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Nature Cancer Jun 2024Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new...
Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies. Here we provide a comprehensive multiomics analysis including deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive MM, plasma cell leukemia and the premalignancy monoclonal gammopathy of undetermined significance, as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells are highly deregulated as compared with healthy plasma cells and is both defined by chromosomal alterations as well as posttranscriptional regulation. A prognostic protein signature was identified that is associated with aggressive disease independent of established risk factors in MM. Integration with functional genetics and single-cell RNA sequencing revealed general and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include potential targets for (immuno)therapies. Our study demonstrates the potential of proteogenomics in cancer and provides an easily accessible resource for investigating protein regulation and new therapeutic approaches in MM.
PubMed: 38942927
DOI: 10.1038/s43018-024-00784-3 -
Cell Death & Disease Jun 2024The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial...
The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial glioblastoma progression. Our findings demonstrate that the mitochondria-derived peptide, humanin, plays a significant role in enhancing glioblastoma progression through the intratumoral activation of the integrin alpha V (ITGAV)-TGF beta (TGFβ) signaling axis. In glioblastoma tissues, humanin showed a significant upregulation in the tumor area compared to the corresponding normal region. Utilizing multiple in vitro pharmacological and genetic approaches, we observed that humanin activates the ITGAV pathway, leading to cellular attachment and filopodia formation. This process aids the subsequent migration and invasion of attached glioblastoma cells through intracellular TGFβR signaling activation. In addition, our in vivo orthotopic glioblastoma model provides further support for the pro-tumoral function of humanin. We observed a correlation between poor survival and aggressive invasiveness in the humanin-treated group, with noticeable tumor protrusions and induced angiogenesis compared to the control. Intriguingly, the in vivo effect of humanin on glioblastoma was significantly reduced by the treatment of TGFBR1 inhibitor. To strengthen these findings, public database analysis revealed a significant association between genes in the ITGAV-TGFβR axis and poor prognosis in glioblastoma patients. These results collectively highlight humanin as a pro-tumoral factor, making it a promising biological target for treating glioblastoma.
Topics: Glioblastoma; Humans; Transforming Growth Factor beta; Animals; Signal Transduction; Disease Progression; Cell Line, Tumor; Integrin alphaV; Mice; Brain Neoplasms; Cell Movement; Mice, Nude; Receptor, Transforming Growth Factor-beta Type I; Neoplasm Invasiveness; Gene Expression Regulation, Neoplastic
PubMed: 38942749
DOI: 10.1038/s41419-024-06790-8 -
Urologic Oncology Jun 2024Similar to bladder cancer, about one third of upper tract urothelial carcinoma (UTUC) present variant histology (VH). We aim to evaluate the incidence, clinical...
INTRODUCTION
Similar to bladder cancer, about one third of upper tract urothelial carcinoma (UTUC) present variant histology (VH). We aim to evaluate the incidence, clinical characteristics and the impact on outcomes of VH in UTUC.
METHODS
We consecutively enrolled 77 patients treated between 2009 and 2022 by radical surgery for UTUC from a secondary and a tertiary referral center. A pathology review of all specimens was performed by 1 independent uropathologist for each center. We compared pure UTUC and UTUC with VH and the accuracy of endoscopic biopsy. Descriptive and comparative analysis was performed to assess the association with clinical characteristics and the Kaplan-Meier estimator to compare outcomes.
RESULTS
Median follow-up after surgery was 51 months. VH was present in 21/77 (28%) patients and 4/21 (19%) patients had multiple variants. The most frequent VH was squamous 12/21 (57%), followed by glandular 7/21 (33%) and micropapillary 3/21 variants (14%). Neuroendocrine carcinoma was present in 2 patients. Nested variant was found in 1 patient. Muscle invasive tumor (≥pT2) was present in 30/56 (54%) patients with pure UTUC and in 18/21 (86%) patients with VH (P < 0.05). Presence of carcinoma in situ was seen in 24/56 (43%) patients with pure UTUC and in 16/21 (76%) with VH (P < 0.05). Cumulative 8/56 (14%) with pure UTUC had a nonintravesical recurrence (6 patients with local and 2 distant recurrence) compared to 8/21 (38%) (3 local, 3 nodal, 2 distant) in the subgroup with VH (P < 0.05). Opposite effect was noted for bladder recurrence: 60% for pure UTUC vs. 29% for tumors with VH (P < 0.05). Review of preoperative endoscopic biopsy did not show the presence of VH in any patients. Differences in outcomes did not reach significance: 3yr-OS 63% vs. 42% (P 0.28) and 3yr-CSS 77% vs. 50% (P 0.7).
CONCLUSION
Almost a third of UTUC present VH. Presence of VH is related to more aggressive tumor characteristics and associated with unfavorable outcomes. Due to a higher rate of extravesical recurrences in UTUC with VH, Follow-up controls should include cross sectional imaging and cystoscopy.
PubMed: 38942714
DOI: 10.1016/j.urolonc.2024.05.005 -
Annals of Vascular Surgery Jun 2024Thoracic endovascular aortic surgery (TEVAR) is the modern standard of treatment for patients with Type B aortic dissection, however it is unclear how the initial length...
INTRODUCTION
Thoracic endovascular aortic surgery (TEVAR) is the modern standard of treatment for patients with Type B aortic dissection, however it is unclear how the initial length of treated aorta affects long-term outcomes. This study aims to elucidate risk factors for secondary intervention after TEVAR for aortic dissection, focusing on length of aortic treatment at index operation.
METHODS
A retrospective multihospital chart review was completed for patients treated between 2011 and 2022 who underwent TEVAR for aortic dissection with at least one year of post-TEVAR imaging and follow-up. Patient demographics and characteristics were analyzed. In this study, aortic zones treated only included those managed with a covered stent graft. The primary outcome measure was any need for secondary intervention.
RESULTS
A total of 151 patients were identified. Demographics included a mean age of 57 years, with 31.8% of the patients being female. Forty-three patients (28.5%) underwent secondary intervention after TEVAR, with a mean follow-up of 1.6 years. The most common indication for secondary intervention was aneurysmal degeneration of the residual false lumen (76%). There was a significant difference in the number of aortic zones treated in patients who did and did not require secondary intervention (2.3 ± 1 vs. 2.7 ± 1, p = 0.04). Additionally, patients with three or more aortic zones of treatment had a significant difference in the need for reintervention (32% secondary intervention vs 52% no secondary intervention, p = 0.02).
CONCLUSIONS
At least three zones of aortic treatment at index TEVAR is associated with a decreased need for overall reintervention. Modern treatment of acute and subacute type B dissection should stress an aggressive initial repair, balanced by the potential increased risk of spinal cord ischemia.
PubMed: 38942367
DOI: 10.1016/j.avsg.2024.05.009 -
Journal of Infection and Chemotherapy :... Jun 2024Enterococci are Gram-positive coccus bacteria that are normally present in the gastrointestinal tract and ordinarily function commensally with humans. Very few studies...
Enterococci are Gram-positive coccus bacteria that are normally present in the gastrointestinal tract and ordinarily function commensally with humans. Very few studies have investigated the characteristics of enterococcal infections. We aimed to characterize patients with urinary tract infections (UTIs) due to Enterococci and their outcomes. This was a retrospective cohort study between June 2012-November 2022. Patients who had clinically and microbiologically confirmed Enterococcal UTI based on a urine culture positive for E. faecalis or E. faecium with a count of ≥ 105 CFU/mL and having urinary tract symptoms were included. A total of 396 patients were eligible and included. The patients had a median age of 61 years and were mostly females (56.8%). The most common characteristics were hospitalization in a non-ICU ward, having a urinary catheter, and recent use of antibiotics within the last 3 months (66.4%, 59.3%, and 51.8%, respectively). Infection with E. faecalis was more common than E. faecium (77.3% vs. 22.7%). However, the latter exhibited higher rates of antibiotic resistance (P<0.001 to several antibiotics) and was associated with significantly higher median C-reactive protein level (26.7 vs. 13 mg/dL; P=0.025), mortality (23% vs. 10.1%; P=0.002), and median length of stay (25 vs. 11.5 days; P<0.001). We found that most patients with enterococcal UTIs had a history of having a urinary catheter and recent antibiotic use and were mostly females and hospitalized in non-ICU wards. E. faecium-infected patients experienced more severe episodes and poorer outcomes compared to patients infected with E. faecalis; thus, would need more aggressive therapy.
PubMed: 38942290
DOI: 10.1016/j.jiac.2024.06.019 -
Acta Biomaterialia Jun 2024A wide variety of microorganisms have been closely linked to metal corrosion in the form of adherent surface biofilms. Biofilms allow the development and maintenance of... (Review)
Review
A wide variety of microorganisms have been closely linked to metal corrosion in the form of adherent surface biofilms. Biofilms allow the development and maintenance of locally corrosive environments and/or permit direct corrosion including pitting corrosion. The presence of numerous genetically distinct microorganisms in the oral environment poses a threat to the integrity and durability of the surface of metallic prostheses and implants used in routine dentistry. However, the association between oral microorganisms and specific corrosion mechanisms is not clear. It is of practical importance to understand how microbial corrosion occurs and the associated risks to metallic materials in the oral environment. This knowledge is also important for researchers and clinicians who are increasingly concerned about the biological activity of the released corrosion products. Accordingly, the main goal was to comprehensively review the current literature regarding oral microbiologically influenced corrosion (MIC) including characteristics of biofilms and of the oral environment, MIC mechanisms, corrosion behavior in the presence of oral microorganisms and potentially mitigating technologies. Findings included that oral MIC has been ascribed mostly to aggressive metabolites secreted during microbial metabolism (metabolite-mediated MIC). However, from a thermodynamic point of view, extracellular electron transfer mechanisms (EET-MIC) through pili or electron transfer compounds cannot be ruled out. Various MIC mitigating methods have been demonstrated to be effective in short term, but long term evaluations are necessary before clinical applications can be considered. Currently most in-vitro studies fail to simulate the complexity of intraoral physiological conditions which may either reduce or exacerbate corrosion risk, which must be addressed in future studies. STATEMENT OF SIGNIFICANCE: A thorough analysis on literature regarding oral MIC (microbiologically influenced corrosion) of biomedical metallic materials has been carried out, including characteristics of oral environment, MIC mechanisms, corrosion behaviors in the presence of typical oral microorganisms and potential mitigating methods (materials design and surface design). There is currently a lack of mechanistic understanding of oral MIC which is very important not only to corrosion researchers but also to dentists and clinicians. This paper discusses the significance of biofilms from a biocorrosion perspective and summarizes several aspects of MIC mechanisms which could be caused by oral microorganisms. Oral MIC has been closely associated with not only the materials research but also the dental/clinical research fields in this work.
PubMed: 38942189
DOI: 10.1016/j.actbio.2024.06.032 -
Annals of Diagnostic Pathology Jun 2024Upper tract urothelial carcinoma (UTUC) is a relatively rare yet aggressive malignancy. While radical nephroureterectomy (RNU) remains the cornerstone treatment, UTUC...
Clinicopathological risk factors associated with tumor relapse of upper tract urothelial carcinoma after radical nephroureterectomy: A single institution 20-year experience.
Upper tract urothelial carcinoma (UTUC) is a relatively rare yet aggressive malignancy. While radical nephroureterectomy (RNU) remains the cornerstone treatment, UTUC has high local and metastatic relapse rates, leading to a dismal prognosis. To identify the clinicopathological factors associated with an increased risk of local and metastatic relapse in UTUC, we conducted a retrospective analysis of 133 consecutive UTUC patients who underwent RNU from 1998 to 2018. Patients lost to follow-up or with a history of bladder cancer were excluded from the study. The remaining 87 patients were categorized into two subgroups: those with tumor recurrence/relapse (40 cases) and those without recurrence/relapse (47 cases). Clinical and pathological characteristics were compared across the two groups. Multiple factors are associated with UTUC recurrence/relapse including larger tumor size, histology divergent differentiations/subtypes, high tumor grade, advanced pathologic T stage, positive margin, lymphovascular invasion (LVI), positive lymph node status, and preoperative hydronephrosis. Multivariate Cox regression analysis revealed that squamous differentiation predicted recurrence/relapse (p = 0.012), independent of tumor stage. Moreover, compared to the conventional histology type, UTUC with squamous differentiation had a significantly higher relapse rate (p = 0.0001) and poorer survival (p = 0.0039). This observation was further validated in invasive high-grade UTUC cases. Our findings suggest that many pathological factors contribute to UTUC recurrence/relapse, particularly, squamous differentiation may serve as an independent risk predictor for relapse and a potent prognosticator for adverse cancer-specific survival in UTUC patients. Recognizing and thoroughly assessing the pathological factors is essential for better oncologic management of UTUC.
PubMed: 38941945
DOI: 10.1016/j.anndiagpath.2024.152357 -
Journal of Reproductive Immunology Jun 2024The roles of IL-10, IL-11, COX-2, BCL6, ZEB1, and ZEB2 genes in the potential correlation between polycystic ovary syndrome (PCOS), inflammation, and cancer remain...
Comparison of serum levels of IL-10 and IL-11 and mRNA expression of IL-10, IL-11, COX-2, BCL6, and ZEB Family in peripheral blood mononuclear cells (PBMC) of women with polycystic ovary syndrome and healthy individuals.
BACKGROUND
The roles of IL-10, IL-11, COX-2, BCL6, ZEB1, and ZEB2 genes in the potential correlation between polycystic ovary syndrome (PCOS), inflammation, and cancer remain controversial.
AIMS
This study aimed to compare serum levels of IL-10 and IL-11 and gene expression of IL-10, IL-11, COX-2, BCL6, ZEB1, and ZEB2 in PBMCs of women with PCOS and healthy controls.
METHODS
A case-control study included 40 women with PCOS as the case group and 40 healthy women as controls. Group matching for age and BMI was performed. Serum levels of IL-10 and IL-11 were assessed using ELISA, while gene expression was measured using real-time PCR. Parameters were compared between groups, and correlations among gene expression and serum levels were explored.
RESULTS
In comparison to healthy women, women with PCOS exhibited a significant decrease in the expression of COX-2 and IL-10 genes (p<0.001), alongside a significant increase in ZEB2 gene expression (p<0.001). There were no significant differences observed in the expression of IL-11, BCL6, and ZEB1 genes. Furthermore, the serum level of IL-10 was significantly lower in women with PCOS compared to the control group (p<0.001), while no significant difference was found in IL-11 levels. Additionally, no significant correlations were identified between gene expression and serum levels.
CONCLUSION
In women with PCOS, reduced IL-10 gene expression may indicate inflammation and serve as a diagnostic biomarker. However, conflicting findings on COX-2 expression complicate understanding. Elevated ZEB2 expression in PCOS women may lead to infertility, epithelial-mesenchymal transition, and aggressive phenotypes.
PubMed: 38941927
DOI: 10.1016/j.jri.2024.104281 -
Cellular & Molecular Immunology Jun 2024Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV...
Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment (TME) changes in mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids and patient samples. Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associated IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73. Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance. The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC. Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth. MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration. EVs derived from BAG6-deficient pancreatic cancer cells induce MC activation via IL33/Il1rl1. The secretome of activated MCs induces tumor proliferation and changes in the TME, particularly shifting fibroblasts into an inflammatory cancer-associated fibroblast (iCAF) phenotype. Blocking EVs or depleting MCs restricts tumor growth.
PubMed: 38942797
DOI: 10.1038/s41423-024-01195-1 -
The Journal of Clinical Investigation Jun 2024Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has...
Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.
Topics: Carcinoma, Renal Cell; Humans; Basic Helix-Loop-Helix Transcription Factors; Kidney Neoplasms; Cell Line, Tumor; Acetate-CoA Ligase; Signal Transduction; Animals; Mice; Gene Expression Regulation, Neoplastic; Von Hippel-Lindau Tumor Suppressor Protein; Ubiquitin-Protein Ligases; Neoplasm Proteins
PubMed: 38941296
DOI: 10.1172/JCI164249