Causal relationship between inflammatory factors and cerebral small vessel disease: Univariate, multivariate, and summary-data-based mendelian randomization analysis.

OBJECTIVE: To explore the impact of inflammatory factors on the incidence of cerebral small vessel disease (CSVD), we performed a mendelian randomization (MR) study to analyze the causal relationship between multiple inflammatory factors and CSVD imaging markers and utilized summary-data-based mendelian randomization (SMR) analysis to infer whether the impact of instrumental variables (IVs) on disease is mediated by gene expression or DNA methylation. METHODS: Using public databases such as UKB and IEU, and original genome-wide association studies, we obtained IVs related to exposure (inflammatory factors) and outcome (CSVD imaging markers). We performed the inverse variance weighted, weighted median, and MR-Egger methods to assess causal effects between exposure and outcome in univariate MR analysis. To evaluate their heterogeneity, a series of sensitivity analyses were conducted, including the Cochrane Q test, MR-Egger intercept test, MR-Presso, and leave-one-out analysis. We also applied mediation and multivariate MR analysis to explore the interactions between positive exposures on the same outcome. Additionally, we conducted the SMR, which utilizes instruments within or near relevant genes in blood or brain tissues, to elucidate the causal associations with CSVD markers. RESULTS: ABO Univariate MR of multiple cohorts revealed that the risk of small vessel stroke (SVS) increases with elevated levels of TNF-related apoptosis-inducing ligand (TRAIL, OR, 1.23, 95% CI, 1.08-1.39) and interleukin-1 receptor-like 2, (IL-1RL2, OR, 1.29, 95% CI, 1.04-1.61). IL-18 was a potential risk factor for extensive basal ganglia perivascular space burden (BGPVS, OR, 1.02, 95% CI, 1.00-1.05). Moreover, the risk of extensive white matter perivascular space burden (WMPVS) decreased with rising levels of E-selectin (OR, .98, 95% CI, .97-1.00), IL-1RL2 (OR, .97, 95% CI, .95-1.00), IL-3 receptor subunit alpha (IL-3Ra, OR, .98, 95% CI, .97-1.00), and IL-5 receptor subunit alpha (IL-5Ra, OR, .98, 95% CI, .97-1.00). Mediation and multivariate MR analysis indicated that E-selectin and IL-3Ra might interact during the pathogenesis of WMPVS. SMR estimates showed that TRAIL-related IVs rs5030044 and rs2304456 increased the risk of SVS by increasing the expression of gene Kininogen-1 (KNG1) in the cerebral cortex, particularly in the frontal cortex (ßsmr = .10, Psmr = .003, FDR = .04). Instruments (rs507666 and rs2519093) related to E-selectin and IL-3Ra could increase the risk of WMPVS by enhancing DNA methylation of the gene ABO in blood tissue (ßsmr = .01-.02, Psmr = .001, FDR = .01-.03). CONCLUSION: According to MR and SMR analysis, higher levels of TRAIL increased the risk of SVS by upregulating gene expression of KNG1 in brain cortex tissues. In addition, protective effects of E-selectin and IL-3a levels on WMPVS were regulated by increased DNA methylation of gene ABO in blood tissue.

Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.

Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood-brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.

Three-dimensional visualization and evaluation of hilar cholangiocarcinoma resectability and proposal of a new classification.

BACKGROUND: As digital medicine has exerted profound influences upon diagnosis and treatment of hepatobiliary diseases, our study aims to investigate the accuracy of three-dimensional visualization and evaluation (3DVE) system in assessing the resectability of hilar cholangiocarcinoma (hCCA), and explores its potential clinical value. MATERIALS AND METHODS: The discovery cohort, containing 111 patients from April 2013 to December 2019, was retrospectively included to determine resectability according to revised criteria for unresectability of hCCA. 3D visualization models were reconstructed to evaluate resectability parameters including biliary infiltration, vascular involvement, hepatic atrophy and metastasis. Evaluation accuracy were compared between contrast-enhanced CT and 3DVE. Logistic analysis was performed to identify independent risk factors of R0 resection. A new comprehensive 3DVE classification of hCCA based on factors influencing resectability was proposed to investigate its role in predicting R0 resection and prognosis. The main outcomes were also analyzed in cohort validation, including 34 patients from January 2020 to August 2022. RESULTS: 3DVE showed an accuracy rate of 91% (95%CI 83.6-95.4%) in preoperatively evaluating hCCA resectability, significantly higher than 81% (95%CI 72.8-87.7%) of that of CT (p = 0.03). By multivariable analysis, hepatic artery involvement in 3DVE was identified an independent risk factor for R1 or R2 resection (OR = 3.5, 95%CI 1.4,8.8, P < 0.01). New 3DVE hCCA classification was valuable in predicting patients' R0 resection rate (p < 0.001) and prognosis (p < 0.0001). The main outcomes were internally validated. CONCLUSIONS: 3DVE exhibited a better efficacy in evaluating hCCA resectability, compared with contrast-enhanced CT. Preoperative 3DVE demonstrated hepatic artery involvement was an independent risk factor for the absence of R0 margin. 3DVE classification of hCCA was valuable in clinical practice.

Acquired perforating dermatosis: A clinicopathologic study, and the features of dermoscopy and reflective confocal microscopy of 37 cases.

BACKGROUND: Acquired perforating dermatosis (APD) is a rare skin condition characterized by degenerated materials eliminated from the dermis. Several retrospective studies on APD have been reported; however, few data are available on Chinese APD and their features on dermoscopy and reflective confocal microscope (RCM) assays. OBJECTIVE: The aim of this study was to retrospectively evaluate the clinical and histopathologic data of 37 acquired perforating dermatosis cases, and assess their features on dermoscopy and RCM. METHODS: Thirty-seven APD patients were retrospectively enrolled in our study. We characterized the clinical histopathological features, concomitant diseases, treatment responses, and the dermoscopy and RCM findings. RESULTS: Pruritus was the most common symptom, with the lower extremities as the most predilection sites (86.5%, n = 32; 91.9%, n = 34, respectively). Concomitant diseases were found in 34 patients (92.6%), among which diabetes mellitus was the most common, followed by thyroid nodules, allergic dermatosis, and chronic renal insufficiency. Dermoscopy and RCM assays were performed in 11 patients. The typical RCM images were hyperreflective cord-like structures from the epidermis to dermis. Dermoscopy features of fully developed lesions showed central ulceration with peripheral hairpin-like or loop-like capillaries with characteristic garland arrangements. CONCLUSION: APD is an uncommon skin disorder associated with various systemic conditions in Chinese individuals. Thyroid disorders are an overlooked complication and may play an important role in the development of APD. The results of this study indicate that noninvasive dermoscopy and RCM examination are helpful in the rapid diagnosis and early intervention of APD.

Uncovering the Secrets of Prostate Cancer's Radiotherapy Resistance: Advances in Mechanism Research.

Prostate cancer (PCa) is a critical global public health issue with its incidence on the rise. Radiation therapy holds a primary role in PCa treatment; however, radiation resistance has become increasingly challenging as we uncover more about PCa's pathogenesis. Our review aims to investigate the multifaceted mechanisms underlying radiation therapy resistance in PCa. Specifically, we will examine how various factors, such as cell cycle regulation, DNA damage repair, hypoxic conditions, oxidative stress, testosterone levels, epithelial-mesenchymal transition, and tumor stem cells, contribute to radiation therapy resistance. By exploring these mechanisms, we hope to offer new insights and directions towards overcoming the challenges of radiation therapy resistance in PCa. This can also provide a theoretical basis for the clinical application of novel ultra-high-dose-rate (FLASH) radiotherapy in the era of PCa.

A radiomics nomogram prediction for survival of patients with "driver gene-negative" lung adenocarcinomas (LUAD).

BACKGROUND: To study the role of computed tomography (CT)-derived radiomics features and clinical characteristics on the prognosis of "driver gene-negative" lung adenocarcinoma (LUAD) and to explore the potential molecular biological which may be helpful for patients' individual postoperative care. METHODS: A total of 180 patients with stage I-III "driver gene-negative" LUAD in the First Affiliated Hospital of Sun Yat-Sen University from September 2003 to June 2015 were retrospectively collected. The Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model was used to screen radiomics features and calculated the Rad-score. The prediction performance of the nomogram model based on radiomics features and clinical characteristics was validated and then assessed with respect to calibration. Gene set enrichment analysis (GSEA) was used to explore the relevant biological pathways. RESULTS: The radiomics and the clinicopathological characteristics were combined to construct a nomogram resulted in better performance for the estimation of OS (C-index: 0.815; 95% confidence interval [CI]: 0.756-0.874) than the clinicopathological nomogram (C-index: 0.765; 95% CI: 0.692-0.837). Decision curve analysis demonstrated that in terms of clinical usefulness, the radiomics nomogram outperformed the traditional staging system and the clinicopathological nomogram. The clinical prognostic risk score of each patient was calculated based on the radiomics nomogram and divided by X-tile into high-risk (> 65.28) and low-risk (≤ 65.28) groups. GSEA results showed that the low-risk score group was directly related to amino acid metabolism, and the high-risk score group was related to immune and metabolism pathways. CONCLUSIONS: The radiomics nomogram was promising to predict the prognosis of patients with "driver gene-negative" LUAD. The metabolism and immune-related pathways may provide new treatment orientation for this genetically unique subset of patients, which may serve as a potential tool to guide individual postoperative care for those patients.

Methylation of N6 adenosine-related long noncoding RNA: effects on prognosis and treatment in 'driver-gene-negative' lung adenocarcinoma.

The improvement of treatment for patients with 'driver-gene-negative' lung adenocarcinoma (LUAD) remains a critical problem to be solved. We aimed to explore the role of methylation of N6 adenosine (m6A)-related long noncoding RNA (lncRNA) in stratifying 'driver-gene-negative' LUAD risk. Patients negative for mutations in EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as 'driver-gene-negative' cases. RNA sequencing was performed in 46 paired tumors and adjacent normal tissues from patients with 'driver-gene-negative' LUAD. Twenty-three m6A regulators and relevant lncRNAs were identified using Pearson's correlation analysis. K-means cluster analysis was used to stratify patients, and a prognostic nomogram was developed. The CIBERSORT and pRRophetic algorithms were employed to quantify the immune microenvironment and chemosensitivity. We identified two clusters highly consistent with the prognosis based on their unique expression profiles for 46 m6AlncRNAs. A risk model constructed from nine m6A lncRNAs could stratify patients into high- and low-risk groups with promising predictive power (C-index = 0.824), and the risk score was an independent prognostic factor. The clusters and risk models were closely related to immune characteristics and chemosensitivity. Additional pan-cancer analysis using the nine m6AlncRNAs showed that the expression of DIO3 opposite strand upstream RNA (DIO3OS) is closely related to the immune/stromal score and tumor stemness in a variety of cancers. Our results show that m6AlncRNAs are a reliable prognostic tool and can aid treatment decision-making in 'driver-gene-negative' LUAD. DIO3OS is associated with the development of various cancers and has potential clinical applications.

Construction of novel magnetic nanoparticles for enrichment of benzo(α)pyrene from edible oils followed by HPLC determination.

A novel method for benzo(α)pyrene (Bαp) enrichment from an oil matrix was developed by using magnetic nanoparticles (Fe3O4@dopamine/graphene oxide, Fe3O4@DA/GO) as extraction absorbents, and the chemical properties of the synthesized nanoparticles were characterized. Various parameters were investigated to optimize the extraction of Bαp from oils. Under optimal conditions (pH, 4; extraction time, 0.5 min; elution solvent, 1 mL; absorbent weight, 20 mg; elution time, 0.5 min), these nanoparticles showed excellent abilities to enrich Bαp from the saponified oil solution and were easily separated by a magnet. High-performance liquid chromatography plus fluorescence detection (HPLC-FLD) was then applied to determine the Bαp content with excellent linearity (R2 = 0.999). The detection limit was 0.13 µg/kg, while the limit of quantification was 0.42 µg/kg. The spiked recoveries of Bαp in oils ranged from 73.5% to 121%. Compared with previous reports, the proposed method displayed many advantages, including a high efficiency of oil matrix removal, short extraction time, and convenient extraction procedure.

A novel signature based on immune-related gene pairs and clinical features to predict prognosis and treatment effect in "driver gene negative" lung adenocarcinoma.

OBJECTIVE: Examining the role of immune-related genes (IRGs) in "driver gene negative" lung adenocarcinoma (LUAD) may provide new ideas for the treatment and study for this LUAD subgroup. We aimed to find the hub immune-related gene pairs can stratify the risk of "driver-gene-negative" LUAD. MATERIALS AND METHODS: IRGs were identified according to ImmPort database based on RNA sequencing results of tumors and normal tissues from 46 patients with "driver gene negative" LUAD at The First Affiliated Hospital of Sun Yat-sen University and cyclically singly paired as immune-related gene pairs (IRGPs). Multivariate Cox analysis was used to construct an immune risk model and a prognostic nomogram combining was also been developed. Immune microenvironment landscape described by CIBERSORT and drug sensitivity calculated by pRRophetic algorithm were used to explore possible treatment improvements. RESULTS: A novel immune risk model with 5-IRGPs (CD1A|CXCL135, CD1A|S100A7L2, IFNA7|CMTM2, IFNA7|CSF3, CAMP|TFR2) can accurately distinguish patients in the high- and low-risk groups. Risk score act as an independent prognostic factor and is related to clinical stage. There are significant differences in tumor immune microenvironment and PD-1/PD-L1/CTLA-4 expression between groups. The low-risk patient may benefit more from the commonly used chemotherapy regimens such as gemcitabine and paclitaxel. CONCLUSION: This study constructed 5-IRGPs as a reliable prognostic tool and may represent genes pairs that are potential rationale for choice of treatment for "driver gene negative" LUAD.

The need for race-specific reference equations for pulmonary diffusing capacity for nitric oxide.

BACKGROUND: Few reference equations exist for healthy adults of various races for pulmonary diffusing capacity for nitric oxide (DLNO). The purpose of this study was to collect pilot data to demonstrate that race-specific reference equations are needed for DLNO. METHODS: African Americans (blacks) were chosen as the comparative racial group. In 2016, a total of 59 healthy black subjects (27 males and 32 females) were recruited to perform a full battery of pulmonary function tests. In the development of DLNO reference equations, a white reference sample (randomly drawn from a population) matched to the black sample for sex, age, and height was used. Multiple linear regression equations for DLNO, alveolar volume (VA), and pulmonary diffusing capacity for carbon monoxide (DLCO) using a 5-6 s breath-hold were developed. RESULTS: Our models demonstrated that sex, age2, race, and height explained 71% of the variance in DLNO and DLCO, with race accounting for approximately 5-10% of the total variance. After normalizing for sex, age2, and height, blacks had a 12.4 and 3.9 mL/min/mmHg lower DLNO and DLCO, respectively, compared to whites. The lower diffusing capacity values in blacks are due, in part, to their 0.6 L lower VA (controlling for sex and height). CONCLUSION: The results of this pilot data reveal small but important and statistically significant racial differences in DLNO and DLCO in adults. Future reference equations should account for racial differences. If these differences are not accounted for, then the risk of falsely diagnosing lung disease increase in blacks when using reference equations for whites.

Acquired Perforating Dermatosis Induced by PD-1 Inhibitor: A Case Report.

ABSTRACT: Acquired perforating dermatoses (APDs) are a group of diverse skin disorders in patients with systemic disease, most commonly chronic renal failure and diabetes mellitus. APD induced by medication has seldom been reported. Anti-PD-1 monoclonal antibody has recently been used as a broad-spectrum, effective, durable, and relatively safe antitumor therapy for various malignancies. Thus far, known side effects involving skin have included rash, pruritus, and vitiligo. Here, we present a rare case of a unilateral linear eruption with histopathologic features of APD in a 36-year-old man during treatment with Terepril monoclonal antibody. To the best of our knowledge, APD induced by the PD-1 inhibitor has not been described in the medical literature.

Dexmedetomidine reduces ventilator-induced lung injury via ERK1/2 pathway activation.

Mechanical ventilation (MV) can contribute to ventilator­induced lung injury (VILI); dexmedetomidine (Dex) treatment attenuates MV­related pulmonary inflammation, but the mechanisms remain unclear. Therefore, the present study aimed to explore the protective effect and the possible molecular mechanisms of Dex in a VILI rodent model. Adult male Sprague­Dawley rats were randomly assigned to one of seven groups (n=24 rats/group). Rats were euthanized after 4 h of continuous MV, and pathological changes, lung wet/dry (W/D) weight ratio, the levels of inflammatory cytokines (IL­1ß, TNF­α and IL­6) in the bronchoalveolar lavage fluid (BALF), and the expression levels of Bcl­2 homologous antagonist/killer (Bak), Bcl­2, pro­caspase­3, cleaved caspase­3 and the phosphorylation of ERK1/2 in the lung tissues were measured. Propidium iodide uptake and TUNEL staining were used to detect epithelial cell death. The Dex pretreatment group exhibited fewer pathological changes, lower W/D ratios and lower expression levels of inflammatory cytokines in BALF compared with the VILI group. Dex significantly attenuated the ratio of Bak/Bcl­2, cleaved caspase­3 expression levels and epithelial cell death, and increased the expression of phosphorylated ERK1/2. The protective effects of Dex could be partially reversed by PD98059, which is a mitogen­activated protein kinase (upstream of ERK1/2) inhibitor. Overall, dexmedetomidine was found to reduce the inflammatory response and epithelial cell death caused by VILI, via the activation of the ERK1/2 signaling pathway.

Spontaneous pneumomediastinum, pneumothorax and subcutaneous emphysema in COVID-19: case report and literature review.

Coronavirus Disease 2019 (COVID-19) has rapidly spread worldwide. Numerous studies have shown its typical and atypical CT findings. We report one COVID-19 patient who presented with a transient pneumothorax, spontaneous pneumomediastinum (SP), as well as subcutaneous emphysema during hospitalization. Chest CT andclinical findings were discussed, and a literature review is presented. The probable cause of SP in COVID-19 was alveolar damage. Once pneumothorax and SP were present, the patient should be carefully monitored to prevent respiratory deterioration, especially when lung lesions are severe.

The Msi1-mTOR pathway drives the pathogenesis of mammary and extramammary Paget's disease.

Mammary and extramammary Paget's Diseases (PD) are a malignant skin cancer characterized by the appearance of Paget cells. Although easily diagnosed, its pathogenesis remains unknown. Here, single-cell RNA-sequencing identified distinct cellular states, novel biomarkers, and signaling pathways - including mTOR, associated with extramammary PD. Interestingly, we identified MSI1 ectopic overexpression in basal epithelial cells of human PD skin, and show that Msi1 overexpression in the epidermal basal layer of mice phenocopies human PD at histopathological, single-cell and molecular levels. Using this mouse model, we identified novel biomarkers of Paget-like cells that translated to human Paget cells. Furthermore, single-cell trajectory, RNA velocity and lineage-tracing analyses revealed a putative keratinocyte-to-Paget-like cell conversion, supporting the in situ transformation theory of disease pathogenesis. Mechanistically, the Msi1-mTOR pathway drives keratinocyte-Paget-like cell conversion, and suppression of mTOR signaling with Rapamycin significantly rescued the Paget-like phenotype in Msi1-overexpressing transgenic mice. Topical Rapamycin treatment improved extramammary PD-associated symptoms in humans, suggesting mTOR inhibition as a novel therapeutic treatment in PD.

Surgical treatment to multiple primary lung cancer patients: a systematic review and meta-analysis.

BACKGROUND: As there is no consensus on the optimal surgery strategy for multiple primary lung cancer (MPLC), we conducted this study to address this issue by comparing the prognosis of MPLC patients underwent different surgical strategies including sublobar resection and the standard resection through a systemic review and meta-analysis. METHODS: Relevant literature was obtained from three databases including PubMed, Embase and Web of Science. Inclusion and exclusion criteria were set for the screening of articles to be selected for further conduction of systemic review and meta-analysis. The HRs of OS of the sublobar group compared with standard resection group were extracted directly or calculated indirectly from included researches. RESULTS: Ten researches published from 2000 to 2017 were included in this study, with 468 and 445 MPLC cases for the standard resection group and sublobar resection group respectively. The result suggested that OS of MPLC patients underwent sublobar resection (segmentectomy or wedge resection for at least one lesion) was comparable with those underwent standard resection approach (lobectomy or pneumonectomy for all lesions), with HR 1.07, 95% CI 0.67-1.71, p = 0.784. Further analysis found no difference in subgroups of synchronous and metachronous (from second metachronous lesion), different population region and dominant sex type. CONCLUSIONS: This study may reveal that sublobar resection is acceptable for patients with MPLC at an early stage, because of the equivalent prognosis to the standard resection and better pulmonary function preservation. Further research is needed to validate these findings.

The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice.

Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that the male Cntnap3-null mice exhibited deficits in social interaction， spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing mechanistic insights into ASD.

Overexpression of the peanut CLAVATA1-like leucine-rich repeat receptor-like kinase AhRLK1 confers increased resistance to bacterial wilt in tobacco.

Bacterial wilt caused by Ralstonia solanacearum is a devastating disease affecting hundreds of plant species, yet the host factors remain poorly characterized. The leucine-rich repeat receptor-like kinase gene AhRLK1, characterized as CLAVATA1, was found to be up-regulated in peanut upon inoculation with R. solanacearum. The AhRLK1 protein was localized in the plasma membrane and cell wall. qPCR results showed AhRLK1 was induced in a susceptible variety but little changed in a resistant cultivar after inoculated with R. solanacearum. Hormones such as salicylic acid, abscisic acid, methyl jasmonate, and ethephon induced AhRLK1 expression. In contrast, AhRLK1 expression was down-regulated under cold and drought treatments. Transient overexpression of AhRLK1 led to a hypersensitive response (HR) in Nicotiana benthamiana. Furthermore, AhRLK1 overexpression in tobacco significantly increased the resistance to R. solanacearum. Besides, the transcripts of most representative defense responsive genes in HR and hormone signal pathways were significantly increased in the transgenic lines. EDS1 and PAD4 in the R gene signaling pathway were also up-regulated, but NDR1 was down-regulated. Accordingly, AhRLK1 may increase the defense response to R. solanacearum via HR and hormone defense signaling, in particular through the EDS1 pathway of R gene signaling. These results provide a new understanding of the CLAVATA1 function and will contribute to genetic enhancement of peanut.

DNA hypomethylation of CBS promoter induced by folate deficiency is a potential noninvasive circulating biomarker for colorectal adenocarcinomas.

Aberrant DNA methylation patterns, which induced by folate deficiency, play important roles in tumorigenesis of colorectal cancer (CRC). Some DNA methylation alterations can also be detected in cell-free DNA (cfDNA) of patients' plasma, making cfDNA an ideal noninvasive circulating biomarker. However, exact DNA methylation alterations induced by folate deficiency in tumorigenesis of CRC and exact potential circulating cfDNA methylation biomarker are still unclear. Therefore, DNA methylation patterns of the normal human colon mucosal epithelial cell line (NCM460), cultured with normal or low folate content, were screened and the DNA hypomethylation of cystathionine-beta-synthase (CBS) promoter was further validated in vitro and vivo. Then, the correlation analysis between folate level, DNA methylation alteration in promoter and expression of CBS was carried out in vitro and vivo. Further, the methylation patterns of CBS promoter in plasma cfDNA were detected and statistically correlated with pathological parameters and clinical outcome. Our study showed that DNA hypomethylation in CBS promoter, induced by folate deficiency, would lead to up-regulation of CBS both in vitro and vivo. Patients with cfDNA hypomethylation of CBS promoter in plasma were correlated with high tumor stage and poor clinical outcome. In addition, cfDNA hypomethylation of CBS promoter in plasma was shown to be an independent prognostic factor for recurrence and cancer-related death in CRC. Our results indicated that DNA hypomethylation of CBS promoter induced by folate deficiency could serve as a potential noninvasive circulating biomarker and may be helpful in developing more effective prognostic markers for CRC.

Congenital Blaschkoid Angiolymphoid Hyperplasia With Eosinophilia of the Anogenital Region.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon, idiopathic vascular disorder. It manifests as dermal or subcutaneous red to brown papules or nodules, most commonly on the head and neck; other less common sites include the trunk, extremities, genitalia, lips, and oral mucosa. Although ALHE is a benign disease, lesions are often persistent and difficult to eradicate. ALHE occurs more frequently in Asian young and middle-aged women. Histologically, it is characterized by a florid vascular proliferation with hobnail epithelioid endothelial cells surrounding by lymphocytic and eosinophilic infiltrate. Here, we reported congenital ALHE in a 2-year-old girl. Unilateral lesions had a blaschkoid segmental distribution in the anogenital region and were successfully treated with the Nd:YAG laser.

Reduced Expression of RECK Protein May Help Differentiate Cutaneous Malignant Melanoma from Melanocytic Nevus.

BACKGROUND: Differentiating between vertical growth cutaneous malignant melanoma (CMM) and predominantly intradermal benign melanocytic nevus (BMN) can be extremely challenging. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is an endogenous inhibitor of many proteins that promote tumor invasion and progression. We investigated the difference in expression of RECK between CMM and BMN to determine whether RECK could assist in their differentiation. MATERIALS AND METHODS: The expression of RECK in skin biopsies of 39 cases, including 20 cases of CMM and 19 cases of BMN, was evaluated by immunohistochemistry. RESULTS: Two out of 20 cases (10%) of CMM were positive for RECK, and all (100%) 19 cases of BMN exhibited positivity at different levels. In 7/8 cases of CMM adjacent to benign nevus cells, malignant melanoma cells did not express RECK, but benign nevus cells stained positively. CONCLUSION: These findings suggest that immunohistochemical staining for RECK could be useful in the differential diagnosis between CMM and BMN.