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1.
Medicine (Baltimore) ; 103(19): e38082, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38728504

ABSTRACT

The efficacy of surgical intervention for perianal infection in patients with hematologic malignancies is not well established. Therefore, our study aimed to investigate the clinical efficacy and complications of surgical treatment of perianal infection in patients with hematologic malignancies. This retrospective study included patients with hematological malignancies who were diagnosed with perianal infections and treated at the China Aerospace Science & Industry Corporation 731 Hospital between 2018 and 2022. Patient characteristics, hematological data, surgical intervention, and complications, including recurrence and mortality, were analyzed. This study included 156 patients with leukemia aged 2 months to 71 years who were treated surgically for perianal infection, comprising 94 males and 62 females. Perianal infection included 36 cases of abscesses, 91 anal fistulas, and 29 anal fissures accompanied by infection. A total of 36 patients developed severe complications postoperatively, including 4 patients who died, 6 patients with severe incision bleeding, 18 patients with severe pain, 6 patients with sepsis, 12 patients who needed reoperation, 15 patients with hospitalization for more than 2 weeks, and 3 patients with anal stenosis; none of the patients developed anal incontinence. Additionally, risk factors for postoperative complications of perianal infection in patients with hematologic malignancies include leukopenia, agranulocytosis, thrombocytopenia, depth of abscess and not undergone an MRI. Surgical intervention may improve the prognosis of patients with perianal abscess formation, particularly in patients who show no improvement with medical therapy and those who develop perianal sepsis. Granulocytopenia and thrombocytopenia should be improved before surgery, which can significantly reduce postoperative complications. Although these findings are from a case series without a comparator, they may be of value to physicians because to the best of our knowledge, no randomized or prospective studies have been conducted on the management of perianal infections in patients with hematological malignancies.


Subject(s)
Abscess , Hematologic Neoplasms , Humans , Male , Female , Retrospective Studies , Middle Aged , Adult , Aged , Hematologic Neoplasms/complications , Hematologic Neoplasms/surgery , Abscess/surgery , Abscess/etiology , Adolescent , Child , Young Adult , Anus Diseases/surgery , Child, Preschool , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Infant , Rectal Fistula/surgery , Rectal Fistula/etiology , Treatment Outcome , Fissure in Ano/surgery
2.
Psychiatry Investig ; 21(4): 387-395, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38695046

ABSTRACT

OBJECTIVE: To explore the efficacy and safety of clonidine adhesive patch in Tourette syndrome (TS) patients with comorbid attentiondeficit/hyperactivity disorder (ADHD). METHODS: This study was conducted on a sample of children and adolescents with TS who had comorbid ADHD between May 2012 and March 2015. The patients were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, and were randomly assigned to four different dose groups: 1.0 mg/week, 1.5 mg/week, 2.0 mg/week and placebo group, and the symptom was evaluated by Swanson, Nolan, and Pelham Rating Scale, Version IV (SNAP-IV) and Yale Global Tic Severity Scale scales every 2 weeks. The primary outcome was tic disorders (TD) effective rate at week 8. RESULTS: One hundred and twenty-seven TS patients with comorbid ADHD in 2.0 mg/week (n=35), 1.5 mg/week (n=27), 1.0 mg/week (n=36) and placebo groups (n=29) were included in this subgroup analysis. The TD effective rate of the 2.0 mg, 1.5 mg, and 1.0 mg groups at week 8 were significantly better than that in placebo group (85.7%, 81.5%, and 86.1% vs. 20.7%, all p<0.0001). All groups demonstrated significant improvements in SNAP-IV total scale scores compared to baseline (p=0.0004), with treatment groups showing only a trend for better performance compared to placebo group at week 8, without statistical differences (22.1±15.41, 21.3±11.96, and 21.2±12.48 vs. 26.0±13.37, p=0.3385). A total of 9 adverse reactions occurred, all recovered spontaneously without additional medication. CONCLUSION: Clonidine adhesive patch could safely and effectively reduce the tic symptoms of TS patients with comorbid ADHD, and might be potentially helpful in the ADHD symptoms control.

3.
Nat Commun ; 15(1): 4058, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38744836

ABSTRACT

Research on the development of cognitive selectivity predominantly focuses on attentional selection. The present study explores another facet of cognitive selectivity-memory selection-by examining the ability to filter attended yet outdated information in young children and adults. Across five experiments involving 130 children and 130 adults, participants are instructed to use specific information to complete a task, and then unexpectedly asked to report this information in a surprise test. The results consistently demonstrate a developmental reversal-like phenomenon, with children outperforming adults in reporting this kind of attended yet outdated information. Furthermore, we provide evidence against the idea that the results are due to different processing strategies or attentional deployments between adults and children. These results suggest that the ability of memory selection is not fully developed in young children, resulting in their inefficient filtering of attended yet outdated information that is not required for memory retention.


Subject(s)
Attention , Memory , Humans , Female , Male , Adult , Attention/physiology , Child , Memory/physiology , Young Adult , Cognition/physiology , Child, Preschool
4.
Oncogene ; 2024 May 14.
Article in English | MEDLINE | ID: mdl-38744954

ABSTRACT

Lung adenocarcinoma (LUAD) is one of the most prevalent types of cancer. Ubiquitination is crucial in modulating cell proliferation and aerobic glycolysis in cancer. The frequency of TP53 mutations in LUAD is approximately 50%. Currently, therapeutic targets for wild-type (WT) p53-expressing LUAD are limited. In the present study, we systemically explored the expression of ubiquitin-specific protease genes using public datasets. Then, we focused on ubiquitin-specific protease 54 (USP54), and explored its prognostic significance in LUAD patients using public datasets, analyses, and an independent cohort from our center. We found that the expression of USP54 was lower in LUAD tissues compared with that in the paracancerous tissues. Low USP54 expression levels were linked to a malignant phenotype and worse survival in patients with LUAD. The results of functional experiments revealed that up-regulation of USP54 suppressed LUAD cell proliferation in vivo and in vitro. USP54 directly interacted with p53 protein and the levels of ubiquitinated p53 were inversely related to USP54 levels, consistent with a role of USP54 in deubiquitinating p53 in p53-WT LUAD cells. Moreover, up-regulation of the USP54 expression inhibited aerobic glycolysis in LUAD cells. Importantly, we confirmed that USP54 inhibited aerobic glycolysis and the growth of tumor cells by a p53-mediated decrease in glucose transporter 1 (GLUT1) expression in p53-WT LUAD cells. Altogether, we determined a novel mechanism of survival in the p53-WT LUAD cells to endure the malnourished tumor microenvironment and provided insights into the role of USP54 in the adaptation of p53-WT LUAD cells to metabolic stress.

5.
Nano Lett ; 24(19): 5847-5854, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38700109

ABSTRACT

We report a new design of polymer phenylacetylene (PA) ligands and the ligand exchange methodology for colloidal noble metal nanoparticles (NPs). PA-terminated poly(ethylene glycol) (PEG) can bind to metal NPs through acetylide (M-C≡C-R) that affords a high grafting density. The ligand-metal interaction can be switched between σ bonding and extended π backbonding by changing grafting conditions. The σ bonding of PEG-PA with NPs is strong and it can compete with other capping ligands including thiols, while the π backbonding is much weaker. The σ bonding is also demonstrated to improve the catalytic performance of Pd for ethanol oxidation and prevent surface absorption of the reaction intermediates. Those unique binding characteristics will enrich the toolbox in the control of colloidal surface chemistry and their applications using polymer ligands.

6.
Thorac Cancer ; 2024 May 08.
Article in English | MEDLINE | ID: mdl-38717936

ABSTRACT

BACKGROUND: Alterations in epigenetic factors are recognized as key contributors to the emergence of human cancer. The active and reversible alteration of N6-methyladenosine (m6A) RNA is crucial for controlling gene activity and determining cellular destiny. Even with these insights, the triggering of KIAA1429 (also called VIRMA) and its role in lung adenocarcinoma (LUAD) is mostly unclear. As a result, the objective of this study was to elucidate how KIAA1429 contributes to cancer development in LUAD. METHODS: This study utilized multiple methods for investigation, encompassing the in vitro functional examination of KIAA1429 in lung adenocarcinoma cells, transcriptome sequencing, methylation RNA immunoprecipitation sequencing (MeRIP-seq), as well as RNA stability tests to ascertain the half-life and stability of the target genes. RESULTS: The results indicated that modifying the expression of KIAA1429 regulated the proliferation and metastasis of LUAD. By employing transcriptome sequencing alongside MeRIP-seq analysis, the research pinpointed genes affected by m6A alterations triggered by KIAA1429. In a more detailed manner, it was discovered that KIAA1429 plays a regulatory role in the expression of ARHGAP30. Suppressing KIAA1429 results in reduced m6A levels in the mRNA of the target gene ARHGAP30, boosting its stability and expression, thus inhibiting tumor proliferation and metastasis. CONCLUSION: This study revealed the activation mechanism and pivotal function of KIAA1429 in LUAD tumor development, paving the way for molecular-based interventions for LUAD.

7.
Brain ; 2024 May 03.
Article in English | MEDLINE | ID: mdl-38701344

ABSTRACT

The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) in depression is a topic of debate, and the underlying mechanisms remain largely unclear. We now elucidate hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviors, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons by using behavioral analyses, microdialysis coupled with mass spectrum, and electrophysiological recording. Moreover, 5-HT2CR modulated neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction through influencing intracellular Ca2+ release, as determined by fiber photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON by specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP, abolished 5-HT2CR inhibition-induced depressive-like behaviors, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and a consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviors in the presence of 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviors and highlight the hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioral consequences of 5-HT2CR inhibition.

8.
Nat Metab ; 2024 May 03.
Article in English | MEDLINE | ID: mdl-38702440

ABSTRACT

Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.

9.
Cancer Rep (Hoboken) ; 7(5): e2003, 2024 May.
Article in English | MEDLINE | ID: mdl-38703000

ABSTRACT

BACKGROUND: Mid-rectal cancer treatment traditionally involves conventional laparoscopic-assisted resection (CLAR). This study aimed to assess the clinical and therapeutic advantages of Natural Orifice Specimen Extraction Surgery (NOSES) over CLAR. AIMS: To compare the clinical outcomes, intraoperative metrics, postoperative recovery, complications, and long-term prognosis between NOSES and CLAR groups. MATERIALS & METHODS: A total of 136 patients were analyzed, with 92 undergoing CLAR and 44 undergoing NOSES. Clinical outcomes were evaluated, and propensity score matching (PSM) was employed to control potential biases. RESULTS: The NOSES group exhibited significant improvements in postoperative recovery, including lower pain scores on days 1, 3, and 5 (p < .001), reduced need for additional analgesics (p = .02), shorter hospital stays (10.8 ± 2.3 vs. 14.2 ± 5.3 days; p < .001), and decreased intraoperative blood loss (48.1 ± 52.7 mL vs. 71.0 ± 55.0 mL; p = .03). Patients undergoing NOSES also reported enhanced satisfaction with postoperative abdominal appearance and better quality of life. Additionally, the NOSES approach resulted in fewer postoperative complications. CONCLUSION: While long-term outcomes (overall survival, disease-free survival, and local recurrence rates) were comparable between the two methods, NOSES demonstrated superior postoperative outcomes compared to CLAR in mid-rectal cancer treatment, while maintaining similar long-term oncological safety. These findings suggest that NOSES could serve as an effective alternative to CLAR without compromising long-term results.


Subject(s)
Laparoscopy , Natural Orifice Endoscopic Surgery , Rectal Neoplasms , Humans , Female , Laparoscopy/methods , Laparoscopy/adverse effects , Male , Rectal Neoplasms/surgery , Rectal Neoplasms/pathology , Rectal Neoplasms/mortality , Middle Aged , Aged , Natural Orifice Endoscopic Surgery/methods , Natural Orifice Endoscopic Surgery/adverse effects , Postoperative Complications/etiology , Postoperative Complications/epidemiology , Retrospective Studies , Length of Stay/statistics & numerical data , Treatment Outcome , Quality of Life , Propensity Score
10.
Infect Drug Resist ; 17: 1781-1790, 2024.
Article in English | MEDLINE | ID: mdl-38736433

ABSTRACT

Carbapenem-resistant Salmonella enterica (S. enterica) pose a significant threat to public health, causing gastroenteritis and invasive infections. We report the first emergence of a carbapenem-resistant S. enterica serovar London strain, A132, carrying the blaNDM-5 gene in China. Whole-genome sequencing and bioinformatics analysis assigned A132 to be ST155, a multidrug-resistant clone frequently reported in China. The strain A132 exhibited resistance to multiple antibiotics, with 20 acquired antibiotic resistance genes (ARGs) identified, predominantly located on the IncFIB plasmid (pA132-1-NDM). Notably, the blaNDM-5 gene was located within an IS26 flanked-class 1 integron-ISCR1 complex, comprising two genetic cassettes. One cassette is the class 1 integron, which may facilitate the transmission of the entire complex, while the other is the blaNDM-5-containing ISCR1-IS26-flanked cassette, carrying multiple other ARGs. Genbank database search based on the blaNDM-5-carrying cassette identified a similar genetic context found in transmissible IncFIA plasmids from Escherichia coli (p91) and Enterobacter hormaechei (p388) with a shared host range, suggesting the potential for cross-species transmission of blaNDM-5. To our knowledge, this is the first reported case of Salmonella serovar London ST155 harboring blaNDM-5 gene. Phylogenetic analysis indicated a close relationship between A132 and eight S. London ST155 strains isolated from the same province. However, A132 differed by carrying the blaNDM-5 gene and four unique ARGs. Given the high transmissibility of the F-type plasmid harboring blaNDM-5 and 18 other ARGs, it is imperative to implement vigilant surveillance and adopt appropriate infection control measures to mitigate the threat to public health.

11.
Transl Lung Cancer Res ; 13(4): 821-838, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38736484

ABSTRACT

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide, and lymph node dissection (LND) is a significant surgical procedure employed in its management. Although some studies suggest benefits of LND, the extent of its impact on survival, the optimal range of lymph nodes to be examined, and the specific patient groups that benefit most remain areas of active debate and investigation. Methods: A population-based analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed with NSCLC between 2004 and 2017, undergoing primary tumor resection, were included. Descriptive, univariate, and multivariate analyses assessed the effect of LND on survival, and a restricted cubic spline method determined the optimal range for lymph node examination. Results: This study of 37,323 NSCLC patients delved into the impact of LND on lung cancer-specific survival. Key findings revealed a median survival of 19.58 months, with 85% mortality. Baseline characteristics included a majority of White patients (81%), distant stage diagnoses (63%), and 64% with Grade IV tumors. LND emerged as a crucial predictor, influencing survival across age, gender, race, and tumor characteristics. Univariate analysis highlighted its significance, with higher T, N, and M categories, advanced stage, and poorer grade associating with elevated hazard ratios. Multivariate Cox proportional hazards (PH) analysis reinforced LND's impact, showcasing lower hazard ratios post-removal. Hazard ratios for biopsy/aspiration and removal of regional lymph nodes were 0.85 [95% confidence interval (CI): 0.81-0.89; P<0.001] and 0.43 (95% CI: 0.39-0.46; P<0.001), underscoring the protective effect. Visualizations and a U-shaped curve analysis identified an optimal range (24-32 nodes) for examination, emphasizing the nuanced benefits across NSCLC stages. Conclusions: The study findings suggest that LND plays a critical role in improving cancer-specific survival in NSCLC patients, particularly when tailored to the early stages of the disease. The optimal range of lymph nodes examined, between 24 and 32, offers crucial insights for personalized NSCLC treatment strategies and may enhance overall survival. These results underscore the need for refined surgical guidelines that incorporate the extent of LND, supporting the utility of a more personalized approach in NSCLC management.

12.
Aging (Albany NY) ; 16(8): 7022-7042, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38637125

ABSTRACT

BACKGROUND: There are often subtle early symptoms of colorectal cancer, a common malignancy of the intestinal tract. However, it is not yet clear how MYC and NCAPG2 are involved in colorectal cancer. METHOD: We obtained colorectal cancer datasets GSE32323 and GSE113513 from the Gene Expression Omnibus (GEO). After downloading, we identified differentially expressed genes (DEGs) and performed Weighted Gene Co-expression Network Analysis (WGCNA). We then undertook functional enrichment assay, gene set enrichment assay (GSEA) and immune infiltration assay. Protein-protein interaction (PPI) network construction and analysis were undertaken. Survival analysis and Comparative Toxicogenomics Database (CTD) analysis were conducted. A gene expression heat map was generated. We used TargetScan to identify miRNAs that are regulators of DEGs. RESULTS: 1117 DEGs were identified. Their predominant enrichment in activities like the cellular phase of the cell cycle, in cell proliferation, in nuclear and cytoplasmic localisation and in binding to protein-containing complexes was revealed by Gene Ontology (GO). When the enrichment data from GSE32323 and GSE113513 colon cancer datasets were merged, the primary enriched DEGs were linked to the cell cycle, protein complex, cell cycle control, calcium signalling and P53 signalling pathways. In particular, MYC, MAD2L1, CENPF, UBE2C, NUF2 and NCAPG2 were identified as highly expressed in colorectal cancer samples. Comparative Toxicogenomics Database (CTD) demonstrated that the core genes were implicated in the following processes: colorectal neoplasia, tumour cell transformation, inflammation and necrosis. CONCLUSIONS: High MYC and NCAPG2 expression has been observed in colorectal cancer, and increased MYC and NCAPG2 expression correlates with worse prognosis.


Subject(s)
Colorectal Neoplasms , Gene Expression Regulation, Neoplastic , Protein Interaction Maps , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Gene Regulatory Networks , Databases, Genetic , MicroRNAs/genetics , MicroRNAs/metabolism , Data Mining , Gene Expression Profiling , Proto-Oncogene Proteins c-myc/metabolism , Proto-Oncogene Proteins c-myc/genetics , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics
13.
Article in English | MEDLINE | ID: mdl-38628984

ABSTRACT

Purpose: This study aimed to explore the correlation of frailty status with disease characteristics and patient-reported outcomes (PROs) in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and determine the sensitivity and specificity of modified COPD PRO scale (mCOPD-PRO) for detecting frailty. Patients and Methods: This cross-sectional study surveyed 315 inpatients with AECOPD from a tertiary hospital in China from August 2022 to June 2023. Patient frailty and PROs were assessed using the validated FRAIL scale and mCOPD-PRO, respectively. Spearman's ρ was used to assess the relevance of lung disease indicators commonly used in clinical practice, and ordinal logistic regression analyses were used to identify the variables associated with frailty status. The validity of mCOPD-PRO in discriminating frail or non-frail individuals was determined using the receiver operating characteristic curve. Results: The participants (N=302, mean age 72.4±9.1 years) were predominantly males (73.2%). Among them, 43 (14.3%) patients were not frail, whereas 123 (40.7%) and 136 (45.0%) patients were pre-frail and frail, respectively. The FRAIL scale was moderately correlated with the mCOPD-PRO scores (Spearman's rank correlation coefficient [Rs]=0.52, P<0.01) for all dimensions (Rs=0.43-0.49, P<0.01). Patients residing in rural areas (odds ratio [OR], 1.67; 95% confidence interval [95% CI], 1.01-2.76) and with higher mCOPD-PRO scores (OR, 4.78; 95% CI, 2.75-8.32) were more likely to be frail. Physically active patients (OR, 0.42; 95% CI, 0.21-0.84) were less likely to be frail. In addition, mCOPD-PRO had good discriminate validity for detecting frailty (area under the curve=0.78), with a sensitivity and specificity of 84.6% and 60.8%, respectively. The optimal probability threshold for mCOPD-PRO was ≥1.52 points. Conclusion: In patients with AECOPD, frailty is closely related to PROs and disease characteristics. Additionally, the mCOPD-PRO score can distinguish well between frail and non-frail patients. Our findings provide support for interventions targeting frail populations with AECOPD.


Patients with chronic obstructive pulmonary disease often have concomitant frailty that may lead to disease deterioration such as acute exacerbations, hospital readmissions, disability, and premature death. Patient-reported outcomes are often used in clinical practice to measure patients' disease characteristics and overall status. Whether patients' frailty state is associated with patient-reported outcomes and if so, which factors are associated with frailty remain unclear. This study, conducted in China, examined their relationship as well as identified factors associated with frailty states. 302 hospitalized patients with acute exacerbations of chronic obstructive pulmonary disease completed a questionnaire answering questions about disease severity, frailty state, anxiety, and depression. The findings suggest that people who live in rural areas, self-reported more severe overall conditions, and are physically inactive are more likely to be frail. Patient-reported outcomes can distinguish between frail and non-frail patients. Therefore, patient-reported outcomes can be used to assess the extent of frailty; early screening of AECOPD combined frailty population and implementation of interventions can help mitigate the adverse effects of frailty.


Subject(s)
Frailty , Pulmonary Disease, Chronic Obstructive , Male , Humans , Middle Aged , Aged , Aged, 80 and over , Female , Pulmonary Disease, Chronic Obstructive/diagnosis , Frailty/diagnosis , Cross-Sectional Studies , Inpatients , China
14.
Alzheimers Dement ; 20(5): 3455-3471, 2024 May.
Article in English | MEDLINE | ID: mdl-38574388

ABSTRACT

INTRODUCTION: Fundamental questions remain about the key mechanisms that initiate Alzheimer's disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically engineered marmosets that carry knock-in (KI) point mutations in the presenilin 1 (PSEN1) gene that can be studied from birth throughout lifespan. METHODS: CRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non-invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures. RESULTS: Prior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non-carriers. Analysis of brain revealed alterations in several enzyme-substrate interactions within the gamma secretase complex prior to adulthood. DISCUSSION: Marmosets carrying KI point mutations in PSEN1 provide the opportunity to study the earliest primate-specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression. HIGHLIGHTS: We report the successful generation of genetically engineered marmosets harboring knock-in point mutations in the PSEN1 gene. PSEN1 marmosets and their germline offspring recapitulate the early emergence of AD-related biomarkers. Studies as early in life as possible in PSEN1 marmosets will enable the identification of primate-specific mechanisms that drive disease progression.


Subject(s)
Alzheimer Disease , Callithrix , Presenilin-1 , Animals , Presenilin-1/genetics , Alzheimer Disease/genetics , Male , Female , Brain/pathology , Brain/metabolism , Amyloid beta-Peptides/metabolism , Disease Models, Animal , Point Mutation/genetics , Animals, Genetically Modified , CRISPR-Cas Systems , Gene Knock-In Techniques , Mutation/genetics , Humans
15.
Nutr Hosp ; 2024 Apr 12.
Article in English | MEDLINE | ID: mdl-38666335

ABSTRACT

BACKGROUND AND AIMS: although sarcopenia is associated with several types of cancer, there is limited research regarding its effect on breast cancer. We aimed to explore the causality between sarcopenia-related traits and the incidence and prognosis of breast cancer. METHODS: two-sample bidirectional and multivariate Mendelian randomization (MR) analyses were utilized in this study. Genome-wide association studies were used to genetically identify sarcopenia-related traits, such as appendicular lean mass, grip strength of both hands, and walking pace. Data on the incidence and prognosis of breast cancer were collected from two extensive cohort studies. Multivariate MR analysis was used to adjust for body mass index, waist circumference, and whole-body fat mass. The primary method used for analysis was inverse-variance weighted analysis. RESULTS: a significant association was found between appendicular lean mass and ER- breast cancer (OR = 0.873, 95 % CI: 0.817-0.933, p = 6.570 × 10-5). Increased grip strength of the left hand was associated with a reduced risk of ER- breast cancer (OR = 0.744, 95 % CI: 0.579-0.958, p = 0.022). Stronger grip strength of the right hand was associated with prolonged survival time of ER+ breast cancer patients (OR = 0.463, 95 % CI: 0.242-0.882, p = 0.019). In the multivariable MR analysis, appendicular lean mass, grip strength of both hands, and walking pace were still genetically associated with the development of total breast cancer and ER-/+ breast cancer. CONCLUSIONS: several sarcopenia-related traits were genetically associated with the occurrence and prognosis of breast cancer. It is crucial for elderly women to increase their strength and muscle mass to help prevent breast cancer.

17.
J Cardiothorac Surg ; 19(1): 200, 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38600565

ABSTRACT

INTRODUCTION: The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. METHOD: We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. RESULTS: In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P < 0.05). Sex was an independent prognostic factor for sMPLC (5-year survival, female vs. male, 88.0% vs. 69.5%, P < 0.05), and in multiple tumors, the highest tumor stage was an independent prognostic factor for all categories of MPLC. CONCLUSIONS: The different disease patterns of MPLC have significantly different characteristics and prognoses. Clinicians should place treatment emphasis on the tumor with the highest stage as it is the main contributor to the prognosis of all categories of MPLC patients.


Subject(s)
Lung Neoplasms , Neoplasms, Multiple Primary , Neoplasms, Second Primary , Humans , Male , Female , Neoplasm Staging , Retrospective Studies , Prognosis , Neoplasms, Second Primary/pathology , Neoplasms, Multiple Primary/pathology , Lung/pathology
18.
Qual Life Res ; 2024 Apr 20.
Article in English | MEDLINE | ID: mdl-38642218

ABSTRACT

BACKGROUND: Because health resources are limited, health programs should be compared to allow the most efficient ones to emerge. To that aim, health utility instruments have been developed to allow the calculation of quality-adjusted life-year (QALY). However, generic instruments, which can be used by any individual regardless of their health profile, typically consider the preferences of the general population when developing their value set. Consequently, they are often criticized for lacking sensitivity in certain domains, such as cancer. In response, the latest version of the Short Form 6-Dimension (SF-6Dv2) has been adapted to suit the preferences of patients with breast or colorectal cancer in the Canadian province of Quebec. By extension, our study's aim was to determine cancer population norms of utility among patients with breast or colorectal cancer in Quebec using the SF-6Dv2. METHOD: To determine the cancer population norms, we exploited the data that were used in the development of a new value set for the SF-6Dv2. This value set was developed considering the preferences of patients with breast or colorectal cancer. Stratification by time of data collection (i.e., T1 and T2), sociodemographic variables (i.e., age, sex, body mass index, and self-reported health problems affecting quality of life), and clinical aspects (i.e., cancer site, histopathological classification, cancer stage at diagnosis, modality, and treatment characteristics) was performed. RESULTS: In 353 observations, patients were more likely to have negative utility scores at T1 than at T2. Males had higher mean utility scores than females considering type of cancer and comorbidities. Considering the SF-6Dv2's dimensions, more females than males reported having health issues, most which concerned physical functioning. Significant differences by sex surfaced for all dimensions except "Role Limitation" and "Mental health." Patients with multifocal cancer had the highest mean and median utility values in all cancer sites considered. CONCLUSION: Cancer population norms can serve as a baseline for interpreting the scores obtained by a given population in comparison to the situation of another group. In this way, our results can assist in comparing utility scores among cancer patients with different sociodemographic groups to other patients/populations groups. To our knowledge, our identified utility norms are the first for patients with breast or colorectal cancer from Quebec.

19.
Angew Chem Int Ed Engl ; : e202404515, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38637293

ABSTRACT

Reductive amination of carbonyl compounds and nitro compounds represents a straightforward way to attain imines or secondary amines, but it is difficult to control the product selectivity. Herein, we report the selective formation of C-N or C=N bond readily manipulated through a solvent-induced hydrogen bond bridge, facilitating the swift photocatalytic reductive coupling process. The reductive-coupling of nitro compounds with carbonyl compounds using formic acid and sodium formate as the hydrogen donors over CdS nanosheets selectively generates imines with C=N bonds in acetonitrile solvent; while taking methanol as solvent, the C=N bonds are readily hydrogenated to the C-N bonds via hydrogen-bonding activation. Experimental and theoretical study reveals that the building of the hydrogen-bond bridge between the hydroxyl groups in methanol and the N atoms of the C=N motifs in imines facilitates the transfer of hydrogen atoms from CdS surface to the N atoms in imines upon illumination, resulting in the rapid hydrogenation of the C=N bonds to give rise to the secondary amines with C-N bonds. Our method provides a simple way to control product selectivity by altering the solvents in photocatalytic organic transformations.

20.
IEEE Trans Med Imaging ; PP2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38557624

ABSTRACT

Magnetic particle imaging (MPI) uses nonlinear response signals to noninvasively detect magnetic nanoparticles in space, and its quantitative properties hold promise for future precise quantitative treatments. In reconstruction, the system matrix based method necessitates suitable regularization terms, such as Tikhonov or non-negative fused lasso (NFL) regularization, to stabilize the solution. While NFL regularization offers clearer edge information than Tikhonov regularization, it carries a biased estimate of the l1 penalty, leading to an underestimation of the reconstructed concentration and adversely affecting the quantitative properties. In this paper, a new nonconvex regularization method including min-max concave (MC) and total variation (TV) regularization is proposed. This method utilized MC penalty to provide nearly unbiased sparse constraints and adds the TV penalty to provide a uniform intensity distribution of images. By combining the alternating direction multiplication method (ADMM) and the two-step parameter selection method, a more accurate quantitative MPI reconstruction was realized. The performance of the proposed method was verified on the simulation data, the Open-MPI dataset, and measured data from a homemade MPI scanner. The results indicate that the proposed method achieves better image quality while maintaining the quantitative properties, thus overcoming the drawback of intensity underestimation by the NFL method while providing edge information. In particular, for the measured data, the proposed method reduced the relative error in the intensity of the reconstruction results from 28% to 8%.

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