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Environmental Toxicology Mar 2024Gastric cancer is the most common malignant tumour of the digestive system, yet there is a lack of reported prognostic biomarkers for STAD patients.
BACKGROUND
Gastric cancer is the most common malignant tumour of the digestive system, yet there is a lack of reported prognostic biomarkers for STAD patients.
METHODS
Transcriptomic expression data of STAD from GEO database, single cell sequencing data from OMIX gastric cancer database. Conservative molecular typing of gastric cancer was constructed using non-negative matrix factorization (NMF). The abundance of 28 immune cells in the tumour samples was assessed using ssGSEA. The R package "oncoPredict" was used to predict chemotherapy response. TIDE website for immunotherapy response prediction. Finally, single cell analysis was performed to clarify the specific type annotation of STAD cells and to analysis their spatial expression.
RESULTS
Hypoxia-score demonstrated excellent prognostic discrimination in TCGA gastric cancer samples. Among multiple deconvolution-based algorithms for immune infiltration, Hypoxia-score presented a general immunosuppressive efficacy across multiple datasets, as evidenced by a broad negative correlation with immune cell infiltration. By the likelihood that each group may have specific drug sensitivity to multiple chemotherapeutic and targeted agents. Results showed that high-risk scoring patients were more sensitive to Staurosporine, Sabutoclax, and AZD8055, while low-risk patients were more sensitive to Bortezomib, Dactinomycin, Docetaxel, Daporinad, Sepantronium, and bromide. In the immunotherapy cohort, the Hypoxia-score presented the ability to discriminate for immunotherapy efficacy. The distribution of Hypoxia-score in single-cell descending space was calculated using AddModuleScore and was found to be distributed across the various cell types annotated in the single-cell analysis. It is suggested that various cells in the tumour microenvironment are involved in hypoxia gene set processes to varying degrees.
CONCLUSION
The Hypoxia-score proves to be a valuable tool for assessing the prognosis of gastric cancer patients and guiding drug treatments, providing significant guidance for clinical diagnosis and treatment in the context of gastric cancer.
Topics: Humans; Prognosis; Stomach Neoplasms; Adenocarcinoma; Docetaxel; Biomarkers; Tumor Microenvironment
PubMed: 38073300
DOI: 10.1002/tox.24064 -
Zoological Science Dec 2023To explore the physiological role and/or pharmacological effects of ommochrome, which is a natural organic pigment widely distributed in Protostomia, we attempted to...
To explore the physiological role and/or pharmacological effects of ommochrome, which is a natural organic pigment widely distributed in Protostomia, we attempted to investigate the influence of ommochrome on RT-PCR and activities of restriction enzymes. It was found that ommin, an ommochrome purified from the diapause eggs of , inhibited the RT-PCR and restriction enzyme activities. The mechanism of these inhibitory reactions is assumed to be the direct binding of ommochrome to DNA rather than acting against the enzymes because, similarly to actinomycin D, there is a phenoxazine ring in the structure of ommin that is known to be intercalated to DNA. To reveal the ommin/DNA interaction, it was investigated by computational approaches such as molecular docking, molecular dynamics simulation, and free energy calculation. From the computational analyses, it was expected that ommin would bind to DNA with almost the same strength as actinomycin D and intercalate into DNA. This is the first report on the pharmacological effect of ommochrome and its inhibitory mechanism obtained from biochemical and computational analyses.
Topics: Animals; Reverse Transcriptase Polymerase Chain Reaction; Dactinomycin; Molecular Docking Simulation; Bombyx; DNA
PubMed: 38064369
DOI: 10.2108/zs230068 -
Journal of the Egyptian National Cancer... Nov 2023Gestational Trophoblastic Neoplasia (GTN) is a disease of the reproductive age group with an incidence rate of <1% among all tumors involving the female reproductive... (Review)
Review
BACKGROUND
Gestational Trophoblastic Neoplasia (GTN) is a disease of the reproductive age group with an incidence rate of <1% among all tumors involving the female reproductive tract. It occurs because of aberrant fertilization. Patients are diagnosed early because of aggravated symptoms during pregnancy. Moreover, patients also bleed from the tumor sites, which leads to early presentation. A cure rate of 100% can be achieved with adequate treatment.
MAIN BODY
In this literature review, the authors have brought to attention the risk factors, classification, and various treatment options in GTN patients according to their stratification as per the WHO scoring system. Patients are categorized into low and high risk based on the FIGO scoring system. Patients with low risk are treated with single-agent methotrexate or actinomycin-D. Despite the superiority of actinomycin-D in terms of efficacy, methotrexate remains the first choice of therapy in low-risk patients due to its better toxicity profile. Multi-agent chemotherapy with etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine (EMA-CO) leads to complete remission in 93% of high-risk GTN patients. Around 40% of patients with incomplete responses are salvaged with platinum-based multi-agent chemotherapy. Isolated chemo-resistant clones can be salvaged with surgical interventions.
CONCLUSION
The mortality in patients with GTN has significantly reduced over time. With adequate multi-disciplinary support, patients with GTN can ultimately be cured and can spend every day healthy reproductive life.
Topics: Pregnancy; Humans; Female; Dactinomycin; Methotrexate; Antineoplastic Combined Chemotherapy Protocols; Gestational Trophoblastic Disease; Etoposide; Cyclophosphamide; Vincristine; Retrospective Studies
PubMed: 38008872
DOI: 10.1186/s43046-023-00195-y -
Carcinogenesis Apr 2024There are three major subtypes of breast cancer, ER+, HER2+ and triple-negative breast cancer (TNBC), namely ER-, PR-, HER2-. TNBC is the most aggressive breast cancer...
OBJECTIVES
There are three major subtypes of breast cancer, ER+, HER2+ and triple-negative breast cancer (TNBC), namely ER-, PR-, HER2-. TNBC is the most aggressive breast cancer with poor prognosis and no target drug up to now. Actinomycin D (ActD) is a bioactive metabolite of marine bacteria that has been reported to have antitumor activity. The aim of study is to investigate whether ActD has a synergetic effect on TNBC with Doxorubicin (Dox), the major chemotherapeutic drug for TNBC, and explore the underlying mechanism.
METHODS
TNBC cell lines HCC1937, MDA-MB-436 and nude mice were used in the study. Drug synergy determination, LDH assay, MMP assay, Hoechst 33342 staining, Flow cytometry, Flexible docking and CESTA assay were carried out. The expression of proteins associated with apoptosis was checked by Western blot and siRNA experiments were performed to investigate the role of P53 and PUMA induced by drugs.
RESULTS
There was much higher apoptosis rate of cells in the ActD + Dox group than that in ActD group or Dox group. Expression of MDM2 and BCL-2 was reduced while expression of P53, PUMA and BAX were increased in the groups treated with ActD + Dox or Dox compared to the control group. Furthermore, P53 siRNA or PUMA siRNA tremendously abrogated the cell apoptosis in the groups treated by ActD, Dox and ActD + Dox. Flexible docking and CESTA showed that ActD can bind MDM2.
CONCLUSIONS
ActD had a synergetic effect on TNBC with Dox via P53-dependent apoptosis and it may be a new choice for treatment of TNBC.
Topics: Animals; Humans; Mice; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Dactinomycin; Doxorubicin; Mice, Nude; RNA, Small Interfering; Triple Negative Breast Neoplasms; Tumor Suppressor Protein p53
PubMed: 37997385
DOI: 10.1093/carcin/bgad086 -
Frontiers in Pediatrics 2023A full-term infant with an unremarkable prenatal course presented at birth with a large midline facial mass and smaller masses in the head and neck. In addition,...
A full-term infant with an unremarkable prenatal course presented at birth with a large midline facial mass and smaller masses in the head and neck. In addition, multiple diffuse flesh-colored nodules spread along all the upper and lower limbs. An extensive evaluation to cover a broad differential diagnosis of infectious, lymphatic/vascular, and oncologic etiology was undertaken. The initial suspicion was confirmed by biopsy of the skin lesion as congenital alveolar rhabdomyosarcoma (RMS). RMS is the most common soft tissue sarcoma that occurs in childhood. However, neonatal RMS is exceedingly rare. The infant's initial treatment included vincristine, dactinomycin, and cyclophosphamide in addition to salvage ifosfamide and etoposide, which were dose-adjusted for age. Herein, we present a case of an infant with RMS who showed initial improvement before relapsing and succumbing to her disease at 5 months of age. A review of the limited literature available on this rare condition and newer treatment regimens with improved mortality rates is performed.
PubMed: 37964815
DOI: 10.3389/fped.2023.1233334 -
Cancer Mar 2024The prognostic impact of positive lymph nodes (LN+) and/or singular loss of heterozygosity (LOH) of 1p or 16q were assessed in children with stage III favorable...
Prognostic impact of lymph node involvement and loss of heterozygosity of 1p or 16q in stage III favorable histology Wilms tumor: A report from Children's Oncology Group Studies AREN03B2 and AREN0532.
INTRODUCTION
The prognostic impact of positive lymph nodes (LN+) and/or singular loss of heterozygosity (LOH) of 1p or 16q were assessed in children with stage III favorable histology Wilms tumor (FHWT) enrolled on AREN0532 or AREN03B2 alone.
PATIENTS AND METHODS
A total of 635 stage III FHWT vincristine/dactinomycin/doxorubicin (DD4A)-treated patients met inclusion criteria. Event-free survival (EFS) and overall survival are reported overall and by LN sampling, LN status, LOH 1p, LOH 16q, and a combination of LN status and singular LOH. Patients with unknown or positive combined LOH of 1p and 16q status and AREN03B2-only patients with unknown outcomes or treatment other than DD4A were excluded.
RESULTS
EFS did not differ by study, supporting pooling. Lack of LN sampling (hazard ratio [HR], 2.12; p = .0037), LN positivity (HR, 2.78; p = .0002), LOH 1p (HR, 2.18; p = .0067), and LOH 16q (HR, 1.72; p = .042) were associated with worse EFS. Compared with patients with both LN- and LOH-, those with negative nodes but positive LOH 1p or 16q and those with LN+ but LOH- for 1p or 16q had significantly worse EFS (HR, 3.05 and 3.57, respectively). Patients positive for both LN and LOH had the worst EFS (HR, 6.33; overall group factor, p < .0001).
CONCLUSION
Findings confirm LN+ status as an adverse prognostic factor amplified by presence of singular LOH 1p or 16q, supporting study of intensified therapy for patients with LN+ in combination with singular LOH in a prospective clinical trial.
Topics: Child; Humans; Prognosis; Kidney Neoplasms; Prospective Studies; Wilms Tumor; Doxorubicin; Loss of Heterozygosity; Lymph Nodes
PubMed: 37902955
DOI: 10.1002/cncr.35084 -
The Journal of Gene Medicine Jan 2024Renal cell carcinoma (RCC) is a grave malignancy that poses a significant global health burden with over 400,000 new cases annually. Disulfidptosis, a newly discovered...
INTRODUCTION
Renal cell carcinoma (RCC) is a grave malignancy that poses a significant global health burden with over 400,000 new cases annually. Disulfidptosis, a newly discovered programmed cell death process, is linked to the actin cytoskeleton, which plays a vital role in maintaining cell shape and survival. The role of disulfidptosis is poorly depicted in the clear cell histologic variant of RCC (ccRCC).
METHODS
Three sets of ccRCC cohorts, ICGC_RECA-EU (n = 91), GSE76207 (n = 32) and TCGA-KIRC (n = 607), were included in our study, the batch effect of which was removed using the "combat" function. Correlation was calculated using the "rcorr" function of the "Hmisc" package for Pearson analysis, which was visualized using the "pheatmap" package. Principal component analysis was performed by the "vegan" package, visualized using the "scatterplot3d" package. Long non-coding RNAs (lncRNAs) associated with disulfidptosis were screened out using least absolute shrinkage and selection operator (LASSO) and COX analysis. Tumor mutation, immune landscaping and immunotherapy prediction were performed for further characterization of two risk groups.
RESULTS
A total of 1822 disulfidptosis-related lncRNAs was selected, among which 308 lncRNAs were found to be significantly associated with the clinical outcome of ccRCC patients. We retained 11 disulfidptosis-related lncRNAs, namely, AP000439.3, RP11-417E7.1, RP11-119D9.1, LINC01510, SNHG3, AC156455.1, RP11-291B21.2, EMX2OS, AC093850.2, HAGLR and RP11-389C8.2, through LASSO and COX analysis for prognosis model construction, which displayed satisfactory accuracy (area under the curve, AUC, values all above 0.6 in multiple cohorts) in stratification of ccRCC prognosis. A nomogram model was constructed by integrating clinical factors with risk score, which further enhanced the prediction efficacy (AUC values all above 0.7 in multiple cohorts). We found that patients of male gender, higher clinical stages and advanced pathological T stage were inclined to have higher risk score values. Dactinomycin_1911, Vinblastine_1004, Daporinad_1248 and Vinorelbine_2048 were identified as promising candidate drugs for treating ccRCC patients of higher risk score value. Moreover, patients of higher risk value were prone to be resistant to immunotherapy.
CONCLUSION
We developed a prognosis predicting model based on 11 selected disulfidptosis-related lncRNAs, the efficacy of which was verified in different cohorts. Furthermore, we delineated an intricate portrait of tumor mutation, immune topography and pharmacosensitivity evaluations within disparate risk stratifications.
Topics: Humans; Male; Carcinoma, Renal Cell; RNA, Long Noncoding; Prognosis; Apoptosis; Kidney Neoplasms
PubMed: 37897262
DOI: 10.1002/jgm.3608 -
Research Square Oct 2023We developed a computational framework that integrates Genome-Wide Association Studies (GWAS) and post-GWAS analyses, designed to facilitate drug repurposing for...
We developed a computational framework that integrates Genome-Wide Association Studies (GWAS) and post-GWAS analyses, designed to facilitate drug repurposing for COVID-19 treatment. The comprehensive approach combines transcriptomic-wide associations, polygenic priority scoring, 3D genomics, viral-host protein-protein interactions, and small-molecule docking. Through GWAS, we identified nine druggable host genes associated with COVID-19 severity and SARS-CoV-2 infection, all of which show differential expression in COVID-19 patients. These genes include IFNAR1, IFNAR2, TYK2, IL10RB, CXCR6, CCR9, and OAS1. We performed an extensive molecular docking analysis of these targets using 553 small molecules derived from five therapeutically enriched categories, namely antibacterials, antivirals, antineoplastics, immunosuppressants, and anti-inflammatories. This analysis, which comprised over 20,000 individual docking analyses, enabled the identification of several promising drug candidates. All results are available via the DockCoV2 database (https://dockcov2.org/drugs/). The computational framework ultimately identified nine potential drug candidates: Peginterferon alfa-2b, Interferon alfa-2b, Interferon beta-1b, Ruxolitinib, Dactinomycin, Rolitetracycline, Irinotecan, Vinblastine, and Oritavancin. While its current focus is on COVID-19, our proposed computational framework can be applied more broadly to assist in drug repurposing efforts for a variety of diseases. Overall, this study underscores the potential of human genetic studies and the utility of a computational framework for drug repurposing in the context of COVID-19 treatment, providing a valuable resource for researchers in this field.
PubMed: 37886583
DOI: 10.21203/rs.3.rs-3443080/v1 -
Gynecologic Oncology Reports Dec 2023Low-risk gestational trophoblastic neoplasia (GTN) is generally treated with single agent chemotherapy, including methotrexate (MTX) or dactinomycin. We present a case...
Low-risk gestational trophoblastic neoplasia (GTN) is generally treated with single agent chemotherapy, including methotrexate (MTX) or dactinomycin. We present a case of a patient with low-risk GTN who underwent single agent MTX therapy, developed pneumonia (PJP), recovered, and ultimately completed consolidation treatment for GTN on single agent MTX. While MTX administration is associated with an increased risk of PJP, this association is best described in rheumatology literature. This is the first case of PJP complicating MTX therapy within the gynecologic oncology literature.
PubMed: 37860081
DOI: 10.1016/j.gore.2023.101286 -
Cureus Sep 2023A 10-year-old boy was evaluated for intermittent colicky abdominal pain, general malaise, and asthenia. Imaging revealed a solid liver lesion. Subsequent biopsy and...
A 10-year-old boy was evaluated for intermittent colicky abdominal pain, general malaise, and asthenia. Imaging revealed a solid liver lesion. Subsequent biopsy and extension studies diagnosed the lesion as undifferentiated embryonal sarcoma of the liver, classified as PRETEXT II, group III according to the postoperative staging system of the Intergroup Study for Soft Tissue Sarcomas. He underwent neoadjuvant chemotherapy using alternating cycles of ifosfamide, doxorubicin, vincristine, D-actinomycin, and cyclophosphamide. This was followed by surgical intervention and two additional adjuvant chemotherapy cycles, resulting in a complete disease response. The patient remains in follow-up and shows no signs of relapse 28 months post-diagnosis. Undifferentiated embryonal sarcoma of the liver is a rare and often misdiagnosed condition that can be mistaken for a benign disease. Its prognosis hinges on timely and accurate diagnosis, which is essential for effectively treating patients with this aggressive pathology with a high mortality risk. Notably, there is no standard treatment approach. In our case, we implemented therapeutic strategies from various literature reports, yielding a promising outcome and positive patient progression.
PubMed: 37814737
DOI: 10.7759/cureus.44923