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Cells Jun 2024Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the...
Lysosome-Disrupting Agents in Combination with Venetoclax Increase Apoptotic Response in Primary Chronic Lymphocytic Leukemia (CLL) Cells Mediated by Lysosomal Cathepsin D Release and Inhibition of Autophagy.
Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the combination could be immunosuppressive. Lysosomes have previously been identified as a target for obinutuzumab cytotoxicity in CLL cells, but the mechanism remains unclear. In addition, studies have shown that lysosomotropic agents can cause synergistic cell death in vitro when combined with the BTK inhibitor, ibrutinib, in primary CLL cells. This indicates that targeting lysosomes could be a treatment strategy for CLL. In this study, we have shown that obinutuzumab induces lysosome membrane permeabilization (LMP) and cathepsin D release in CLL cells. Inhibition of cathepsins reduced obinutuzumab-induced cell death in CLL cells. We further determined that the lysosomotropic agent siramesine in combination with venetoclax increased cell death in primary CLL cells through an increase in reactive oxygen species (ROS) and cathepsin release. Siramesine treatment also induced synergistic cytotoxicity when combined with venetoclax. Microenvironmental factors IL4 and CD40L or incubation with HS-5 stromal cells failed to significantly protect CLL cells from siramesine- and venetoclax-induced apoptosis. We also found that siramesine treatment inhibited autophagy through reduced autolysosomes. Finally, the autophagy inhibitor chloroquine failed to further increase siramesine-induced cell death. Taken together, lysosome-targeting drugs could be an effective strategy in combination with venetoclax to overcome drug resistance in CLL.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides; Lysosomes; Apoptosis; Autophagy; Cathepsin D; Reactive Oxygen Species; Drug Synergism; Cell Line, Tumor
PubMed: 38920669
DOI: 10.3390/cells13121041 -
Frontiers in Immunology 2024CD46 has been revealed to be a key factor in malignant transformation and cancer treatment. However, the clinical significance of CD46 in cervical cancer remains...
BACKGROUND
CD46 has been revealed to be a key factor in malignant transformation and cancer treatment. However, the clinical significance of CD46 in cervical cancer remains unclear, and this study aimed to evaluate its role in cervical cancer diagnosis and prognosis evaluation.
METHODS
A total of 180 patients with an initial diagnosis of cervical cancer were enrolled at Taizhou Hospital of Zhejiang Province, China. The plasma levels of soluble CD46 (sCD46) and the expression of membrane-bound CD46 (mCD46) were detected by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), respectively.
RESULTS
CD46 was found to be significantly upregulated in cervical cancer tissues normal tissues, while no CD46 staining was detected in paired adjacent noncancerous tissues. CD46 staining was more pronounced in cancer cells than in stromal cells (in tissues). Moreover, the plasma levels of sCD46 were able to some extent discriminate between cancer patients and healthy women (AUC=0.6847, 95% CI:0.6152-0.7541). Analysis of Kaplan-Meier survival curves revealed that patients with low CD46 expression had slightly longer overall survival (OS) than patients with high CD46 expression in the tumor microenvironment, but no significant difference. Univariate Cox regression analysis revealed that CD46 (=0.034) is an independent risk factor for OS in cervical cancer patients.
CONCLUSION
The present study demonstrated that cervical cancer patients exhibit aberrant expression of CD46, which is closely associated with a poor prognosis, suggesting that CD46 plays a key role in promoting cervical carcinogenesis and that CD46 could serve as a promising potential target for precision therapy for cervical cancer.
Topics: Humans; Female; Uterine Cervical Neoplasms; Membrane Cofactor Protein; Biomarkers, Tumor; Middle Aged; Prognosis; Adult; Aged; Kaplan-Meier Estimate
PubMed: 38919630
DOI: 10.3389/fimmu.2024.1421778 -
The American Journal of Surgical... Jun 2024Wolffian tumor and its nosologic relative, the recently defined STK11 adnexal tumor are rare neoplasms thought to arise from mesonephric remnants. These tumors typically...
Wolffian tumor and its nosologic relative, the recently defined STK11 adnexal tumor are rare neoplasms thought to arise from mesonephric remnants. These tumors typically arise in the broad ligament, fallopian tube, and ovarian hilum and although most are associated with a good prognosis, up to 50% of STK11 adnexal tumors demonstrate aggressive clinical behavior. The chief differential diagnoses include endometrioid adenocarcinoma and sex cord stromal tumors. However, the morphologic and immunohistochemical features of these tumors exhibit considerable overlap with peritoneal mesothelioma. To fully characterize their immunophenotypic signature, we examined a total of 21 cases (18 Wolffian and 3 STK11 adnexal tumors) with standard markers used in the diagnosis of mesothelioma. Morphologic and immunohistochemical (IHC) features were reviewed and additional IHC performed for cases with available material. Patient age ranged from 25 to 73 (mean: 51) years. Sites included adnexa/broad ligament (6, 28%), paratubal (5, 24%), ovary/paraovarian (5, 24%), tubal (intraluminal) (2, 9.5%), pelvis (2, 9.5%), and liver (1, 5%). The mean tumor size was 9.3 cm (range: 0.2 to 22 cm). The histomorphology in most cases (14/21, 66%) consisted of tubular to solid sheets of neoplastic cells lined by columnar to cuboidal cells containing uniform round to oval nuclei. Compressed tubules with slit-like lumens and sieve-like pattern were also seen in at least 7 (33%) cases. Three cases demonstrated interanastomosing cords and trabeculae of epithelioid cells with cribriform and microacinar patterns growing within prominent myxoid stroma as described in STK11 adnexal tumors. In the cases with available IHC for 3 mesothelial markers (calretinin, WT1, D2-40), 55.5% (5 of 9) showed reactivity with all 3 markers. In cases with at least 2 available mesothelial markers, 69% (11/16) were positive for 2 markers (mostly calretinin and WT1). Claudin-4, MOC31, and BER-EP4 were negative in most cases tested (78% [7/9], 71.4% [5/7], and 100% [6/6], respectively). Given the resemblance to mesothelioma, there was initial strong consideration and/or actual misdiagnosis of mesothelioma in 3 cases (14%). In summary, the morphologic and immunohistochemical features of Wolffian tumor and its recently defined relative, STK11 adnexal tumor, can lead to misdiagnosis of mesothelioma, particularly when encountered in the disseminated or metastatic setting. Wolffian tumor and STK11 adnexal tumor should be considered in the differential diagnosis of all pelvic and peritoneal mesotheliomas.
PubMed: 38919071
DOI: 10.1097/PAS.0000000000002237 -
Acta Dermatovenerologica Alpina,... Jun 2024This study explores the immunogenetic associations of human leukocyte antigens (HLA) and the calcium release-activated calcium modulator 1 (ORAI1) and stromal...
INTRODUCTION
This study explores the immunogenetic associations of human leukocyte antigens (HLA) and the calcium release-activated calcium modulator 1 (ORAI1) and stromal interaction molecule 1 (STIM1) genes in HIV-1‒positive patients with HIV-related skin disorders.
METHODS
This study assessed the distribution of variants of HLA class II alleles and expression levels of ORAI1 and STIM1 genes in the blood between HIV-1‒positive patients with HIV-related skin disorders and the control group with no HIV within the Latvian population.
RESULTS
The research group comprised 115 HIV-1‒positive patients with HIV-related skin disorders, and the control group included 80 healthy individuals. Risk alleles (HLA- DQB1*02:01-0301 and HLA-DQA1*01:01-0501) and protective alleles (HLA-DRB1*07-13, DRB1*01-13, DRB1*04-11, and HLA-DQA1*05:01-0501) showed statistical significance in the groups. In 38 out of 115 patients, higher expression levels of ORAI1 and STIM1 genes were detected in the blood at the beginning of treatment. A significantly higher level of the microribonucleic acid (mRNA) ORAI1 gene was also found in the control group.
CONCLUSIONS
The results demonstrate that HLA class II alleles are associated with a trend toward risk/protection concerning HIV-related skin disorders in HIV-1‒positive patients. It was also shown that a low level of ORAI1 mRNA and the risk allele HLA-DQB1*0201-0301 were simultaneously present in the research group.
Topics: Humans; ORAI1 Protein; Male; Latvia; Female; Stromal Interaction Molecule 1; Adult; HIV Infections; Middle Aged; Polymorphism, Genetic; Skin Diseases; Case-Control Studies; Neoplasm Proteins; Genetic Predisposition to Disease
PubMed: 38918943
DOI: No ID Found -
Asian Pacific Journal of Cancer... Jun 2024Nasopharyngeal carcinoma (NPC) is a common type of cancer in Southeast Asia. This cancer usually spreads locally and to nearby lymph nodes. One unique feature of NPC is...
BACKGROUND
Nasopharyngeal carcinoma (NPC) is a common type of cancer in Southeast Asia. This cancer usually spreads locally and to nearby lymph nodes. One unique feature of NPC is its many immune cells called tumor-infiltrating lymphocytes (TILs). Recent studies have suggested that TILs in many types of cancer can indicate a better prognosis. However, the role of TILs in NPC is still a matter of debate. Further research is necessary to determine whether TILs can be used as a prognostic factor of NPC's outcome.
METHOD
A retrospective cohort study was conducted at Sardjito Hospital to examine the records and pathological sections of patients treated for the undifferentiated subtype of NPC. Two pathologists analyzed the presence of TILs using HE-stained slides. TILs were evaluated in stromal compartments, and their association with clinicopathological variables was analyzed using the Chi-square and Fisher exact tests. The study compared overall survival in tumor patients with varying TIL levels using Kaplan-Meier survival curves and the log-rank test. A Cox regression model was used for univariate and multivariate analyses to test the significance of different factors.
RESULT
Out of the total 61 subjects, 16 (26.2%) had high stromal TILs (≥ 70%), and 45 (73.8%) had low stromal TILs (<70%). The subjects' sex, age, and tumor stage did not affect the OS. However, high stromal TILs (≥ 70%) showed a significant association with a longer OS (log-rank test p = 0.006, HR 0.37, 95% CI 0.17-0.79, log-rank p = 0.006). Moreover, multivariate analysis confirmed that TILs were an independent prognostic indicator for OS (aHR 0.015).
CONCLUSION
TILs correlate positively with overall survival in the undifferentiated NPC subtype and are an independent prognostic indicator.
Topics: Humans; Lymphocytes, Tumor-Infiltrating; Male; Female; Prognosis; Retrospective Studies; Nasopharyngeal Neoplasms; Middle Aged; Nasopharyngeal Carcinoma; Survival Rate; Adult; Carcinoma; Follow-Up Studies; Aged; Neoplasm Staging
PubMed: 38918661
DOI: 10.31557/APJCP.2024.25.6.1997 -
Medical Oncology (Northwood, London,... Jun 2024Glioblastoma (GBM) is the most common malignant brain tumor, which, despite significant progress made in the last years in the field of neuro-oncology, remains an... (Review)
Review
Glioblastoma (GBM) is the most common malignant brain tumor, which, despite significant progress made in the last years in the field of neuro-oncology, remains an incurable disease. GBM has a poor prognosis with a median survival of 12-15 months, and its aggressive clinical course is related to rapid growth, extensive infiltration of adjacent tissues, resistance to chemotherapy, radiotherapy and immunotherapy, and frequent relapse. Currently, several molecular biomarkers are used in clinical practice to predict patient prognosis and response to treatment. However, due to the overall unsatisfactory efficacy of standard multimodal treatment and the remaining poor prognosis, there is an urgent need for new biomarkers and therapeutic strategies for GBM. Recent evidence suggests that GBM tumorigenesis is associated with crosstalk between cancer, immune and stromal cells mediated by various cytokines. One of the key factors involved in this process appears to be interleukin-17 (IL-17), a pro-inflammatory cytokine that is significantly upregulated in the serum and tissue of GBM patients. IL-17 plays a key role in tumorigenesis, angiogenesis, and recurrence of GBM by activating pro-oncogenic signaling pathways and promoting cell survival, proliferation, and invasion. IL-17 facilitates the immunomodulation of the tumor microenvironment by promoting immune cells infiltration and cytokine secretion. In this article we review the latest scientific reports to provide an update on the role of IL-17 role in tumorigenesis, tumor microenvironment, diagnosis, prognosis, and treatment of GBM.
Topics: Humans; Glioblastoma; Brain Neoplasms; Interleukin-17; Tumor Microenvironment; Biomarkers, Tumor; Prognosis
PubMed: 38918274
DOI: 10.1007/s12032-024-02434-1 -
Rhode Island Medical Journal (2013) Jul 2024Syringocystadenoma papilliferum (SCAP) is a benign adnexal tumor commonly found on the scalp and face, and often associated with nevus sebaceous, with about half of...
Syringocystadenoma papilliferum (SCAP) is a benign adnexal tumor commonly found on the scalp and face, and often associated with nevus sebaceous, with about half of cases appearing in early childhood. SCAP exhibits cystic invaginations with papillary structures and a double-layered glandular epithelium linked to the epidermal surface and stromal plasma cells. We are reporting a rare instance of intradermal SCAP in a 55-year-old male. He sought evaluation for a long-standing asymptomatic dark-pink papule in his left popliteal fossa, measuring 0.7 x 0.5 x 0.4 cm. A shave biopsy revealed papillary dermal fibrosis, glandular epithelium with apocrine secretion, and papillary projections without an epidermal connection. Infundibulofollicular keratinization was observed, along with stromal plasma cells. The patient chose local excision as the treatment option. This case highlights the rarity of intradermal SCAP, especially in the left popliteal fossa, with only one other reported case in the literature.
Topics: Humans; Male; Middle Aged; Sweat Gland Neoplasms; Tubular Sweat Gland Adenomas; Biopsy
PubMed: 38917308
DOI: No ID Found -
European Journal of Endocrinology Jun 2024Neuroendocrine tumors (NET) are malignant neoplasms that can be associated with specific hormonal syndromes. We describe a novel syndrome of postmenopausal vaginal...
Neuroendocrine tumors (NET) are malignant neoplasms that can be associated with specific hormonal syndromes. We describe a novel syndrome of postmenopausal vaginal bleeding and ovarian estradiol overproduction due to ovarian NET localizations. An extensive workup was performed for two index patients with ovarian metastases of small bowel neuroendocrine tumors and symptoms of postmenopausal vaginal bleeding. Clinically significant ovarian estrogen production was demonstrated by a combination of ovarian vein sampling and normalization of circulating estrogen levels after oophorectomy. Immunohistochemical analyses revealed marked aromatase immunoactivity in the ovarian NET cells, while CYP17A1 and SF-1 were detected in the adjacent ovarian stromal cells but not the NET cells. Ex vivo and in vivo endocrine tests were unable to identify a paracrine mechanism of ovarian estradiol overproduction by NET cells. A retrospective search of electronic medical records revealed that 21% (14/66) of postmenopausal patients with an ovarian NET localization reported symptoms of vaginal blood loss. Together, these findings support the presence of a novel NET-associated hormonal syndrome.
PubMed: 38917055
DOI: 10.1093/ejendo/lvae075 -
Journal of Cancer Research and Clinical... Jun 2024Hepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the...
PURPOSE
Hepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the chemokine ligand 17 (CCL17) and its receptor CCR4 as pivotal players in the tumor microenvironment (TME) of various cancers. This investigation aims to delineate the roles of CCL17 and CCR4 in modulating the tumor's immune landscape, assessing their potential as therapeutic interventions and prognostic markers in HCC.
METHODS
873 HCC patients post-radical surgery from 2008 to 2012 at Zhongshan Hospital, Fudan University were retrospectively examined. These individuals were stratified into a training cohort (n = 354) and a validation cohort (n = 519). Through immunohistochemical analysis on HCC tissue arrays, the expressions of CCL17, CCR4, CD73, CD47, HHLA2, and PD-L1 were quantified. Survival metrics were analyzed using the Cox model, and a prognostic nomogram was devised via R software.
RESULTS
The investigation confirmed the presence of CCL17 and CCR4 within the cancerous and stromal compartments of HCC tissues, associating their heightened expression with adverse clinical markers and survival outcomes. Notably, the interplay between CD73 and CCR4 expression in tumor stroma highlighted a novel cellular entity, CCR4 + CD73 + stromal cells, impacting overall and relapse-free survival. A prognostic nomogram amalgamating these immunological markers and clinical variables was established, offering refined prognostic insights and aiding in the management of HCC. The findings suggest that reduced CCR4 and CCR4 + CD73 + cell prevalence may forecast improved outcomes post-TACE.
CONCLUSION
This comprehensive evaluation of CCR4, CCL17, and associated markers introduces a nuanced understanding of the HCC immunological milieu, proposing CCR4 + CD73 + stromal cells as critical to HCC pathogenesis and patient stratification.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Chemokine CCL17; Female; Male; Prognosis; Receptors, CCR4; Middle Aged; Biomarkers, Tumor; 5'-Nucleotidase; Retrospective Studies; Tumor Microenvironment; GPI-Linked Proteins; Aged; Adult
PubMed: 38914802
DOI: 10.1007/s00432-024-05832-0 -
Journal of Applied Biomedicine Jun 2024Diffuse large B-cell lymphoma (DLBCL) stands out as the most common type of malignant cancer, representing the majority of cases of non-Hodgkin's lymphoma. Ethyl...
Diffuse large B-cell lymphoma (DLBCL) stands out as the most common type of malignant cancer, representing the majority of cases of non-Hodgkin's lymphoma. Ethyl pyruvate (EP) is a derivative of pyruvic acid and found to have potent anti-tumor properties. Despite its potential benefits, the impact of EP on DLBCL remains ambiguous. Our objective is to elucidate the role of EP in modulating the development of DLBCL. Analysis of cholecystokinin-8 (CCK-8) revealed that treatment with EP significantly diminished the viability of DLBCL cells. Furthermore, EP administration suppressed colony formation and hindered cell adhesion and invasion in DLBCL cells. Examination of cell cycle progression showed that EP treatment induced arrest at the G1 phase and subsequently reduced the S phase population in DLBCL cells. EP treatment consistently exhibited apoptosis-inducing properties in Annexin-V assays, and notably downregulated the expression of Bcl-2 while increasing levels of proapoptotic cleaved caspase 3 and BAX in DLBCL cells. Additionally, EP treatment decreased the overexpression of c-Jun in c-Jun-transfected DLBCL cells. Further, EP demonstrated DNA-damaging effects in TUNEL assays. In vivo, xenograft animal models revealed that EP treatment significantly mitigated DLBCL tumor growth and suppressed DLBCL cell adhesion to bone marrow stromal cells. In summary, these findings suggest that EP mitigates DLBCL progression by inducing apoptosis, inducing cell cycle arrest, and promoting DNA damage.
Topics: Pyruvates; Lymphoma, Large B-Cell, Diffuse; Humans; Animals; Cell Adhesion; Cell Proliferation; Cell Line, Tumor; Mice; Apoptosis; Proto-Oncogene Proteins c-jun; Xenograft Model Antitumor Assays
PubMed: 38912866
DOI: 10.32725/jab.2024.014