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Cancer Genomics & Proteomics 2023Angioleiomyoma is a benign tumor, occurs at any age, and arises most frequently in the lower extremities. Genetic information on angioleiomyomas is restricted to six...
BACKGROUND/AIM
Angioleiomyoma is a benign tumor, occurs at any age, and arises most frequently in the lower extremities. Genetic information on angioleiomyomas is restricted to six reported abnormal karyotypes, losses in chromosome 22 and gains in Xq found by comparative genomic hybridization, and mutation analysis of notch receptor 2 (NOTCH2), NOTCH3, platelet-derived growth factor receptor beta (PDGFRB), and mediator complex subunit 12 (MED12) in a few tumors. Herein, we report the genetic findings in another three angioleiomyomas.
MATERIALS AND METHODS
The tumors were examined using G-banding and karyotyping, RNA sequencing, reverse transcription-polymerase chain reaction, Sanger sequencing, and expression analysis.
RESULTS
The first tumor carried a t(4;5)(p12;q32) translocation resulting in fusion of the cardiac mesoderm enhancer-associated non-coding RNA (CARMN in 5q32) with the TXK tyrosine kinase gene (TXK in 4p12) leading to overexpression of TXK. To our knowledge, this is the first time that a recurrent chromosome translocation and its resulting fusion gene have been described in angioleiomyomas. The second tumor carried a four-way translocation, t(X;3;4;16)(q22;p11;q11;p13) which fused the myosin heavy chain 11 gene (MYH11 in 16p13) with intergenic sequences from Xq22 that mapped a few kilobase pairs distal to the insulin receptor substrate 4 gene (IRS4), resulting in enhanced IRS4 expression. The third angioleiomyoma carried another rearrangement of chromosome band Xq22, t(X;9)(q22;q32), as the sole cytogenetic aberration, but no material was available for further molecular investigation.
CONCLUSION
Our data, together with previously reported abnormal karyotypes in angioleiomyomas, show the presence of two recurrent genetic pathways in this tumor type: The first is characterized by presence of the translocation t(4;5)(p12;q32), which generates a CARMN::TXK chimera. The second is recurrent rearrangement of Xq22 resulting in overexpression of IRS4.
Topics: Humans; Angiomyoma; Comparative Genomic Hybridization; Chromosome Aberrations; Translocation, Genetic; Transcription Factors; Abnormal Karyotype
PubMed: 37889065
DOI: 10.21873/cgp.20405 -
Frontiers in Cellular and Infection... 2023Dysbiosis of the female reproductive tract is closely associated with gynecologic diseases. Here, we aim to explore the association between dysbiosis in the genital... (Observational Study)
Observational Study
Dysbiosis of the female reproductive tract is closely associated with gynecologic diseases. Here, we aim to explore the association between dysbiosis in the genital tract and uterine fibroids (UFs) to further provide new insights into UF etiology. We present an observational study to profile vaginal and cervical microbiome from 29 women with UFs and 38 healthy women, and 125 samples were obtained and sequenced. By comparing the microbial profiles between different parts of the reproductive tract, there is no significant difference in microbial diversity between healthy subjects and UF patients. However, alpha diversity of UF patients was negatively correlated with the number of fibroids. Increased Firmicutes were observed in both the cervical and vaginal microbiome of UF patients at the phylum level. In differential analysis of relative abundance, some genera were shown to be significantly enriched (e.g., , , and ) and depleted (e.g., UCG-003 and ) in UF patients. Furthermore, the microbial co-occurrence networks of UF patients showed lower connectivity and complexity, suggesting reduced interactions and stability of the cervical and vaginal microbiota in UF patients. In summary, our findings revealed the perturbation of microbiome in the presence of UFs and a distinct pattern of characteristic vaginal and cervical microbiome involved in UFs, offering new options to further improve prevention and management strategies.
Topics: Female; Humans; Dysbiosis; Vagina; Microbiota; Leiomyoma; Microbial Consortia; Firmicutes
PubMed: 37743857
DOI: 10.3389/fcimb.2023.1196823 -
Japanese Journal of Clinical Oncology Nov 2023Alveolar soft part sarcoma is a rare neoplasm of uncertain histogenesis that belongs to a newly defined category of ultra-rare sarcomas. The neoplasm is characterized by... (Review)
Review
Alveolar soft part sarcoma is a rare neoplasm of uncertain histogenesis that belongs to a newly defined category of ultra-rare sarcomas. The neoplasm is characterized by a specific chromosomal translocation, der (17) t(X; 17)(p11.2;q25), that results in ASPSCR1-TFE3 gene fusion. The natural history of alveolar soft part sarcoma describes indolent behaviour with slow progression in deep soft tissues of the extremities, trunk and head/neck in adolescents and young adults. A high rate of detection of distant metastasis at presentation has been reported, and the most common metastatic sites in decreasing order of frequency are the lung, bone and brain. Complete surgical resection remains the standard treatment strategy, whereas radiotherapy is indicated for patients with inadequate surgical margins or unresectable tumours. Although alveolar soft part sarcoma is refractory to conventional doxorubicin-based chemotherapy, monotherapy or combination therapy using tyrosine kinase inhibitors and immune checkpoint inhibitors have provided antitumor activity and emerged as new treatment strategies. This article provides an overview of the current understanding of this ultra-rare sarcoma and recent advancements in treatments according to the clinical stage of alveolar soft part sarcoma.
Topics: Adolescent; Young Adult; Humans; Sarcoma, Alveolar Soft Part; Oncogene Proteins, Fusion; Soft Tissue Neoplasms; Translocation, Genetic; Combined Modality Therapy
PubMed: 37626447
DOI: 10.1093/jjco/hyad102 -
Journal of Experimental & Clinical... Nov 2023Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, whose prognosis is still poor especially for metastatic, high-grade, and relapsed RMS. New...
BACKGROUND
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, whose prognosis is still poor especially for metastatic, high-grade, and relapsed RMS. New treatments are urgently needed, especially systemic therapies. Chimeric Antigen Receptor T cells (CAR Ts) are very effective against hematological malignancies, but their efficacy against solid tumors needs to be improved. CD276 (B7-H3) is a target upregulated in RMS and detected at low levels in normal tissues. FGFR4 is a very specific target for RMS. Here, we optimized CAR Ts for these two targets, alone or in combination, and tested their anti-tumor activity in vitro and in vivo.
METHODS
Four different single-domain antibodies were used to select the most specific FGFR4-CAR construct. RMS cell killing and cytokine production by CD276- and FGFR4-CAR Ts expressing CD8α or CD28 HD/TM domains in combination with 4-1BB and/or CD28 co-stimulatory domains were tested in vitro. The most effective CD276- and FGFR4-CAR Ts were used to generate Dual-CAR Ts. Tumor killing was evaluated in vivo in three orthotopic RMS mouse models.
RESULTS
CD276.V-CAR Ts (276.MG.CD28HD/TM.CD28CSD.3ζ) showed the strongest killing of RMS cells, and the highest release of IFN-γ and Granzyme B in vitro. FGFR4.V-CAR Ts (F8-FR4.CD28HD/TM.CD28CSD.3ζ) showed the most specific killing. CD276-CAR Ts successfully eradicated RD- and Rh4-derived RMS tumors in vivo, achieving complete remission in 3/5 and 5/5 mice, respectively. In CD276 JR-tumors, however, they achieved complete remission in only 1/5 mice. FGFR4 CAR Ts instead delayed Rh4 tumor growth. Dual-CAR Ts promoted Rh4-tumors clearance in 5/5 mice.
CONCLUSIONS
CD276- and CD276/FGFR4-directed CAR Ts showed effective RMS cell killing in vitro and eradication of CD276 RMS tumors in vivo. CD276 tumors escaped the therapy highlighting a correlation between antigen density and effectiveness. FGFR4-CAR Ts showed specific killing in vitro but could only delay RMS growth in vivo. Our results demonstrate that combined expression of CD276-CAR with other CAR does not reduce its benefit. Introducing immunotherapy with CD276-CAR Ts in RMS seems to be feasible and promising, although CAR constructs design and target combinations have to be further improved to eradicate tumors with low target expression.
Topics: Animals; Mice; B7 Antigens; CD28 Antigens; Cell Line, Tumor; Neoplasm Recurrence, Local; Receptor, Fibroblast Growth Factor, Type 4; Rhabdomyosarcoma; T-Lymphocytes
PubMed: 37924157
DOI: 10.1186/s13046-023-02838-3 -
Circulation. Cardiovascular Imaging Oct 2023Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere,... (Observational Study)
Observational Study
BACKGROUND
Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin.
METHODS
In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy.
RESULTS
Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; =0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; =0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (=0.009 and =0.008, respectively), T1 and T2 mapping (=0.001 and =0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (=0.013).
CONCLUSIONS
Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy P-metabolism alongside structural skeletal muscle changes.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT04467411.
Topics: Female; Humans; Middle Aged; Adenosine Triphosphate; Anthracyclines; Antibiotics, Antineoplastic; Biomarkers; Breast Neoplasms; Epirubicin; Longitudinal Studies; Muscle, Skeletal; Phosphocreatine; Prospective Studies; Stroke Volume; Ventricular Function, Left
PubMed: 37847761
DOI: 10.1161/CIRCIMAGING.123.015782 -
Medicina (Kaunas, Lithuania) Jul 2023: The uterine smooth muscle tumors of uncertain malignant potential (STUMP) are tumors with pathological characteristics similar to leiomyosarcoma, but that do not... (Review)
Review
: The uterine smooth muscle tumors of uncertain malignant potential (STUMP) are tumors with pathological characteristics similar to leiomyosarcoma, but that do not satisfy histological criteria for leiomyoma. These are problematic lesions with intermediate morphologic features; thus, diagnosis and treatment are difficult. This narrative review aims to review data in the literature about STUMPs, particularly focusing on management and therapeutic options and strategies for women who desire to preserve fertility. : authors searched for "uterine smooth muscle tumor of uncertain malignant potential" in PubMed and Scopus databases, from 2000 to March 2023. Pertinent articles were obtained in full-text format and screened for additional references. Only articles in English language were included. Studies including full case description of patients with histopathological diagnosis of STUMP in accordance with Stanford criteria were included. : The median age was 43 years old. Symptoms are similar to those of leiomyomas, with a mean diameter of 8.0 cm. Total hysterectomy with or without bilateral salpingo-oophorectomy is the standard care for women if fertility desire is satisfied. Myomectomy alone can be considered for young patients. Although these tumors have not a high malignant potential, several studies described recurrence and metastases. : STUMPs are complex uterine smooth muscle tumors, with a rare but reasoned clinical-diagnostic management. Considering the high clinical and histological complexity of these tumors, high level of expertise is mandatory.
Topics: Adult; Female; Humans; Databases, Factual; Leiomyoma; Smooth Muscle Tumor; Uterine Myomectomy; Uterus
PubMed: 37629661
DOI: 10.3390/medicina59081371 -
Nature Communications Jul 2023Nearly 70% of Uterine fibroid (UF) tumors are driven by recurrent MED12 hotspot mutations. Unfortunately, no cellular models could be generated because the mutant cells...
Nearly 70% of Uterine fibroid (UF) tumors are driven by recurrent MED12 hotspot mutations. Unfortunately, no cellular models could be generated because the mutant cells have lower fitness in 2D culture conditions. To address this, we employ CRISPR to precisely engineer MED12 Gly44 mutations in UF-relevant myometrial smooth muscle cells. The engineered mutant cells recapitulate several UF-like cellular, transcriptional, and metabolic alterations, including altered Tryptophan/kynurenine metabolism. The aberrant gene expression program in the mutant cells is, in part, driven by a substantial 3D genome compartmentalization switch. At the cellular level, the mutant cells gain enhanced proliferation rates in 3D spheres and form larger lesions in vivo with elevated production of collagen and extracellular matrix deposition. These findings indicate that the engineered cellular model faithfully models key features of UF tumors and provides a platform for the broader scientific community to characterize genomics of recurrent MED12 mutations.
Topics: Humans; Leiomyoma; Myocytes, Smooth Muscle; Mutation; Genomics; Clustered Regularly Interspaced Short Palindromic Repeats; Transcription Factors; Mediator Complex
PubMed: 37429859
DOI: 10.1038/s41467-023-39684-y -
Frontiers in Immunology 2023Metastatic rhabdomyosarcoma (RMS) is a challenging tumor entity that evades conventional treatments and endogenous antitumor immune responses, highlighting the need for...
INTRODUCTION
Metastatic rhabdomyosarcoma (RMS) is a challenging tumor entity that evades conventional treatments and endogenous antitumor immune responses, highlighting the need for novel therapeutic strategies. Applying chimeric antigen receptor (CAR) technology to natural killer (NK) cells may offer safe, effective, and affordable therapies that enhance cancer immune surveillance.
METHODS
Here, we assess the efficacy of clinically usable CAR-engineered NK cell line NK-92/5.28.z against ErbB2-positive RMS and in a metastatic xenograft mouse model.
RESULTS
Our results show that NK-92/5.28.z cells effectively kill RMS cells and significantly prolong survival and inhibit tumor progression in mice. The persistence of NK-92/5.28.z cells at tumor sites demonstrates efficient antitumor response, which could help overcome current obstacles in the treatment of solid tumors.
DISCUSSION
These findings encourage further development of NK-92/5.28.z cells as off-the-shelf immunotherapy for the treatment of metastatic RMS.
Topics: Humans; Animals; Mice; Rhabdomyosarcoma, Alveolar; Receptors, Chimeric Antigen; Immunotherapy; Rhabdomyosarcoma; Disease Models, Animal; Killer Cells, Natural; Neoplasms, Second Primary
PubMed: 37662907
DOI: 10.3389/fimmu.2023.1228894 -
PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors.Nature Communications Nov 2023Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma....
Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.
Topics: Animals; Child; Humans; Mice; Cell Line, Tumor; Endothelial Cells; Forkhead Box Protein O1; Gene Expression Regulation, Neoplastic; Muscle, Skeletal; Oncogene Proteins, Fusion; Paired Box Transcription Factors; PAX3 Transcription Factor; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar
PubMed: 37968277
DOI: 10.1038/s41467-023-43044-1 -
BMC Women's Health Sep 2023Intravenous leiomyomatosis (IVL) is a rare and specific type of smooth muscle tumor that is histologically benign but has a malignant biological behavior. It is commonly...
BACKGROUND
Intravenous leiomyomatosis (IVL) is a rare and specific type of smooth muscle tumor that is histologically benign but has a malignant biological behavior. It is commonly associated with a history of uterine leiomyomas.
CASE PRESENTATION
A 36-year-old woman, G1P1, presented to the hospital with left lower abdominal pain for 2 months and she has accepted hysteroscopic myomectomy about 1 year ago. Ultrasound venography, echocardiography and computed tomography venography (CTV) of inferior vena cava were performed, which revealed IVL located in left intramural myometrium walls growing along the left ovarian vein reaching the level of the lumbar 5-sacral 1 disc. Laparoscopic bilateral salpingo-oophorectomy and hysterectomyis were scheduled. The IVL in the left ovarian vein and parauterine venous plexus were detected and excised completely during surgery. IVL was diagnosed by postoperative pathology and immunohistochemistry. The patient recovered well after surgery. No surgical-related or anesthesia-related complications occurred.The 3-month follow-up CTV of inferior vena cava and echocardiography examination revealed normal.
CONCLUSIONS
The cause of IVL is unknown, this observation demonstrates that hysteroscopic myomectomy might lead to the occurrence of IVL.
Topics: Female; Humans; Adult; Leiomyomatosis; Abdominal Pain; Echocardiography; Myometrium; Pelvis
PubMed: 37697329
DOI: 10.1186/s12905-023-02618-3