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Current Cancer Drug Targets 2023Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death globally. The mechanisms underlying the development of HCC are mostly unknown till now.
BACKGROUND
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death globally. The mechanisms underlying the development of HCC are mostly unknown till now.
OBJECTIVE
The main goal of this study was to identify potential drug target proteins and agents for the treatment of HCC.
METHODS
The publicly available three independent mRNA expression profile datasets were downloaded from the NCBI-GEO database to explore common differentially expressed genes (cDEGs) between HCC and control samples using the Statistical LIMMA approach. Hub-cDEGs as drug targets highlighting their functions, pathways, and regulators were identified by using integrated bioinformatics tools and databases. Finally, Hub-cDEGs-guided top-ranked drug agents were identified by molecular docking study for HCC.
RESULTS
We identified 160 common DEGs (cDEGs) from three independent mRNA expression datasets in which ten cDEGs (, and) were selected as Hub-cDEGs. The GO functional and KEGG pathway enrichment analysis of Hub-cDEGs revealed some crucial cancer-stimulating biological processes, molecular functions, cellular components, and signaling pathways. The interaction network analysis identified three TF proteins and five miRNAs as the key transcriptional and post-transcriptional regulators of HubcDEGs. Then, we detected the proposed Hub-cDEGs guided top-ranked three anti-HCC drug molecules (Dactinomycin, Vincristine, Sirolimus) that were also highly supported by the already published top-ranked HCC-causing Hub-DEGs mediated receptors.
CONCLUSION
The findings of this study would be useful resources for diagnosis, prognosis, and therapies of HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Molecular Docking Simulation; Gene Expression Profiling; Gene Regulatory Networks; Computational Biology; RNA, Messenger; Protein Serine-Threonine Kinases; Ubiquitin-Conjugating Enzymes
PubMed: 36786134
DOI: 10.2174/1568009623666230214100159 -
International Journal of Molecular... Jan 2023The opportunistic fungus causes a set of diseases ranging from allergy to lethal invasive mycosis. Within the human airways, is embedded in a biofilm that forms not...
The opportunistic fungus causes a set of diseases ranging from allergy to lethal invasive mycosis. Within the human airways, is embedded in a biofilm that forms not only a barrier against the host immune defense system, but also creates a physical barrier protecting the fungi from chemicals such as antifungal drugs. Novel therapeutic strategies aim at combining drugs that inhibit biofilm synthesis or disrupt existing biofilm with classical antimicrobials. One of the major constituents of biofilm is the polysaccharide galactosaminogalactan (GAG) composed of α1,4-linked N-acetylgalactosamine, galactosamine, and galactose residues. GAG is synthesized on the cytosolic face of the plasma membrane and is extruded in the extracellular space, where it is partially deacetylated. The deacetylase Agd3 that mediates this last step is essential for the biofilm formation and full virulence of the fungus. In this work, a previously described enzyme-linked lectin assay, based on the adhesion of deacetylated GAG to negatively charged plates and quantification with biotinylated soybean agglutinin was adapted to screen microbial natural compounds, as well as compounds identified in in silico screening of drug libraries. Actinomycin X2, actinomycin D, rifaximin, and imatinib were shown to inhibit Agd3 activity in vitro. At a concentration of 100 µM, actinomycin D and imatinib showed a clear reduction in the biofilm biomass without affecting the fungal growth. Finally, imatinib reduced the virulence of in a infection model in an Agd3-dependent manner.
Topics: Humans; Dactinomycin; Imatinib Mesylate; Polysaccharides; Aspergillus fumigatus; Biofilms
PubMed: 36768176
DOI: 10.3390/ijms24031851 -
Caspian Journal of Internal Medicine 2023Methotrexate (MTX) and actinomycin D (ActD) have been used as first-line chemotherapy agents in the treatment of low-risk gestational trophoblastic neoplasia (GTN)....
BACKGROUND
Methotrexate (MTX) and actinomycin D (ActD) have been used as first-line chemotherapy agents in the treatment of low-risk gestational trophoblastic neoplasia (GTN). Although low-risk GTN is considered a curable disease, its reported primary remission rates of 49 to 93% reflect the difficulties of treatment and different factors influencing it. Hence, this study aimed to determine the remission rates and related factors of single-agent chemotherapy resistance in low-risk GTN patients.
METHODS
This retrospective study included patients with diagnosed low-risk GTN who received either MTX once a week (IM, 30mg/m2) or ActD once every two weeks (pulsed IV, 1.25mg/m2). Then, the patients were followed-up until complete remission or single-agent treatment failure to assess resistance rate and related factors.
RESULTS
Eighty-four patients were included in the study (18 patients were receiving MTX and 66 patients were receiving ActD). 85.7% of all participants achieved complete remission after first-line chemotherapy (72.2% in MTX vs 89.4% in ActD). There was a significant association for higher tumor size (P=0.046), the occurrence of metastasis (P=0.019), and pretreatment β-HCG levels (P=0.005) with resistance to treatment.
CONCLUSION
This study demonstrated higher tumor size, the occurrence of metastasis, and pretreatment β-HCG levels have been associated with increased resistance to first-line chemotherapy agents.
PubMed: 36741497
DOI: 10.22088/cjim.14.1.47 -
Journal of the Formosan Medical... Aug 2023The purpose of this study was to clarify the effect of ZC3H13 on the growth of papillary thyroid carcinoma (PTC).
PURPOSE
The purpose of this study was to clarify the effect of ZC3H13 on the growth of papillary thyroid carcinoma (PTC).
METHODS
Firstly, we used qRT-PCR and Western blot to compare the difference in the expression of ZC3H13 between normal thyroid epithelial cells and PTC cell lines. Then, ZC3H13 overexpression/knockout thyroid cancer cells were constructed by lentivirus transfection, and the effects of overexpression of ZC3H13 on the proliferation, migration and invasion of PTC cells were detected by CCK8 and transwell experiments. Lastly, MeRIP-qPCR, RIP and o Actinomycin D were used to verify that ZC3H13 regulated the expression of downstream target gene IQGAP1 through m6A modification.
RESULTS
ZC3H13 expression was decreased in PTC cell lines BCPAP, KTC-1, k1, HTH83, and TPC-1. Proliferation, invasion, and migration of PTC cells were inhibited by overexpressed ZC3H13 but increased by knockdown of ZC3H13. IQGAP1 expression was suppressed by ZC3H13 overexpression but enhanced by ZC3H13 knockdown. In ZC3H13-overexpressed PTC cells, the m6A level of IQGAP1 mRNA was increased, and the IQGAP1 mRNA expression was decreased with the increasing time of Actinomycin D treatment. YTHDF2 enriched more IQGAP1 mRNA than IgG and knockdown of YTHDF2 reversed the effect of ZC3H13 overexpression on IQGAP1 mRNA stability. The xenograft tumor experiment in nude mice confirmed that the overexpression of ZC3H13 inhibited tumor growth, while overexpression of IQGAP1 could reverse the inhibitory effect of ZC3H13 overexpression on tumor growth.
CONCLUSION
ZC3H13 mediates IQGAP1 mRNA degradation by promoting m6A modification of IQGAP1 mRNA, this provides a prospective therapeutic target for PTC.
Topics: Mice; Animals; Humans; Thyroid Cancer, Papillary; MicroRNAs; Mice, Nude; Dactinomycin; Cell Line, Tumor; Cell Proliferation; Neoplasm Invasiveness; Cell Movement; Thyroid Neoplasms; RNA, Messenger; Gene Expression Regulation, Neoplastic; Nuclear Proteins; RNA-Binding Proteins
PubMed: 36739231
DOI: 10.1016/j.jfma.2022.12.019 -
Organic & Biomolecular Chemistry Feb 2023Three novel actinomycins, actimomycin S (1), neo-actinomycins C and D (2 and 3), and one new benzo[]oxazole alkaloid (4) were isolated from the sp. strain S22, along...
Three novel actinomycins, actimomycin S (1), neo-actinomycins C and D (2 and 3), and one new benzo[]oxazole alkaloid (4) were isolated from the sp. strain S22, along with three known congeners F (5), X (6) and X (7) and 2-acetylamino-3-hydroxyl-4-methyl-benzoic acid methyl ester (8). The structures of the new products were elucidated by spectroscopic methods, and the absolute configuration of amino acid residues was determined by Marfey's analysis. Actinomycin S contains an aspartic acid (Asp) residue in the β-peptidolactone ring. This is the first report of an Asp residue within an actinomycin-type natural product. Notably, neo-actinomycins C and D feature a rare tetracyclic 5-oxazolo[4,5-]phenoxazine chromophore. Among these, neo-actinomycin D, with an unprecedented molecular formula, represents the highest molecular weight member in the actinomycin family. Actinomycins 1-3 exhibited antimicrobial activity against multiple resistant "ESKAPE" pathogens with MIC values ranging from 1.25 to 80.0 μg mL. In addition, 1-3 showed potent cytotoxic activities against the HepG2 liver carcinoma cell line with IC values of 0.10, 0.32, and 0.024 μM, respectively. Furthermore, 1 inhibited cell proliferation by inducing G0-G1 phase arrest in the cell cycle.
Topics: Dactinomycin; Streptomyces; Antineoplastic Agents; Spectrum Analysis; Amino Acids
PubMed: 36723156
DOI: 10.1039/d2ob02247h -
Gynecologic Oncology Mar 2023To investigate the efficacy and toxicity of etoposide, methotrexate, actinomycin D alternating with cyclophosphamide, and vincristine (EMACO) for treatment of...
OBJECTIVE
To investigate the efficacy and toxicity of etoposide, methotrexate, actinomycin D alternating with cyclophosphamide, and vincristine (EMACO) for treatment of gestational trophoblastic neoplasia, and for factors independently associated with EMACO resistance and disease-specific death in an international cohort.
METHODS
Medical records of GTN patients who received EMACO during 1986-2019 from gestational trophoblastic disease centers from four countries including the USA, Thailand, Hungary, and Brazil, were retrospectively reviewed. Among 335 GTN patients, 266 patients who received EMACO as primary chemotherapy were included in the primary treatment group, and 69 patients who received EMACO after relapse/resistance to single-agent chemotherapy were included in the prior treatment group.
RESULTS
Three-quarters (76.1%) of all patients achieved remission, and the survival rate was 89%. The prior treatment group had better outcomes than the primary treatment group relative to remission rate (87.0% vs. 73.3%, p = 0.014) and number of EMACO cycles to achieve remission (3 vs. 6 cycles, p < 0.001). Sustained remission increased to 87.2% in EMACO-resistant patients treated with later-line chemotherapy. Number of metastatic organs ≥2 (adjusted odds ratio [aOR]: 2.33, p = 0.049) was the only independent predictor of EMACO resistance among overall patients. Interval from index pregnancy ≥7 months (aOR: 4.34, p = 0.001), and pretreatment hCG >100,000 IU/L (aOR: 2.85, p = 0.028) were independent predictors of EMACO resistance in the high-risk subgroup. The only factor independently associated with disease-specific death was EMACO resistance (aOR: 176.04, p < 0.001).
CONCLUSIONS
EMACO is an effective treatment for GTN. Number of metastatic organs and EMACO resistance were the independent predictors of EMACO resistance and disease-specific death, respectively.
Topics: Female; Humans; Pregnancy; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dactinomycin; Etoposide; Gestational Trophoblastic Disease; Methotrexate; Neoplasm Recurrence, Local; Retrospective Studies; Vincristine; Drug Resistance, Neoplasm
PubMed: 36682089
DOI: 10.1016/j.ygyno.2022.12.020 -
BJOG : An International Journal of... Apr 2023High-risk gestational trophoblastic neoplasia (GTN) is rare and treated with diverse approaches. Limited published institutional data has yet to be systematically... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
High-risk gestational trophoblastic neoplasia (GTN) is rare and treated with diverse approaches. Limited published institutional data has yet to be systematically reviewed.
OBJECTIVES
To compile global high-risk GTN (prognostic score ≥7) cohorts to summarise treatments and outcomes by disease characteristics and primary chemotherapy.
SEARCH STRATEGY
MEDLINE, Embase, Scopus, ClinicalTrials.gov and Cochrane were searched through March 2021.
SELECTION CRITERIA
Full-text manuscripts reporting mortality among ≥10 high-risk GTN patients.
DATA COLLECTION AND ANALYSIS
Binomial proportions were summed, and random-effects meta-analyses performed.
MAIN RESULTS
From 1137 records, we included 35 studies, representing 20 countries. Among 2276 unique high-risk GTN patients, 99.7% received chemotherapy, 35.8% surgery and 4.9% radiation. Mortality was 10.9% (243/2236; meta-analysis: 10%, 95% confidence interval [CI] 7-12%) and likelihood of complete response to primary chemotherapy was 79.7% (1506/1890; meta-analysis: 78%, 95% CI: 74-83%). Across 24 reporting studies, modern preferred chemotherapy (EMA/CO or EMA/EP) was associated with lower mortality (overall: 8.8 versus 9.5%; comparative meta-analysis: 8.1 versus 12.4%, OR 0.42, 95% CI: 0.20-0.90%, 14 studies) and higher likelihood of complete response (overall: 76.6 versus 72.8%; comparative meta-analysis: 75.9 versus 60.7%, OR 2.98, 95% CI: 1.06-8.35%, 14 studies), though studies focused on non-preferred regimens reported comparable outcomes. Mortality was increased for ultra-high-risk disease (30 versus 7.5% high-risk; meta-analysis OR 7.44, 95% CI: 4.29-12.9%) and disease following term delivery (20.8 versus 7.3% following molar pregnancy; meta-analysis OR 2.64, 95% CI: 1.10-6.31%). Relapse rate estimates ranged from 3 to 6%.
CONCLUSIONS
High-risk GTN is responsive to several chemotherapy regimens, with EMA/CO or EMA/EP associated with improved outcomes. Mortality is increased in patients with ultra-high-risk, relapsed and post-term pregnancy disease.
Topics: Pregnancy; Female; Humans; Methotrexate; Dactinomycin; Neoplasm Recurrence, Local; Gestational Trophoblastic Disease; Hydatidiform Mole; Retrospective Studies
PubMed: 36648416
DOI: 10.1111/1471-0528.17374 -
Natural Product Research May 2024Hemiactinomycin (), an intermediate derivative of actinomycin biosynthesis, together with three known actinomycins (-) , were isolated from the ethanolic extract of...
Hemiactinomycin (), an intermediate derivative of actinomycin biosynthesis, together with three known actinomycins (-) , were isolated from the ethanolic extract of H41-55 fermentation mycelium by using various column chromatography. The structure of the derivative was established by extensive spectroscopic analysis, including HRESIMS, 1D, and 2D NMR spectroscopy. In addition, the anti-inflammatory activities of all the isolates were tested. The derivative () showed inhibiting NO release activities in LPS-induced RAW 264.7 macrophages with the IC values of 15.41 ± 0.66 μM.
Topics: Streptomyces antibioticus; Dactinomycin; Streptomyces; Actinobacteria; Actinomyces
PubMed: 36564053
DOI: 10.1080/14786419.2022.2161541 -
Frontiers in Oncology 2022Invasive moles are a subtype of gestational trophoblastic neoplasia (GTN) that usually develops after hydatidiform molar pregnancies. Uterine rupture in high-risk GTN is...
BACKGROUND
Invasive moles are a subtype of gestational trophoblastic neoplasia (GTN) that usually develops after hydatidiform molar pregnancies. Uterine rupture in high-risk GTN is a rare and potentially catastrophic event. The treatment of invasive mole perforation with uterine rupture is particularly challenging in young women who desire fertility preservation.
CASE PRESENTATION
We present the case of a 22-year-old woman with a rapidly transformed invasive mole after two evacuations for a complete molar pregnancy. Within 21 days of the second molar evacuation, the serum β-hCG level surged from 5,718 mIU/ml to 444,617 mIU/ml. An ultrasonography examination showed the uterus was 9.2×8.9×7.8 cm in size with an uneven echo area of 6.9×5.2 cm near the fundus of the uterine cavity; the convex anterior wall had no normal muscle layer, and the outer margin was about 0.24 cm from the serosal layer. The patient was diagnosed with an invasive mole. Since she desired fertility preservation, we proposed a methotrexate (MTX) chemotherapy regimen. Before the planned chemotherapy, she experienced sudden abdominal pain accompanied by a blood pressure of 76/48 mmHg and a pulse rate of 116 bpm. An emergency abdominal ultrasound scan showed acute intra-abdominal bleeding (approximately 2,000 ml), and blood tests showed a hemoglobin concentration of 7.9 g/dL. Immediate uterine artery embolization was performed, and 35 mg MTX was administered bilaterally through the uterine arteries. The next day, the serum β-hCG decreased to 83,530 mIU/ml, and the vital signs remained stable. Seven days later, the patient received a combination of etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMACO), and the serum β-hCG level normalized after cycle five. At the 13-month follow-up after therapy completion, the woman was disease-free with a normal β-hCG level.
CONCLUSION
Our experience highlights the potential feasibility and efficacy of conservative treatment for fertility preservation in such scenarios.
PubMed: 36561530
DOI: 10.3389/fonc.2022.1019082 -
Journal of Medical Case Reports Dec 2022Paratesticular rhabdomyosarcoma is a rare and aggressive mesenchymal tumor, accounting for only 7% of all rhabdomyosarcomas. It is mainly encountered in children and...
INTRODUCTION
Paratesticular rhabdomyosarcoma is a rare and aggressive mesenchymal tumor, accounting for only 7% of all rhabdomyosarcomas. It is mainly encountered in children and adolescents. The standard treatment consists of radical orchidectomy with negative surgical margins. However, chemotherapy is recommended to control retroperitoneal micrometastasis. The place of surgery for progressive retroperitoneal lymph node metastases remains controversial. We present a case of paratesticular rhabdomyosarcoma with progressive retroperitoneal lymph node metastases treated with surgery.
CASE REPORT
We report a case of a 17-year-old North African male with no particular medical history who presented with a left scrotal mass that had been evolving for several months. Beta-human chorionic gonadotropin, alpha-fetoprotein, and lactate dehydrogenase were normal. Scrotal ultrasonography revealed the presence of a 6 cm heterogeneous hypoechogenic tissular mass with cystic areas adherent to the left scrotal wall, which was thickened in some places and vascularized by color Doppler. It exerted a mass effect on the homolateral testicle, which was of average volume. The thoracic-abdominal-pelvic computed tomography scan showed the presence of suspicious paraaortic lymph nodes. The most voluminous one measured 16 × 23 mm. A left orchidectomy was performed. The final pathology report revealed an 8 cm paratesticular rhabdomyosarcoma of the embryonic type that displaced the testicle without invading it. Without going beyond it, it infiltrated the epididymis, the rete testis, and the albuginea. The surgical margin at the level of the spermatic cord was free. The patient had adjuvant chemotherapy (ifosfamide, vincristine, and dactinomycin). The patient had a challenging paraaortic lymph node dissection since the mass enlaced the left ureter and renal vessels. On histological examination, the paraaortic lymph nodes were metastatic.
CONCLUSION
Rhabdomyosarcoma is an aggressive malignancy with high metastatic potential. Therefore, only an accurate diagnosis and early treatment can ensure better survival. Surgery in expert hands seems to be a good option for progressive retroperitoneal nodes. However, further studies are needed to determine the place of surgery in this setting.
Topics: Child; Adolescent; Humans; Male; Testicular Neoplasms; Lymphatic Metastasis; Rhabdomyosarcoma; Orchiectomy
PubMed: 36550579
DOI: 10.1186/s13256-022-03707-x