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SLAS Discovery : Advancing Life... Mar 2024Combination therapies have improved outcomes for patients with acute myeloid leukemia (AML). However, these patients still have poor overall survival. Although many...
Combination therapies have improved outcomes for patients with acute myeloid leukemia (AML). However, these patients still have poor overall survival. Although many combination therapies are identified with high-throughput screening (HTS), these approaches are constrained to disease models that can be grown in large volumes (e.g., immortalized cell lines), which have limited translational utility. To identify more effective and personalized treatments, we need better strategies for screening and exploring potential combination therapies. Our objective was to develop an HTS platform for identifying effective combination therapies with highly translatable ex vivo disease models that use size-limited, primary samples from patients with leukemia (AML and myelodysplastic syndrome). We developed a system, ComboFlow, that comprises three main components: MiniFlow, ComboPooler, and AutoGater. MiniFlow conducts ex vivo drug screening with a miniaturized flow-cytometry assay that uses minimal amounts of patient sample to maximize throughput. ComboPooler incorporates computational methods to design efficient screens of pooled drug combinations. AutoGater is an automated gating classifier for flow cytometry that uses machine learning to rapidly analyze the large datasets generated by the assay. We used ComboFlow to efficiently screen more than 3000 drug combinations across 20 patient samples using only 6 million cells per patient sample. In this screen, ComboFlow identified the known synergistic combination of bortezomib and panobinostat. ComboFlow also identified a novel drug combination, dactinomycin and fludarabine, that synergistically killed leukemic cells in 35 % of AML samples. This combination also had limited effects in normal, hematopoietic progenitors. In conclusion, ComboFlow enables exploration of massive landscapes of drug combinations that were previously inaccessible in ex vivo models. We envision that ComboFlow can be used to discover more effective and personalized combination therapies for cancers amenable to ex vivo models.
Topics: Humans; Drug Synergism; Drug Combinations; Leukemia, Myeloid, Acute; Panobinostat; Hematologic Neoplasms
PubMed: 38101570
DOI: 10.1016/j.slasd.2023.12.001 -
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 -
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 -
Microbiology Spectrum Dec 2023As a current biocontrol resource, entomopathogenic nematodes and their symbiotic bacterium can produce many toxin factors to trigger insect sepsis, having the potential...
As a current biocontrol resource, entomopathogenic nematodes and their symbiotic bacterium can produce many toxin factors to trigger insect sepsis, having the potential to promote sustainable pest management. In this study, we found and were highly virulent against the insects. After infective juvenile injection, quickly turned black and softened with increasing esterase activity. Simultaneously, attacked hemocytes and released toxic components, resulting in extensive hemolysis and sepsis. Then, we applied high-resolution mass spectrometry-based metabolomics and found multiple substances were upregulated in the host hemolymph. We found extremely hazardous actinomycin D produced via 3-hydroxyanthranilic acid metabolites. Moreover, a combined transcriptomic analysis revealed that gene expression of proteins associated with actinomycin D was upregulated. Our research revealed actinomycin D might be responsible for the infestation activity of , indicating a new direction for exploring the sepsis mechanism and developing novel biotic pesticides.
Topics: Animals; Dactinomycin; Insecta; Diptera; Rhabditida; Symbiosis; Sepsis
PubMed: 37787562
DOI: 10.1128/spectrum.01422-23 -
Clinical Case Reports Oct 2023Choriocarcinoma of the fallopian tube is extremely rare and highly susceptible to early metastasis. Clinical manifestations of ectopic pregnancy and choriocarcinoma are...
KEY CLINICAL MESSAGE
Choriocarcinoma of the fallopian tube is extremely rare and highly susceptible to early metastasis. Clinical manifestations of ectopic pregnancy and choriocarcinoma are the same, and all patients with ectopic pregnancy should be evaluated for choriocarcinoma based on histopathological findings. Adjuvant chemotherapy (after surgery) is the proposed treatment for tubal choriocarcinoma.
ABSTRACT
Choriocarcinoma is a malignant epithelial tumor of the chorionic villi that often manifests after a normal or molar pregnancy. The primary tubal choriocarcinoma associated with ectopic pregnancy is extremely rare and can be misdiagnosed as an ectopic pregnancy since symptoms including vaginal bleeding, amenorrhea, elevated beta-human chorionic gonadotropin (BHCG) levels, and pelvic pain are shared. A 34-year-old G4P3003 woman presented with a one-week history of vaginal bleeding and right lower abdominal pain, which had intensified a day before admission. Clinical and paraclinical examinations pointed to a ruptured tubal pregnancy; hence, an emergency laparotomy was performed, and a right salpingectomy was carried out on the patient. However, a nonsignificant decline in BHCG level was observed, and histological examination revealed tubal choriocarcinoma; hence, a metastasis workup was carried out, yet no metastasis was detected. Six sessions of chemotherapy consisting of Etoposide, Methotrexate, Dactinomycin, Cyclophosphamide, and Vincristine (EMA-CO) were administered without complication, in such a way that the BHCG level normalized after three sessions of chemotherapy. Evaluations after 1 year from the completion of chemotherapy revealed that the patient had no subsequent problems. Choriocarcinoma of the fallopian tube is extremely rare and highly susceptible to early metastasis. Clinical manifestations of ectopic pregnancy and choriocarcinoma are the same, and all patients with ectopic pregnancy should be evaluated for choriocarcinoma based on histopathological findings. Metastasis workup should be considered for all individuals with choriocarcinoma. Adjuvant chemotherapy (after surgery) is the proposed treatment for tubal choriocarcinoma.
PubMed: 37780932
DOI: 10.1002/ccr3.7977 -
Molecules (Basel, Switzerland) Aug 2023Actinobacteria produce a broad spectrum of bioactive substances that are used in the pharmaceutical, agricultural, and biotechnology industries. This study investigates...
Actinobacteria produce a broad spectrum of bioactive substances that are used in the pharmaceutical, agricultural, and biotechnology industries. This study investigates the production of bioactive substances in , isolated from soil under five tropical plants, focusing on their potential as natural antibacterial dyes for silk fabrics. Out of 194 isolates, 44 produced pigments on broken rice as a solid substrate culture. Eight antibacterial pigmented isolates from under (TBRC 15924, TBRC 15927, TBRC 15931), (TBRC 15925, TBRC 15926, TBRC 15928, TBRC 15930), and (TBRC 15929) were studied in more detail. TBRC 15927 was the only isolate where all the crude extracts inhibited the growth of the test organisms, TISTR 518 and DMST 4745. The bioactive compounds present in TBRC 15927 were identified through LC-MS/MS analysis as belonging to the actinomycin group, actinomycin D (or X), X, and X. Also, the ethyl acetate crude extract exhibited non-toxicity at an IC value of 0.029 ± 0.008 µg/mL on the mouse fibroblast L-929 assay. From the 16S rRNA gene sequence analysis, TBRC 15927 had 100% identity with JR-43. Raw silk dyed with the positive antimicrobial TBRC 15927 extract (8.35 mg/mL) had significant (>99.99%) antibacterial properties. TBRC 15927 is the first actinomycin-producing strain reported to grow on broken rice and shows promise for antibacterial silk dyeing.
Topics: Animals; Mice; Dactinomycin; Soil; Silk; Chromatography, Liquid; RNA, Ribosomal, 16S; Staphylococcus aureus; Tandem Mass Spectrometry; Anti-Bacterial Agents; Streptomyces
PubMed: 37630201
DOI: 10.3390/molecules28165949 -
BMC Cancer Aug 2023Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various...
Comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for low-risk gestational trophoblastic neoplasia (FIGO Score 0-4): study protocol for a prospective, multicentre, randomized trial.
BACKGROUND
Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various methotrexate-based and actinomycin D-based single-agent regimens can be used. However, there is insufficient evidence to determine the superior regimen. To guide doctors in selecting a single-agent chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia, we will compare two regimens.
METHODS
We will conduct a multicentre, randomized, prospective clinical trial. Selected low-risk gestational trophoblastic neoplasia patients (FIGO score 0-4) will be randomized 1:1 to a biweekly single-dose actinomycin D group or a multiday methotrexate therapy group. The actinomycin D group will receive IV pulse actinomycin D (1.25 mg/m) every 14 days, and the methotrexate group will receive methotrexate (50 mg) intramuscularly on days 1, 3, 5, and 7 (4 doses per cycle) and leucovorin (15 mg) intramuscularly on days 2, 4, 6, and 8. This process will be repeated every 14 days. The primary endpoints will include the complete remission rate by single-agent therapy and the overall complete remission rate. The secondary endpoints will include the duration needed to achieve complete remission after single-agent chemotherapy, number of courses needed to achieve complete remission after single-agent chemotherapy, incidence and severity of adverse effects, effects on menstrual conditions and ovarian function based on the anti-Mullerian hormone level, and patient-reported quality of life.
DISCUSSION
Previous clinical trials comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for treating low-risk gestational trophoblastic neoplasia patients failed to meet the expected case number. Through this multicentre study, the complete remission ratio and efficacy difference between biweekly single-dose actinomycin D and multiday methotrexate therapy will be obtained. This study will also provide the basis for formulating a preferred regimen for treating patients with low-risk gestational trophoblastic neoplasia.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT04562558, Registered on 13 September 2020 (Protocol version 2020-9-24, version 1.0).
Topics: Humans; Pregnancy; Female; Dactinomycin; Methotrexate; Prospective Studies; Quality of Life; Gestational Trophoblastic Disease; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37612621
DOI: 10.1186/s12885-023-11225-2 -
Clinics (Sao Paulo, Brazil) 2023To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as...
OBJECTIVE
To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment.
METHODS
Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board.
RESULTS
Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab.
CONCLUSION
Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.
Topics: Pregnancy; Female; Humans; Methotrexate; Dactinomycin; Brazil; Gestational Trophoblastic Disease; Immunotherapy; Retrospective Studies
PubMed: 37523979
DOI: 10.1016/j.clinsp.2023.100260