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European Journal of Obstetrics,... Jun 2024Primary ovarian insufficiency (POI) is defined as cessation of ovarian function before the age of 40 years, which is characterized by amenorrhoea, infertility, elevated...
BACKGROUND
Primary ovarian insufficiency (POI) is defined as cessation of ovarian function before the age of 40 years, which is characterized by amenorrhoea, infertility, elevated gonadotrophin level and sex-steroid deficiency. The phenotypes of POI are heterogeneous, including isolated and syndromic forms. Perrault syndrome (PS), characterized by sensorineural hearing loss (SNHL) and ovarian dysfunction before 40 years in females, is one type of syndromic POI. Genetic defects play a vital role in the pathogenesis of POI.
METHODS AND RESULTS
To illustrate the genetic causation of Perrault syndrome, we performed whole exome sequencing (WES) in one pedigree with the disease, and identified a novel homozygous mutation in TWNK (c.1388G > A, p.R463Q). TWNK encodes a hexameric DNA helicase in mitochondria and plays a critical role in mtDNA replication. In order to determine the effect of the novel mutation on the mitochondrial function, we generated immortalized cell lines by infecting lymphocytes from the family members with EB virus in vitro. Functional studies found that TWNK p.R463Q impaired mtDNA replication and the respiration potential of mitochondria, while the ROS level remains unaffected.
CONCLUSION
Our study provided evidence that TWNK mutation impaired the ovarian function by dysfunctional mitochondria. Moreover, considering the patients here presented POI onset earlier than SNHL, specific variants localizing in different locus of TWNK might induce heterogeneous phenotypes, indicating that the genetic screening of patients with POI would be useful for early recognition of other disease or other phenotypes of syndromic POI.
PubMed: 38852317
DOI: 10.1016/j.ejogrb.2024.05.041 -
JCO Global Oncology Jun 2024In high-income countries, 2%-10% of tumor genomic profiling (TGP) reports reveal incidental pathogenic germline variants. A third of these patients would not qualify for...
PURPOSE
In high-income countries, 2%-10% of tumor genomic profiling (TGP) reports reveal incidental pathogenic germline variants. A third of these patients would not qualify for genetic testing on the basis of current guidelines. Our study determined the prevalence of potentially pathogenic germline variants (PPGVs) in TGP results of adult patients with solid malignancies in the Philippines.
METHODS
Annotated reports of patients with solid cancers who underwent TGP using FoundationOne or FoundationOne Heme between January 2021 and July 2023 were reviewed. PPGV criteria include having a variant allele frequency of >30% and were categorized as (1) high penetrance gene (HP), founder variant (FV), or variant associated with clinical presentation (VA). Pathogenicity was crosschecked through the ClinVar database.
RESULTS
Of 446 patients, 13 PPGV variants were found in 50 (11.2%) patients at a median age of 60.5 years. Of them, 28 (56%) had HP (, , , , , , ), 25 (50%) patients had VA (, , , , ), and two patients with lung cancer had a FV ( p.Thr790Met). Six patients had more than one PPGV. PPGVs were primarily found in patients with colorectal (42% of 50 patients with PPGVs), breast (16%), ovarian (6%), and lung (6%) cancer ( < .001). HP genes were mostly found in female patients (71.4%; = .03).
CONCLUSION
With a PPGV prevalence of 11% in this study, it is important to recognize PPGVs as it can prompt genetic counseling and confirmatory germline testing.
Topics: Humans; Female; Male; Philippines; Middle Aged; Germ-Line Mutation; Neoplasms; Aged; Adult; Prevalence; Genetic Predisposition to Disease; Genetic Testing; Aged, 80 and over; Genomics
PubMed: 38843470
DOI: 10.1200/GO.24.00019 -
Microbiology Spectrum Jul 2024The study aimed to investigate the antibacterial activity, cytotoxicity, and mechanism of action of the non-ionic, cyclic lipopeptide, serrawettin W2-FL10 against ....
UNLABELLED
The study aimed to investigate the antibacterial activity, cytotoxicity, and mechanism of action of the non-ionic, cyclic lipopeptide, serrawettin W2-FL10 against . W2-FL10 exhibited potent activity against the Gram-positive bacteria , , , and , with minimum inhibitory concentration (MIC) values ranging from 6.3 to 31.3 μg/mL, while no activity was observed against Gram-negative bacteria. Broth microdilution assays showed that W2-FL10 interacted with key cell membrane components, such as lipid phosphatidyl glycerol and lipoteichoic acid of . Upon membrane interaction, W2-FL10 dissipated membrane potential within 12 min and increased membrane permeability within 28-40 min, albeit at slower rates and higher concentrations than the lytic peptide melittin. The observed membrane permeability, as detected with propidium iodide (PI), may be attributed to transmembrane pores/lesions, possibly dependent on dimer-driven lipopeptide oligomerization in the membrane. Scanning electron microscopy (SEM) imaging also visually confirmed the formation of lesions in the cell wall of one of the strains, and cell damage within 1 h of exposure to W2-FL10, corroborating the rapid time-kill kinetics of the strains. This bactericidal action against the strains corresponded to membrane permeabilization by W2-FL10, indicating that self-promoted uptake into the cytosol may be part of the mode of action. Finally, this lipopeptide exhibited low to moderate cytotoxicity to the Chinese hamster ovarian (CHO) cell line in comparison to the control (emetine) with an optimal lipophilicity range (log D value of 2.5), signifying its potential as an antibiotic candidate.
IMPORTANCE
Antimicrobial resistance is a major public health concern, urgently requiring antibacterial compounds exhibiting low adverse health effects. In this study, a novel antibacterial lipopeptide analog is described, serrawettin W2-FL10 (derived from ), with potent activity displayed against . Mechanistic studies revealed that W2-FL10 targets the cell membrane of , causing depolarization and permeabilization because of transmembrane lesions/pores, resulting in the leakage of intracellular components, possible cytosolic uptake of W2-FL10, and ultimately cell death. This study provides the first insight into the mode of action of a non-ionic lipopeptide. The low to moderate cytotoxicity of W2-FL10 also highlights its application as a promising therapeutic agent for the treatment of bacterial infections.
Topics: Anti-Bacterial Agents; Lipopeptides; Microbial Sensitivity Tests; Cell Membrane; Animals; Staphylococcus aureus; Gram-Positive Bacteria; Cell Membrane Permeability; Teichoic Acids; Gram-Negative Bacteria
PubMed: 38842361
DOI: 10.1128/spectrum.02952-23 -
Blood Jun 2024Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by ADAMTS13 deficiency. Caplacizumab, an anti-VWF nanobody, is...
Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by ADAMTS13 deficiency. Caplacizumab, an anti-VWF nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet count recovery and survival. We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased after the first caplacizumab dose. Baseline characteristics and patient outcomes were compared with a control group of 59 patients with iTTP, receiving frontline treatment with TPE, caplacizumab, and immunosuppression. The main outcome was the time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, iTTP-related deaths, and the time to platelet count doubling. The median time to platelet count normalization was similar between the two cohorts (3 and 4 days; P = 0.31). There were no significant differences in clinical response, exacerbations, refractoriness, iTTP-related deaths, or time to platelet count doubling reflecting the short-term treatment response. Four patients did not respond to the first caplacizumab dose and TPE was subsequently initiated. Cytomegalovirus infection, HIV/hepatitis B co-infection, an ovarian teratoma with associated anti-platelet antibodies, and multiple platelet transfusion before the correct diagnosis may have impeded immediate treatment response in these patients. In conclusion, caplacizumab and immunosuppression alone, without TPE, rapidly controlled thrombotic microangiopathy and achieved a sustained clinical response in iTTP. Our study provides a basis for TPE-free iTTP management in experienced centers via shared decision-making between patients and treating physicians.
PubMed: 38838300
DOI: 10.1182/blood.2023023780 -
International Journal of Surgery Case... Jul 2024Fallopian tube cancer is a rare tumor, representing between 0.3 and 1.8 % of all malignant tumors in the gynecological sphere. Due to the proximity of the uterus and...
INTRODUCTION
Fallopian tube cancer is a rare tumor, representing between 0.3 and 1.8 % of all malignant tumors in the gynecological sphere. Due to the proximity of the uterus and ovary, the diagnosis of primary fallopian tube cancer is very difficult to establish and relies on very strict criteria. The endometrioid form is exceptional and of controversial etiopathogenesis. Only a few cases have been previously reported. Diagnosis most often occurs incidentally during histological examination. This case presents a distinctive aspect with the rare occurrence of endometrioid-type fallopian tube cancer, notably associated with endometriosis, and initially misdiagnosed as an infected endometrioma. It underscores the diagnostic complexities encountered in identifying primary fallopian tube cancer.
CASE REPORT
We present the case of a 49-year-old patient, followed for chronic pelvic pain associated with menorrhagia. Imaging revealed a myomatous and adenomyotic uterus, a right ovarian endometrioma, and a left multicystic ovarian formation with thick walls, measuring 135 mm, requiring histological verification. She underwent an exploratory laparotomy. During the procedure, extensive retro- and supravaginal adhesive tissue involving the uterus, both adnexa, and the digestive tract was found. Careful adhesiolysis was performed. The left adnexa harbored a formation suggestive of an infected endometrioma. A total hysterectomy with bilateral adnexectomy and peritoneal washing was performed. The postoperative course was uneventful. Histopathological examination revealed an endometrioid carcinoma of the left fallopian tube, classified as pT1a according to FIGO guidelines.
DISCUSSION
Tubal cancer is a rare cancer of unknown etiology, underestimated, and sometimes confused with ovarian pathology. Preoperative diagnosis is difficult because the clinical presentation is polymorphic and imaging is nonspecific. The endometrioid form is exceptional and of controversial etiopathogenesis. Treatment mirrors that of malignant epithelial ovarian tumors, with prognosis depending on FIGO stage and histological type.
CONCLUSION
Due to its unpredictable nature, fallopian tube cancer should not be overlooked as a differential diagnosis for any adnexal mass.
PubMed: 38833903
DOI: 10.1016/j.ijscr.2024.109796 -
Journal of Infection and Chemotherapy :... Jun 2024We present a case of tubo-ovarian abscess (TOA) caused by Clostridioides difficile (CD) in a 43-year-old female. Despite lacking a history of sexually transmitted...
We present a case of tubo-ovarian abscess (TOA) caused by Clostridioides difficile (CD) in a 43-year-old female. Despite lacking a history of sexually transmitted diseases, the patient had undergone paraovarian cystectomy nine months before admission. Transvaginal ultrasonography performed eight months post-surgery revealed left ovarian enlargement, accompanied by subsequent lower abdominal pain and fever exceeding 38 °C. As oral antibiotic treatment was ineffective, the patient was admitted to our hospital. Computed tomography upon admission revealed a massive TOA. Surgical drainage of the abscess was performed, and CD was identified in the culture from the pus. The TOA was treated with a three-month course of metronidazole and oral amoxicillin/clavulanic acid. While CD is commonly associated with colitis, extraintestinal manifestations are exceptionally rare. This case represents the inaugural report of TOA resulting from CD. A literature review on abdominal and pelvic CD abscesses found that patients undergoing surgical drainage had a favorable prognosis. Therefore, surgical intervention plays an important role in the management of CD abscesses.
PubMed: 38825001
DOI: 10.1016/j.jiac.2024.05.012 -
Anticancer Research Jun 2024The COVID-19 pandemic brought unprecedented global changes, necessitating adjustments to address public health challenges. The impact on advanced epithelial ovarian...
BACKGROUND/AIM
The COVID-19 pandemic brought unprecedented global changes, necessitating adjustments to address public health challenges. The impact on advanced epithelial ovarian cancer (EOC) surgery, marked by increased perioperative risks, and changes in management plans was explored in this study based on promptly published British Gynaecologic Cancer Society (BGCS) and European Society of Gynaecologic Oncology (ESGO) guidelines.
PATIENTS AND METHODS
Retrospective data from 332 patients with advanced EOC who underwent cytoreductive surgery at a UK tertiary center were analyzed, and the outcomes were compared between pre-COVID-19 (2018-2019) (n=189) and COVID-19 era (2020-2021) (n=143) cohorts, covering the same timeframe (March to December). Primary outcomes included residual disease (RD) and progression-free survival (PFS), while secondary outcomes were the ESGO quality indicators (QIs) for advanced EOC surgery. Kaplan-Meier curves were produced to illustrate PFS.
RESULTS
Complete cytoreduction rates remained comparable at 74.07% and 72.03% for pre-COVID-19 and COVID-19 groups, respectively. Differences were observed in ECOG performance status (p=0.015), Intensive Care Unit (ICU) admissions (p=0.039) with less interval debulking surgeries (p=0.03), lower surgical complexity scores (p=0.02), and longer operative times in the COVID-19 group (p=0.01) compared to the pre-COVID-19 group. The median PFS rates were 37 months and 34 months in the pre-COVID-19 and COVID-19 groups, respectively (p=0.08). The surgical QIs 1-3 remained uncompromised during the COVID-19 era.
CONCLUSION
Management modifications prompted by the COVID-19 pandemic did not adversely impact cytoreduction rates or PFS.
Topics: Humans; Female; COVID-19; Cytoreduction Surgical Procedures; Middle Aged; Ovarian Neoplasms; Retrospective Studies; Aged; Carcinoma, Ovarian Epithelial; Adult; SARS-CoV-2; Progression-Free Survival; Neoplasm, Residual; Aged, 80 and over; Treatment Outcome; United Kingdom
PubMed: 38821579
DOI: 10.21873/anticanres.17071 -
Frontiers in Bioscience (Landmark... Apr 2024Ovarian cancer is a highly lethal gynecologic malignancy. ARHGAP10, a member of Rho GTPase-activating proteins, is a potential tumor suppressor in ovarian cancer....
BACKGROUND
Ovarian cancer is a highly lethal gynecologic malignancy. ARHGAP10, a member of Rho GTPase-activating proteins, is a potential tumor suppressor in ovarian cancer. However, its role and the involved mechanism need further examination. Here, we investigated whether ARHGAP10 is also associated with ferroptosis.
METHODS
Lentivirus infection was used for gene overexpression or silencing. Real-time polymerase chain reaction (RT-PCR) and Western blot were used to assess mRNA and protein levels, respectively. Cell viability was assessed by Cell Counting Kit-8 (CCK-8) assay. Lipid reactive oxygen species level was measured by flow cytometry. A tumorigenicity assay was performed to evaluate tumor growth , and sections of mouse tumor tissues were examined by immunofluorescence microscopy. Chromatin Immunoprecipitation (ChIP) assay was used to assess the binding of H3K9ac to the promoter region of ARHGAP10.
RESULTS
ARHGAP10 overexpression promoted ferroptosis in ovarian cancer cells, resulting in decreased cell viability, and increased lipid reactive oxygen species (ROS) level. Further, it decreased and increased GPX4 and PTGS2 expression, respectively, and also induced suppression of tumor growth in mice. Fer-1, a potent inhibitor of ferroptosis, suppressed the above effects of ARHGAP10. Contrarily, ARHGAP10 silencing alleviated ferroptosis in ovarian cancer cells, which was reversed by RSL3, a ferroptosis-inducing agent. Lastly, sodium butyrate (SB) was found to transcriptionally regulate ARHGAP10, thereby also contributing to the ferroptosis of ovarian cancer cells.
CONCLUSIONS
Our results suggest that SB/ARHGAP10/GPX4 is a new signaling axis involved in inducing ferroptosis in ovarian cancer cells and suppressing tumor growth, which has potential clinical significance.
Topics: Ferroptosis; Female; Ovarian Neoplasms; Humans; Animals; GTPase-Activating Proteins; Cell Line, Tumor; Reactive Oxygen Species; Butyric Acid; Gene Expression Regulation, Neoplastic; Mice; Mice, Nude; Cell Survival; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 38812318
DOI: 10.31083/j.fbl2905167 -
The Journal of Obstetrics and... May 2024Septic pelvic thrombophlebitis (SPT) is a rare condition that forms thrombosis in the pelvic veins, typically the ovarian veins, with subsequent infection and...
Delayed onset septic pelvic thrombophlebitis treated by tissue-plasminogen activator following initial treatment for massive right ovarian vein thrombosis and methicillin-resistant Staphylococcus aureus bacteremia: A case report.
Septic pelvic thrombophlebitis (SPT) is a rare condition that forms thrombosis in the pelvic veins, typically the ovarian veins, with subsequent infection and inflammation. We present a case of right ovarian vein thrombosis (ROVT), methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, and delayed onset of SPT symptoms, requiring tissue-plasminogen activator. A 40-year-old woman, G3P2, at 38 weeks' gestation, was admitted with a fever of 39°C. She had cervical insufficiency and had been often on bed rest. Blood culture revealed MRSA and computed tomography revealed a large ROVT. She received vancomycin and direct oral anticoagulant, and her fever resolved by day 3. On day 16, fever recurred with severe pain over the ROVT. Second computed tomography showed thickening of venous wall with enhancement around ROVT, consistent with SPT. Since pain and fever gradually exacerbated despite treatment with DOAC and antimicrobials, she was started on heparin and tissue plasminogen activator on days 23 and 25, respectively. Along with recanalization on the thrombosis by day 29, fever and abdominal pain resolved. We experienced a case of delayed onset SPT associated with MRSA bacteremia and a large ROVT. MRSA bacteremia might cause the originally existing ROVT to become an infection source, resulting in SPT with recurrent symptoms and long-term treatment. Early and strict anticoagulation is crucial in cases with a large thrombosis and bacteremia, due to the high risk of progression to SPT. This case highlights the importance of recanalization for the treatment of SPT and usefulness of administration of tissue-plasminogen activator for the massive thrombosis.
PubMed: 38807344
DOI: 10.1111/jog.15991 -
Proceedings of the National Academy of... Jun 2024The phylum (kingdom , realm ) is a broad assemblage of diverse viruses with comparatively short double-stranded DNA genomes (<50 kbp) that produce icosahedral capsids...
The phylum (kingdom , realm ) is a broad assemblage of diverse viruses with comparatively short double-stranded DNA genomes (<50 kbp) that produce icosahedral capsids built from double jelly-roll major capsid proteins. Preplasmiviricots infect hosts from all cellular domains, testifying to their ancient origin, and, in particular, are associated with six of the seven supergroups of eukaryotes. Preplasmiviricots comprise four major groups of viruses, namely, polintons, polinton-like viruses (PLVs), virophages, and adenovirids. We used protein structure modeling and analysis to show that protein-primed DNA polymerases (pPolBs) of polintons, virophages, and cytoplasmic linear plasmids encompass an N-terminal domain homologous to the terminal proteins (TPs) of prokaryotic PRD1-like tectivirids and eukaryotic adenovirids that are involved in protein-primed replication initiation, followed by a viral ovarian tumor-like cysteine deubiquitinylase (vOTU) domain. The vOTU domain is likely responsible for the cleavage of the TP from the large pPolB polypeptide and is inactivated in adenovirids, in which TP is a separate protein. Many PLVs and transpovirons encode a distinct derivative of polinton-like pPolB that retains the TP, vOTU, and pPolB polymerization palm domains but lacks the exonuclease domain and instead contains a superfamily 1 helicase domain. Analysis of the presence/absence and inactivation of the vOTU domains and replacement of pPolB with other DNA polymerases in eukaryotic preplasmiviricots enabled us to outline a complete scenario for their origin and evolution.
Topics: Capsid Proteins; DNA Viruses; Eukaryota; DNA-Directed DNA Polymerase; Models, Molecular; Phylogeny
PubMed: 38805295
DOI: 10.1073/pnas.2405771121