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Drugs Oct 2023After more than 2 decades of recommending an escalating strategy for the treatment of most patients with multiple sclerosis, there has recently been considerable...
After more than 2 decades of recommending an escalating strategy for the treatment of most patients with multiple sclerosis, there has recently been considerable interest in the use of high-efficacy therapies in the early stage of the disease. Early intervention with induction/high-efficacy disease-modifying therapy may have the best risk-benefit profile for patients with relapsing-remitting multiple sclerosis who are young and have active disease, numerous focal T2 lesions on spinal and brain magnetic resonance imaging, and no irreversible disability. Although we have no curative treatment, at least seven classes of high-efficacy drugs are available, with two main strategies. The first strategy involves the use of high-efficacy drugs (e.g., natalizumab, sphingosine 1-phosphate receptor modulators, or anti-CD20 drugs) to achieve sustained immunosuppression. These can be used as a first-line therapy in many countries. The second strategy entails the use of one of the induction drugs (short-term use of mitoxantrone, alemtuzumab, cladribine, or autologous hematopoietic stem cell transplant) that are mainly recommended as a second-line or third-line treatment in patients with very active or aggressive multiple sclerosis disease. Early sustained immunosuppression exposes patients to heightened risks of infection and cancer proportionate to cumulative exposure, and induction drugs expose patients to similar risks during the initial post-treatment period, although these risks decrease over time. Their initial potential safety risks should now be revisited, taking account of long-term data and some major changes in their regimens: natalizumab with the long-term monitoring of John Cunningham virus; use of monthly courses of mitoxantrone with maximum cumulative doses of 36-72 mg/m, followed by a safer disease-modifying drug; cladribine with only 2-weekly treatment courses required in years 1 and 2 and no systematic treatment for the following 2 years; alemtuzumab, whose safety and clinical impacts have now been documented for more than 6 years after the last infusion; and autologous haematopoietic stem cell transplant, which dramatically reduces transplantation-related mortality with a new regimen and guidelines. Escalation and induction/high-efficacy treatments need rigorous magnetic resonance imaging monitoring. Monitoring over the first few years, using the MAGNIMS score or American Academy of Neurology guidelines, considerably improves prediction accuracy and facilitates the selection of patients with relapsing-remitting multiple sclerosis requiring aggressive treatment.
Topics: Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Immunosuppressive Agents; Natalizumab; Cladribine; Alemtuzumab; Mitoxantrone
PubMed: 37725259
DOI: 10.1007/s40265-023-01942-0 -
Cureus Oct 2023This comprehensive literature review underscores the potential of stem cell transplantation (SCT) as a therapeutic intervention for multiple sclerosis (MS). By... (Review)
Review
This comprehensive literature review underscores the potential of stem cell transplantation (SCT) as a therapeutic intervention for multiple sclerosis (MS). By amalgamating evidence from various sources, including randomized controlled trials (RCTs), observational, retrospective, and comparative studies, this review offers a holistic understanding of SCT's effectiveness, safety, and feasibility in diverse contexts of MS management. SCT has shown promise in mitigating disease activity and progression, particularly in relapsing-remitting MS (RRMS). RCTs like the high dose immunoablation and autologous hematopoietic stem cell transplantation in MS (ASTIMS) versus mitoxantrone therapy in severe multiple sclerosis and multiple sclerosis international stem cell transplant (MIST) trials reveal SCT's capacity to reduce new lesion occurrences and inflammatory activity. However, variability exists in disability score improvements among these studies. Observational and retrospective investigations further affirm SCT's potential, highlighting decreased relapse rates, enhanced expanded disability status scale (EDSS) scores, and a noteworthy proportion of patients achieving no evidence of disease activity (NEDA). The initial literature search using all of the search items produced a total of 3,636 articles. After title, abstract, and article type screening and article retrieving, 147 articles were assessed for eligibility using the inclusion criteria. At the end of the literature search, 37 articles met the eligibility criteria. They were included in our review according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Patients treated with hematopoietic stem cell transplantation (HSCT) present lower progression and relapse rates, suppression of inflammatory activity, and a greater reduction in T2 lesions on MRI than those treated with disease-modifying therapies (DMTs). In summary, while SCT presents promise as a therapeutic option for MS, its deployment should be tailored to individual patient characteristics, disease stages, and responses.
PubMed: 38034162
DOI: 10.7759/cureus.47972 -
Nucleic Acids Research Dec 2023DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of...
DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of iM recognition by proteins or small molecules is limited to a few examples. We designed a DNA microarray containing 10976 genomic iM sequences to examine the binding profiles of four iM-binding proteins, mitoxantrone and the iMab antibody. iMab microarray screens demonstrated that pH 6.5, 5% BSA buffer was optimal, and fluorescence was correlated with iM C-tract length. hnRNP K broadly recognizes diverse iM sequences, favoring 3-5 cytosine repeats flanked by thymine-rich loops of 1-3 nucleotides. Array binding mirrored public ChIP-Seq datasets, in which 35% of well-bound array iMs are enriched in hnRNP K peaks. In contrast, other reported iM-binding proteins had weaker binding or preferred G-quadruplex (G4) sequences instead. Mitoxantrone broadly binds both shorter iMs and G4s, consistent with an intercalation mechanism. These results suggest that hnRNP K may play a role in iM-mediated regulation of gene expression in vivo, whereas hnRNP A1 and ASF/SF2 are possibly more selective in their binding preferences. This powerful approach represents the most comprehensive investigation of how biomolecules selectively recognize genomic iMs to date.
Topics: DNA; G-Quadruplexes; Heterogeneous-Nuclear Ribonucleoprotein K; Mitoxantrone; Nucleotide Motifs; Humans; Oligonucleotide Array Sequence Analysis
PubMed: 37962331
DOI: 10.1093/nar/gkad981 -
Aging Jul 2023In this study, we compared the prognosis, tumor immune microenvironment (TIM), and drug treatment response between left-sided (LCC) and right-sided (RCC) colon cancer to...
Comparative analyses of the prognosis, tumor immune microenvironment, and drug treatment response between left-sided and right-sided colon cancer by integrating scRNA-seq and bulk RNA-seq data.
BACKGROUND
In this study, we compared the prognosis, tumor immune microenvironment (TIM), and drug treatment response between left-sided (LCC) and right-sided (RCC) colon cancer to predict outcomes in patients with LCC and RCC.
METHODS
Based on identified differentially expressed genes and using single-cell RNA sequencing data, we constructed and validated a prognostic model for LCC and RCC patients in the TCGA-COAD cohort and GSE103479 cohort. Moreover, we compared the differences of TIM characteristics and drug treatment response between LCC and RCC patients.
RESULTS
We constructed and validated a five-gene prognostic model for LCC patients and a four-gene prognostic model for RCC patients, and both showed excellent performance. The RCC patients with higher risk scores were significantly associated with greater metastasis ( = 2.6×10), N stage ( = 0.012), advanced pathological stage ( = 1.4×10), and more stable microsatellite status ( = 0.007) but not T stage ( = 0.200). For LCC patients, the risk scores were not significantly associated with tumor stage and microsatellite status ( > 0.05). Additionally, immune infiltration by CD8 and regulatory T cells and M0, M1, and M2 macrophages differed significantly between LCC and RCC patients ( < 0.05). and mutations were significantly more common in LCC patients ( < 0.05). In contrast, , , and mutations were significantly more common in RCC patients ( < 0.05). In addition, tumor mutation burden values were significantly higher in RCC patients than in LCC patients ( = 5.9×10). Moreover, the expression of immune checkpoint targets was significantly higher in RCC patients than in LCC patients ( < 0.05), indicating that RCC patients maybe more sensitive to immunotherapy. However, LCC and RCC patients did not differ significantly in their sensitivity to eight selected chemicals or target drugs ( > 0.05). The average half-maximal inhibitory concentrations for camptothecin, teniposide, vinorelbine, and mitoxantrone were significantly lower in low-risk than in high-risk RCC patients ( < 0.05), indicating that the lower risk score of RCC patients, the more sensitive they were to these four drugs.
CONCLUSIONS
We investigated the differences in prognosis, TIM, and drug treatment response between LCC and RCC patients, which may contribute to accurate colon cancer prognosis and treatment of colon cancer.
Topics: Humans; Carcinoma, Renal Cell; RNA-Seq; Single-Cell Gene Expression Analysis; Prognosis; Colonic Neoplasms; Kidney Neoplasms; Tumor Microenvironment
PubMed: 37480572
DOI: 10.18632/aging.204894 -
Biomaterials Jan 2021We developed a novel treatment strategy for metastatic cancer by synergizing photothermal therapy (PTT), chemotherapy, and immunotherapy through a nanosystem to trigger...
We developed a novel treatment strategy for metastatic cancer by synergizing photothermal therapy (PTT), chemotherapy, and immunotherapy through a nanosystem to trigger host antitumor immunity. The nanosystem was constructed by loading mitoxantrone (MTX), a chemotherapeutic agent, and SB-431542 (SB), a transforming growth factor beta (TGF-β) inhibitor, onto reduced graphene oxide (rGO). Intratumoral administration of rGO/MTX/SB, followed by non-invasive irradiation of a near-infrared laser, destroyed local primary tumors and inhibited distant metastases in 4T1 mouse mammary tumor model, which is poorly immunogenic and highly metastatic. After treatment, 70% of the tumor-bearing mice became long-term survivors and developed a tumor type-specific immunity to resist rechallenged tumor cells. We found that rGO-based PTT provided an immunogenic antigen source, forming in situ vaccination with rGO as an immune-adjuvant. The use of SB changed the tumor microenvironment and improved the therapeutic effect of MTX-generated chemotherapy and rGO-based PTT. The immunological functions of MTX, SB, and rGO acted synergistically to induce an effective tumor vaccination, as evidenced by the increased infiltration of tumor-specific cytotoxic CD8 T lymphocytes and decreased infiltration of regulatory T cells (Tregs) in distal tumors. Collectively, we demonstrated that rGO/MTX/SB combined with laser irradiation provided a synergistic chemo-immuno-photothermal effect against tumors by in situ vaccination and inhibition of immunosuppressive microenvironment. This unique combination embodies a promising approach to treat metastatic cancers by inducing a systemic antitumor response through a local intervention.
Topics: Animals; Cell Line, Tumor; Graphite; Immunotherapy; Mice; Mice, Inbred BALB C; Neoplasms; Phototherapy
PubMed: 32992117
DOI: 10.1016/j.biomaterials.2020.120421 -
Frontiers in Cardiovascular Medicine 2021The cardiovascular toxicity of anticancer drugs promotes the development of cardiovascular diseases. Therefore, cardiovascular toxicity is an important safety issue that... (Review)
Review
The cardiovascular toxicity of anticancer drugs promotes the development of cardiovascular diseases. Therefore, cardiovascular toxicity is an important safety issue that must be considered when developing medications and therapeutic applications to treat cancer. Among anticancer drugs, members of the anthracycline family, such as doxorubicin, daunorubicin and mitoxantrone, are known to cause cardiotoxicity and even heart failure. Using human-induced pluripotent stem cell-derived cardiomyocytes in combination with "Omic" technologies, we identified several cardiotoxicity mechanisms and signal transduction pathways. Moreover, these drugs acted as cardiovascular toxicants through a syndrome of mechanisms, including epigenetic ones. Herein, we discuss the main cardiovascular toxicity mechanisms, with an emphasis on those associated with reactive oxygen species and mitochondria that contribute to cardiotoxic epigenetic modifications. We also discuss how to mitigate the cardiotoxic effects of anticancer drugs using available pharmaceutical "weapons."
PubMed: 33987212
DOI: 10.3389/fcvm.2021.658900 -
Der Nervenarzt Oct 2021Multiple sclerosis (MS) is a disease continuum from a clinically isolated syndrome through relapsing remitting MS to secondary progressive MS (SPMS). There are numerous... (Review)
Review
BACKGROUND
Multiple sclerosis (MS) is a disease continuum from a clinically isolated syndrome through relapsing remitting MS to secondary progressive MS (SPMS). There are numerous therapeutic approaches with proven efficacy on relapse and focal inflammatory disease aspects, whereas treatment of secondary progression and associated neuropathological aspects continues to be a challenge.
OBJECTIVE
Overview of the current options for disease-modifying treatment of SPMS.
MATERIAL AND METHODS
Results of randomized clinical trials are presented and evaluated on a substance-specific basis.
RESULTS
Randomized SPMS trials showed inconsistent results regarding disability progression for beta interferons and negative results for natalizumab. Oral cladribine and ocrelizumab reduced disability progression in relapsing MS but have not been specifically studied in an SPMS population. Positive results for mitoxantrone are only partially applicable to current SPMS patients. For siponimod, a substance that crosses the blood-brain barrier, the EXPAND trial demonstrated a significant reduction in the risk of disability progression in typical SPMS. Subgroup analyses suggest a higher efficacy of siponimod in younger patients with active SPMS.
CONCLUSION
There is limited evidence for the use of previously available disease-modifying treatment in SPMS. Siponimod represents a new therapeutic option for active SPMS, defined by relapses or focal inflammatory MRI activity. To establish the therapeutic indications for siponimod, early detection of relapse-independent progression as well as differentiation of active SPMS from inactive disease are of critical importance.
Topics: Cladribine; Disease Progression; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Natalizumab
PubMed: 33656569
DOI: 10.1007/s00115-021-01080-6 -
European Journal of Pharmaceutical... Nov 2020Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates...
Mitoxantrone, pixantrone and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia.
Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates transcription factor NF-κB and production of proinflammatory cytokines. TLR4 contributes to the development or progression of various diseases including stroke, neuropathic pain, multiple sclerosis, rheumatoid arthritis and cancer, and better therapeutics are currently sought for these conditions. In this study, a library of 140 000 compounds was virtually screened and a resulting hit-list of 1000 compounds was tested using a cellular reporter system. The topoisomerase II inhibitor mitoxantrone and its analogues pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were identified as inhibitors of TLR4 and NF-κB activation. Mitoxantrone was shown to bind directly to the TLR4, and pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were shown to inhibit the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα) in primary microglia. The inhibitory effect on NF-κB activation or on TNFα production was not mediated through cytotoxity at ≤ 1 µM concentration for pixantrone and mitoxantrone (2-hydroxyethyl)piperazine treated cells, as assessed by ATP counts. This study thus identifies a new mechanism of action for mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine through the TLR4.
Topics: Isoquinolines; Microglia; Mitoxantrone; NF-kappa B; Piperazine; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 32730846
DOI: 10.1016/j.ejps.2020.105493 -
Journal of Cellular and Molecular... Dec 2023The role of NETosis and its related molecules remains unclear in gastric cancer. The data used in this study was directly downloaded from the Cancer Genome Atlas (TCGA)...
The role of NETosis and its related molecules remains unclear in gastric cancer. The data used in this study was directly downloaded from the Cancer Genome Atlas (TCGA) database. All analysis and plots are completed in R software using diverse R packages. In our study, we collected the list of NETosis-related genes from previous publications. Based on the list and expression profile of gastric cancer patients from the TCGA database, we identified the NETosis-related genes significantly correlated with patients survival. Then, CLEC6A, BST1 and TLR7 were identified through LASSO regression and multivariate Cox regression analysis for prognosis model construction. This prognosis model showed great predictive efficiency in both training and validation cohorts. We noticed that the high-risk patients might have a worse survival performance. Next, we explored the biological enrichment difference between high- and low-risk patients and found that many carcinogenic pathways were upregulated in the high-risk patients. Meanwhile, we investigated the genomic instability, mutation burden and immune microenvironment difference between high- and low-risk patients. Moreover, we noticed that low-risk patients were more sensitive to immunotherapy (85.95% vs. 56.22%). High-risk patients were more sensitive to some small molecules compounds like camptothecin_1003, cisplatin_1005, cytarabine_1006, nutlin-3a (-)_1047, gemcitabine_1190, WZ4003_1614, selumetinib_1736 and mitoxantrone_1810. In summary, our study comprehensively explored the role of NETosis-related genes in gastric cancer, which can provide direction for relevant studies.
PubMed: 38146607
DOI: 10.1111/jcmm.18087 -
Journal of Pharmaceutical Sciences Aug 2022The human papillomavirus (HPV) is responsible for over 90% of all cervical cancer cases. The use of vaginal gels is often indicated for local vaginal drug delivery....
BACKGROUND
The human papillomavirus (HPV) is responsible for over 90% of all cervical cancer cases. The use of vaginal gels is often indicated for local vaginal drug delivery. Previous studies have shown that Thymus vulgaris essential oil (TEO) exhibits anticancer properties besides antifungal and antibacterial properties. Its activity derives from a specific increase in free radicals and oxidative stress caused in cancer cells. Furthermore, mitoxantrone (MTX), an anthracenedione, and C, an acridine orange derivative, were shown to inhibit the growth of the cervical cancer cell line HeLa.
RESULTS
The results showed that TEO + C is the most promising formulation in terms of viscosity and osmolality properties in vaginal fluid simulant (VFS). The combined action of TEO with the compounds MTX and C resulted in HeLa cell viability reduction compared with the effect obtained with the individual formulations containing each one of the compounds.
CONCLUSIONS
The formulation TEO + C holds promise in terms of cost-benefit and topical application of the active compound for the HeLa cells.
Topics: Alphapapillomavirus; Drug Compounding; Female; HeLa Cells; Humans; Oils, Volatile; Papillomaviridae; Uterine Cervical Neoplasms
PubMed: 35182543
DOI: 10.1016/j.xphs.2022.02.004