-
Acta Neuropathologica Communications Jun 2024Wasteosomes (or corpora amylacea) are polyglucosan bodies that appear in the human brain with aging and in some neurodegenerative diseases, and have been suggested to...
Wasteosomes (or corpora amylacea) are polyglucosan bodies that appear in the human brain with aging and in some neurodegenerative diseases, and have been suggested to have a potential role in a nervous system cleaning mechanism. Despite previous studies in several neurodegenerative disorders, their status in frontotemporal lobar degeneration (FTLD) remains unexplored. Our study aims to characterize wasteosomes in the three primary FTLD proteinopathies, assessing frequency, distribution, protein detection, and association with aging or disease duration. Wasteosome scores were obtained in various brain regions from 124 post-mortem diagnosed sporadic FTLD patients, including 75 participants with tau (FTLD-tau), 42 with TAR DNA-binding protein 43 (FTLD-TDP), and 7 with Fused in Sarcoma (FTLD-FUS) proteinopathies, along with 29 control subjects. The wasteosome amount in each brain region for the different FLTD patients was assessed with a permutation test with age at death and sex as covariables, and multiple regressions explored associations with age at death and disease duration. Double immunofluorescence studies examined altered proteins linked to FTLD in wasteosomes. FTLD patients showed a higher accumulation of wasteosomes than control subjects, especially those with FTLD-FUS. Unlike FTLD-TDP and control subjects, wasteosome accumulation did not increase with age in FTLD-tau and FTLD-FUS. Cases with shorter disease duration in FTLD-tau and FTLD-FUS seemed to exhibit higher wasteosome quantities, whereas FTLD-TDP appeared to show an increase with disease progression. Immunofluorescence studies revealed the presence of tau and phosphorylated-TDP-43 in the periphery of isolated wasteosomes in some patients with FTLD-tau and FTLD-TDP, respectively. Central inclusions of FUS were observed in a higher number of wasteosomes in FTLD-FUS patients. These findings suggest a role of wasteosomes in FTLD, especially in the more aggressive forms of FLTD-FUS. Detecting these proteins, particularly FUS, in wasteosomes from cerebrospinal fluid could be a potential biomarker for FTLD.
Topics: Humans; Frontotemporal Lobar Degeneration; Female; Male; RNA-Binding Protein FUS; Aged; tau Proteins; Middle Aged; Aged, 80 and over; DNA-Binding Proteins; Brain
PubMed: 38879502
DOI: 10.1186/s40478-024-01812-0 -
BMC Cancer Jun 2024The addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients with HER2 + breast cancer (BC), has...
BACKGROUND
The addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients with HER2 + breast cancer (BC), has shown to increase the pathological complete response (pCR) rate, without main safety concerns. The aim of NeoPowER trial is to evaluate safety and efficacy of P + H + CT in a real-world population.
METHODS
We retrospectively reviewed the medical records of stage II-III, HER2 + BC patients treated with NaT: who received P + H + CT (neopower group) in 5 Emilia Romagna institutions were compared with an historical group who received H + CT (control group). The primary endpoint was the safety, secondary endpoints were pCR rate, DRFS and OS and their correlation to NaT and other potential variables.
RESULTS
260 patients were included, 48% received P + H + CT, of whom 44% was given anthraciclynes as part of CT, compared to 83% in the control group. The toxicity profile was similar, excluding diarrhea more frequent in the neopower group (20% vs. 9%). Three patients experienced significant reductions in left ventricular ejection fraction (LVEF), all receiving anthracyclines. The pCR rate was 46% (P + H + CT) and 40% (H + CT) (p = 0.39). The addition of P had statistically correlation with pCR only in the patients receiving anthra-free regimens (OR = 3.05,p = 0.047). Preoperative use of anthracyclines (OR = 1.81,p = 0.03) and duration of NaT (OR = 1.18,p = 0.02) were statistically related to pCR. 12/21 distant-relapse events and 14/17 deaths occurred in the control group. Patients who achieve pCR had a significant increase in DRFS (HR = 0.23,p = 0.009).
CONCLUSIONS
Adding neoadjuvant P to H and CT is safe. With the exception of diarrhea, rate of adverse events of grade > 2 did not differ between the two groups. P did not increase the cardiotoxicity when added to H + CT, nevertheless in our population all cardiac events occurred in patients who received anthracycline-containing regimens. Not statistically significant, higher pCR rate is achievable in patients receiving neoadjuvant P + H + CT. The study did not show a statistically significant correlation between the addition of P and long-term outcomes.
Topics: Humans; Female; Breast Neoplasms; Trastuzumab; Neoadjuvant Therapy; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal, Humanized; Retrospective Studies; Receptor, ErbB-2; Adult; Aged; Treatment Outcome; Neoplasm Staging
PubMed: 38879498
DOI: 10.1186/s12885-024-12506-0 -
Cell Stress & Chaperones Jun 2024The evolutionary conserved molecular chaperone HSP90 plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although, the functionality of... (Review)
Review
The evolutionary conserved molecular chaperone HSP90 plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although, the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov. Among these trials, 60% have been completed, 10% are currently active, while 30% have been suspended, terminated, or withdrawn. HSP90 inhibitors have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90 inhibitors are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90 inhibitors have shown limited clinical activity due to drug related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune check point inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past five years regarding HSP90 inhibitors and their implications in anti-cancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90 inhibitors as promising therapeutic agents in cancer treatment.
PubMed: 38878853
DOI: 10.1016/j.cstres.2024.05.005 -
Clinical and Translational Medicine Jun 2024Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is...
BACKGROUND
Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease.
METHODS
We describe an integrated whole-exome sequencing and transcriptomic study of 37 iCCAs patients in Germany.
RESULTS
We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs.
CONCLUSIONS
By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.
Topics: Humans; Cholangiocarcinoma; Pre-B-Cell Leukemia Transcription Factor 1; Male; Proto-Oncogene Proteins; Female; Prognosis; Middle Aged; Aged; Bile Duct Neoplasms; Germany; Biomarkers, Tumor; Adult; Genomics; Protein-Tyrosine Kinases
PubMed: 38877653
DOI: 10.1002/ctm2.1723 -
Acta Neuropathologica Communications Jun 2024MYC dysregulation is pivotal in the onset and progression of IDH-mutant gliomas, mostly driven by copy-number alterations, regulatory element alterations, or epigenetic...
MYC dysregulation is pivotal in the onset and progression of IDH-mutant gliomas, mostly driven by copy-number alterations, regulatory element alterations, or epigenetic changes. Our pilot analysis uncovered instances of relative MYC overexpression without alterations in the proximal MYC network (PMN), prompting a deeper investigation into potential novel oncogenic mechanisms. Analysing comprehensive genomics profiles of 236 "IDH-mutant 1p/19q non-co-deleted" lower-grade gliomas from The Cancer Genome Atlas, we identified somatic genomic alterations within the PMN. In tumours without PMN-alterations but with MYC-overexpression, genes correlated with MYC-overexpression were identified. Our analyses yielded that 86/236 of astrocytomas exhibited no PMN-alterations, a subset of 21/86 displaying relative MYC overexpression. Within this subset, we discovered 42 genes inversely correlated with relative MYC expression, all on 19q. Further analysis pinpointed a minimal common region at 19q13.43, encompassing 15 genes. The inverse correlations of these 15 genes with relative MYC overexpression were re-confirmed using independent scRNAseq data. Further, the micro-deleted astrocytoma subset displayed significantly higher genomic instability compared to WT cases, but lower instability compared to PMN-hit cases. This newly identified 19q micro-deletion represents a potential novel mechanism underlying MYC dysregulation in astrocytomas. Given the prominence of 19q loss in IDH-mutant gliomas, our findings bear significant implications for understanding gliomagenesis.
Topics: Humans; Isocitrate Dehydrogenase; Astrocytoma; Brain Neoplasms; Proto-Oncogene Proteins c-myc; Chromosomes, Human, Pair 19; Chromosome Deletion; Mutation
PubMed: 38877600
DOI: 10.1186/s40478-024-01811-1 -
Cellular & Molecular Biology Letters Jun 2024Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the...
Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited HO-induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future.
Topics: Ferroptosis; Animals; Osteoarthritis; Ketoglutaric Acids; Signal Transduction; Rats; Phospholipid Hydroperoxide Glutathione Peroxidase; Amino Acid Transport System y+; Male; Proto-Oncogene Proteins c-ets; Rats, Sprague-Dawley; Apoptosis; Reactive Oxygen Species
PubMed: 38877424
DOI: 10.1186/s11658-024-00605-6 -
Scientific Reports Jun 2024Glucagon-like peptide 1 receptor (GLP-1R) agonist is an emerging anti-diabetic medication whose effects on the risk and progression of cholangiocarcinoma (CCA) are...
Glucagon-like peptide 1 receptor (GLP-1R) agonist is an emerging anti-diabetic medication whose effects on the risk and progression of cholangiocarcinoma (CCA) are controversial. This study aimed to elucidate the roles of GLP-1R and its agonists on intrahepatic CCA (iCCA) progression. Expressions of GLP-1R in iCCA tissues investigated by immunohistochemistry showed that GLP-1R expressions were significantly associated with poor histological grading (P = 0.027). iCCA cell lines, KKU-055 and KKU-213A, were treated with exendin-4 and liraglutide, GLP-1R agonists, and their effects on proliferation and migration were assessed. Exendin-4 and liraglutide did not affect CCA cell proliferation in vitro, but liraglutide significantly suppressed the migration of CCA cells, partly by inhibiting epithelial-mesenchymal transition. In contrast, liraglutide significantly reduced CCA tumor volumes and weights in xenografted mice (P = 0.046). GLP-1R appeared downregulated when CCA cells were treated with liraglutide in vitro and in vivo. In addition, liraglutide treatment significantly suppressed Akt and STAT3 signaling in CCA cells, by reducing their phosphorylation levels. These results suggested that liraglutide potentially slows down CCA progression, and further clinical investigation would benefit the treatment of CCA with diabetes mellitus.
Topics: Liraglutide; Cholangiocarcinoma; Humans; Animals; Cell Line, Tumor; Glucagon-Like Peptide-1 Receptor; Mice; Male; Bile Duct Neoplasms; Cell Proliferation; Epithelial-Mesenchymal Transition; Cell Movement; Female; Xenograft Model Antitumor Assays; Disease Progression; Middle Aged; Signal Transduction; Aged; Antineoplastic Agents; STAT3 Transcription Factor; Exenatide; Mice, Nude; Proto-Oncogene Proteins c-akt
PubMed: 38877189
DOI: 10.1038/s41598-024-64774-2 -
Nature Communications Jun 2024Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in...
Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy.
Topics: Humans; Neoplasms; Oncogene Proteins, Fusion; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-ret; Translocation, Genetic; Anaplastic Lymphoma Kinase; Receptor, trkA; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Signal Transduction; Cell Line, Tumor
PubMed: 38877018
DOI: 10.1038/s41467-024-49499-0 -
Cancer Control : Journal of the Moffitt... 2024The present study aimed to evaluate the frequencies of , and mutations and their possible associations with clinicopathological features in 249 Moroccan patients with...
OBJECTIVES
The present study aimed to evaluate the frequencies of , and mutations and their possible associations with clinicopathological features in 249 Moroccan patients with colorectal cancer (CRC).
METHODS
A retrospective investigation of a cohort of formalin-fixed paraffin-embedded tissues of 249 patients with CRC was screened for // mutations using Idylla™ technology and pyrosequencing.
RESULTS
, and mutations were revealed in 46.6% (116/249), 5.6% (14/249), and 2.4% (6/249) of patients. exon 2 mutations were identified in 87.9% of patients (102/116). G12D and G12 C were the most frequent, at 32.8% and 12.93%, respectively. Among the patients with exon 2 wild-type (wt), 27.6% (32/116) harbored additional mutations. Concurrent mutations were identified in 9.5% (11/116); including six in codon 146 (A146P/T/V), three in codon 61 (Q61H/L/R), one in codon 12 (G12 A and Q61H), and one in codon 13 (G13D and Q61 L). Among the exon 2 wt patients, 64.3% (9/14) harbored additional mutations. Concurrent mutations were identified in 28.6% (4/14) of -mutant patients. Since 3.2% wt were identified with mutations, concomitant and mutations were identified in 2.4% (6/249) of patients. mutations were higher in the >50-year-old age-group ( = .031), and the tumor location was revealed to be significantly associated with mutations ( = .028) predominantly in left colon (27.5%) and colon (42.2%) locations. mutations were most prevalent in the left colon (42.8%) and in well-differentiated tumors (64.2%).
CONCLUSION
Detection of mutations, particularly the G12 C subtype, may be significant for patients with CRC and has possible therapeutic implications. However, rare concomitant mutations in CRC patients suggest that each individual may present distinct therapeutic responses. testing alongside the identification of other affected genes in the same patient will make the treatments even more personalized by contributing more accurately to the clinical decision process. Overall, early diagnosis using novel molecular techniques may improve the management of CRC by providing the most efficient therapies for Moroccan patients.
Topics: Humans; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Male; Female; Proto-Oncogene Proteins p21(ras); Membrane Proteins; Middle Aged; GTP Phosphohydrolases; Morocco; Mutation; Retrospective Studies; Aged; Adult; Aged, 80 and over; DNA Mutational Analysis
PubMed: 38875469
DOI: 10.1177/10732748241262179 -
Medicine Jun 2024To explore the value of machine learning (ML) models based on contrast-enhanced cone-beam breast computed tomography (CE-CBBCT) radiomics features for the preoperative...
To explore the value of machine learning (ML) models based on contrast-enhanced cone-beam breast computed tomography (CE-CBBCT) radiomics features for the preoperative prediction of human epidermal growth factor receptor 2 (HER2)-low expression breast cancer (BC). Fifty-six patients with HER2-negative invasive BC who underwent preoperative CE-CBBCT were prospectively analyzed. Patients were randomly divided into training and validation cohorts at approximately 7:3. A total of 1046 quantitative radiomic features were extracted from CE-CBBCT images and normalized using z-scores. The Pearson correlation coefficient and recursive feature elimination were used to identify the optimal features. Six ML models were constructed based on the selected features: linear discriminant analysis (LDA), random forest (RF), support vector machine (SVM), logistic regression (LR), AdaBoost (AB), and decision tree (DT). To evaluate the performance of these models, receiver operating characteristic curves and area under the curve (AUC) were used. Seven features were selected as the optimal features for constructing the ML models. In the training cohort, the AUC values for SVM, LDA, RF, LR, AB, and DT were 0.984, 0.981, 1.000, 0.970, 1.000, and 1.000, respectively. In the validation cohort, the AUC values for the SVM, LDA, RF, LR, AB, and DT were 0.859, 0.880, 0.781, 0.880, 0.750, and 0.713, respectively. Among all ML models, the LDA and LR models demonstrated the best performance. The DeLong test showed that there were no significant differences among the receiver operating characteristic curves in all ML models in the training cohort (P > .05); however, in the validation cohort, the DeLong test showed that the differences between the AUCs of LDA and RF, AB, and DT were statistically significant (P = .037, .003, .046). The AUCs of LR and RF, AB, and DT were statistically significant (P = .023, .005, .030). Nevertheless, no statistically significant differences were observed when compared to the other ML models. ML models based on CE-CBBCT radiomics features achieved excellent performance in the preoperative prediction of HER2-low BC and could potentially serve as an effective tool to assist in precise and personalized targeted therapy.
Topics: Humans; Female; Breast Neoplasms; Prospective Studies; Middle Aged; Receptor, ErbB-2; Adult; Machine Learning; Cone-Beam Computed Tomography; Contrast Media; ROC Curve; Aged; Support Vector Machine; Area Under Curve; Radiomics
PubMed: 38875420
DOI: 10.1097/MD.0000000000038513