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Nutrients Jun 2024Taurine, a non-proteogenic amino acid and commonly used nutritional supplement, can protect various tissues from degeneration associated with the action of the...
Taurine, a non-proteogenic amino acid and commonly used nutritional supplement, can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We found that OC ascites-derived cells contained significantly more intracellular taurine than cell culture-modeled OC. In culture, elevation of intracellular taurine concentration to OC ascites-cell-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse-phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant or wild-type p53 binding to DNA, activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurine's suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage-sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurine's ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurine's cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth and metabolism, and activate cell protective mechanisms involving mTOR and DNA damage-sensing signal transducti.
Topics: Taurine; Humans; TOR Serine-Threonine Kinases; Female; Ovarian Neoplasms; DNA Damage; Cisplatin; Tumor Suppressor Protein p53; Cell Line, Tumor; Cell Proliferation; Signal Transduction; Glycolysis; Extracellular Signal-Regulated MAP Kinases; Antineoplastic Agents
PubMed: 38931171
DOI: 10.3390/nu16121816 -
International Journal of Molecular... Jun 2024Platinum-resistant high-grade serous carcinoma (HGSC) is an incurable disease, so biomarkers that could help with timely treatment adjustments and personalized approach...
Higher EpCAM-Positive Extracellular Vesicle Concentration in Ascites Is Associated with Shorter Progression-Free Survival of Patients with Advanced High-Grade Serous Carcinoma.
Platinum-resistant high-grade serous carcinoma (HGSC) is an incurable disease, so biomarkers that could help with timely treatment adjustments and personalized approach are extensively being sought. Tumor-derived extracellular vesicles (EVs) that can be isolated from ascites and blood of HGSC patients are such promising biomarkers. Epithelial cell adhesion molecule (EpCAM) expression is upregulated in most epithelium-derived tumors; however, studies on prognostic value of EpCAM overexpression in ovarian carcinoma have shown contradictory results. The aim of our study was to evaluate the potential of total and EpCAM-positive EVs as prognostic and predictive biomarkers for advanced HGSC. Flow cytometry was used to determine the concentration of total and EpCAM-positive EVs in paired pretreatment ascites and plasma samples of 37 patients with advanced HGSC who underwent different first-line therapy. We found that higher EpCAM-positive EVs concentration in ascites is associated with shorter progression-free survival (PFS) regardless of treatment strategy. We also found a strong correlation of EpCAM-positive EVs concentration between ascites and plasma. Our findings indicate that EpCAM-positive EVs in ascites of patients with advanced HGSC have the potential to serve as prognostic biomarkers for predicting early recurrence and thereby likelihood of more aggressive tumor biology and development of chemoresistance.
Topics: Humans; Epithelial Cell Adhesion Molecule; Extracellular Vesicles; Female; Ascites; Middle Aged; Aged; Biomarkers, Tumor; Progression-Free Survival; Cystadenocarcinoma, Serous; Ovarian Neoplasms; Prognosis; Adult; Neoplasm Grading
PubMed: 38928484
DOI: 10.3390/ijms25126780 -
ImmunoHorizons Jun 2024PD-1 blockade has been approved for head and neck squamous cell carcinoma (HNSCC) patients. However, many HNSCC patients do not respond to this treatment, and other...
PD-1 blockade has been approved for head and neck squamous cell carcinoma (HNSCC) patients. However, many HNSCC patients do not respond to this treatment, and other tumor microenvironmental factors may promote resistance to PD-1 blockade. We previously identified increased expression of the inhibitory receptor NKG2A on CD8+ T cells in HNSCC tumors compared with T cells in matching PBMC samples. Mechanisms that promote NKG2A expression and the role of NKG2A on human T cells in the tumor microenvironment, however, are uncertain. In this study, we show that tumor-conditioned media (TCM) of HNSCC cancer cell lines or ascites fluid from colorectal carcinoma patients is sufficient to induce the expression of NKG2A and other inhibitory receptors on activated CD8+ T cells isolated from PBMCs of healthy donors. Boiling or small molecular mass cutoff filtering did not eliminate the effect of TCM, suggesting that a small molecule promotes NKG2A. T cell activation in TCM decreased the basal and maximal mitochondrial respiration to metabolically restrain CD8+ T cells. Functionally, T cell activation in TCM reduced CD8+ T cell cytotoxicity as shown by lower production of cytokines, granzyme B, and perforin. Furthermore, TCM prevented CD8+ T cells from killing cancer cells in response to an anti-CD19/anti-CD3 bispecific T cell engager. Thus, a small secreted molecule from HNSCC cells can induce NKG2A expression and promote T cell dysfunction. Our findings may lead to targets for novel cancer therapies or biomarkers for NKG2A blockade response and provide a model to study T cell dysfunction and impaired metabolism.
Topics: Humans; CD8-Positive T-Lymphocytes; NK Cell Lectin-Like Receptor Subfamily C; Cell Line, Tumor; Squamous Cell Carcinoma of Head and Neck; Culture Media, Conditioned; Tumor Microenvironment; Lymphocyte Activation; Head and Neck Neoplasms; Colorectal Neoplasms
PubMed: 38922288
DOI: 10.4049/immunohorizons.2400046 -
Cureus May 2024Chylothorax is a rare condition that results from thoracic duct disruption with malignant and nonmalignant etiologies manifesting as a pleural effusion. Typically,...
Chylothorax is a rare condition that results from thoracic duct disruption with malignant and nonmalignant etiologies manifesting as a pleural effusion. Typically, chylothorax in the setting of cirrhosis is associated with the migration of chylous ascites. We present the case of a 64-year-old male with prior liver transplant who presented with new-onset transudative chylothorax without chylous ascites who responded to transjugular intrahepatic portosystemic shunt revision, diuresis, and serial thoracentesis.
PubMed: 38916011
DOI: 10.7759/cureus.60996 -
BMC Genomics Jun 2024Peritoneal carcinomatosis was the main reason leading to gastric cancer (GC)-related death. We aimed to explore the roles of dysregulated microRNAs (miRNAs) and related...
BACKGROUND
Peritoneal carcinomatosis was the main reason leading to gastric cancer (GC)-related death. We aimed to explore the roles of dysregulated microRNAs (miRNAs) and related immune regulation activities in GC-associated malignant ascites.
METHODS
GSE126399 were downloaded from GEO database. Differentially expressed miRNAs in GC ascites samples was firstly screened, and critical miRNAs were further investigated by LASSO (least absolute shrinkage and selection operator) logistic regression and random forest (RF) algorithm. Receiver operating characteristic of critical miRNAs was also constructed. Moreover, functional analysis, immune cell infiltration associated with differentially expressed mRNAs were further analyzed. After selecting key modules by weighted gene co-expression network analysis, mRNAs related with survival performance and transcription factor (TF)-miRNA-mRNA network were constructed.
RESULTS
Hsa-miR-181b-5p was confirmed as critical differentially expressed miRNAs in GC ascites. Then, the tumor samples were divided into high- and low- expression groups divided by mean expression levels of hsa-miR-181b-5p, and subjects with high hsa-miR-181b-5p levels had better survival outcomes. In total, 197 differentially expressed mRNAs associated with hsa-miR-181b-5p levels were obtained, and these mRNAs were mainly enriched in muscle activity and vascular smooth muscle contraction. Hsa-miR-181b-5 was positively related with activated CD4 T cells and negatively related with eosinophil. 17 mRNAs were selected as mRNAs significantly related with prognosis of GC, such as PDK4 and RAMP1. Finally, 75 TF-miRNA-mRNA relationships were obtained, including 15 TFs, hsa-miR-181b-5p, and five mRNAs.
CONCLUSION
Our data suggest that the differentially expressed hsa-miR-181b-5p in ascites samples of GC patients may be a valuable prognostic marker and a potential target for therapeutic intervention, which should be validated in the near future.
Topics: Humans; MicroRNAs; Stomach Neoplasms; Ascites; Prognosis; Biomarkers, Tumor; Gene Expression Profiling; Gene Regulatory Networks; Gene Expression Regulation, Neoplastic; RNA, Messenger
PubMed: 38914980
DOI: 10.1186/s12864-024-10359-2 -
Cureus May 2024Small-cell carcinoma of the ovary, the hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young females. It is a monogenic disorder caused by...
Small-cell carcinoma of the ovary, the hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young females. It is a monogenic disorder caused by germline and/or somatic mutations. Here, we report a case of SCCOHT harboring multiple previously unreported somatic mutations in (c.2866_2867delC>T; c.3543del). A 28-year-old breastfeeding Japanese female presented to a previous hospital with nausea and vomiting. She had no family history of relevant malignancies, including ovarian cancer. Based on an evaluation performed at another institution, she was referred to a gynecologist for suspected ovarian cancer. Imaging studies revealed a 16×15 cm heterogenous enhancing mass within the right ovary without lymph node or distant metastasis. She had mild ascites without peritoneal dissemination, but there was an elevation in the serum calcium level (15.1 mg/dL). The patient underwent cytoreductive surgery and was pathologically diagnosed with SCCOHT. Auxiliary immunohistochemical staining confirmed the loss of SMARCA4 protein expression. The patient was diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) 2014 stage IA (pT1a pN0 M0). The serum calcium levels returned to normal post-surgery. Matched-pair analysis using tumor tissue and peripheral blood revealed multiple somatic mutations in , but no deleterious germline mutations were present. Microsatellite instability was not significant, and the patients had a heterozygous mutation of . She underwent six cycles of irinotecan hydrochloride plus cisplatin chemotherapy and achieved complete remission. The patient was finally examined and evaluated 45 months postoperatively; there was no evidence of the disease. Overall, the genetic findings will not aid in the SCCOHT diagnosis and relevant genetic counseling; however, they may have implications for the treatment of this disease in the future.
PubMed: 38903333
DOI: 10.7759/cureus.60802 -
Cureus May 2024Peritonitis, an inflammation of the peritoneal cavity, can be caused by various factors. The presence of ascites in a cancer patient is concerning for either metastasis...
Peritonitis, an inflammation of the peritoneal cavity, can be caused by various factors. The presence of ascites in a cancer patient is concerning for either metastasis or advanced cancer. Diagnosing acute peritonitis in a patient with cancer-related ascites can be quite challenging and often requires additional diagnostic procedures, such as paracentesis, to confirm the diagnosis and identify the exact cause of the ascites. Even with paracentesis, determining the exact cause of ascites can be a diagnostic challenge. Peritoneal carcinomatosis, with a poor survival rate, can originate from the peritoneal lining itself or result from intra-abdominal cancer, and trying to determine its origin can be difficult. We present the case of a 68-year-old female patient with a known history of cancer experiencing worsening ascites and peritonitis.
PubMed: 38899262
DOI: 10.7759/cureus.60705 -
Nature Communications Jun 2024Ovarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and...
Ovarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and after chemotherapy and in vitro therapy-induced secretomes, we show that molecules secreted by ovarian cancer cells upon therapy promote cisplatin resistance and enhance DNA damage repair in recipient cancer cells. Even a short-term incubation of chemonaive ovarian cancer cells with therapy-induced secretomes induces changes resembling those that are observed in chemoresistant patient-derived tumor cells after long-term therapy. Using integrative omics techniques, we find that both ex vivo and in vitro therapy-induced secretomes are enriched with spliceosomal components, which relocalize from the nucleus to the cytoplasm and subsequently into the extracellular vesicles upon treatment. We demonstrate that these molecules substantially contribute to the phenotypic effects of therapy-induced secretomes. Thus, SNU13 and SYNCRIP spliceosomal proteins promote therapy resistance, while the exogenous U12 and U6atac snRNAs stimulate tumor growth. These findings demonstrate the significance of spliceosomal network perturbation during therapy and further highlight that extracellular signaling might be a key factor contributing to the emergence of ovarian cancer therapy resistance.
Topics: Female; Humans; Ovarian Neoplasms; Spliceosomes; Cisplatin; Cell Line, Tumor; Drug Resistance, Neoplasm; Animals; Mice; Extracellular Vesicles; Cell Survival; Antineoplastic Agents; RNA, Small Nuclear; DNA Repair
PubMed: 38898005
DOI: 10.1038/s41467-024-49512-6 -
Molecules (Basel, Switzerland) May 2024A Cucurbita phloem exudate lectin (CPL) from summer squash () fruits was isolated and its sugar-binding properties and biological activities were studied. The lectin was...
A Cucurbita phloem exudate lectin (CPL) from summer squash () fruits was isolated and its sugar-binding properties and biological activities were studied. The lectin was purified by affinity chromatography and the hemagglutination assay method was used to determine its pH, heat stability, metal-dependency and sugar specificity. Antimicrobial and anticancer activities were also studied by disc diffusion assays and in vivo and in vitro methods. The molecular weight of CPL was 30 ± 1 KDa and it was stable at different pH (5.0 to 9.0) and temperatures (30 to 60 °C). CPL recovered its hemagglutination activity in the presence of Ca. 4-nitrophenyl-α-D-glucopyranoside, lactose, rhamnose and -acetyl-D-glucosamine strongly inhibited the activity. With an LC value of 265 µg/mL, CPL was moderately toxic and exhibited bacteriostatic, bactericidal and antibiofilm activities against different pathogenic bacteria. It also exhibited marked antifungal activity against and agglutinated spores. In vivo antiproliferative activity against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice was observed when CPL exerted 36.44% and 66.66% growth inhibition at doses of 3.0 mg/kg/day and 6.0 mg/kg/day, respectively. A 12-day treatment by CPL could reverse their RBC and WBC counts as well as restore the hemoglobin percentage to normal levels. The MTT assay of CPL performed against human breast (MCF-7) and lung (A-549) cancer cell lines showed 29.53% and 18.30% of inhibitory activity at concentrations of 128 and 256 µg/mL, respectively.
Topics: Cucurbita; Animals; Plant Lectins; Mice; Humans; Anti-Infective Agents; Antineoplastic Agents; Cell Line, Tumor; Carcinoma, Ehrlich Tumor
PubMed: 38893406
DOI: 10.3390/molecules29112531 -
Journal of Primary Care & Community... 2024Chronic hepatitis B virus infection (CHBVI) is a major public health problem affecting about 296 million people worldwide. HBV infects the liver, and when it becomes...
INTRODUCTION/OBJECTIVES
Chronic hepatitis B virus infection (CHBVI) is a major public health problem affecting about 296 million people worldwide. HBV infects the liver, and when it becomes chronic, may cause cirrhosis and hepatocellular carcinoma (HCC). The aim of our study was to identify the risk factors and comorbid medical conditions that were associated with HCC in patients who had CHBVI.
METHODS
We performed a retrospective electronic medical record review of adult patients diagnosed with CHBVI, who presented to our primary care office between October 1, 2017 and October 21, 2022. Selected variables in patients with CHBVI with HCC (HCC group) were compared to those without HCC (NoHCC group).
RESULTS
Among 125 patients with CHBVI, 24% had HCC and 76% did not have HCC. There were higher frequencies of association of certain comorbidities in the HCC group compared to NoHCC group, such as anemia (63.3% vs 26.3%; < .001), ascites (53.3% vs 1.1%; < .001), portal hypertension (43.3% vs 0.0%; < .001), chronic kidney disease (40.0% vs 13.7%; = .002), and HCV coinfection (13.3% vs 7.4%; < .001). The logistic regression model showed increased odds of HCC for each year of increase in age (OR = 1.06, 95% CI = 1.01-1.11; = .014), and increased odds in men (OR = 5.96, 95% CI = 1.71-20.73; = .005). Although Asians represented the racial majority in both the groups, there was no significant difference in the race distribution between the two groups.
CONCLUSION
In patients with CHBVI, increasing age and male sex are factors associated with increased odds of having HCC. Patients with CHBVI and HCC have higher frequencies of association of tobacco use, recreational drug use, anemia, ascites, portal hypertension, chronic kidney disease, and co-infection with HCV.
Topics: Humans; Male; Carcinoma, Hepatocellular; Female; Liver Neoplasms; Middle Aged; Retrospective Studies; Risk Factors; Hepatitis B, Chronic; Comorbidity; Adult; Aged
PubMed: 38884145
DOI: 10.1177/21501319241259413