PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma.

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergo large-cell transformation (LCT) in the late stage, manifesting aggressive behavior, resistance to treatments, and poor prognosis, but the mechanisms involved remain unclear. To identify the molecular driver of LCT, we collected tumor samples from 133 MF patients and performed whole-transcriptome sequencing on 49 advanced-stage MF patients, followed by integrated copy number inference and genomic hybridization. Tumors with LCT showed unique transcriptional programs and enriched expressions of genes at chr7q. Paternally expressed gene 10 (PEG10), an imprinted gene at 7q21.3, was ectopically expressed in malignant T cells from LCT, driven by 7q21.3 amplification. Mechanistically, aberrant PEG10 expression increased cell size, promoted cell proliferation, and conferred treatment resistance by a PEG10/KLF2/NF-κB axis in in vitro and in vivo models. Pharmacologically targeting PEG10 reversed the phenotypes of proliferation and treatment resistance in LCT. Our findings reveal new molecular mechanisms underlying LCT and suggest that PEG10 inhibition may serve as a promising therapeutic approach in late-stage aggressive T-cell lymphoma.

Pathogenic variations in MAML2 and MAMLD1 contribute to congenital hypothyroidism due to dyshormonogenesis by regulating the Notch signalling pathway.

BACKGROUND: In several countries, thyroid dyshormonogenesis is more common than thyroid dysgenesis in patients with congenital hypothyroidism (CH). However, known pathogenic genes are limited to those directly involved in hormone biosynthesis. The aetiology and pathogenesis of thyroid dyshormonogenesis remain unknown in many patients. METHODS: To identify additional candidate pathogenetic genes, we performed next-generation sequencing in 538 patients with CH and then confirmed the functions of the identified genes in vitro using HEK293T and Nthy-ori 3.1 cells, and in vivo using zebrafish and mouse model organisms. RESULTS: We identified one pathogenic MAML2 variant and two pathogenic MAMLD1 variants that downregulated canonical Notch signalling in three patients with CH. Zebrafish and mice treated with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butylester, a γ-secretase inhibitor exhibited clinical manifestations of hypothyroidism and thyroid dyshormonogenesis. Through organoid culture of primary mouse thyroid cells and transcriptome sequencing, we demonstrated that Notch signalling within thyroid cells directly affects thyroid hormone biosynthesis rather than follicular formation. Additionally, these three variants blocked the expression of genes associated with thyroid hormone biosynthesis, which was restored by HES1 expression. The MAML2 variant exerted a dominant-negative effect on both the canonical pathway and thyroid hormone biosynthesis. MAMLD1 also regulated hormone biosynthesis through the expression of HES3, the target gene of the non-canonical pathway. CONCLUSIONS: This study identified three mastermind-like family gene variants in CH and revealed that both canonical and non-canonical Notch signalling affected thyroid hormone biosynthesis.

Altered gut microbiome composition in nontreated plaque psoriasis patients.

Recent studies have demonstrated that dysbiosis of the gut microbiota is associated with psoriasis, but these studies showed some conflicting results. Our study examined differences in microbiome composition associated in people with psoriasis and those without. Comparing individuals with their healthy partners was a second strategy. We explored the fecal microbiota among 32 nontreated plaque psoriasis patients, 15 healthy controls and 17 healthy couples by metagenomic gene sequencing. The relative levels of intestinal microbiota of the psoriasis cohort differed from those in healthy controls and these patients' partners. However, there was no microbial diversity among these three cohorts. On the level of the phylum, Firmicutes and Bacteroidetes' relative abundances were reversed. Escherichia coli was significantly enriched in the psoriasis group compared with the healthy people and the healthy spouses. Gene functional analysis indicated that Ribosome (ko03010) was upregulated, Flagellar assembly (ko02040) and Bacterial chemotaxis (ko02030) were downregulated in the psoriasis cohort compared with the healthy individuals and the healthy spouses. The microbiota in severe psoriasis patients differed from those with milder conditions. These findings strongly support the association between intestinal flora and psoriasis. It is necessary to perform more meaningful experiments to identify whether the differences of gut microbiota are the cause or consequences of psoriasis in future.

Free triiodothyronine predicts the risk of developing diabetic kidney disease.

BACKGROUND: Low levels of Free Triiodothyronine (FT3) are associated with poor survival in chronic kidney disease, and the aim of this study was to further assess the relationship between changes in FT3 levels and renal damage in patients with type 2 diabetes based on glomerular and tubular markers. METHODS: We retrospectively studied 452 type 2 diabetic patients, measured glomerular damage markers (UACR, eGFR) and tubular damage markers (NAG/Cr,ß2-MG), analyzed the relationship between FT3 and renal damage by logistic regression models, and plotted restrictive cubic splines. RESULTS: 41.6% of subjects had diabetic kidney disease (DKD), and the prevalence of DKD decreased progressively with increasing FT3 levels in the third quartile. Spearman correlation analysis showed that FT3 was negatively associated with UACR, NAG/Cr and ß2-MG, while eGFR was positively associated with FT3. Multifactorial analysis, after adjusting for relevant confounders, revealed that compared with the lowest quartile of FT3, the highest quartile reduced the risk of developing urinary albumin (OR = 0.499,95% CI:0.289-0.856), moderate to severe impairment of glomerular filtration rate (OR = 0.106,95% CI:0.032-0.354), renal tubular marker ß2 -MG positive (OR = 0.516,95% CI:0.299 to 0.883) and the risk of DKD occurrence (OR = 0.450,95% CI:0.260 to 0.774). In the sample model, FT3 levels below 4.39 pmol/L were associated with an increased risk of glomerular tubule injury and DKD occurrence. CONCLUSIONS: FT3 is closely associated with glomerular tubular injury and is a protective factor. As FT3 levels (< 4.39 pmol/L) decrease, the risk of developing DKD becomes higher, and FT3 can be used as an independent predictor of developing DKD.

Anti-Inflammatory Constituents of Antrodia camphorata on RAW 264.7 Cells Induced by Polyinosinic-Polycytidylic Acid.

Antrodia camphorata is an endemic mushroom in Taiwan. This study was designed to screen anti-inflammatory compounds from the methanolic extract of the mycelium of A. camphorata on nitric oxide (NO) production in RAW 264.7 cells induced by polyinosinic-polycytidylic acid (poly I:C), a synthetic analog of double-stranded RNA (dsRNA) known to be present in viral infection. A combination of bioactivity-guided isolation with an NMR-based identification led to the isolation of 4-acetylantroquinonol B (1), along with seven compounds. The structure of new compounds (4 and 5) was elucidated by spectroscopic experiments, including MS, IR, and NMR analysis. The anti-inflammatory activity of all isolated compounds was assessed at non-cytotoxic concentrations. 4-Acetylantroquinonol B (1) was the most potent compound against poly I:C-induced NO production in RAW 264.7 cells with an IC50 value of 0.57 ± 0.06 µM.

High Expression of IKZF2 in Malignant T Cells Promotes Disease Progression in Cutaneous T Cell Lymphoma.

Cutaneous T cell lymphoma is a generally indolent disease derived from skin-homing mature T cells. However, in advanced stages, cutaneous T cell lymphoma may manifest aggressive clinical behaviour and lead to a poor prognosis. The mechanism of disease progression in cutaneous T cell lymphoma remains unknown. This study, based on a large clinical cohort, found that IKZF2, an essential transcription factor during T cell development and differentiation, showed stage- dependent overexpression in the malignant T cells in mycosis fungoides lesions. IKZF2 is specifically over- expressed in advanced-stage mycosis fungoides lesions, and correlates with poor prognosis. Mechanistically, overexpression of IKZF2 promotes cutaneous T cell lymphoma progression via inhibiting malignant cell apoptosis and may contribute to tumour immune escape by downregulating major histocompatibility complex II molecules and up-regulating the production of anti-inflammatory cytokine interleukin-10 by malignant T cells. These results demonstrate the important role of IKZF2 in high-risk cutaneous T cell lymphoma and pave the way for future targeted therapy.

A Retrospective Study of Treatment Outcomes and Prognostic Factors of Intense Pulsed Light Therapy Combined With Meibomian Gland Expression in Patients With Meibomian Gland Dysfunction.

OBJECTIVES: To evaluate clinical changes after intense pulsed light and meibomian gland expression (IPL/MGX) treatment in meibomian gland dysfunction (MGD) patients, and to identify ideal candidates, and the therapeutic window, for IPL/MGX. METHODS: This retrospective study reviewed the medical records of 44 MGD patients (44 eyes). The IPL/MGX treatment was applied on the eyelids three times at intervals of 4 weeks. Age, sex, relevant ocular history, Standard Patient Evaluation of Eye Dryness (SPEED), Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), corneal fluorescein staining score (CFSS), meiboscore, meibomian gland loss score (MGLS), meibomian glands yielding secretion score (MGYSS), meibomian glands yielding clear secretion (MGYCS), and meibomian glands yielding liquid secretion (MGYLS) were analyzed. RESULTS: Standard Patient Evaluation of Eye Dryness, OSDI, TBUT, CFSS, MGYSS, MGYLS, and MGYCS were significantly improved after three IPL/MGX treatments, but the meiboscore and MGLS remained unchanged. In patients who had better treatment outcomes (improvement in MGYSS >7), younger age (36.0, 22.5 vs. 53.0, 25.0 years; P=0.012), a longer TBUT (8.0, 4.5 vs. 6.0, 3.0 sec; P=0.010), better meiboscore (1.0, 0.5 vs. 2.0, 1.0; P=0.012), and less gland loss (19.8%, 20.3% vs. 41.1%, 30.2%; P=0.008) before IPL/MGX were noted. Sex, relevant ocular history, SPEED, OSDI, MGYSS, MGYLS, and MGYCS before IPL/MGX showed no significant differences between patients with an improvement in MGYSS >7 versus those with an improvement of ≤7. Meibomian glands yielding secretion score changes in patients who had a meiboscore of 0 to 1 and MGYSS of 0 before IPL/MGX (12.0, 10.0) were significantly higher than those who had a meiboscore of 2 to 3 and MGYSS of 0 (6.5, 9.3; P=0.031), or a meiboscore of 0 to 1 and MGYSS >0 (5.0, 11.5; P=0.041). CONCLUSIONS: Improved dry eye symptoms, TBUT, corneal staining, and meibomian gland secretion were observed in MGD patients after IPL/MGX. Patients in the early stages of MGD maybe benefited most from IPL/MGX treatment.

Tea consumption and risk of diabetes in the Chinese population: a multi-centre, cross-sectional study.

The aim of the present study was to explore the influence of tea consumption on diabetes mellitus in the Chinese population. This multi-centre, cross-sectional study was conducted in eight sites from south, east, north, west and middle regions in China by enrolling 12 017 subjects aged 20-70 years. Socio-demographic and general information was collected by a standardised questionnaire. A standard procedure was used to measure anthropometric characteristics and to obtain blood samples. The diagnosis of diabetes was determined using a standard 75-g oral glucose tolerance test. In the final analysis, 10 825 participants were included and multiple logistic models and interaction effect analysis were applied for assessing the association between tea drinking with diabetes. Compared with non-tea drinkers, the multivariable-adjusted OR for newly diagnosed diabetes were 0·80 (95 % CI 0·67, 0·97), 0·88 (95 % CI 0·71, 1·09) and 0·86 (95 % CI 0·67, 1·11) for daily tea drinkers, occasional tea drinkers and seldom tea drinkers, respectively. Furthermore, drinking tea daily was related to decreased risk of diabetes in females by 32 %, elderly (>45 years) by 24 % and obese (BMI > 30 kg/m2) by 34 %. Moreover, drinking dark tea was associated with reduced risk of diabetes by 45 % (OR 0·55; 95 % CI 0·42, 0·72; P < 0·01). The results imply that drinking tea daily was negatively related to risk of diabetes in female, elderly and obese people. In addition, drinking dark tea was associated with decreased risk of type 2 diabetes mellitus.

Cytotoxic and Anti-inflammatory Terpenoids from the Whole Plant of Vaccinium emarginatum.

Two new Δ12 ursene-type triterpenoid coumaroyl esters (1: and 2: ), one new Δ7,15 isopimarane-type diterpenoid glycoside (20: ), and two new irido-δ-lactone-type iridoids (21: and 22: ), together with 17 known pentacyclic triterpenoids (3:  - 19: ), were isolated during the phytochemical investigation of a methanol extract of the whole plant of Vaccinium emarginatum. Their structures were determined by detailed analysis of standard spectroscopic data (MS, IR, 1D, and 2D NMR) and comparison with data of known analogs. The isolates were evaluated for their cytotoxicity against the PC-3 and Du145 prostate cancer cell lines (as assessed by an MTT cell proliferation assay), as well as for their anti-inflammatory activity via the inhibition of nitric oxide production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among the isolates, the triterpenoid coumaroyl and feruloyl esters (1, 3: , and 4: ) exhibited strong cytotoxicity against PC-3 prostate cancer cells, with 85.6 - 90.2% inhibition at 10.0 µg/mL. The pomolic acid coumaroyl and feruloyl esters (1: and 3: ) also showed moderate anti-inflammatory activity against nitric oxide production in lipopolysaccharide-induced RAW 264.7 cells, with 59.2 (± 1.0) and 47.1% (± 0.2) inhibition at 12.5 µg/mL, respectively.

Prognostic Nutritional Index Predicts Outcomes of Patients after Gastrectomy for Cancer: A Systematic Review and Meta-Analysis of Nonrandomized Studies.

OBJECTIVE: The primary aim of this systematic review was to evaluate the survival predication value of preoperative prognostic nutritional index (PNI) in patients with gastric cancer. The second aim was to explore the relationship between preoperative PNI and clinicopathological features. METHODS: A systematic search of the electronic databases identified studies that investigated the association of preoperative PNI with short or long-term outcomes among patients after gastrectomy for cancer. Qualitative and quantitative analysis of results was conducted. RESULTS: Twenty-five studies with a total of 14,403 patients with gastric cancer met inclusion criteria for this review. Pooled analysis demonstrated that low preoperative PNI was associated with significantly reduced overall survival (HR 1.81, 95% CI: 1.56-2.09; P = 0.000), cancer-specific survival (HR 1.61, 95% CI: 1.24-2.10; P = 0.000), and recurrence-free survival (HR 1.82, 95% CI: 1.20-2.77; P = 0.005). In addition, risk of postoperative complications (POCs) and mortality was significantly higher in patients with lower preoperative PNI (RR 1.77, 95% CI: 1.44-2.17; P = 0.000 and RR 5.14, 95% CI: 2.23-11.79; P = 0.000, respectively). CONCLUSION: This study suggests that patients with low preoperative PNI may have a high incidence of POCs and poor prognosis following gastrectomy for cancer.

Rapid remission of Stevens-Johnson syndrome by combination therapy using etanercept and intravenous immunoglobulin and a review of the literature.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are spectrum of rare, acute, and life-threatening delayed-type drug hypersensitivity reactions that are associated with high mortality rates. However, no therapeutic standard has been proposed for SJS/TEN. Here, we report a case of a patient diagnosed with Stevens-Johnson syndrome whose disease progression was halted by a single dose of etanercept and was treated successfully. In addition, we reviewed the literature reporting patients with SJS/TEN treated with similar regimens.

Phytochemical Investigation of Tradescantia Albiflora and Anti-Inflammatory Butenolide Derivatives.

Phytochemical investigation of the whole plant of Tradescantia albiflora Kunth led to the isolation and characterization of a butanolide, rosmarinosin B (1), that was isolated from natural sources for the first time, a new butenolide, 5-O-acetyl bracteanolide A (2), and a new apocarotenoid, 2ß-hydroxyisololiolide (11), together with 25 known compounds (compounds 3-10 and 12-28). The structures of the new compounds were elucidated by analysis of their spectroscopic data, including MS, 1D, and 2D NMR experiments, and comparison with literature data of known compounds. Furthermore, four butenolides 4a-4d were synthesized as novel derivatives of bracteanolide A. The isolates and the synthesized derivatives were evaluated for their preliminary anti-inflammatory activity against lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production in RAW 264.7 cells. Among them, the synthesized butenolide derivative n-butyl bracteanolide A (4d) showed enhanced NO inhibitory activity compared to the original compound, with an IC50 value of 4.32 ± 0.09 µg/mL.

Impaired Skin Barrier Function and Downregulated Expression of Caspase-14 in Moderate to Severe Chronic Hand Eczema.

AIM: To investigate whether the skin barrier function is impaired with regard to the pH value, water content, transepidermal water loss (TEWL), and the integrity of the stratum corneum, and whether the expression of caspase-14 is altered in moderate to severe chronic hand eczema (CHE). METHODS: Thirty patients with moderate to severe CHE treated at our institute and 30 healthy volunteers were included in this study. The pH value, water content, TEWL, and the integrity of the stratum corneum were measured in all subjects. RESULTS: Significantly increased pH value, decreased water content, elevated TEWL, and impaired integrity of the stratum corneum were observed in the lesional skin of CHE patients compared with the nonlesional skin of CHE patients and the normal skin of healthy volunteers. The expression of caspase-14 decreased in the lesional and nonlesional skin of CHE patients compared with the normal skin of healthy volunteers, especially prominent in the nonlesional skin. The mean optical density (OD) value of immunohistochemical staining for caspase-14 was significantly lower in the nonlesional skin than in the lesional skin and normal skin (p < 0.01 for both). Although the mean OD value was lower in the lesional skin than in the normal skin, the difference was not statistically significant (p > 0.05). CONCLUSION: Skin barrier dysfunction indeed occurs in CHE patients, which may be related to mechanisms associated with a downregulated expression of caspase-14.

A dose-finding study for hemoporfin in photodynamic therapy for port-wine stain: A multicenter randomized double-blind phase IIb trial.

BACKGROUND/PURPOSE: Previous studies have shown that hemoporfin-mediated photodynamic therapy (PDT) was a treatment for port-wine stain (PWS). Our current study aimed to identify optimal hemoporfin dose. METHODS: A prospective, multicenter, double-blind, randomized clinical trial was conducted. Patients were assigned into low- or high-dose hemoporfin (2.5 mg/kg and 5 mg/kg intravenously, respectively), or control (placebo) group, at a rate of 2:2:1. Treatment efficacy was evaluated at week 8. Then, patients in control group were randomly assigned into either high- or low-dose hemoporfin group. Treatment reactions and adverse events were analyzed at week 16. RESULTS: A total of 100 patients (40, 40, 20 in low-, high-dose hemoporfin, and control group, respectively) were enrolled. Compared to low dose (40%) and control group (15%), a higher proportion of patients in high-dose group (75%) had achieved skin lesion improvements. Treatment satisfactions were graded highest in high-dose group. Compared to low-dose group (14.3%), high-dose group (46.0%) had more frequent skin hyperpigmentation, which disappeared 3-6 months after treatment. Other treatment reactions and adverse events were comparable between two groups. CONCLUSIONS: Photodynamic therapy with 5 mg/kg hemoporfin could be an effective and safe treatment for PWS.

Frequent immunoglobulin G4 expression in a common variant of primary cutaneous marginal zone B-cell lymphoma.

Immunoglobulin (Ig)G4 expression was recently observed in a proportion of primary cutaneous marginal zone B-cell lymphoma (PCMZL) with plasmacytic differentiation. IgG4-related disease is characterised by polyclonal lymphoplasmacytic infiltration with IgG4 expression, storiform fibrosis and obliterative phlebitis in histopathology. Here we report three cases of common variants of PCMZL with predominant and varied IgG4 expression, suggesting there is an underlying clonal progression between these two entities.

Thermo-Fluid Characteristics of High Temperature Molten Salt Flowing in Single-Leaf Type Hollow Paddles.

A single-leaf type paddle heat exchanger with molten salt as the working fluid is a proper option in high temperature heating processes of materials. In this paper, based on computational fluid dynamics (CFD) simulations, we present the thermo-fluid characteristics of high temperature molten salt flowing in single-leaf type hollow paddles in the view of both the first law and the second law of thermodynamics. The results show that the heat transfer rate of the hollow paddles is significantly greater than that of solid paddles. The penalty of the heat transfer enhancement is additional pressure drop and larger total irreversibility (i.e., total entropy generation rate). Increasing the volume of the fluid space helps to enhance the heat transfer, but there exists an upper limit. Hollow paddles are more favorable in heat transfer enhancement for designs with a larger height of the paddles, flow rate of molten salt and material-side heat transfer coefficient. The diameter of the flow holes influences the pressure drop strongly, but their position is not important for heat transfer in the studied range. Other measures of modifying the fluid flow and heat transfer like internal baffles, more flow holes or multiple channels for small fluid volume are further discussed. For few baffles, their effects are limited. More flow holes reduce the pressure drop obviously. For the hollow paddles with small fluid volume, it is possible to increase the heat transfer rate with more fluid channels. The trade-off among fluid flow, heat transfer and mechanical strength is necessary. The thermo-fluid characteristics revealed in this paper will provide guidance for practical designs.

A Topical Medication of All-Trans Retinoic Acid Reduces Sebum Excretion Rate in Patients With Forehead Acne.

Acne is a disease of the hair follicles of the face, chest, and back that affects almost all teenagers during puberty. This study is conducted to investigate if all-trans retinoic acid (ATRA) could reduce sebum excretion rate (SER) in acne patients by influencing content of skin-surface lipid production. Thirty-nine patients with forehead acne were topically treated with cream base (vehicle) and 0.025% ATRA cream once a night for 7 days. Separation and identification of sebum production collected from the skin on the acne were performed using thin-layer chromatography. SER was calculated according to the total amount of individual sebum productions that were quantified by using Alphaimager IS-2200 imaging analysis. Our data showed that the value of SER on the acne-affected skin was significantly decreased in the ATRA-treated patients as compared with ones treated with vehicle (P < 0.01). Treatment with ATRA resulted in inducing significant decreases in the contents of wax esters (WE), triglycerides and fatty acids, and free fatty acids (FFA) productions (all P < 0.01). In further analysis, the changes in the data before and after treatments with vehicle and ATRA were compared with significant differences exhibited in the values of SER, WE, and FFA (all P < 0.05). This study indicates that the topical application of ATRA in treatment of acne patients induces decrease in SER by inhibiting the excretion of WE and FFA productions.

Primary cutaneous anaplastic large cell lymphoma with intralymphatic involvement associated with chronic lymphedema.

Chronic lymphedema predisposes to develop malignant cutaneous tumors, including angiosarcoma, Kaposi's sarcoma and B-cell lymphoma. T-cell malignancy has rarely been associated with chronic lymph stasis. Here, we report a case of primary cutaneous anaplastic large cell lymphoma (pcALCL) with lymphatic spread associated with chronic lymphedema. The patient is a 56-year-old man who received orchiectomy and right inguinal lymphadenectomy for malignant seminoma 10 years ago, which led to prominent lymphedema of the right leg. He developed extensive skin nodules on the lymphedematous area for 3 months. Histopathology findings confirmed a diagnosis of pcALCL, which is a subtype of cutaneous T-cell lymphoma characterized by the presence of CD30+ T cells. Intralymphatic infiltration of malignant cells is prominent. The pathogenesis of intralymphatic cutaneous anaplastic large cell lymphoma is largely unknown. Our case suggests that chronic lymphedema resulted in persistent CD4+ T-cell inflammation, which then may contribute to the development of pcALCL.