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Frontiers in Cardiovascular Medicine 2024Hypertrophic cardiomyopathy (HCM) is a very prevalent inherited disease with a wide global distribution and a prevalence rate of approximately 0.2% in the general... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a very prevalent inherited disease with a wide global distribution and a prevalence rate of approximately 0.2% in the general population. Left ventricular hypertrophy (LVH) caused by sarcomere mutation is the primary reason of HCM. The histopathology feature is that cardiomyocyte hypertrophy, myocyte disorder and myocardial fibrosis lead to diminished diastolic function, left ventricular outflow tract obstruction (LVOTO) and arrhythmia, all of which result in serious cardiac complications. Previously, HCM was considered a malignant disease that was almost untreatable. With the improvement of medical standards and increasing awareness of HCM, it has become a highly treatable disease in contemporary times, with a significant decrease in mortality rates. However, there are still significant unmet requirements in the therapy of HCM. This paper draws on more than 100 references from the past four decades and summarizes current advances in the treatment of HCM. The article will review the pathogenesis and types, recent development in pharmacotherapy, invasive treatments and gene therapies, as well as dilemma and future development of HCM.
PubMed: 38887447
DOI: 10.3389/fcvm.2024.1387596 -
Scientific Reports Jun 2024Breast cancer is one of the tumors with the highest prevalence rate among women in the world, and its BRCA1/2 gene is a common mutation site. Talazoparib, as a targeted...
Breast cancer is one of the tumors with the highest prevalence rate among women in the world, and its BRCA1/2 gene is a common mutation site. Talazoparib, as a targeted PARP inhibitor, can effectively control the occurrence and development of breast cancer with BRCA1/2 gene mutation, and play a therapeutic role. Based on the findings from the Phase III EMBRACE trial (NCT01945775 clinical trial), our analysis reveals that the talazoparib group demonstrated a significant extension in progression-free survival, along with improved response markers and patient-reported outcomes when compared to conventional therapies. This study aims to assess the cost-effectiveness of talazoparib for treating advanced breast cancer with germline BRCA1/2 mutations and HER2 negativity, considering the perspectives of health services in China and the United States. The results obtained will serve as a valuable reference for promoting rational drug utilization and enhancing medical resource efficiency. To evaluate the cost-effectiveness of Talazoparib more scientifically and provide clinicians with chemotherapy options, this paper developed a Markov model based on the EMBRACA clinical trial (clinical Trails.gov No., NCT01945775) to simulate the survival events of breast cancer patients in the Talazoparib group and the standard treatment group. The state transition probability and clinical data of breast cancer patients during treatment were extracted from the phase III EMBRACA clinical trial. The cost data generated during the treatment process comes from local hospital pricing, other references, and expert consultation. This article uses US dollars to calculate the treatment cost and incremental cost-effectiveness ratio. Health outcomes are expressed in Quality Adjusted Life Years (QALYs). In addition, Outcomes were measured in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio, which robustness was evaluated by deterministic and probabilistic sensitivity analyses. This article establishes a Markov model for single-item sensitivity analysis. The results show that the economic benefits of using Talazoparib as a new treatment strategy in both China and the United States are higher than other drugs, and it is cost-effective. Compared to the control group, the incremental cost incurred by the Talazoparib treatment group in China was $2484.48/QALY, with an incremental QALY of 1.5. However, Talazoparib in the United States holds a dominant position, saving costs of $10,223.43 and increasing QALYs by 1.5. The clinical treatment effect of Talazoparib group in BRCA1/2 mutant advanced breast cancer patients is better than that of the standard treatment group, and the progression free survival period is significantly prolonged. From the perspective of medical and health services in China and the United States, the Talazoparib group is more economical than the standard treatment group in treating patients with BRCA1/2 mutant advanced breast cancer.
Topics: Humans; Female; Phthalazines; Breast Neoplasms; Cost-Benefit Analysis; China; Germ-Line Mutation; Receptor, ErbB-2; BRCA2 Protein; United States; BRCA1 Protein; Poly(ADP-ribose) Polymerase Inhibitors; Quality-Adjusted Life Years; Middle Aged; Markov Chains; Adult; Progression-Free Survival
PubMed: 38886516
DOI: 10.1038/s41598-024-64343-7 -
PLoS Biology Jun 2024The rates at which mutations accumulate across human cell types vary. To identify causes of this variation, mutations are often decomposed into a combination of the...
The rates at which mutations accumulate across human cell types vary. To identify causes of this variation, mutations are often decomposed into a combination of the single-base substitution (SBS) "signatures" observed in germline, soma, and tumors, with the idea that each signature corresponds to one or a small number of underlying mutagenic processes. Two such signatures turn out to be ubiquitous across cell types: SBS signature 1, which consists primarily of transitions at methylated CpG sites thought to be caused by spontaneous deamination, and the more diffuse SBS signature 5, which is of unknown etiology. In cancers, the number of mutations attributed to these 2 signatures accumulates linearly with age of diagnosis, and thus the signatures have been termed "clock-like." To better understand this clock-like behavior, we develop a mathematical model that includes DNA replication errors, unrepaired damage, and damage repaired incorrectly. We show that mutational signatures can exhibit clock-like behavior because cell divisions occur at a constant rate and/or because damage rates remain constant over time, and that these distinct sources can be teased apart by comparing cell lineages that divide at different rates. With this goal in mind, we analyze the rate of accumulation of mutations in multiple cell types, including soma as well as male and female germline. We find no detectable increase in SBS signature 1 mutations in neurons and only a very weak increase in mutations assigned to the female germline, but a significant increase with time in rapidly dividing cells, suggesting that SBS signature 1 is driven by rounds of DNA replication occurring at a relatively fixed rate. In contrast, SBS signature 5 increases with time in all cell types, including postmitotic ones, indicating that it accumulates independently of cell divisions; this observation points to errors in DNA repair as the key underlying mechanism. Thus, the two "clock-like" signatures observed across cell types likely have distinct origins, one set by rates of cell division, the other by damage rates.
Topics: Humans; DNA Repair; DNA Damage; Germ-Line Mutation; Mutation; Germ Cells; Models, Genetic; Neoplasms; DNA Methylation; DNA Replication
PubMed: 38885262
DOI: 10.1371/journal.pbio.3002678 -
The Oncologist Jun 2024The activity of PARP inhibitors (PARPi) in patients with homologous recombination repair (HRR) mutations and metastatic castration-resistant prostate cancer has been...
TRIUMPH: phase II trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer harboring germline homologous recombination repair gene mutations.
BACKGROUND
The activity of PARP inhibitors (PARPi) in patients with homologous recombination repair (HRR) mutations and metastatic castration-resistant prostate cancer has been established. We hypothesized that the benefit of PARPi can be maintained in the absence of androgen deprivation therapy (ADT) in an HRR-mutated population. We report the results of a phase II clinical trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
METHODS
This was a multi-center, single-arm phase II trial (NCT03413995) for patients with asymptomatic, mHSPC. Patients were required to have a pathogenic germline mutation in an HRR gene for eligibility. All patients received rucaparib 600 mg by mouth twice daily, without androgen deprivation. The primary endpoint was a confirmed PSA50 response rate.
RESULTS
Twelve patients were enrolled, 7 with a BRCA1/2 mutation and 5 with a CHEK2 mutation. The confirmed PSA50 response rate to rucaparib was 41.7% (N = 5/12, 95% CI: 15.2-72.3%, one-sided P = .81 against the 50% null), which did not meet the pre-specified efficacy boundary to enroll additional patients. In patients with measurable disease, the objective response rate was 60% (N = 3/5), all with a BRCA2 mutation. The median radiographic progression-free survival on rucaparib was estimated at 12.0 months (95% CI: 8.0-NR months). The majority of adverse events were grade ≤2, and expected.
CONCLUSION
Rucaparib can induce clinical responses in a biomarker-selected metastatic prostate cancer population without concurrent ADT. However, the pre-specified efficacy threshold was not met, and enrolment was truncated. Although durable responses were observed in a subset of patients, further study of PARPi treatment without ADT in mHSPC is unlikely to change clinical practice.
PubMed: 38885246
DOI: 10.1093/oncolo/oyae120 -
Journal of Thoracic Disease May 2024The preoperative differential diagnosis of nodular lung adenocarcinoma has long been a challenging issue for thoracic surgeons. This study aimed to explore differential...
BACKGROUND
The preoperative differential diagnosis of nodular lung adenocarcinoma has long been a challenging issue for thoracic surgeons. This study aimed to explore differential diagnosis of nodular lung adenocarcinoma by comprehensively analyzing its clinical, computed tomography (CT) imaging, and postoperative pathological and genetic features.
METHODS
The clinical, CT imaging, and postoperative pathological features of different classifications of nodular lung adenocarcinoma were retrospectively analyzed through univariate and multivariate statistical methods.
RESULTS
There were 132 patients with nodular lung adenocarcinoma enrolled. Firstly, compared with ground-glass nodular lung adenocarcinoma, solid nodular lung adenocarcinoma was more common in women [odds ratio (OR), 3.662; 95% confidence interval (CI): 1.066-12.577] and older adults (OR, 1.061; 95% CI: 1.007-1.119), and CT signs were mostly lobulation (OR, 4.957; 95% CI: 1.714-14.337) and spiculation (OR, 8.214; 95% CI: 2.740-24.621); the mean CT (CT) value of solid nodular lung adenocarcinoma was significantly higher than that of ground-glass nodular lung adenocarcinoma, and the optimal diagnostic threshold was -267.5 Hounsfield units (HU). Secondly, the maximum diameter of nodule size (NS) of invasive adenocarcinoma (IAC) was significantly greater than that of minimally IAC (MIA; OR, 6.306; 95% CI: 1.191-33.400) or atypical adenomatous hyperplasia (AAH)/adenocarcinoma in situ (AIS; OR, 189.539; 95% CI: 4.720-7,610.476), and the optimal diagnostic threshold between IAC and MIA was 1.35 cm; the CT value of IAC was significantly higher than that of MIA, and the optimal diagnostic threshold was -460.75 HU. Thirdly, lepidic-predominant adenocarcinoma (LPA) manifest more commonly as pure ground-glass nodule (pGGN; OR, 6.252; 95% CI: 1.429-27.358) or mixed ground-glass nodule (mGGN; OR, 4.224; 95% CI: 1.223-14.585). Moreover, the mutation rate of epidermal growth factor receptor () in IAC was 70.69% (41/58). The mutation rates of mGGNs (OR, 8.794; 95% CI: 1.489-51.933) and solid nodules (SNs; OR, 12.912; 95% CI: 1.597-104.383) were significantly higher than that of pGGNs. Furthermore, compared with those of micropapillary-predominant adenocarcinoma (MPA), solid-predominant adenocarcinoma (SPA), or invasive mucinous adenocarcinoma (IMA), there were significantly higher mutation rates in acinar-predominant adenocarcinoma/papillary-predominant adenocarcinoma (APA/PPA; OR, 55.925; 95% CI: 4.045-773.284) and LPA (OR, 38.265; 95% CI: 2.307-634.596).
CONCLUSIONS
Different classifications of nodular lung adenocarcinoma have their own clinicopathological and CT imaging features, and the latter is the main predictor.
PubMed: 38883620
DOI: 10.21037/jtd-24-510 -
Translational Cancer Research May 2024Stomach adenocarcinoma (STAD), a frequently occurring gastrointestinal tumour, is often detected late and has a poor prognosis. Long non-coding RNAs (lncRNAs)...
BACKGROUND
Stomach adenocarcinoma (STAD), a frequently occurring gastrointestinal tumour, is often detected late and has a poor prognosis. Long non-coding RNAs (lncRNAs) significantly affect tumour development. Recent studies have identified disulfidptosis as a previously unexplained form of cell death. Herein, we aimed to examine the predictive value of disulfidptosis-related lncRNA models for the clinical prognosis and immunotherapy of STAD.
METHODS
STAD-related transcriptomic data were obtained from The Cancer Genome Atlas (TCGA), whereas genes associated with disulfidptosis were identified from previously published papers. A risk prediction model for disulfidptosis-related lncRNAs was developed using the Cox regression and least absolute shrinkage selection algorithm methods. The accuracy of the model was confirmed using calibration curves, and the biological functions were analysed using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA). Finally, the tumour mutation burden (TMB) and tumour immune dysfunction and exclusion (TIDE) algorithms were used to screen drugs that are sensitive to STAD.
RESULTS
The risk prediction models were constructed using seven disulfidptosis-related lncRNAs. The validated results were consistent with the predicted ones, with significant survival differences. When combined with clinical data, the risk scores were used as independent prognostic markers. Based on the tumour mutation load, the high-risk patient group had a poorer survival rate as compared with the low-risk patient group. Further studies were conducted to understand the different groups' inconsistent responses to immune status; subsequently, relatively sensitive drugs were identified.
CONCLUSIONS
Overall, seven markers of disulfidptosis-related lncRNAs associated with STAD were found to facilitate prognostic prediction, suggesting new ideas for immunotherapy and clinical applications.
PubMed: 38881918
DOI: 10.21037/tcr-23-2067 -
Frontiers in Microbiology 2024Cloning and transfer of long-stranded DNA in the size of a bacterial whole genome has become possible by recent advancements in synthetic biology. For the whole genome...
Cloning and transfer of long-stranded DNA in the size of a bacterial whole genome has become possible by recent advancements in synthetic biology. For the whole genome cloning and whole genome transplantation, bacteria with small genomes have been mainly used, such as mycoplasmas and related species. The key benefits of whole genome cloning include the effective maintenance and preservation of an organism's complete genome within a yeast host, the capability to modify these genome sequences through yeast-based genetic engineering systems, and the subsequent use of these cloned genomes for further experiments. This approach provides a versatile platform for in-depth genomic studies and applications in synthetic biology. Here, we cloned an entire genome of an insect-associated bacterium, , in yeast. The 1.12 Mbp whole genome was successfully cloned in yeast, and sequences of several clones were confirmed by Illumina sequencing. The cloning efficiency was high, and the clones contained only a few mutations, averaging 1.2 nucleotides per clone with a mutation rate of 4 × 10. The cloned genomes could be distributed and used for further research. This study serves as an initial step in the synthetic biology approach to .
PubMed: 38881660
DOI: 10.3389/fmicb.2024.1411609 -
Journal of Thoracic Oncology : Official... Jun 2024There is limited literature on the prevalence of EGFR mutations in early-stage non-small cell lung cancer (NSCLC). EARLY-EGFR (NCT04742192), a cross-sectional study,...
BACKGROUND
There is limited literature on the prevalence of EGFR mutations in early-stage non-small cell lung cancer (NSCLC). EARLY-EGFR (NCT04742192), a cross-sectional study, determined the prevalence of EGFR mutations in early-stage NSCLC.
METHODS
This non-interventional, real-world study enrolled consecutive patients with resected stage IA-IIIB (American Joint Committee on Cancer 8 edition) NSCLC from 14 countries across Asia, Latin America, and Middle East and Africa. The primary endpoint was prevalence of EGFR mutations and secondary endpoints included prevalence of EGFR mutation subtypes and treatment patterns.
RESULTS
Of 601 patients (median [range] age: 62.0 [30.0-86.0] years) enrolled, 52.7% were females and 64.2% were non-smokers. The majority had stage IA-IB NSCLC (64.1%) and adenocarcinoma histology (98.7%). Overall prevalence of EGFR mutations was 51.0%; majority reported exon-19 deletions (48.5%) followed by exon-21 L858R mutations (34.0%). Women had a higher EGFR mutation rate than men (64.0% versus 36.4%). Compared with no EGFR mutations, patients with EGFR mutations were more likely to be non-smokers (35.1% versus 60.9%) and have stage I NSCLC compared to stage II and III NSCLC (54.8% versus 47.3% and 35.6%). Systemic adjuvant therapy was planned in 33.8% patients with stage IB to IIIB disease and adjuvant chemoradiotherapy in 6.8% patients. Age ≥60 years, females, and Asians were found to have a significantly (p < 0.05) higher odds of EGFR mutations, while smoking history and stage III disease had lower odds of EGFR mutations.
CONCLUSION
The EARLY-EGFR study provides an overview of EGFR mutations and subtype prevalence in patients with early-stage NSCLC. The study highlights the limited adherence to treatment guidelines suggesting an unmet need for improved adjuvant therapy.
PubMed: 38880172
DOI: 10.1016/j.jtho.2024.06.008 -
ESMO Open Jun 2024Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR)... (Observational Study)
Observational Study
BACKGROUND
Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted.
PATIENTS AND METHODS
The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method.
RESULTS
Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy.
CONCLUSION
The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Retrospective Studies; Acrylamides; Lung Neoplasms; ErbB Receptors; Aniline Compounds; Male; Female; Middle Aged; Mutation; Aged; Adult; Aged, 80 and over; Antineoplastic Agents; Protein Kinase Inhibitors; Indoles; Pyrimidines
PubMed: 38878323
DOI: 10.1016/j.esmoop.2024.103592 -
Scientific Reports Jun 2024Mayo Imaging Classification (MIC) for predicting future kidney growth in autosomal dominant polycystic kidney disease (ADPKD) patients is calculated from a single MRI/CT...
Mayo Imaging Classification (MIC) for predicting future kidney growth in autosomal dominant polycystic kidney disease (ADPKD) patients is calculated from a single MRI/CT scan assuming exponential kidney volume growth and height-adjusted total kidney volume at birth to be 150 mL/m. However, when multiple scans are available, how this information should be combined to improve prediction accuracy is unclear. Herein, we studied ADPKD subjects ( ) with 8+ years imaging follow-up (mean = 11 years) to establish ground truth kidney growth trajectory. MIC annual kidney growth rate predictions were compared to ground truth as well as 1- and 2-parameter least squares fitting. The annualized mean absolute error in MIC for predicting total kidney volume growth rate was compared to ( ) for a 2-parameter fit to the same exponential growth curve used for MIC when 4 measurements were available or ( ) with 3 measurements averaging together with MIC. On univariate analysis, male sex ( ) and PKD2 mutation ( ) were associated with poorer MIC performance. In ADPKD patients with 3 or more CT/MRI scans, 2-parameter least squares fitting predicted kidney volume growth rate better than MIC, especially in males and with PKD2 mutations where MIC was less accurate.
Topics: Humans; Polycystic Kidney, Autosomal Dominant; Male; Female; Kidney; Least-Squares Analysis; Adult; Organ Size; Magnetic Resonance Imaging; Middle Aged; Tomography, X-Ray Computed
PubMed: 38877066
DOI: 10.1038/s41598-024-62776-8