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International Journal of Molecular... Jun 2024Periodontitis is a common oral condition that can have a significant impact on the overall health of the body. In recent years, attention has been paid to potential... (Review)
Review
Periodontitis is a common oral condition that can have a significant impact on the overall health of the body. In recent years, attention has been paid to potential relationships between periodontitis and various hematological disorders. This publication aims to present information available in the literature on this relationship, focusing on examples of red blood cell disorders (such as aplastic anemia and sickle cell anemia) and white blood cell disorders (such as cyclic neutropenia, maladaptive trained immunity, clonal hematopoiesis, leukemia, and multiple myeloma). Understanding these associations can help physicians and dentists better diagnose, monitor, and treat patients associated with both groups of conditions, highlighting the need for interdisciplinary care for patients with oral disorders and hematologic diseases.
Topics: Humans; Periodontitis; Hematologic Diseases
PubMed: 38892299
DOI: 10.3390/ijms25116115 -
International Journal of Molecular... May 2024MicroRNAs (miRNAs), particularly miR-16 and miR-21, play a crucial role in multiple myeloma (MM) pathogenesis by regulating gene expression. This study evaluated the...
MicroRNAs (miRNAs), particularly miR-16 and miR-21, play a crucial role in multiple myeloma (MM) pathogenesis by regulating gene expression. This study evaluated the prognostic significance of circulating miR-16 and miR-21 expression levels in 48 patients with MM at diagnosis treated with lenalidomide-dexamethasone (LD) compared with 15 healthy individuals (HI). All patients were treated with LD, 13 at first line and 35 at relapse, of whom 21 were tested twice at diagnosis and before LD initiation. The results revealed significantly lower levels of miR-16 and miR-21 in patients than in HIs, both at diagnosis and relapse, with decreased miR-16 levels at diagnosis, indicating improved overall survival (OS) ( value 0.024). Furthermore, miR-16 and miR-21 levels were associated with disease markers, while both correlated with the depth of response and mir-16 with sustained response to LD treatment. Ratios of both miR-16 and miR-21 expression levels (prior to LD treatment/diagnosis) below two predicted a shorter time to response ( = 0.027) and a longer time to next treatment ( = 0.042), respectively. These findings suggested a prognostic value for serum miR-16 and miR-21 levels in MM, as their expression levels correlated with disease variables and treatment outcomes.
Topics: Humans; Multiple Myeloma; MicroRNAs; Lenalidomide; Male; Female; Aged; Middle Aged; Prognosis; Thalidomide; Biomarkers, Tumor; Dexamethasone; Aged, 80 and over; Adult; Gene Expression Regulation, Neoplastic; Circulating MicroRNA; Treatment Outcome
PubMed: 38892251
DOI: 10.3390/ijms25116065 -
International Journal of Molecular... May 2024The tumor suppressor gene F-box and WD repeat domain-containing (FBXW) 7 reduces cancer stemness properties by promoting the protein degradation of pluripotent stem cell...
The tumor suppressor gene F-box and WD repeat domain-containing (FBXW) 7 reduces cancer stemness properties by promoting the protein degradation of pluripotent stem cell markers. We recently demonstrated the transcriptional repression of FBXW7 by the three-dimensional (3D) spheroid formation of several cancer cells. In the present study, we found that the transcriptional activity of FBXW7 was promoted by the inhibition of the Ca-activated K channel, K1.1, in a 3D spheroid model of human prostate cancer LNCaP cells through the Akt-Nrf2 signaling pathway. The transcriptional activity of FBXW7 was reduced by the siRNA-mediated inhibition of the CCAAT-enhancer-binding protein C/EBP δ (CEBPD) after the transfection of miR223 mimics in the LNCaP spheroid model, suggesting the transcriptional regulation of FBXW7 through the Akt-Nrf2-CEBPD-miR223 transcriptional axis in the LNCaP spheroid model. Furthermore, the K1.1 inhibition-induced activation of FBXW7 reduced (1) K1.1 activity and protein levels in the plasma membrane and (2) the protein level of the cancer stem cell (CSC) markers, c-Myc, which is a molecule degraded by FBXW7, in the LNCaP spheroid model, indicating that K1.1 inhibition-induced FBXW7 activation suppressed CSC conversion in K1.1-positive cancer cells.
Topics: Humans; F-Box-WD Repeat-Containing Protein 7; Male; NF-E2-Related Factor 2; Prostatic Neoplasms; Signal Transduction; Spheroids, Cellular; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Up-Regulation; Intermediate-Conductance Calcium-Activated Potassium Channels; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; MicroRNAs; Proto-Oncogene Proteins c-akt
PubMed: 38892210
DOI: 10.3390/ijms25116019 -
International Journal of Molecular... May 2024Pinin (PNN) is a desmosome-associated protein that reinforces the organization of keratin intermediate filaments and stabilizes the anchoring of the cytoskeleton network...
Pinin (PNN) is a desmosome-associated protein that reinforces the organization of keratin intermediate filaments and stabilizes the anchoring of the cytoskeleton network to the lateral surface of the plasma membrane. The aberrant expression of PNN affects the strength of cell adhesion as well as modifies the intracellular signal transduction pathways leading to the onset of CRC. In our previous studies, we characterized the role of miR-195-5p in the regulation of desmosome junctions and in CRC progression. Here, with the aim of investigating additional mechanisms related to the desmosome complex, we identified PNN as a miR-195-5p putative target. Using a public data repository, we found that PNN was a negative prognostic factor and was overexpressed in colon cancer tissues from stage 1 of the disease. Then, we assessed PNN expression in CRC tissue specimens, confirming the overexpression of PNN in tumor sections. The increase in intracellular levels of miR-195-5p revealed a significant decrease in PNN at the mRNA and protein levels. As a consequence of PNN regulation by miR-195-5p, the expression of KRT8 and KRT19, closely connected to PNN, was affected. Finally, we investigated the in vivo effect of miR-195-5p on PNN expression in the colon of AOM/DSS-treated mice. In conclusion, we have revealed a new mechanism driven by miR-195-5p in the regulation of desmosome components, suggesting a potential pharmacological target for CRC therapy.
Topics: MicroRNAs; Colorectal Neoplasms; Humans; Animals; Mice; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Male; Female
PubMed: 38892168
DOI: 10.3390/ijms25115980 -
International Journal of Molecular... May 2024CAR-T cell therapy is at the forefront of next-generation multiple myeloma (MM) management, with two B-cell maturation antigen (BCMA)-targeted products recently...
CAR-T cell therapy is at the forefront of next-generation multiple myeloma (MM) management, with two B-cell maturation antigen (BCMA)-targeted products recently approved. However, these products are incapable of breaking the infamous pattern of patient relapse. Two contributing factors are the use of BCMA as a target molecule and the artificial scFv format that is responsible for antigen recognition. Tackling both points of improvement in the present study, we used previously characterized VHHs that specifically target the idiotype of murine 5T33 MM cells. This idiotype represents one of the most promising yet challenging MM target antigens, as it is highly cancer- but also patient-specific. These VHHs were incorporated into VHH-based CAR modules, the format of which has advantages compared to scFv-based CARs. This allowed a side-by-side comparison of the influence of the targeting domain on T cell activation. Surprisingly, VHHs previously selected as lead compounds for targeted MM radiotherapy are not the best (CAR-) T cell activators. Moreover, the majority of the evaluated VHHs are incapable of inducing any T cell activation. As such, we highlight the importance of specific VHH selection, depending on its intended use, and thereby raise an important shortcoming of current common CAR development approaches.
Topics: Multiple Myeloma; Humans; Animals; Immunotherapy, Adoptive; Mice; T-Lymphocytes; Cell Line, Tumor; Antibodies, Anti-Idiotypic; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; Immunoglobulin Heavy Chains; Single-Chain Antibodies; Single-Domain Antibodies; Lymphocyte Activation
PubMed: 38891821
DOI: 10.3390/ijms25115634 -
Cells May 2024Plasma gelsolin (pGSN) overexpression in ovarian cancer (OVCA) disarms immune function, contributing to chemoresistance. The aim of this study was to investigate the...
Plasma gelsolin (pGSN) overexpression in ovarian cancer (OVCA) disarms immune function, contributing to chemoresistance. The aim of this study was to investigate the immunoregulatory effects of pGSN expression on natural killer (NK) cell function in OVCA. OVCA tissues from primary surgeries underwent immunofluorescent staining of pGSN and the activated NK cell marker natural cytotoxicity triggering receptor 1 to analyze the prognostic impact of pGSN expression and activated NK cell infiltration. The immunoregulatory effects of pGSN on NK cells were assessed using apoptosis assay, cytokine secretion, immune checkpoint-receptor expression, and phosphorylation of STAT3. In OVCA tissue analyses, activated NK cell infiltration provided survival advantages to patients. However, high pGSN expression attenuated the survival benefits of activated NK cell infiltration. In the in vitro experiment, pGSN in OVCA cells induced NK cell death through cell-to-cell contact. pGSN increased T-cell immunoglobulin and mucin-domain-containing-3 expression (TIM-3) on activated NK cells. Further, it decreased interferon-γ production in activated TIM-3+ NK cells, attenuating their anti-tumor effects. Thus, increased pGSN expression suppresses the anti-tumor functions of NK cells. The study provides insights into why immunotherapy is rarely effective in patients with OVCA and suggests novel treatment strategies.
Topics: Humans; Killer Cells, Natural; Female; Gelsolin; Carcinoma, Ovarian Epithelial; Drug Resistance, Neoplasm; Ovarian Neoplasms; Cell Line, Tumor; Middle Aged; Hepatitis A Virus Cellular Receptor 2; Apoptosis; STAT3 Transcription Factor; Interferon-gamma
PubMed: 38891037
DOI: 10.3390/cells13110905 -
Journal of Hematology & Oncology Jun 2024Esophageal cancer (EC) is a highly lethal disease lacking early detection approaches. We previously identified that OTOP2 and KCNA3 were specifically hypermethylated in...
Non-invasive diagnosis of esophageal cancer by a simplified circulating cell-free DNA methylation assay targeting OTOP2 and KCNA3: a double-blinded, multicenter, prospective study.
BACKGROUND
Esophageal cancer (EC) is a highly lethal disease lacking early detection approaches. We previously identified that OTOP2 and KCNA3 were specifically hypermethylated in circulating cell-free DNA from patients with EC. We then developed a blood-based methylation assay targeting OTOP2 and KCNA3 (named "IEsohunter") for esophageal cancer noninvasive detection. This double-blinded, multicenter, prospective study aimed to comprehensively evaluate its clinical diagnostic performance.
METHODS
Participants with EC, high-grade intraepithelial neoplasia (HGIN), other malignancies, benign gastrointestinal lesions, or no abnormalities were prospectively enrolled from 5 tertiary referral centers across China. Peripheral blood samples were collected, followed by plasma cell-free DNA methylation analysis using the IEsohunter test based on multiplex quantitative polymerase chain reaction adopting an algorithm-free interpretation strategy. The primary outcome was the diagnostic accuracy of IEsohunter test for EC.
RESULTS
We prospectively enrolled 1116 participants, including 334 patients with EC, 71 with HGIN, and 711 controls. The areas under the receiver operating characteristic curves of the IEsohunter test for detecting EC and HGIN were 0.903 (95% CI 0.880-0.927) and 0.727 (95% CI 0.653-0.801), respectively. IEsohunter test showed sensitivities of 78.5% (95% CI 69.1-85.6), 87.3% (95% CI 79.4-92.4), 92.5% (95% CI 85.9-96.2), and 96.9% (95% CI 84.3-99.8) for stage I-IV EC, respectively, with an overall sensitivity of 87.4% (95% CI 83.4-90.6) and specificity of 93.3% (95% CI 91.2-94.9) for EC detection. The IEsohunter test status turned negative (100.0%, 47/47) after surgical resection of EC.
CONCLUSIONS
The IEsohunter test showed high diagnostic accuracy for EC detection, indicating that it could potentially serve as a tool for noninvasive early detection and surveillance of EC.
Topics: Humans; Esophageal Neoplasms; Male; Female; Prospective Studies; Middle Aged; DNA Methylation; Double-Blind Method; Aged; Biomarkers, Tumor; Cell-Free Nucleic Acids; Adult
PubMed: 38890756
DOI: 10.1186/s13045-024-01565-2 -
Scientific Reports Jun 2024Programmed Death Receptor 1 (PD-1) inhibitors, when combined with chemotherapy, have exhibited notable effectiveness in enhancing the survival outcomes of patients...
Programmed Death Receptor 1 (PD-1) inhibitors, when combined with chemotherapy, have exhibited notable effectiveness in enhancing the survival outcomes of patients afflicted with advanced gastric cancer. However, it is important to acknowledge that not all patients derive substantial benefits from this therapeutic approach, highlighting the crucial necessity of identifying efficacious biomarkers to inform immunotherapy interventions. In this study, we sought to investigate the predictive utility of circulating tumor DNA (ctDNA) as a biomarker in a cohort of 30 patients diagnosed with advanced gastric cancer, all of whom underwent first-line treatment involving PD-1 inhibitor administration alongside chemotherapy. We procured peripheral blood samples both at baseline and following the completion of two treatment cycles. Additionally, baseline tissue specimens were collected for the purpose of genomic alteration assessment, employing both 47-gene and 737-gene next-generation sequencing panels for plasma and tumor tissue, respectively. We delineated a ctDNA response as the eradication of maximum variant allele frequencies relative to baseline levels. Notably, the objective response rate among individuals exhibiting a ctDNA response proved significantly superior in comparison to non-responders (P = 0.0073). Furthermore, patients who manifested a ctDNA response experienced markedly prolonged progression-free survival (PFS) and overall survival (OS) when juxtaposed with those devoid of a ctDNA response (median PFS: 15.6 vs. 6.0 months, P = 0.003; median OS: not reached [NR] vs. 9.0 months, P = 0.011). In summation, patients with advanced gastric cancer receiving first-line treatment with PD-1 inhibitors and chemotherapy, dynamic changes in ctDNA can serve as a potential biomarker for predicting treatment efficacy and long-term outcomes.
Topics: Humans; Stomach Neoplasms; Circulating Tumor DNA; Male; Female; Middle Aged; Aged; Immune Checkpoint Inhibitors; Biomarkers, Tumor; Programmed Cell Death 1 Receptor; Adult; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; High-Throughput Nucleotide Sequencing
PubMed: 38890392
DOI: 10.1038/s41598-024-63486-x -
Environmental Health Perspectives Jun 2024Accumulating evidence suggests that domestic water hardness is linked to health outcomes, but its association to all-cause and cause-specific cancers warrants...
BACKGROUND
Accumulating evidence suggests that domestic water hardness is linked to health outcomes, but its association to all-cause and cause-specific cancers warrants investigation.
OBJECTIVE
The aim of this study was to investigate the association of domestic hard water with all-cause and cause-specific cancers.
METHODS
In the prospective cohort study, a total of 447,996 participants from UK Biobank who were free of cancer at baseline were included and followed up for 16 y. All-cause and 22 common cause-specific cancer diagnoses were ascertained using hospital inpatient records and self-reported data until 30 November 2022. Domestic water hardness, measured by concentrations, was obtained from the local water supply companies across England, Scotland, and Wales in 2005. Data were analyzed using Cox proportional hazard models, with adjustments for known measured confounders, including demographic, socioeconomic, clinical, biochemical, lifestyle, and environmental factors.
RESULTS
Over a median follow-up of 13.6 y (range: 12.7-14.4 y), 58,028 all-cause cancer events were documented. A U-shaped relationship between domestic water hardness and all-cause cancers was observed ( for nonlinearity ). In comparison with individuals exposed to soft water (), the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause cancer were 1.00 (95% CI: 0.98, 1.02) for those exposed to moderate hard water (), 0.88 (95% CI: 0.84, 0.91) for those exposed to hard water () and 1.06 (95% CI: 1.04, 1.08) for those exposed to very hard water (). Additionally, domestic water hardness was associated with 11 of 22 cause-specific cancers, including cancers of the esophagus, stomach, colorectal tract, lung, breast, prostate, and bladder, as well as non-Hodgkin lymphoma, multiple myeloma, malignant melanoma, and hematological malignancies. Moreover, we observed a positive linear relationship between water hardness and bladder cancer.
DISCUSSION
Our findings suggest that domestic water hardness was associated with all-cause and multiple cause-specific cancers. Findings from the UK Biobank support a potentially beneficial association between hard water and the incidence of all-cause cancer. However, very hard water may increase the risk of all-cause cancer. https://doi.org/10.1289/EHP13606.
Topics: Humans; Neoplasms; Prospective Studies; Male; Female; Middle Aged; United Kingdom; Aged; Water Supply; Adult; Biological Specimen Banks; Proportional Hazards Models; Environmental Exposure; UK Biobank
PubMed: 38889166
DOI: 10.1289/EHP13606 -
Journal of Investigational Allergology... Jun 2024
Successful Desensitization to Isatuximab in a Patient With Refractory Multiple Myeloma and Indolent Systemic Mastocytosis. Reply to: Anaphylactic Shock due to Isatuximab and Successful Desensitization.
Topics: Humans; Multiple Myeloma; Anaphylaxis; Mastocytosis, Systemic; Desensitization, Immunologic; Antibodies, Monoclonal, Humanized; Drug Hypersensitivity
PubMed: 38888584
DOI: 10.18176/jiaci.0990