Single-port transaxillary robotic submandibular gland excision: A case report.

Submandibular gland (SMG) excision via axillary is a brand new technique and we presented its own unique advantages compared with retroauricular and transoral approaches. The single-port (SP) robotic system offers improved visualization of the view and enhanced flexibility of instruments, ensuring optimal stability and dissection in this surgery. We reported the first case of transaxillary SMG excision using single-port robotic system made in China. A 26-year-old female patient presented with complaint of a painless mass in submandibular region. Ultrasound and computed tomography showed a lesion in submandibular gland. We performed single-port transaxillary robotic SMG excision without any complications. The present case suggests that SMG excision via transaxillary approach is technically feasible and safe with the SP robotic system; however, further exploration and research are needed.

Exploring epigenetic dynamics unveils a super-enhancer-mediated NDRG1-ß-catenin axis in modulating gemcitabine resistance in pancreatic cancer.

Chemoresistance remains a formidable challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, necessitating a comprehensive exploration of underlying molecular mechanisms. This work aims to investigate the dynamic epigenetic landscape during the development of gemcitabine resistance in PDAC, with a specific focus on super-enhancers and their regulatory effects. We employed well-established gemcitabine-resistant (Gem-R) PDAC cell lines to perform high-throughput analyses of the epigenome, enhancer connectome, and transcriptome. Our findings revealed notable alterations in the epigenetic landscape and genome architecture during the transition from gemcitabine-sensitive to -resistant PDAC cells. Remarkably, we observed substantial plasticity in the activation status of super-enhancers, with a considerable proportion of these cis-elements becoming deactivated in chemo-resistant cells. Furthermore, we pinpointed the NDRG1 super-enhancer (NDRG1-SE) as a crucial regulator in gemcitabine resistance among the loss-of-function super-enhancers. NDRG1-SE deactivation induced activation of WNT/ß-catenin signaling, thereby conferring gemcitabine resistance. This work underscores a NDRG1 super-enhancer deactivation-driven ß-catenin pathway activation as a crucial regulator in the acquisition of gemcitabine-resistance. These findings advance our understanding of PDAC biology and provide valuable insights for the development of effective therapeutic approaches against chemoresistance in this malignant disease.

Diagnostic value of rEBUS-TBLB combined distance measurement method based on ultrasound images in bronchoscopy for peripheral lung lesions.

Traditional imaging methods have limitations in the diagnosis of peripheral lung lesions. The aim of this study is to evaluate the diagnostic value of the distance measurement method based on ultrasound image-based inverted electrostrain (rEBUS) combined with thoracoscopic lung biopsy (TBLB) for peripheral lung lesions. A group of patients with peripheral lung lesions were recruited for the study, and rEBUS examination was performed simultaneously during TBLB. Using rEBUS ultrasound images combined with electrostrain information, evaluate the morphological characteristics of peripheral lung lesions and the elastic properties of internal tissues. By comparing with pathological examination results, both rEBUS-D-TBLB and rEBUS-GS-TBLB have a higher positive diagnostic rate for PPL under bronchoscopy. However, rEBUS-D-TBLB is more effective in diagnosing benign PPL with ≥ 3cm PPL than rEBUS-GS-TBLB. The rEBUS-TBLB combined ranging method has shown high accuracy and sensitivity in diagnosing peripheral lung lesions. Ultrasound images provide clear morphological features of the tumor, while the electrical strain information of rEBUS provides elastic information of the internal tissue of the tumor, further improving the accuracy of diagnosis.

ADAR1 Promotes Myogenic Proliferation and Differentiation of Goat Skeletal Muscle Satellite Cells.

As one of the most important economic traits for domestic animal husbandry, skeletal muscle is regulated by an intricate molecular network. Adenosine deaminase acting on RNA (ADAR1) involves various physiological processes and diseases, such as innate immunity and the development of lung adenocarcinoma, breast cancer, gastric cancer, etc. However, its role in skeletal muscle growth requires further clarification. Here, we explored the functions of ADAR1 in the myogenic process of goat skeletal muscle satellite cells (MuSCs). The ADAR1 transcripts were noticeably enriched in goat visceral tissues compared to skeletal muscle. Additionally, its levels in slow oxidative muscles like the psoas major and minor muscles were higher than in the fast oxidative glycolytic and fast glycolytic muscles. Among the two common isoforms from ADAR1, p110 is more abundant than p150. Moreover, overexpressing ADAR1 enhanced the proliferation and myogenic differentiation of MuSCs. The mRNA-seq performed on MuSCs' knockdown of ADAR1 obtained 146 differentially expressed genes (DEGs), 87 upregulated and 59 downregulated. These DEGs were concentrated in muscle development and process pathways, such as the MAPK and cAMP signaling pathways. Furthermore, many DEGs as the key nodes defined by protein-protein interaction networks (PPI), including STAT3, MYH3/8, TGFß2, and ACTN4, were closely related to the myogenic process. Finally, RNA immunoprecipitation combined with qPCR (RIP-qPCR) showed that ADAR1 binds to PAX7 and MyoD mRNA. This study indicates that ADAR1 promotes the myogenic development of goat MuSCs, which provides a useful scientific reference for further exploring the ADAR1-related regulatory networks underlying mammal skeletal muscle growth.

TRPS1, a sensitive marker for different histological and molecular types of breast cancer.

OBJECTIVES: We explored Trichorhinophalangeal syndrome type 1 (TRPS1) expression in special types of breast carcinoma, and analyzed the correlation between TRPS1 and androgen receptor (AR) expression in triple-negative breast cancer (TNBC). METHODS: TRPS1 expression was analyzed in 801 patients with special types of breast carcinoma. A total of 969 TNBC were used to analyze the correlation between the expression of TRPS1 and AR. TRPS1 expression was evaluated in 1975 cases of breast cancer with different molecular types. RESULTS: A total of 801 special types of breast cancers were stained with TRPS1.TRPS1 was positive in 100% (63/63) of mucinous carcinoma, 100% (7/7) adenoid cystic carcinomas (4 classic adenoid cystic carcinomas and 3 solid-basaloid adenoid cystic carcinomas), 100% (4/4) tubular carcinomas, 100% (2/2) secretory carcinomas, and 99.59% (243/244) invasive lobular carcinomas, 99.26% (267/269) invasive micropapillary carcinomas, 97.44% (38/39) ER-positive neuroendocrine tumors, 94.44% (34/36) metaplastic breast carcinomas (MBCs), 63.73% (65/102) apocrine carcinomas. TRPS1 was negative in all triple-negative neuroendocrine carcinomas (0/7).TRPS1 was positive in 92.86% (26/28) of metastatic special types of breast cancer. TRPS1 and AR expression were analyzed in 969 cases of TNBC. 90.40% were positive for TRPS1, and 42.41% were positive for AR. A significant inverse correlation between TRPS1 and AR expression was shown in TNBC (p < .001). TRPS1 showed a higher positive rate (93.13%) in TNBC compared to GATA binding protein 3 (GATA3), gross cystic disease fluid protein 15 (GCDFP-15) and forkhead box transcription Factor C 1 (FOXC1). CONCLUSIONS: In conclusion, our study demonstrated that TRPS1 is a highly sensitive marker for most special types of breast carcinoma. TRPS1 was positive in 63.73% of apocrine carcinomas. TRPS1 and AR expression was inversely correlated in TNBC.

Gender Disparities in the Association Between Educational Attainment and Cardiovascular-Kidney-Metabolic Syndrome: Cross-Sectional Study.

Background: Cardiovascular-kidney-metabolic (CKM) health is affected by social determinants of health, especially education. CKM syndrome has not been evaluated in Chinese population, and the association of education with CKM syndrome in different sexes and its intertwined relation with lifestyles have not been explored. Objective: We aimed to explore the association between educational attainment and the prevalence of CKM syndrome stages in middle-aged and older Chinese men and women as well as the potential role of health behavior based on Life's Essential 8 construct. Methods: This study used data from the nationwide, community-based REACTION (Risk Evaluation of Cancers in Chinese diabetic individuals: a longitudinal study). A total of 132,085 participants with complete information to determine CKM syndrome stage and education level were included. Educational attainment was assessed by the self-reported highest educational level achieved by the participants and recategorized as low (elementary school or no formal education) or high (middle school, high school, technical school/college, or above). CKM syndrome was ascertained and classified into 5 stages according to the American Heart Association presidential advisory released in 2023. Results: Among 132,085 participants (mean age 56.95, SD 9.19 years; n=86,675, 65.62% women) included, most had moderate-risk CKM syndrome (stages 1 and 2), and a lower proportion were at higher risk of CKM (stages 3 and 4). Along the CKM continuum, low education was associated with 34% increased odds of moderate-risk CKM syndrome for women (odds ratio 1.36, 95% CI 1.23-1.49) with a significant sex disparity, but was positively correlated with high-risk CKM for both sexes. The association between low education and high-risk CKM was more evident in women with poor health behavior but not in men, which was also interactive with and partly mediated by behavior. Conclusions: Low education was associated with adverse CKM health for both sexes but was especially detrimental to women. Such sex-specific educational disparity was closely correlated with health behavior but could not be completely attenuated by behavior modification. These findings highlight the disadvantage faced by women in CKM health ascribed to low education, underscoring the need for public health support to address this inequality.

Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma.

Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.

Association between dietary niacin intake and lung function among American adults: A cross-sectional analysis from national health and nutrition examination survey, 2007-2012.

Background: The pathogenesis of pulmonary senescence involves immune system dysregulation, oxidative stress, and mitochondrial dysfunction. The effects on lung function of niacin, an essential coenzyme involved in mitochondrial energy metabolism with known antioxidant properties, are poorly understood. Methods: This cross-sectional study used data from the 2007-2012 National Health and Nutrition Examination Survey, including spirometry data and niacin intake information of 9706 adults. This study investigated various spirometry measures, such as forced expiratory volume in 1 s, forced vital capacity, pulse expiratory flow, (forced expiratory volume in 1 s)/(forced vital capacity)ratio, and predicted forced expiratory volume in 1 s and forced vital capacity percentages. Additionally, a secondary analysis was conducted using Global Initiative for Chronic Obstructive Lung Disease and chronic obstructive pulmonary disease. Foundation Spirometry Grade criteria to assess the relationship between niacin intake, airflow limitation, and obstruction. Multivariate regression models were used to adjust for relevant covariates. Results: The study included 9706 U S. adults (4788 men and 4918 women) with a median age of 46.2 years. After adjusting for relevant factors, a positive correlation was observed between niacin intake and lung function. Compared to the lowest quintile of niacin intake (Q1, ≤14.5 mg/day), individuals in the highest quintile (Q5, >34.5 mg/day) exhibited significant increases in lung function parameters, including forced expiratory volume in 1s (69.84 mL, p = 0.003), pulse expiratory flow (254.48 mL, p < 0.001), (forced expiratory volume in 1 s)/(forced vital capacity)(0.01, p = 0.041), percent predicted forced expiratory volume in 1 s(2.05, p = 0.002), and percent predicted forced vital capacity(1.29, p = 0.042).Subset analyses of individuals with spirometry-defined airflow obstruction showed associations of high niacin intake with significantly improved forced expiratory volume, pulse expiratory flow, and percent predicted pulse expiratory flow and an interaction among race, education, and smoking status with respect to the relationship between niacin intake and lung function parameters. Conclusions: Higher niacin intake was associated with increased measures of lung function. A diet rich in niacin-containing foods may play a role in improving lung health.

An updated patent review of stimulator of interferon genes agonists (2021 - present).

INTRODUCTION: Stimulator of Interferon Genes (STING) is an innate immune sensor. Activation of STING triggers a downstream response that results in the expression of proinflammatory cytokines (TNF-α, IL-1ß) via nuclear factor kappa-B (NF-κB) or the expression of type I interferons (IFNs) via an interferon regulatory factor 3 (IRF3). IFNs can eventually result in promotion of the adaptive immune response including activation of tumor-specific CD8+ T cells to abolish the tumor. Consequently, activation of STING has been considered as a potential strategy for cancer treatment. AREAS COVERED: This article provides an overview on structures and pharmacological data of CDN-like and non-nucleotide STING agonists acting as anticancer agents (January 2021 to October 2023) from a medicinal chemistry perspective. The data in this review come from EPO, WIPO, RCSB PDB, CDDI. EXPERT OPINION: In recent years, several structurally diverse STING agonists have been identified. As an immune enhancer, they are used in the treatment of tumors, which has received extensive attention from scientific community and pharmaceutical companies. Despite the multiple challenges that have appeared, STING agonists may offer opportunities for immunotherapy.

Development and validation of a nomogram for predicting poor operative visibility during FESS in Chinese adult patients with CRS.

Objective: The purpose of this study is to develop and evaluate a nomogram that is capable of predicting poor operative visibility during functional endoscopic sinus surgery. Method: To identify potential risk factors, patients with chronic rhinosinusitis who underwent functional endoscopic sinus surgery (FESS) between January 2019 and December 2022 were selected from our hospital's electronic medical record system. Data on general patient information, clinical manifestations, clotting-related test indices, Lund-Machay score of sinuses CT scanning, Lund-kennedy score of nasal endoscopies, anesthesia methods, intraoperative blood pressure and heart rate, and Boezaart bleeding score were collected. Minimum absolute convergence and selection operator (LASSO) regression, as well as multivariate logistic regression, were used to determine the risk factors. A nomogram was developed in order to predict poor operating visibility during FESS, and its performance was evaluated utilizing both the training and verification datasets via various measures including receiver operating characteristic (ROC) curve analysis, area under the curve (AUC), Hosmer-Lemeshow goodness-of-fit test, calibration curve, and decision curve analysis. Results: Of the 369 patients who met the inclusion criteria, 88 of them exhibited POV during FESS. By deploying LASSO and multivariate logistic regression analyses, six risk factors were identified and used to construct a nomogram for predicting POV during FESS. These factors include prothrombin time (PT), prothrombin activity (PTA), Lund-Mackay score (LMS), Lund-Kennedy score (LKS), anesthetic method, and intraoperative hypertension. The AUC of the training set was found to be 0.820 while that of the verification set was 0.852. The Hosmer-Lemeshow goodness-of-fit test and calibration curve analysis revealed good consistency between predicted and actual probabilities. Also, the decision curve demonstrated that the nomogram had a high degree of clinical usefulness and net benefit. Conclusion: The constructed nomogram has a strong ability to predict the poor intraoperative field in patients with chronic rhinosinusitis, which can help preoperative judgment of high-risk patients and provide evidence for perioperative management and preoperative plan formulation.

Prognostic and predictive value of interstitial lung abnormalities and EGFR mutation status in patients with non-small cell lung cancer.

BACKGROUND: To determine the predictive value of interstitial lung abnormalities (ILA) for epidermal growth factor receptor (EGFR) mutation status and assess the prognostic significance of EGFR and ILA in patients with non-small cell lung cancer (NSCLC). METHODS: We reviewed 797 consecutive patients with a histologically proven diagnosis of primary NSCLC from January 2013 to October 2018. Of these, 109 patients with NSCLC were found to have concomitant ILA. Multivariate logistic regression analysis was used to identify the significant clinical and computed tomography (CT) findings in predicting EGFR mutations. Cox proportional hazard models were used to identify significant prognostic factors. RESULTS: EGFR mutations were identified in 22 of 109 tumors (20.2%). Multivariate analysis showed that the models incorporating clinical, tumor CT and ILA CT features yielded areas under the receiver operating characteristic curve (AUC) values of 0.749, 0.838, and 0.849, respectively. When combining the three models, the independent predictive factors for EGFR mutations were non-fibrotic ILA, female sex, and small tumor size, with an AUC value of 0.920 (95% confidence interval[CI]: 0.861-0.978, p < 0.001). In the multivariate Cox model, EGFR mutations (hazard ratio = 0.169, 95% CI = 0.042-0.675, p = 0.012; 692 days vs. 301 days) were independently associated with extended overall survival compared to the wild-type. CONCLUSION: Non-fibrotic ILA independently predicts the presence of EGFR mutations, and the presence of EGFR mutations rather than non-fibrotic ILA serves as an independent good prognostic factor for patients with NSCLC.

The updated surgical steps of gasless transaxillary endoscopic thyroidectomy with neck level and region orientation for thyroid cancer.

Introduction: We previously made a detailed expansion to the gasless transaxillary endoscopic thyroidectomy(GTET) procedure described in the previous literatures. In this study, we optimized the procedure focused on the limitation of the approach in terms of trauma and lymph node dissection and made a comparison with the early procedure. Materials and methods: This paper gave a detailed description of the updated procedure and prospectively collected data about patients with papillary thyroid carcinoma(PTC) performed by the two procedures from December 2020 to April 2023. The differences in surgical outcome, surgical trauma and parathyroid gland(PG) function protection were analyzed. Results: Of the 302 patients, 184 underwent with early procedure(EP), and 118 underwent with updated procedure(UP). The surgical outcomes of operative time, time of thyroidectomy and central neck dissection, blood loss, drainage and postoperative hospital stay were shorter in UP than that of the EP. The mean number of lymph nodes retrieved and weight of dissection lymphatic tissue in the UP were significantly more than that in EP without increasing the mean number of metastatic lymph nodes. Postoperative complications did not differ between the two procedures. The UP had more advantages in the identification and preservation of the superior parathyroid gland, however, it did not improve the preservation in situ of the inferior parathyroid gland. The visual analog scale score for pain and the changes among inflammation factors was lower in the UP. Conclusion: The UP of GTET could perform safely and efficiently while reducing surgical trauma in selected patients.

Venetoclax plus a hypomethylating agent versus cytarabine, aclarubicin, and granulocyte colony-stimulating factor chemotherapy as a first-line therapy for newly diagnosed acute myeloid leukemia: A propensity score-matched analysis.

BACKGROUND: Both venetoclax plus a hypomethylating agent (VEN/HMA) and cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG) are low-intensity regimens for older patients with acute myeloid leukemia (AML) that show good efficacy and safety. It is unknown how VEN/HMA compares with the CAG regimen for the treatment of newly diagnosed AML. METHODS: The outcomes of patients with newly diagnosed AML treated with VEN/HMA were compared with those of patients treated with a CAG-based regimen. Propensity score matching between these two cohorts at a 1:1 ratio was performed according to age at diagnosis, sex, Eastern Cooperative Oncology Group performance status, state of fitness, and European LeukemiaNet (ELN) 2022 risk stratification to minimize bias. RESULTS: A total of 84 of 96 patients in the VEN/HMA cohort were matched with 84 of 147 patients in the CAG cohort. VEN/HMA resulted in a better response than the CAG-based regimens, as indicated by a higher composite complete remission (CRc) rate (82.1% vs. 60.7%; p = .002) and minimal residual disease negativity rate (88.2% vs. 68.2%; p = .009). In patients with an ELN adverse risk, VEN/HMA was associated with a higher CRc rate compared to CAG (80.5% vs. 58.3%; p = .006). VEN/HMA was associated with longer event-free survival (EFS) (median EFS, not reached vs. 4.5 months; p = .0004), whereas overall survival (OS) was comparable between the two cohorts (median OS, not reached vs. 18 months; p = .078). CONCLUSIONS: The VEN/HMA regimen may result in a better response than CAG-based treatment in older patients with newly diagnosed AML.

Response to anti-HER2 neoadjuvant chemotherapy in HER2-positive invasive breast cancers with different HER2 FISH patterns.

AIMS: Human epidermal growth factor receptor 2 (HER2)-positive patients with breast cancer may have different HER2/CEP17 ratios and HER2 copy numbers, with inconsistent responses to anti-HER2 neoadjuvant chemotherapy (NACT). Our study aimed to explore the relationship between different HER2 fluorescence in situ hybridisation (FISH) patterns in HER2-positive patients with breast cancer and responses to anti-HER2 NACT. METHODS: 527 patients with HER2-positive invasive breast cancer who received anti-HER2 NACT from 2015 to 2022 were included and divided into three groups by FISH results, namely group A: HER2/CEP17<2.0 and HER2 copy numbers ≥6.0, HER2 immunohistochemistry 2/3+; group B: HER2/CEP17≥2.0 and HER2 copy numbers ≥4.0 and <6.0; group C: HER2/CEP17≥2.0 and HER2 copy numbers ≥6.0. We compared clinicopathological characteristics and pathological complete response (pCR) rates of different groups. RESULTS: According to HER2 FISH results, 12 patients (2.3%, 12/527) were in group A, 40 (7.6%, 40/527) were in group B and 475 (90.1%, 475/527) were in group C. The pCR rate was the lowest in group B (5.0%), while the pCR rates in group A and group C were 33.3% and 44.4%, respectively (p (group A vs. B) =0.021, p (group C vs. B) < 0.001). Both univariate and multivariate analyses revealed that HER2 FISH pattern was correlated with pCR rate (p (group C vs. B) < 0.001, p (group C vs. B) = 0.025). CONCLUSIONS: Patients with HER2/CEP17≥2.0 and HER2 copy numbers ≥4.0 and <6.0 do not benefit to the same extent from current anti-HER2 therapies as FISH-positive patients with other patterns.

Genome-wide profiling of piggyBac transposon insertion mutants reveals loss of the F1F0 ATPase complex causes fluconazole resistance in Candida glabrata.

Invasive candidiasis caused by non-albicans species has been on the rise, with Candida glabrata emerging as the second most common etiological agent. Candida glabrata possesses an intrinsically lower susceptibility to azoles and an alarming propensity to rapidly develop high-level azole resistance during treatment. In this study, we have developed an efficient piggyBac (PB) transposon-mediated mutagenesis system in C. glabrata to conduct genome-wide genetic screens and applied it to profile genes that contribute to azole resistance. When challenged with the antifungal drug fluconazole, PB insertion into 270 genes led to significant resistance. A large subset of these genes has a role in the mitochondria, including almost all genes encoding the subunits of the F1F0 ATPase complex. We show that deleting ATP3 or ATP22 results in increased azole resistance but does not affect susceptibility to polyenes and echinocandins. The increased azole resistance is due to increased expression of PDR1 that encodes a transcription factor known to promote drug efflux pump expression. Deleting PDR1 in the atp3Δ or atp22Δ mutant resulted in hypersensitivity to fluconazole. Our results shed light on the mechanisms contributing to azole resistance in C. glabrata. This PB transposon-mediated mutagenesis system can significantly facilitate future genome-wide genetic screens.

Associations of sleeping patterns and isotemporal substitution of other behavior with the prevalence of CKD in Chinese adults.

Studies have found a U-shaped relationship between sleep duration and chronic kidney disease (CKD) risk, but limited research evaluated the association of reallocating excessive sleep to other behavior with CKD. We included 104 538 participants from the nationwide cohort of the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study, with self-reported time of daily-life behavior. Using isotemporal substitution models, we found that substituting 1 h of sleeping with sitting, walking, or moderate-to-vigorous physical activity was associated with a lower CKD prevalence. Leisure-time physical activity displacement was associated with a greater prevalence reduction than occupational physical activity in working population. In stratified analysis, a lower CKD prevalence related to substitution toward physical activity was found in long sleepers. More pronounced correlations were observed in long sleepers with diabetes than in those with prediabetes, and they benefited from other behavior substitutions toward a more active way. The U-shaped association between sleep duration and CKD prevalence implied the potential effects of insufficient and excessive sleep on the kidneys, in which the pernicious link with oversleep could be reversed by time reallocation to physical activity. The divergence in the predicted effect on CKD following time reallocation to behavior of different domains and intensities and in subpopulations with diverse metabolic statuses underlined the importance of optimizing sleeping patterns and adjusting integral behavioral composition.

Cytochrome c regulates hyphal morphogenesis by interfering with cAMP-PKA signaling in Candida albicans.

In the human fungal pathogen Candida albicans, invasive hyphal growth is a well-recognized virulence trait. We employed transposon-mediated genome-wide mutagenesis, revealing that inactivating CTM1 blocks hyphal growth. CTM1 encodes a lysine (K) methyltransferase, which trimethylates cytochrome c (Cyc1) at K79. Mutants lacking CTM1 or expressing cyc1K79A grow as yeast under hyphae-inducing conditions, indicating that unmethylated Cyc1 suppresses hyphal growth. Transcriptomic analyses detected increased levels of the hyphal repressor NRG1 and decreased levels of hyphae-specific genes in ctm1Δ/Δ and cyc1K79A mutants, suggesting cyclic AMP (cAMP)-protein kinase A (PKA) signaling suppression. Co-immunoprecipitation and in vitro kinase assays demonstrated that unmethylated Cyc1 inhibits PKA kinase activity. Surprisingly, hyphae-defective ctm1Δ/Δ and cyc1K79A mutants remain virulent in mice due to accelerated proliferation. Our results unveil a critical role for cytochrome c in maintaining the virulence of C. albicans by orchestrating proliferation, growth mode, and metabolism. Importantly, this study identifies a biological function for lysine methylation on cytochrome c.

POH1 facilitates pancreatic carcinogenesis through MYC-driven acinar-to-ductal metaplasia and is a potential therapeutic target.

Pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), a necessary process for pancreatic ductal adenocarcinoma (PDAC) initiation. However, the regulatory role of POH1, a deubiquitinase linked to several types of cancer, in ADM and PDAC is unclear. In this study, we investigated the role of POH1 in ADM and PDAC using murine models. Our findings suggest that pancreatic-specific deletion of Poh1 alleles attenuates ADM and impairs pancreatic carcinogenesis, improving murine survival. Mechanistically, POH1 deubiquitinates and stabilizes the MYC protein, which potentiates ADM and PDAC. Furthermore, POH1 is highly expressed in PDAC samples, and clinical evidence establishes a positive correlation between aberrantly expressed POH1 and poor prognosis in PDAC patients. Targeting POH1 with a specific small-molecule inhibitor significantly reduces pancreatic tumor formation, highlighting POH1 as a promising therapeutic target for PDAC treatment. Overall, POH1-mediated MYC deubiquitination is crucial for ADM and PDAC onset, and targeting POH1 could be an effective strategy for PDAC treatment, offering new avenues for PDAC targeted therapy.

Analysis of single-cell sequencing results of an elderly patient with myeloid leukemia reveals high expression of multiple oncogenes in monocytes and hematopoietic stem cells.

OBJECTIVE: Older patients with acute myeloid leukemia (AML) face a higher risk of death. This study analyzed the gene sequencing results of an elderly AML patient to provide new ideas for treatment. METHODS: This study performed single-cell RNA sequencing (scRNA-seq) bioinformatics analysis of blood cells in the peripheral blood and bone marrow of a 64-year-old AML-M5 patient before chemotherapy. The differentially expressed genes (DEGs) were identified, and functional enrichment analyses were performed. RESULTS: A total of 7990 and 123 DEGs were identified in monocytes and hematopoietic stem cells (HSCs), respectively. Among the top 40 DEGs analyzed, MYB showed high expression in peripheral blood monocytes, while 13 other tumor-related genes exhibited high expression in monocytes in the bone marrow. Peripheral blood and bone marrow HSCs had 6 and 12 highly expressed tumor-related genes respectively, including MCL1, JUN, and JUNB. These genes may form a interconnected network contributing to the progression and heterogeneity of AML, which can have an impact on patient treatment and prognosis. CONCLUSIONS: In conclusion, when treating elderly AML patients, it is important to consider their individual characteristics in order to optimize treatment strategies.