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Drug Design, Development and Therapy 2024Chemotherapy-induced myelosuppression (CIM) is a common adverse reaction with a high incidence rate that seriously affects human health. Shengyu Decoction (SYD) is often...
BACKGROUND
Chemotherapy-induced myelosuppression (CIM) is a common adverse reaction with a high incidence rate that seriously affects human health. Shengyu Decoction (SYD) is often used to treat CIM. However, its pharmacodynamic basis and therapeutic mechanisms remain unclear.
PURPOSE
This study aimed to clarify the active components and mechanisms of SYD in CIM.
METHODS
LC-QTOF/MS was used to identify the absorbable components of SYD. A series of network pharmacology methods have been applied to explore hub targets and potential mechanisms. Molecular docking was used to identify the binding ability of potential active ingredients and hub targets. Finally, in vitro experiments were performed to validate these findings.
RESULTS
In this study, 33 absorbable prototype components were identified using LC-QTOF/MS. A total of 62 possible targets of SYD in myelosuppression were identified. KEGG pathway enrichment analyses showed that some signaling pathways such as PI3K-Akt and HIF-1 may be the mechanisms by which it functions. Among them, we verified the PI3K-Akt pathway. 6 Hub proteins were screened by Protein-protein interaction (PPI) network analysis. Molecular docking results showed that four absorbable components in SYD showed good binding with six Hub targets. The effectiveness of the four predicted compounds and the mechanism were verified in vitro. It has also been shown that the active component could promote the proliferation of bone marrow stromal cells (BMSCs) and block apoptosis of BMSCs, which may be related to the PI3K-Akt pathway. This result is consistent with the network pharmacology approach and molecular docking predictions.
CONCLUSION
Our results provided not only the candidate active component of SYD, but also a new insights into mechanism of SYD in the treatment of CIM.
Topics: Drugs, Chinese Herbal; Network Pharmacology; Molecular Docking Simulation; Humans; Cell Proliferation; Cells, Cultured; Animals; Mesenchymal Stem Cells; Protein Interaction Maps
PubMed: 38915868
DOI: 10.2147/DDDT.S458953 -
BioRxiv : the Preprint Server For... Jun 2024Epigenetic modifications to DNA and chromatin control oncogenic and tumor suppressive mechanisms in melanoma. EZH2, the catalytic component of the Polycomb repressive...
Epigenetic modifications to DNA and chromatin control oncogenic and tumor suppressive mechanisms in melanoma. EZH2, the catalytic component of the Polycomb repressive complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant interacts with the immune regulator Stat3 and together they affect anti-tumor immunity. However, given the numerous downstream targets and pathways affected by EZH2, many mechanisms that determine its oncogenic activity remain largely unexplored. Using genetically engineered mouse models we further investigated the role of pathways downstream of EZH2 in melanoma carcinogenesis and identified significant enrichment in several autophagy signatures, along with increased expression of autophagy regulators, such as Atg7. In this study, we investigated the effect of Atg7 on melanoma growth and tumor immunity within the context of an epigenetic state. We found that expression of Atg7 is largely dependent on Stat3 expression and that deletion of Atg7 slows down melanoma cell growth , but not . Atg7 deletion also results in increased CD8+ T cells and reduced myelosuppressive cell infiltration in the tumor microenvironment, suggesting a strong immune system contribution in the role of Atg7 in melanoma progression. These findings highlight the complex interplay between genetic mutations, epigenetic regulators, and autophagy in shaping tumor immunity in melanoma.
PubMed: 38915518
DOI: 10.1101/2024.06.10.598284 -
BMC Cancer Jun 2024Diffuse midline glioma (DMG), H3 K27M-mutant is a type of diffuse high-grade glioma that occurs in the brain midline carrying an extremely poor prognosis under the best...
PURPOSE
Diffuse midline glioma (DMG), H3 K27M-mutant is a type of diffuse high-grade glioma that occurs in the brain midline carrying an extremely poor prognosis under the best efforts of surgery, radiation, and other therapies. For better therapy, we explored the efficacy and toxicity of a novel therapy that combines apatinib and temozolomide in DMG.
METHODS
A retrospective analysis of 32 patients with DMG who underwent apatinib plus temozolomide treatment was performed. Apatinib was given 500 mg in adults, 250 mg in pediatric patients once daily. Temozolomide was administered at 200 mg/m/d according to the standard 5/28 days regimen. The main clinical data included basic information of patients, radiological and pathological characteristics of tumors, treatment, adverse reactions, prognosis.
RESULTS
The objective response rate was 24.1%, and the disease control rate was 79.3%. The median PFS of all patients was 5.8 months, and median OS was 10.3 months. A total of 236 cycles of treatment were available for safety assessment and the toxicity of the combination therapy was relatively well tolerated. The most common grade 3 toxicities were myelosuppression including leukopenia (5.08%), neutropenia (4.24%), lymphopenia (2.12%), thrombocytopenia (1.69%) and anemia (1.27%). Grade 4 toxicities included neutropenia (2.12%), thrombocytopenia (2.12%) and proteinuria (1.69%). All the adverse events were relieved after symptomatic treatment or dose reduction.
CONCLUSIONS
Apatinib plus temozolomide could be an effective regimen with manageable toxicities and favorable efficacy and may outperform temozolomide monotherapy, particularly in newly diagnosed adults with tumors located outside the pons. The novel therapy deserves further investigation in adult DMG patients.
Topics: Humans; Temozolomide; Female; Male; Adult; Pyridines; Glioma; Adolescent; Retrospective Studies; Child; Brain Neoplasms; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Middle Aged; Treatment Outcome
PubMed: 38907215
DOI: 10.1186/s12885-024-12373-9 -
Frontiers in Pharmacology 2024[Equidae; Asini Corri Colla] (donkey-hide gelatin, E-Jiao) is a traditional Chinese medicine renowned for its exceptional blood-supplementing effect. However, the...
Blood-supplementing effect of low molecular weight peptides of E-Jiao on chemotherapy-induced myelosuppression: evaluation of pharmacological activity and identification of bioactive peptides released .
[Equidae; Asini Corri Colla] (donkey-hide gelatin, E-Jiao) is a traditional Chinese medicine renowned for its exceptional blood-supplementing effect. However, the specific components that contribute to its efficacy remain elusive. This study aimed to demonstrate that peptides are responsible for E-Jiao's blood-supplementing effect and to explore the specific peptides contributing to its efficacy. The low molecular weight peptides of E-Jiao (LMEJ) were obtained using an digestion method. LMEJ and peptides in the rat bloodstream were characterized by peptidomics analysis. The blood-supplementing effect of LMEJ was assessed using blood-deficient zebrafish and mouse models. The effect of the peptides detected in rat blood was evaluated using the same zebrafish model, and network pharmacology analysis was performed to investigate the underlying mechanisms. A total of 660 unique peptides were identified within LMEJ. Both E-Jiao and LMEJ significantly alleviated myelosuppression in mice but only LMEJ attenuated myelosuppression in zebrafish. After the administration of E-Jiao to rats, 67 E-Jiao-derived peptides were detected in the bloodstream, 41 of which were identical to those identified in LMEJ. Out of these 41 peptides, five were synthesized. Subsequent verification of their effects revealed that two of them were able to alleviate myelosuppression in zebrafish. Network pharmacology study suggested that E-Jiao may exert a blood-supplementing effect by regulating signaling pathways such as JAK-STAT, IL-17 and others. These results indicated that peptides are at least partially responsible for E-Jiao's efficacy. This study provides a crucial foundation for further exploration of the bioactive components of E-Jiao.
PubMed: 38904003
DOI: 10.3389/fphar.2024.1366407 -
Scientific Reports Jun 2024This study aimed to investigate impacts of Omicron infection on cancer patients in China. A retrospective study was conducted, including 347 cancer patients undergoing...
Completion rates and myelosuppression degrees of cancer patients receiving radiotherapy or chemoradiotherapy unchanged regardless of delay duration after Omicron infection.
This study aimed to investigate impacts of Omicron infection on cancer patients in China. A retrospective study was conducted, including 347 cancer patients undergoing radiotherapy or chemoradiotherapy between July 2022 and March 2023. Three groups involved: 108 patients without SARS-CoV-2 infection (non-COVID-19 group), 102 patients beginning treatment 10 days after first SARS-CoV-2 infection (≥ 10 days COVID-19 group), and 137 patients beginning treatment less than 10 days after first SARS-CoV-2 infection (< 10 days COVID-19 group). SAA, hsCRP, ALT, etc., were used to assess COVID-19 infection. Serum levels of SAA, hsCRP and IL-6 were all raised in two COVID-19-infected groups (SAA < 0.01, hsCRP < 0.01, IL-6 < 0.05), but PCT, ALT, LDH and HBDH levels were only elevated in ≥ 10 days COVID-19 group (PCT = 0.0478, ALT = 0.0022, LDH = 0.0313, HBDH = 0.0077). Moreover, moderate and severe infected cases were higher in ≥ 10 days COVID-19 group than < 10 days COVID-19 group (12/102 vs 5/137, p = 0.0211), but no significance in myelosuppression and completion rates among three groups. Omicron infection led to inflammation, liver and cardiovascular injury on cancer patients, but delay duration of radiotherapy or chemoradiotherapy after infection did not affect the completion rates and myelosuppression of current therapy. Besides, severity of Omicron infection was even worse among cancer patients who received delayed treatment.
Topics: Humans; COVID-19; Female; Male; Middle Aged; Neoplasms; Chemoradiotherapy; Retrospective Studies; Aged; SARS-CoV-2; Adult; China
PubMed: 38902401
DOI: 10.1038/s41598-024-65019-y -
BioRxiv : the Preprint Server For... Jun 2024Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell...
BACKGROUND
Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.e. immune "reset"). Here we present a paradigm to understand SCT as a cellular therapy for immune diseases and reveal how SCT re-establishes cellular immunity utilizing high-dimensional cellular phenotyping and functional studies of the stem cell grafts.
METHODS
Immunophenotyping using CyTOF, single cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing was performed on peripheral blood and intestinal tissue samples from refractory CD patients who underwent SCT. The stem cell graft from these patients was analyzed using flow cytometry and functionally interrogated using a murine model for engraftment.
RESULTS
Our study revealed a remodeling of intestinal macrophages capable of supporting mucosal healing that was independently validated using multimodal studies of immune reconstitution events including CyTOF and scRNA-seq. Functional interrogation of hematopoietic stem cells (HSCs) using a xenograft model demonstrated that HSCs shape the timing of immune reconstitution, the selected reconstitution of specific cell lineages and potentially the clinical efficacy of SCT.
CONCLUSIONS
These studies indicate that SCT serves as a myeloid-directed cellular therapy re-establishing homeostatic intestinal macrophages that support intestinal healing and suggest refractory CD evolves from impairment of restorative functions in myeloid cells. Furthermore, we report heterogeneity among HSCs from CD patients which may drive SCT outcomes and suggests an unrecognized impact of CD pathophysiology on HSC in the marrow niche.
PubMed: 38895305
DOI: 10.1101/2024.05.30.596699 -
International Journal of Molecular... May 2024Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA)...
Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA) compound ([At]PSMA-5) exhibited excellent tumor growth suppression in a xenograft model. We conducted preclinical biodistribution and toxicity studies for the first-in-human clinical trial. [At]PSMA-5 was administered to both normal male ICR mice ( = 85) and cynomolgus monkeys ( = 2). The mice were divided into four groups for the toxicity study: 5 MBq/kg, 12 MBq/kg, 35 MBq/kg, and vehicle control, with follow-ups at 1 day ( = 10 per group) and 14 days ( = 5 per group). Monkeys were observed 24 h post-administration of [At]PSMA-5 (9 MBq/kg). Blood tests and histopathological examinations were performed at the end of the observation period. Blood tests in mice indicated no significant myelosuppression or renal dysfunction. However, the monkeys displayed mild leukopenia 24 h post-administration. Despite the high accumulation in the kidneys and thyroid, histological analysis revealed no abnormalities. On day 1, dose-dependent single-cell necrosis/apoptosis was observed in the salivary glands of mice and intestinal tracts of both mice and monkeys. Additionally, tingible body macrophages in the spleen and lymph nodes indicated phagocytosis of apoptotic B lymphocytes. Cortical lymphopenia (2/10) in the thymus and a decrease in the bone marrow cells (9/10) were observed in the 35 MBq/kg group in mice. These changes were transient, with no irreversible toxicity observed in mice 14 days post-administration. This study identified no severe toxicities associated with [At]PSMA-5, highlighting its potential as a next-generation targeted alpha therapy for prostate cancer. The sustainable production of At using a cyclotron supports its applicability for clinical use.
Topics: Animals; Male; Prostatic Neoplasms; Mice; Tissue Distribution; Mice, Inbred ICR; Astatine; Alpha Particles; Humans; Macaca fascicularis; Glutamate Carboxypeptidase II; Radiopharmaceuticals
PubMed: 38891856
DOI: 10.3390/ijms25115667 -
The Lancet. Infectious Diseases Jun 2024In 2020, WHO guidelines prioritised the use of a standard fully oral short treatment regimen (STR) consisting of bedaquiline, levofloxacin or moxifloxacin, ethionamide,...
BACKGROUND
In 2020, WHO guidelines prioritised the use of a standard fully oral short treatment regimen (STR) consisting of bedaquiline, levofloxacin or moxifloxacin, ethionamide, ethambutol, high-dose isoniazid, pyrazinamide, and clofazimine for the management of rifampicin-resistant tuberculosis. A high prevalence of resistance to constituent drugs precluded its widespread use by countries in the WHO European region. We evaluated three 9-month fully oral modified STRs (mSTRs) in which ethionamide, ethambutol, isoniazid, and pyrazinamide were replaced by linezolid, cycloserine, or delamanid (or a combination).
METHODS
This multicountry, prospective, single-arm, cohort study examined the effectiveness and safety of mSTRs for fluoroquinolone-susceptible, rifampicin-resistant pulmonary tuberculosis in 13 countries in the WHO European region during 2020-23. We enrolled adults and children of all ages with bacteriologically confirmed rifampicin-resistant, fluoroquinolone-susceptible pulmonary tuberculosis, and children (aged 0-18 years) with clinically diagnosed disease and a confirmed contact with rifampicin-resistant, fluoroquinolone-susceptible tuberculosis. Participants aged 6 years or older received one of two regimens: bedaquiline, linezolid, levofloxacin, clofazimine, and cycloserine; or bedaquiline, linezolid, levofloxacin, clofazimine, and delamanid. Children younger than 6 years received delamanid, linezolid, levofloxacin, and clofazimine. Participants were followed up for 12 months after successful treatment completion to detect recurrence and death. The primary outcome was the cumulative probability of not having an unsuccessful study outcome (defined as treatment failure, on-treatment loss to follow-up, death, or recurrence) before 22 months of study follow-up. The primary safety outcome was the incidence of each adverse event of interest (peripheral neuropathy, optic neuritis, myelosuppression, hepatitis, prolonged QT interval, hypokalaemia, and acute kidney injury) of grade 3 or higher severity during the treatment course.
FINDINGS
Between Aug 28, 2020 and May 26, 2021, 7272 patients were screened and 2636 were included in the treatment cohort. 1966 (74·6%) were male, 670 (25·4%) were female, and median age was 43 years (IQR 33-53). Treatment success was recorded for 2181 (82·7%) participants. The cumulative probability of not having an unsuccessful study outcome 22 months after treatment initiation was 79% (95% CI 78-81). Increasing age (adjusted hazard ratio 2·61 [95% CI 1·70-4·04] for people aged >64 years vs 35-44 years), HIV-positive status (1·53 [1·16-2·01]), presence of bilateral cavities (1·68 [1·29-2·19]), smoking history (1·34 [1·05-1·71]), baseline anaemia (1·46 [1·15-1·86]), unemployment (1·37 [1·04-1·80]), elevated baseline liver enzymes (1·40 [1·13-1·73]), and excessive alcohol use (1·47 [1·14-1·89]) were positively associated with unsuccessful study outcomes. In the safety cohort of 2813 participants who received at least one dose, 301 adverse events of interest were recorded in 252 (9·0%) participants with the most frequent being myelosuppression (139 [4·9%] participants, 157 [52·2%] events).
INTERPRETATION
The high treatment success and good safety results indicate considerable potential for the use of mSTRs in programmatic conditions, especially for individuals not eligible for the current WHO-recommended 6-month regimen and in settings with a need for alternative options.
FUNDING
The Global Fund to Fight AIDS, Tuberculosis and Malaria; United States Agency for International Development; Government of Germany; and WHO.
TRANSLATION
For the Russian translation of the abstract see Supplementary Materials section.
PubMed: 38880112
DOI: 10.1016/S1473-3099(24)00228-7 -
Cancer Treatment and Research... May 2024Myelosuppression, a challenge in cancer treatment, often results in severe complications. Prophylactic granulocyte colony-stimulating factors, particularly... (Review)
Review
INTRODUCTION
Myelosuppression, a challenge in cancer treatment, often results in severe complications. Prophylactic granulocyte colony-stimulating factors, particularly pegfilgrastim, mitigate chemotherapy-induced neutropenia. This narrative review evaluates the role of on-body injector (OBI) devices for pegfilgrastim administration. A comprehensive search strategy of PubMed and AI-powered intuitive search tools, complemented by authors' contributions, yielded a body of papers presenting evidence on OBI devices, their effectiveness and safety, the benefits and challenges of OBI versus pre-filled syringe administration, patient preferences for pegfilgrastim administration, and economic considerations.
DISCUSSION
OBI devices prove effective and safe, with advantages such as reduced clinic visits and enhanced adherence. Studies highlight cost-efficiency and expanded access, emphasizing the socioeconomic context. Patient and provider preferences underscore the potential of OBI devices in cancer care, with implications for healthcare resource utilization and pharmacoeconomics.
CONCLUSION
The value proposition of OBI devices lies in improving patient outcomes, convenience, resource optimization, and enhancing the overall cancer care experience. As biosimilar OBIs enter the market, they may offer cost savings, further influencing their adoption and their positioning as a cost-efficient alternative in cancer care. Ongoing research and technological advancements are expected to contribute to the broader acceptance of OBI devices in cancer care delivery.
PubMed: 38865836
DOI: 10.1016/j.ctarc.2024.100824