antibodies does not often result in sustained effects in reversing the immunosuppressive tumor microenvironment (TME), which may be due to the spatiotemporal dynamic changes of immune checkpoints. Herein, we reported a novel immune checkpoint reprogramming strategy for gastrointestinal cancer immunotherapy. It was achieved by the sequential delivery of siPD-L1 (siRNA for programmed cell death ligand 1) and pOX40L (plasmid for OX40 ligand), which were complexed with two cationic polymer brush-grafted carbon nanotubes (dense short (DS) and dense long (DL)) designed based on the structural characteristics of nucleic acids and brush architectures. Upon administrating DL/pOX40L for the first three dosages, then followed by DS/siPD-L1 for the next three dosages to the TME, it upregulated the stimulatory checkpoint OX40L on dendritic cells (DCs) and downregulated inhibitory checkpoint PD-L1 on tumor cells and DCs in a sequential reprogramming manner. Compared with other combination treatments, this sequential strategy drastically boosted the DCs maturation, and CD8+ cytotoxic T lymphocytes infiltration in tumor site. Furthermore, it could augment the local antitumor response and improve the T cell infiltration in tumor-draining lymph nodes to reverse the peripheral immunosuppression. Our study demonstrated that sequential nucleic acid delivery strategy via personalized nanoplatforms effectively reversed the immunosuppression status in both tumor microenvironment and peripheral immune landscape, which significantly enhanced the systemic antitumor immune responses and established an optimal immunotherapy strategy against gastrointestinal cancer.

Patient Enrollment per Month (Accrual) in Clinical Trials Leading to the FDA Approval of New Cancer Drugs.

Insufficient patient enrollment per month (=accrual) is the leading cause of cancer trial termination. To identify and quantify factors associated with patient accrual in trials leading to the US Food and Drug Administration (FDA) approval of new cancer drugs. All anti-cancer drugs with FDA approval were identified in the Drugs@FDA database (2000-2022). Data on drug indication's background-, treatment-, disease-, and trial-related factors were collected from FDA labels, clinicaltrials.gov, and the Global Burden of Disease study. The association between patient accrual and collected variables was assessed in Poisson regression models reporting adjusted rate ratios (aRR). We identified 170 drugs with approval in 455 cancer indications on the basis of 292 randomized and 163 single-arm trials. Among randomized trials, median enrollment per month was 38 patients (interquartile range [IQR]: 26-54) for non-orphan, 21 (IQR: 15-38, aRR 0.88, p = 0.361) for common orphan, 20 (IQR: 10-35, aRR 0.73, p <0.001) for rare orphan, and 8 (IQR 6-12, aRR 0.30, p < 0.001) for ultra-rare orphan indications. Patient enrollment was positively associated with disease burden [aRR: 1.0003 per disability-adjusted life year (DALY), p < 0.001), trial sites (aRR: 1.001 per site, p < 0.001), participating countries (aRR: 1.02 per country, p < 0.001), and phase 3 vs. 1/2 trials (aRR: 1.64, p = 0.037). Enrollment was negatively associated with advanced-line vs. first-line treatments (aRR: 0.81, p = 0.010) and monotherapy vs. combination treatments (aRR: 0.80, p = 0.007). Patient enrollment per month was similar between indications with and without a biomarker (median: 27 vs. 32, aRR 0.80, p = 0.117). Patient enrollment per month was substantially lower in government-sponsored than industry-sponsored trials (median: 14 vs. 32, aRR 0.80, p = 0.209). Enrollment was not associated with randomization ratios, crossover, and study blinding. Disease incidence and disease burden alongside the number of study sites and participating countries are the main drivers of patient enrollment in clinical trials. For rare disease trials, greater financial incentives could help expedite patient enrollment. Novel trial design features, including skewed randomization, crossover, or open-label masking, did not entice patient enrollment.

High myopia: Reviews of myopia control strategies and myopia complications.

Myopia and especially high myopia are recognised as major public health concerns. Although the prevalence of high myopia in young children is low, 10-20% of high school children in Asia have high myopia, with many still progressing, and one in three patients with high myopia develop visual impairment with age. Most participants in myopia control studies have low and moderate myopia; relatively little is known about myopia control in high myopia. Literature searches were undertaken in MEDLINE and EMBASE to identify publications in English, investigating (Aim 1) the efficacy of myopia control strategies (environmental, pharmacological and optical) in high myopia (≤-6.00 D) and (Aim 2) the complications of high myopia using keywords. Outcomes included change in spherical equivalent refractive error (SE) and/or axial length (AL) to evaluate progression in high myopia. Aim 1: Twelve studies were identified that reported the efficacy of optical and pharmacological (none on environmental) interventions on AL and SE for high myopia control. A statistically significant reduction in progression of SE and AL in high myopes was reported with 1% and 0.5% atropine. Defocus Incorporated Multiple Segment spectacle lenses had lower efficacy in slowing high myopia progression compared to moderate and low myopia. Ortho-K lenses were equally effective in reducing myopia progression in low, moderate and high myopia. Aim 2: Myopic patients have an increased risk of myopic macular degeneration, retinal detachment, cataract and glaucoma, with the risk increasing with the level of myopia. High myopia has significant effects on quality of life, risk of pathological complications and vision impairment. Young children, excluding those with some syndromic associations, who are fast progressing moderate and high myopes require early intervention and close monitoring. Further research investigating the efficacy of myopia control strategies in highly myopic patients, both independently and through combination treatments, are necessary.

Calcipotriol/Betamethasone Dipropionate for the Treatment of Psoriasis: Mechanism of Action and Evidence of Efficacy and Safety versus Topical Corticosteroids

The combined treatment with calcipotriol (Cal) and betamethasone dipropionate (BDP) has emerged as the leading anti-psoriatic topical treatment. Fixed-dose Cal/BDP is available in different formulations, including ointment, gel, foam, and cream. This review examines the mechanism of action of Cal/BDP underlying its therapeutic effect and compiles the evidence regarding its efficacy and safety compared to monotherapy with topical corticosteroids. The dual-action of Cal/BDP targets the inflammatory pathways and abnormal keratinocyte proliferation, both of them fundamental mechanisms of psoriasis pathogenesis. A large number of randomized, double-blind studies support Cal/BDP superiority over topical corticosteroids, demonstrating its broad efficacy across several degrees of psoriasis severity and its capability to provide early significant clinical improvements. This increased efficacy is achieved without negative effects on the safety profile, since the incidence of adverse effects reported with Cal/BDP is usually similar to that of BDP and even lower than that of Cal alone. The combination therapy rapid onset of action, coupled with a simplified dosing regimen, has been identified as crucial for improving long-term adherence and patient outcomes. In conclusion, Cal/BDP is confirmed as a versatile, effective, and convenient option for the patient in psoriasis management.

Evaluating The Effectiveness of Wastewater Treatment In the Reusable Packaging Industry: A Case Study of ALNER’S WWTP In Indonesia

The widespread use of single-use plastic packaging has become a significant environmental issue, particularly in the Global South. This study examines the innovative approach of the startup Alner, which employs a combination of electrochemical treatment and Moving Bed Biofilm Reactor (MBBR) technology in its wastewater treatment plant (WWTP) to manage wastewater generated from the cleaning of reusable packaging. Wastewater samples were collected before and after treatment, and analyzed for key parameters such as Chemical Oxygen Demand (COD), Biological Oxygen Demand (BOD5), Total Suspended Solids (TSS), oil and grease, ammonia, surfactants, and phosphates. The results demonstrated a significant reduction in all measured pollutants, with COD reduced by 99.58% and BOD5 by 99.56%. Post-treatment values for all parameters were well within the regulatory limits set by the Ministry of Environment and Forestry Regulation No. P68/MenLHK/Setjen/Kum.1/8/2016. This study underscores the potential of reuse models in reducing single-use plastic waste and highlights the importance of effective wastewater treatment in maintaining environmental sustainability. Alner's approach provides a scalable and environmentally friendly solution, setting a benchmark for similar initiatives in the industry, and supports the feasibility and sustainability of integrating advanced wastewater treatment technologies in the reusable packaging sector, offering a comprehensive solution to plastic pollution.

A case of pediatric brain abscess secondary to rhinosinusitis

Acute bacterial rhinosinusitis is a common childhood infection and a frequent complication of viral infections or allergic inflammations of the upper respiratory tract. Untreated cases may have serious complications as meningitis, orbital cellulitis, epidural and brain abscesses (1,2). Brain abscesses rarely seen pediatric infections with high mortality and morbidity rates, are mostly observed secondary to extrasinus spread of rhinosinusitis and acute otitis media, hematogenous spread and penetrating trauma (3). The most common predisposing factors are immunodeficiencies, cyanotic heart and hematologic diseases. A 16-year-old boy was admitted to the emergency service due to seizure. It was learned from his history that he was admitted to the hospital 10 days ago due to headache and high fever. With the diagnosis of acute sinusitis, azithromycin and ornidazole treatment was started, but there was no improvement in his complaints.. On physical examination, clouding of consciousness and postnasal purulent discharge were detected. Remarkable laboratory test results: WBC: 22.500/mm3; platelets 156.000/mm3, C-reactive protein 226 mg/L. Brain tomography revealed a 4-cm suspicious abscess or mass lesion in the right frontal region of the brain compatible with right frontal and ethmoid sinusitis. Upon consultation with pediatric neurology and neurosurgery departments, cranial MRI and MR spectrometry were performed which revealed a lesion compatible with a 4- cm brain abscess, brain edema , shift, and acute sinusitis in the right frontal region. Treatment with cefotaxime, vancomycin and metroinidazole was started for acute sinusitis, and hypertonic sodium infusion and leveteresitam treatment for brain edema. Surgical drainage of the abscess &gt; 2 cm was performed by neurosurgery. Gram staining and culture of the abscess material were unremarkable. Upon evaluation by pediatric immunology, cardiology and hematology departments, immunodeficiency, cyanotic heart disease and hematologic disease were not detected. The lesion was evaluated as inappropriately treated brain abscess secondary to acute sinusitis. In the 2nd week of treatment, edema surrounding the abscess, shift and pressure regressed, but the the abscess did not shrink, so the treatment with meropenem, vancomycin and metroinidazole was initiated. Antiedema therapy was discontinued, and antibiotherapy was maintained for 9 weeks until the abscess size was &lt; 2 cm. When the abscess shrinked below 1 cm in the control cranial images he was discharged with follow-up recommendations. Acute bacterial sinusitis is one of the common, and clinically diagnosed infectious diseases of childhood. And current guidelines recommend amoxicillin, amoxicillin-clavulanic acid and cephalosporins (ie.cefdinir) as the first-line treatment. Considering the high drug resistance in our country, macrolides are not the first choice in patients without a history of penicillin allergy (2). If not treated appropriately, serious cranial complications preventable with timely appropriate antibiotherapy may develop. Brain abscesses are rare but mortal infectious diseases in childhood. The most common cause is the extrasinus spread of infections such as acute rhinosinusitis (3). Combination of medical and surgical treatment is usually recommended for abscesses &gt; 2 cm. For abscesses &lt; 2 cm and inoperable multiple abscesses only medical treatment is an option. Although the duration of treatment depends on the size, location, causative agent and treatment response, medical treatment is recommended for approximately 6-12 weeks until the abscess is &lt; 2 cm (4)

Investigations on structure and properties of poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) reinforced by diss fibers: Effect of various surface treatments

The paper reports some experimental results on the effect of different chemical modifications of Diss fibers on the properties of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) biocomposites involving alkaline, combined alkaline/peroxide and combined alkaline/silane treatments. The biocomposite samples loaded at 20 wt% were prepared by melt compounding. Scanning Electron Microscopy (SEM) showed a better fiber-matrix interaction between Diss fiber and matrix after surface fiber treatment. Differential Scanning Calorimetry (DSC) and X-ray Diffraction (XRD) results indicated an increase in crystallinity index of the biocomposites. In addition, the incorporation of Diss fibers treated with alkali-silane resulted in an improvement in Heat Deflection Temperature (HDT) and shore D hardness from 141.1 °C and 75.1–145.7°C and 86.2, respectively, in comparison with the neat matrix. This also agreed with the flexural properties results, which showed a significant increase in flexural modulus by almost 30 % compared to the neat PHBV. The same trend was observed for water absorption. Overall, combined alkali-silane treatment was found to be most efficient surface treatment method to develop strong interfacial adhesion between PHBV and Diss fiber, increasing the scope of application in manufacturing of light weight green composites.

A tumor targeted nano micelle carrying astragaloside IV for combination treatment of bladder cancer

Immune checkpoint inhibitors (ICIs) are effective agents for tumor immunotherapy. However, their clinical effectiveness is unsatisfactory due to off-target effects and a suppressive immune microenvironment. This study developed a nanodrug delivery system for bladder cancer (BCa) using PCL-MPEG and PCL-PEG-CHO to synthesize internal hydrophobic and external hydrophilic micelles (PP) that encapsulated water-insoluble astragaloside IV (PPA). The aldehyde group on the surface of PPA reacted with the amino group of aPD-L1, allowing the decoration of this antibody on the surface of the micelles. The resultingPPA@aPD-L1effectively piggybacked astragaloside IV and aPD-L1 antibody. These findings suggest that PPA@aPD-L1 is relatively stable in circulation and efficiently binds to BCa cells with the aid of aPD-L1. Additionally, this strategy prolongs the drug’s retention time in tumors. Compared to PBS, PP, and PPA with PPA + aPD-L1 groups, PPA@aPD-L1significantly prolonged the survival of mice with BCa and reduced tumor volume. Mechanistic studies showed that PPA inhibited the NF-κB and STAT3 signaling pathways in tumor cells. Additionally, PPA@aPD-L1increased IFN-γ and decreased IL-10 expression in bladder tumors, affecting the number and type of intratumorally infiltrating T cells. Our study presents a simple and effective drug delivery system that combines herbal monomers with ICIs. It has demonstrated a potent ability to suppress tumor growth and holds potential for future applications.

Efficacy and safety of HAIC combined with tyrosine kinase inhibitors versus HAIC monotherapy for advanced hepatocellular carcinoma: a multicenter propensity score matching analysis

PurposeThis study aimed to assess the clinical efficacy and safety of the combined approach involving hepatic arterial infusion chemotherapy (HAIC) and tyrosine kinase inhibitors (TKIs) for the treatment of advanced hepatocellular carcinoma (HCC).Patients and methodsIn this multicenter retrospective study conducted from January 2020 to December 2023, we reviewed advanced HCC patients who were treated either with HAIC alone or with a combination of HAIC and TKIs. To address initial disparities between the two groups, we employed propensity score matching (PSM). Tumor response evaluation was performed following RECIST 1.1 criteria. We compared survival outcomes, including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), between the two treatment groups. Safety assessments were conducted for all patients.ResultsFollowing the eligibility review, 138 patients underwent combined treatment with HAIC and TKIs (HT group), while 198 patients received HAIC monotherapy (HA group) and met the inclusion criteria for enrollment in this study. After PSM, 107 patients were assigned to each group. The HT group exhibited a longer median OS (18.0 versus 8.8 months; hazard ratio [HR], 0.52, p &amp;lt; 0.001) compared to the HA group. Median PFS was also longer in the HT group, although without statistical significance (6.0 versus 4.7 months; HR, 0.85, p = 0.265). The HT group demonstrated a higher ORR (41.1% versus 25.2%; p = 0.020). No significant differences were observed between the two groups in the incidence of all adverse events (AEs) or grade 3/4 AEs (any grade: 81.2% for HT versus 78.8% for HA, p = 0.68; grade 3/4: 18.1% for HT versus 13.6% for HA, p = 0.29). Importantly, all AEs were manageable and acceptable. Notably, no grade 5 AEs occurred in either group.ConclusionCombination therapy involving HAIC and TKIs effectively prolonged survival in advanced HCC patients. It represented a preferable alternative to HAIC monotherapy, with manageable safety.

Clinical, Genomic, and Transcriptomic Characteristics of Patients with Metastatic Renal Cell Carcinoma Who Developed Thromboembolic Events.

Thromboembolic events (TE) are a common complication in patients with metastatic renal cell carcinoma (mRCC) and are associated with poorer clinical outcomes. However, the incidence of TE and clinical and genomic characteristics of patients with mRCC who develop this complication are poorly understood. Herein, we describe the incidence and clinical features of patients with mRCC with or without TE at our institution, and examine their association with the underlying genomic and transcriptomic characteristics of the tumor. This retrospective study included all consecutive cases of mRCC seen at our institution. A CLIA-certified lab performed tumor genomics and transcriptomics. Patients were classified based on the presence of a TE within the first year of diagnosis. Three hundred and seventy patients with mRCC were included in the study. TE was seen in 11% (42) of the patients. Patients with favorable International mRCC Database Consortium (IMDC) risk were less likely to develop a TE. In contrast, patients receiving combination treatment with a tyrosine kinase inhibitor (TKI) and an immune checkpoint inhibitor were more likely to develop a TE. No difference in overall survival among patients with or without TE was observed (52 vs. 55 months; HR 0.85, 95% CI 0.5574-1.293, p = 0.24). The most upregulated pathways in mRCC with TEs versus those without were the xenobiotic metabolism and mTORC1 signaling pathways. Our findings suggest potential biomarkers that, after external validation, could be used to better select patients who would benefit from prophylactic anticoagulation.

The influence of soil types and agricultural management practices on soil chemical properties and microbial dynamics

Soil provides essential nutrients for plant growth, but excess salts hinder development, making crops more vulnerable under climate change conditions. Soil microorganisms play a significant role in nutrient cycling. However, limited information is available on microbial behavior/community changes, and functional diversity in different soil types (normal, sodic, and highly sodic) and cropping systems [rice-wheat (RW); rice-wheat-mungbean (RWMb); maize-wheat-mungbean (MWMb)] and management practices in the north-western Indo-Gangetic Plains of India. We investigated the influence of different soil types on physical and chemical properties at the surface level (0–15 cm) in relation to soil microbial population, activities, and functional diversity, focusing on community-level physiological profiling (CLPP) under different agriculture systems. Seven treatment combinations of soil types, cropping systems, and management practices were evaluated. Soil pHs were found to be lower in zero-till (ZT)-based sodic soil than in conventional-till (CT) sodic soil. Soil organic carbon (SOC) (0.91 and 0.90%) content and available N (154.46 and 132.74 kg ha−1) were higher with the ZT-based system under normal (N) soils (ZT-RWMb-N and ZT-MWMb-N) than in CT-based normal soil (0.67 and 121.04 kg ha−1). Similarly, higher SOC and N (0.85 and 76.11 kg ha−1) were found under ZT management in sodic soils (S) than under CT management (0.73% and 121.05 kg ha−1). Substrate utilization (amino acids, amines, carbohydrates, carboxylic acids, phenolic compounds, and polymers) increased with the incubation period. During 0–120 h of incubation, the highest utilization of amino acids, amines, carboxylic acids, phenolic compounds, and polymers was observed for ZT-MWMb-S soils, while the lowest was recorded for ZT-MWMb-N soils. Under high salt conditions, soil enzymatic activities (dehydrogenase, acid phosphatase, alkaline phosphatase, etc.) declined significantly compared to normal soils, affecting soil chemical and physical conditions. Microbial population and enzyme activities decreased with increasing salt stress across all cropping systems. These findings suggest that adopting efficient crop management practices can help mitigate the adverse effects of soil salinity on microbial diversity and soil health, thereby enhancing sustainable agricultural productivity in salt-affected regions.

Cervical Cancer Evades the Host Immune System Through the Inhibition of Type I Interferon and CXCL9 by LIF.

Cervical cancer (CC) is a viral-associated tumor caused by the infection with the human papilloma virus. CC is then an immunogenic cancer that expresses viral antigens. Despite being immunogenic, CC does not fully respond to immune checkpoint inhibitors (ICI). LIF is a crucial cytokine in embryo implantation, involved in maternal tolerance that acts as an immunomodulatory factor in cancer. LIF is expressed in CC and high levels of LIF is associated with poor prognosis in CC. We evaluated the impact of LIF on the immune response to ICI using primary plasmocytoid dendritic cells (pDCs) and macrophage cultures, syngeneic animals and patient-derived models that recapitulate the human tumor microenvironment. We found that the viral proteins E6 and E7 induce the expression of LIF via the NFκB pathway. The secreted LIF can then repress type I interferon expressed in pDCs, and CXCL9 expressed in tumor associated macrophages. Blockade of LIF promotes the induction of type I interferon and CXCL9 inducing the tumor infiltration of CD8 T cell. This results in the sensitization of the tumor to ICI. Importantly, we observed that patients with CC expressing high levels of LIF tent to be resistant to ICI. Our data show that the HPV virus induces the expression of LIF to provide a selective advantage to the tumor cell by generating local immunosuppression via the repression of type I interferon and CXCL9. Combinatory treatment with blocking antibodies against LIF and ICI could be effective against CC expressing high levels of LIF.

Investigating the role of GTPase in inhibiting HBV replication and enhancing interferon therapy efficacy in chronic hepatitis B patients

BackgroundInterferon-alpha (IFNα) is a common treatment for chronic hepatitis B virus (HBV) infection, but its efficacy varies widely among patients. GTPASE, an interferon-stimulated gene (ISG), has recently been identified as a factor in antiviral immunity, though its role in HBV infection is not fully understood. ObjectiveThis study investigates the role of GTPASE in enhancing the antiviral effects of IFNα against HBV and elucidates its mechanism of action. MethodsWe analyzed the impact of GTPASE overexpression and silencing on HBV replication and clearance in HBV-infected cells. Molecular docking studies assessed the interaction between GTPASE and HBV surface antigens (HBs). Clinical samples from HBV patients undergoing Peg-IFNα treatment were also evaluated for GTPASE expression and its correlation with treatment efficacy. ResultsOverexpression of GTPASE led to significant inhibition of HBV replication, increased HBeAg seroconversion, and enhanced HBsAg clearance. GTPASE directly bound to HBs proteins, reducing their levels and affecting viral particle formation. Silencing GTPASE reduced these effects, while combined treatment with Peg-IFNα and GTPASE overexpression further improved antiviral outcomes. Mutational analysis revealed that specific sites in GTPASE are crucial for its antiviral activity. ConclusionsGTPASE acts as a positive regulator in IFNα-induced antiviral immunity against HBV. It enhances the therapeutic efficacy of IFNα by targeting HBs and modulating viral replication. GTPASE levels may serve as a predictive biomarker for response to Peg-IFNα therapy, highlighting its potential for improving individualized treatment strategies for chronic HBV infection.

Single and joint bioaccumulation and toxicity of isoproturon and cadmium in green algae (Chlamydomonas reinhardtii)

BackgroundXenobiotics like pesticide isoproturon (IPU) and heavy metal cadmium (Cd) are environmental contaminants posing serious impacts on ecosystem. Understanding their toxic and accumulative processes is crucial to uncover insightful mechanisms and minimize health risks. However, the joint effect of IPU and Cd on microorganisms in aquatic ecosystems remains elusive. In this study, Chlamydomonas reinhardtii was selected as a model unicellular organism to evaluate the ecotoxicological effects of IPU and Cd, focusing on biological responses, bioaccumulation capacity, and environmental adaptation.ResultsThe combined treatment with IPU (0.24 μmol L−1) and/or Cd (20 μmol L−1) for 60 h can induce acute toxicity to C. reinhardtii, reducing chlorophyll and photosynthetic fluorescence, while increasing oxidative damage manifested by lipid membrane peroxides and electrical conductivity. IPU and Cd were accumulated in C. reinhardtii. Interestingly, IPU accumulation in algae was significantly repressed in the presence of Cd, showing a remarkable decrease of 116.7% compared to the IPU treatment alone. Similarly, the Cd concentration in the cells exposed to IPU was reduced by 23.5% compared to Cd treatment alone. Calculation of the bioconcentration factors revealed lower accumulation values of IPU or Cd in algae under Cd+IPU exposure compared to IPU or Cd stress, suggesting an antagonistic interaction between IPU and Cd during absorption by the algae. Furthermore, the activities and transcriptional expression of enzymatic antioxidants such as SOD and APX were significantly induced by Cd stress, whereas the activities of CAT, APX, and PPO significantly increased elevated by IPU.ConclusionsThis study provides compelling evidence of the ecotoxicological effects of combined IPU and cadmium contamination on algae, highlighting the potential of algae for bioremediation of environments contaminated with IPU and cadmium.Graphical

Enhancing mitotane efficacy in adrenocortical carcinoma by calcineurin inhibition with cyclosporine A

Aims: The aim of this study is to determine the effect of calcineurin (CaN) in adrenocortical cancer (ACC) cells, which is a rare but aggressive type of cancer resistant to mitotane therapy. The intracellular calcium signaling pathway is one of the most important mechanisms for cells. The effect of intracellular calcium concentration [(Ca2+i)] on the function of cancer cells is also known. CaN, activated by the binding of calmodulin and Ca2+, is critical in this pathway. Methods: H295 adrenocortical cancer cells were treated with mitotane, cyclosporine A (CsA), and a combination of both. Cell viability, apoptosis, cell cycle, and gene expression levels of apoptosis-related genes (BCL2, BAX, TP53) were analyzed. Western blotting was used to measure CaN protein levels, and wound healing assays assessed cell migration. Results: CsA significantly suppressed CaN protein levels in a dose-dependent manner, reducing cell viability and increasing apoptosis in H295 cells. Mitotane alone also suppressed CaN protein, but the combination of mitotane and CsA had a synergistic effect, further decreasing cell viability and increasing apoptosis. The combination treatment led to significant suppression of the BCL2 gene and upregulation of TP53. Cell cycle analysis showed increased arrest in the G0/G1 phase with combination treatment. Conclusion: Suppression of CaN by CsA enhances the cytotoxic effects of mitotane on ACC cells, suggesting a potential therapeutic strategy to improve ACC treatment outcomes. This study highlights the importance of targeting intracellular calcium signaling pathways to overcome resistance and enhance the efficacy of existing cancer therapies.

Breaking Dormancy of Salak Seeds Using Various Concentration and Soaking Time of Gibberellins GA3

Dormancy is one of the obstacles in cultivating zalacca plants which have hard skin and seeds making them difficult to grow. Soaking using growth hormones is an alternative for growing seeds well. This research aims to determine the concentration of Gibberellin and determine the appropriate length of soaking time for Gibberellin (GA3) in germinating zalacca seeds. The research was carried out at the Seed Science and Technology Laboratory, Faculty of Agriculture, Tadulako University, Palu in January - February 2023 using a Completely Randomized Design with a factorial pattern. The first factor is the Gibberellin’s concentration which consists of 40, 60, and 80 ppm. The second factor was the length of Gibberellin’s soaking time which consists of 15, 55, and 95 minutes so that 9 treatment combinations were obtained which were repeated three times to obtain 27 experimental units. Each experiment used 20 seeds, therefore 540 zalacca seeds were needed, with 5 samples per experimental unit. The results show that gibberellin concentrations of 60 ppm and 80 ppm and soaking times of 55 and 95 minutes were treatments that provided good growth in germination capacity, germination time, plumule length, radicle length and dry weight of zalacca seed sprouts

Exploring the Therapeutic Potential of 5-Fluorouracil-Loaded Calcium Carbonate Nanoparticles Combined with Natural Compound Thymoquinone for Colon Cancer Treatment

Given the need for novel and effective therapies for colon cancer, this study aimed to investigate the effects of 5-fluorouracil-loaded calcium carbonate nanoparticles (5FU-CaCO3np) combined with thymoquinone (TQ) against colon cancer. A shaking incubator and a high-speed homogenizer were used to prepare the optimal 5FU-CaCO3np, with characterizations of physicochemical properties, in vitro drug release profile, and biocompatibility. In vitro experiments and molecular docking were employed to evaluate the therapeutic potential of the combination for colon cancer treatment. Study results revealed that 5FU-CaCO3np with a size of approximately 130 nm was synthesized using the high-speed homogenizer. Its favorable biocompatibility, pH sensitivity, and sustained release properties facilitated reduced toxic side effects of 5-FU on NIH3T3 normal cells and enhanced inhibitory effects on CT26 colon cancer cells. The combination of 5FU-CaCO3np (1.875 μM) and TQ (30 μM) showed significantly superior anti-colon cancer effects to 5FU-CaCO3np alone in terms of cell proliferation and migration inhibition, cell apoptosis induction, and spheroid growth suppression in CT26 cells (p &lt; 0.05), with strong interactions between the drugs and targets (E-cadherin, Bcl-2, PCNA, and MMP-2). These results provide evidence for 5FU-CaCO3np as a novel regimen against colon cancer. Combining 5FU-CaCO3np and TQ may offer a new perspective for colon cancer therapy.

Iron Removal from Low-Grade Pyrophyllite Ore by Microwave Irradiation and Dry Magnetic Separation

Owing to its unique properties, pyrophyllite is an economical alternative to many minerals in different applications. The presence of iron-bearing minerals in Saudi pyrophyllite hampers its industrial uses. The aim of this study was to examine the removal of iron from Saudi low-grade pyrophyllite ore using two approaches. The first approach involves dry high-intensity magnetic separation, whereas the second approach involves microwave pretreatment of the ore before dry magnetic separation. For the first approach, the studied operating parameters were roll speed; feed rate, field intensity, and feed particle size. For the alternative approach, microwave treatment followed by dry magnetic separation, the microwave irradiation time and the magnetic field intensity were studied. The results show that the combined microwave treatment and dry separation method could provide high-purity pyrophyllite for filler industries. Microwave irradiation for 30 min was optimal to change impurity phases (i.e., pyrite, hematite) into ferromagnetic phases in microwave-treated pyrophyllite samples. At a magnetic field intensity of 2000 Gauss, the 30 min microwave-irradiated pyrophyllite sample achieved an iron recovery of 11.2% in non-magnetic fractions, with a removal efficiency of 89% with an alumina recovery of 91.31%.

π-π Stacking Network-Based Supramolecular Peptide Nanoprobe for Visualization of the ICB-Enhanced Ferroptosis Process.

The construction of coassembled peptide nanoprobes based on structural adaptation provides an effective template for stable monitoring of the molecular events in physiological and pathological processes. This also greatly expands their applications in biomedicine, such as multimodal combined diagnosis and treatment. However, the insufficient understanding of the physicochemical properties and structural features of different molecules still makes it difficult to construct the coassembled probes with mutually reinforcing functions, leading to unpredictable effects. Here, we showed how to utilize the π-π stacking network on β-sheets formed by PD-L1-targeting peptides to capture small molecules with ferroptosis functions, thus, coassembling them into a visual probe with synergistic effects. Compared with individual components, the coassembled strategy could significantly improve the stability of the nanoprobe, inducing stronger ferroptosis effects and immune checkpoint blocking effects, and track and reflect the process. This study provides new insights into the design of multicomponent collaborative coassembly systems with biological effects.

In Vitro and In Vivo Effects of Melatonin-Containing Combinations in Human Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis and high mortality rates. Therefore, it is necessary to identify new targets and therapeutic strategies to improve the prognosis of patients with PDAC. Integrative therapies are increasingly being used to boost the efficacy of the known anticancer therapeutic approaches. Hence, this study aimed to evaluate the effects of a novel combination of different potential anticancer molecules, melatonin (MLT), cannabidiol (CBD), and oxygen-ozone (O2/O3) to treat PDAC using in vitro and in vivo models of human PDAC. The effect of this combination was investigated in combination with gemcitabine (GEM), the most common chemotherapeutic drug used for PDAC treatment. The combination of MLT + CBD + O2/O3 was more effective than the individual treatments in inhibiting PDAC cell viability and proliferation, inducing cell death, and modulating the RAS pathway protein levels. Moreover, different combinations of treatments reduced tumor mass in the PDAC mouse model, thus promoting the effect of GEM. In conclusion, a mixture of MLT + CBD + O2/O3 couldserve as a potential adjuvant therapeutic strategy for PDAC.