Effectiveness of narrowband ultraviolet B monotherapy versus combination therapy with systemic agents in patients with early-stage mycosis fungoides and the association with plaque lesions.

OBJECTIVE: Narrowband ultraviolet B (NB-UVB) has been recommended as first-line therapy for early-stage mycosis fungoides (MF) in international guidelines. NB-UVB can be used as monotherapy or part of a multimodality treatment regimen. There is limited evidence on the effectiveness and optimal patients of NB-UVB in combination with systemic therapies in MF. We aimed to assess the effectiveness of the combination versus NB-UVB monotherapy in early-stage MF and if plaque lesion status was related to these effects. METHODS: This observational cohort study included 247 early-stage MF patients who had received NB-UVB combined with systemic therapies vs. NB-UVB monotherapy from 2009 to 2021. The primary outcome was partial or complete response. Overall response rate and median time to response were calculated. Hazard ratios (HRs) were estimated using the Cox model. RESULTS: In 139 plaque-stage patients, the response rate for combination therapy group was higher than that of monotherapy group (79.0% vs. 54.3%, p = 0.006). The adjusted HR for combination therapy compared with NB-UVB monotherapy was 3.11 (95% CI 1.72-5.63). The combination therapy group also showed shorter time to response (4 vs. 6 months, p = 0.002). In 108 patch-stage patients, the response rate and time to response in two treatment groups showed no significant difference. There was therefore an observed interaction with patients' plaque lesion status for the effect size of NB-UVB combination therapy. No serious adverse events were observed. CONCLUSIONS: Adding systemic treatments to NB-UVB did not improve the treatment outcome of patch-stage patients, but it surpassed NB-UVB monotherapy for early-stage patients with plaques.

Prognostic Factors and Survival Outcomes Among Patients With Mycosis Fungoides in China: A 12-Year Review.

Importance: There are limited prognostic statistics and data available on survival outcomes for patients with mycosis fungoides (MF) in Asia. Objective: To determine the prognostic factors and survival outcomes of patients with MF among a cohort in China. Design, Setting, and Participants: This was a retrospective cohort study of patients with MF who received treatment at a tertiary referral center for skin lymphoma (Peking University First Hospital, Beijing, China) from August 1, 2009, to August 31, 2021. Data were analyzed from September 1, 2021, to December 31, 2022. Main Outcomes and Measures: Overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS); for prognostic factors, hazard ratios (HRs), and adjusted HRs (aHRs; adjusted for sex, age, and overall TNMB [tumor, node, metastasis, blood] stage) determined using the Cox proportional hazards model. Results: The study cohort comprised 461 patients with MF (median [range] age at diagnosis, 46 [5-87] years; 275 [59.7%] men and 186 [40.3%] women; 461 [100%] Chinese). The overall 5-year rate was 82.2% for OS, 83.5% for DSS, and 79.6% for PFS. Stage-specific 5-year OS rates were 95.7% for stage IA, 93.2% for IB, 95.7% for IIA, 70.1% for IIB, 55.3% for III, and 23.6% for IV. Compared with a UK cohort, our Chinese cohort had a younger median age at diagnosis (46 years vs 54 years) and a more favorable 5-year OS (82.2% vs 75.0%); however, after adjusting for age, the discrepancy in the 5-year OS rate was diminished (77.3% vs 76.4%). Cox models revealed that unfavorable predictors of OS, PFS, and DSS, respectively, were: age older than 60 years (aHR [95% CI], 2.25 [1.28-3.96]; 2.09 [1.16-3.76]; 2.27 [1.39-3.72]); advanced TNMB stage; advanced overall stage; large-cell transformation (aHR [95% CI], 2.16 [1.17-3.99]; 2.29 [1.21-4.33]; 2.21 [1.26-3.86]); and elevated lactate dehydrogenase levels (aHR [95% CI], 3.92 [1.64-9.36]; 4.77 [1.86-12.22]; 5.05 [2.23-11.42]). Biological sex and plaque lesion type were not associated with prognosis among this study cohort. Conclusion and Relevance: The findings of this retrospective cohort study of patients with MF in China suggest that Asian patients are diagnosed at a younger age and have a higher 5-year OS compared with patients of other races in studies in other countries (predominantly White). Prognostic factors were similar to those of previous studies, except for patient sex and plaque lesion type.

HLA-DR Helps to Differentiate Erythrodermic Cutaneous T-cell Lymphoma from Erythrodermic Inflammatory Dermatoses in Flow Cytometry.

Differential diagnosis of erythroderma is challenging in dermatology, especially in differentiating erythrodermic cutaneous T-cell lymphoma from erythrodermic inflammatory dermatoses. This study retrospectively reviewed the peripheral blood flow cytometric results of 73 patients diagnosed with erythroderma at Peking University First Hospital from 2014 to 2019. The flow cytometry antibody panel included white blood cell markers, T-cell markers, B-cell markers, T-cell activation markers, and T helper cell differentiation markers. Features of the cell surface antigens were compared between 34 patients with erythrodermic cutaneous T-cell lymphoma and 39 patients with erythrodermic inflammatory dermatoses. The percentage of HLA-DR+/CD4+T cells was the most pronounced marker to distinguish erythrodermic cutaneous T-cell lymphoma from erythrodermic inflammatory dermatoses, with a threshold of 20.85% (sensitivity 96.77%, specificity 70.37%, p = 0.000, area under the curve (AUC) 0.882), suggesting its potential capability in the differential diagnosis of erythrodermic cutaneous T-cell lymphoma from erythrodermic inflammatory dermatoses. Moreover, in contrast to erythrodermic inflammatory dermatoses, the percentage of Th17 cells was significantly downregulated in erythrodermic cutaneous T-cell lymphoma (p = 0.001), demonstrating a dysregulated immune environment in erythrodermic cutaneous T-cell lymphoma.

Single-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma.

Cutaneous T cell lymphoma (CTCL) represents a heterogeneous group of non-Hodgkin lymphoma distinguished by the presence of clonal malignant T cells. The heterogeneity of malignant T cells and the complex tumor microenvironment remain poorly characterized. With single-cell RNA analysis and bulk whole-exome sequencing on 19 skin lesions from 15 CTCL patients, we decipher the intra-tumor and inter-lesion diversity of CTCL patients and propose a multi-step tumor evolution model. We further establish a subtyping scheme based on the molecular features of malignant T cells and their pro-tumorigenic microenvironments: the TCyEM group, demonstrating a cytotoxic effector memory T cell phenotype, shows more M2 macrophages infiltration, while the TCM group, featured by a central memory T cell phenotype and adverse patient outcome, is infiltrated by highly exhausted CD8+ reactive T cells, B cells and Tregs with suppressive activities. Our results establish a solid basis for understanding the nature of CTCL and pave the way for future precision medicine for CTCL patients.

Predictors of preoperative cognitive dysfunction in adults with Moyamoya disease: a preliminary research.

OBJECTIVE: To explore potential risk factors of preoperative cognitive dysfunction in adult patients with moyamoya disease (MMD) and discuss significance of moyamoya vessels. METHODS: The author reviewed adult MMD patients harboring no parenchymal infarction or hemorrhage underwent a standardized neuropsychological assessment test battery from December 2018 to May 2019. The authors defined patients with cognitive dysfunction as cognitive impairment shown on 3 or more neuropsychological tests. According to the presence of cerebral angiography, arterial stenosis, moyamoya vessels, and compensatory arteries were conducted. Univariate and multivariate analyses were performed to identify predictors for cognitive dysfunction before surgery. Subgroup analyses by onset type and Suzuki stage were carried out to identify specific predictors for preoperative cognitive dysfunction. RESULTS: In total, 29 of 92 (31.52%) patients had cognitive dysfunction. Multivariate analysis showed that moyamoya vessels generating from left hemisphere was recognized as independent predictor for cognitive dysfunction (P = 0.025, OR [95%CI], 0.085 [0.012-0.874]). For patients in left ICA-moyamoya subgroup, 19 of 45 (42.22%) cases with sparse moyamoya vessels had cognitive dysfunction (P = 0.031), while 22 (91.67%) of patients with dense moyamoya vessels had normal cognition (P = 0.004). Moyamoya vessels arising from ophthalmic artery had no significant association with cognitive dysfunction (P = 0.111). Multivariate analysis found that moyamoya vessels originating from left ICA was recognized as independent predictors for preoperative cognitive dysfunction (P = 0.048, OR [95%CI], 0.394 [0.132-0.926]). CONCLUSIONS: Moyamoya vessels arising from left hemisphere was a risk factor for the preoperative cognitive dysfunction in adult patients with MMD, with the denser moyamoya vessels, the less cognitive dysfunction. The current study offers a new perspective of moyamoya vessels and supporting data for choosing MMD candidates on cerebral revascularization.

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.

Icariin activates autophagy to trigger TGFß1 upregulation and promote angiogenesis in EA.hy926 human vascular endothelial cells.

Angiogenesis plays an important role in tissue development and repair, and how to regulate angiogenesis effectively is a widely studied problem in the biomedical field. In recent years, the role of autophagy in vascular endothelial cells has attracted extensive attention. Icariin (ICA) is a traditional Chinese medicine that has been proven to have outstanding protective effects on the vascular system and to regulate cellular autophagy effectively. However, at present, it has not been reported whether ICA can affect the angiogenic ability of endothelial cells by affecting autophagy. In this study, we aimed to investigate whether ICA affects the angiogenesis capacity of EA.hy926 human vascular endothelial cells through autophagy and explain the underlying potential mechanisms. First, we determined that ICA at appropriate concentrations has the ability to promote cell migration and angiogenesis using wound healing assays and tube formation assays. Then, at the molecular level, we observed the upregulation of VEGFA, VEGFR2, ANGI, ANGII, and Tie2 mRNA and detected the upregulation of TGFß1 protein by Western blotting. We also demonstrated that angiogenic concentrations of ICA can effectively activate autophagy. The autophagy inhibitor 3-MA significantly suppressed TGFß1 expression and tube formation in EA.hy926 cells. Overall, we hope that our studies might help to further understand the effect of ICA on vascular endothelial cells and provide a theoretical basis for future angiogenic applications of ICA.

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.

Anxiety and Depression in Patients With Pulmonary Arterial Hypertension in Northwest China: A Cross-Sectional Study.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare life-threatening and incurable disease. Although symptoms of depression and anxiety have been widely reported, these traits and associated factors have not been systematically assessed in Northwest China. METHODS: A cross-sectional study was conducted between March 2020 and February 2021. 106 PAH patients in Northwest China were evaluated by Self-rating Anxiety Scale (SAS) and the Self Rating Depression Scale (SDS) questionnaire. RESULTS: Overall, the included patients had particularly high depressive symptoms (70.09%), while anxiety among them was 17.55%. Multivariate linear regression revealed that patients with lower age (p = 0.04), female (p < 0.01), smoking (p < 0.01), WHO functional class III/IV (p < 0.01), higher mean pulmonary hypertension (p < 0.01), lower left ventricular ejection fraction (p < 0.01), and lower 6-min walking distance (p < 0.01) had higher anxiety scores. Patients who lived in rural areas (p = 0.01), smoking (p < 0.01), WHO functional class III/IV (p < 0.01), higher mean pulmonary hypertension (p = 0.04), lower 6-min walking distance (p < 0.01), and college degree or above had higher depression scores (p = 0.02). CONCLUSIONS: Mental health problems such as depression are common among patients with PAH in Northwest China. Patients' characteristics such as smoking status, WHO functional class, and 6-min walking distance were related to anxiety and depression scores. Thus, early detection of mental health problems such as depression and anxiety should be detected in PAH patients. Meanwhile, interventions against these problems should be used to improve such patients' mental status.

Differential SATB1 Expression Reveals Heterogeneity of Cutaneous T-Cell Lymphoma.

SATB1 is an important T-cell specific chromatin organizer in cutaneous T-cell lymphoma, whereas its expression and function in mycosis fungoides (MF) remain ambiguous. Our study aimed to investigate the clinicopathological significance of SATB1 in a cohort of 170 patients with MF. SATB1 expression was heterogeneous among the patients with MF in each clinical stage. High SATB1 expression was associated with epidermal hyperplasia, eosinophil infiltration, less large-cell transformation, and favorable prognosis in MF cases. SATB1 and CD30 coexpression distinguished cutaneous CD30+ lymphoproliferative disorders from MF large-cell transformation. SATB1 silencing in MF lines showed that SATB1 upregulated the genes involved in eosinophil recruitment, including signal transducer and activator of transcription 3 and IL13, and downregulated the genes in cell-cycle progression, which may explain the inferior prognosis for low SATB1-expressing cases. Moreover, SATB1 was inversely correlated with PD-1 expression, indicating an exhausted status of SATB1-negative malignant T cells. SATB1 was positively correlated with toll-like receptors expression, suggesting innate immune activation in high SATB1-expressing MF cases. Therefore, variable SATB1 expression promotes heterogeneity in pathology and clinical outcome of patients with MF.

An HBT-based fluorescent dye with enhanced quantum yield in water system and its application for constructing NQO1 fluorescent probe.

A novel HBT-based fluorescent dye HBTM, which exhibited long wavelength emission (~600 nm) and large Stokes shift (~203 nm) due to the intrinsic mechanism of ESIPT coupled ICT process, was reasonably designed and synthesized by conjugating neutral pyrimidine moiety as the electron acceptor to 2-(benzo[d]thiazol-2-yl)-4-methylphenol scaffold. Fluorescence emission of HBTM showed less significant spectral dependency on solvents nature, delivering excellent anti-hypochromatic properties, and notably enhanced quantum yield (Φ = 25.5%) in water system was obtained. Furthermore, a "Turn-On" fluorescent probe HBTMP was developed for the detection of NQO1 by masking the hydroxyl group of HBTM with quinone propionic acid (QPA) as the sensing group. Probe HBTMP displayed a highly sensitive and selective response to NQO1 with a linear relationship in the range of 60-180 ng/mL and low detection limit of 1.6 ng/mL, and was successfully applied in detecting endogenous NQO1 in living cancer cells.

Real-time cell analysis of the cytotoxicity of a pH-responsive drug-delivery matrix based on mesoporous silica materials functionalized with ferrocenecarboxylic acid.

During the past decade, accumulating studies have been conducted on the mesoporous silica materials as the matrix of controlled drug-delivery, in which the complicated post-synthesis procedures are often involved with the molecular design to achieve the efficacy. In this study, a simplified drug delivery system of anti-cancer drug of doxorubicin (DOX) based on mesoporous SBA-15 functionalized with ferrocenecarboxylic acid (FCA) was constructed. Through a combination of physicochemical characterizations, the presence of FCA that was anchored inside the pore wall of amine groups grafted SBA-15 exhibits electron-accessible behavior without affecting the intactness of composite material. The pH-responsive release of drug molecules was achieved through the conjugation of DOX with FCA in the interior channels of mesoporous composites, which also favors the more coverage of DOX. Furthermore, the real-time cell analysis was performed to monitor the release of DOX from the mesopores and resulting cytotoxicity of cancer cell of A549 was evaluated, which results in a calculated IC50 of 43.8 µg/ml (24 h). The constructed mesoporous FCA-SBA-15 composite material provides an integrated nanoplatform to exert controlled-delivery of anti-cancer drug molecules.

Fms-Like Tyrosine Kinase 3-Ligand Contributes to the Development and Function of the Subpopulation of CD8α+ Plasmacytoid Precursor Dendritic Cells in CD8+ /TCR- Facilitating Cells.

Facilitating cells (FC) are a CD8+ TCR- bone marrow subpopulation that enhance engraftment of purified hematopoietic stem cells (HSC) and induce antigen-specific CD4+ CD25+ FoxP3+ regulatory T cell (Treg) in vivo. The major subpopulation in FC resembles plasmacytoid precursor dendritic cells (p-preDC) both phenotypically and functionally. Here, we report that the number of FC was significantly reduced in Fms-like tyrosine kinase 3-ligand-knockout (Flt3-L-KO) mice. Specifically, there was a selective decrease in the B220+ CD11c+ CD11b- p-preDC FC subpopulation. The p-preDC FC subpopulation in FC total is restored after Flt3-L administration to Flt3-L-KO mice. FC from Flt3-L-KO donors exhibit impaired facilitation of allogeneic HSC engraftment in ablatively conditioned mice (B6 → NOD) as well as in mice conditioned with reduced intensity conditioning (B6 → BALB/c). In addition, the number of CD4+ CD25+ Foxp3+ Treg from Flt3-L-KO mice is significantly decreased. This was associated with the expression of chemokine receptor CXCR3+ or CCR5+ on Treg. Treg from the spleen of Flt3-L-KO mice showed impaired facilitation of engraftment of allogeneic HSC compared to wild-type Treg. Flt3-L treatment significantly expanded Treg, and restored their facilitating function. These results suggest that Flt3-L is an important growth factor in the development and homeostasis of p-preDC FC and in the role of FC inducing generation of Treg. Flt3-L provides potent immunoregulatory properties that may be clinically useful to improve tolerance induction and enhance the function of allogeneic cell therapies. Stem Cells 2018;36:1567-1577.

Impact of childhood trauma on sensorimotor gating in Chinese patients with chronic schizophrenia.

We investigated the relationship between childhood trauma (CT) and sensorimotor gating in Chinese patients diagnosed with chronic schizophrenia. Seventy-five patients were assessed with the Childhood Trauma Questionnaire-Short Form (CTQ-SF), and then the modified paradigm, perceived spatial separation-induced prepulse inhibition (PSS PPI) and the perceived spatial co-location PPI (PSC PPI or classical PPI) were applied to test sensorimotor gating. Startling stimuli (90 dB) were presented either alone or preceded by discrete prepulse stimuli of 4 dB in a background 60-dB noise level. Associations between CT and various PPI paradigms were statistically analyzed. Univariate analysis revealed the absence of a significant correlation between CT and PPI paradigms (p > 0.05). However, multiple linear regression analyses revealed that sexual abuse and the positive and negative syndrome scale (PANSS) score were negatively correlated with PSS PPI (p = 0.029 and 0.008, respectively). On the other hand, female sex and history of smoking were positively correlated with PSS PPI (p = 0.044 and 0.043, respectively). In conclusion, the results of this study suggest that CT can be a predisposing factor that affects sensorimotor gating in schizophrenia patients.

Facilitating cells: Translation of hematopoietic chimerism to achieve clinical tolerance.

For over 50 y the association between hematopoietic chimerism and tolerance has been recognized. This originated with the brilliant observation by Dr. Ray Owen that freemartin cattle twins that shared a common placental blood supply were red blood cell chimeras, which led to the discovery that hematopoietic chimerism resulted in actively acquired tolerance. This was first confirmed in neonatal mice by Medawar et al. and subsequently in adult rodents. Fifty years later this concept has been successfully translated to solid organ transplant recipients in the clinic. The field is new, but cell-based therapies are being used with increasing frequency to induce tolerance and immunomodulation. The future is bright. This review focuses on chimerism and tolerance: past, present and prospects for the future.

DOCK2 is critical for CD8(+) TCR(-) graft facilitating cells to enhance engraftment of hematopoietic stem and progenitor cells.

CD8(+) TCR(-) graft facilitating cells (FCs) enhance engraftment of hematopoietic stem cells (HSCs) in allogeneic and syngeneic recipients. The mechanisms by which FCs promote HSC engraftment and tolerance induction have not been fully elucidated. Here, we provide data to support a critical role for dedicator of cytokinesis 2 (DOCK2) in multiple aspects of FCs function. DOCK2(-/-) FCs exhibit compromised facilitative function in vivo as evidenced by the loss of engraftment-enhancing capability for c-Kit(+) Sca-1(+) lineage(-) (KSL) cells, and compromised ability to promote KSL cell homing and lodgment in hematopoietic niche. Deletion of DOCK2 abrogates the ability of FCs to induce differentiation of naïve CD4(+) CD25(-) T cells into FoxP3(+) regulatory T cells and interleukin-10-producing type 1 regulatory T cells in vitro. Moreover, DOCK2(-/-) FCs are unable to promote survival of KSL cells when cocultured with KSL cells. DOCK2(-/-) FCs also exhibit compromised migration to stroma-derived factor-1 in vitro and impaired homing to the bone marrow in vivo. In conclusion, our results demonstrate that DOCK2 is critical for FCs to maintain its immunomodulatory function and exert its trophic effects on KSL cells. These findings may have direct clinical relevance to promote HSC engraftment for treatment of autoimmunity, hemoglobinopathies, and to induce transplantation tolerance.

A critical role for the TLR4/TRIF pathway in allogeneic hematopoietic cell rejection by innate immune cells.

We show for the first time that signaling through the TLR4/TRIF pathway plays a critical role in allogeneic bone marrow cell (BMC) rejection. This appears to be unique to BMCs as organ allografts are rejected mainly via MyD88 signaling. Using T- or T-/B-cell-deficient mice, we found that BMC allorejection occurred early before T-cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. We further demonstrated the innate immune signaling in BMC allorejection by showing superior engraftment in mice deficient in TRIF or TLR4 but not in MyD88 or TLR3. The restored cytotoxicity in TRIF-deficient recipients transferred with wild-type F4/80(+) or NK1.1(+) cells suggests TRIF signaling dependence on macrophages or NK cells in early BMC rejection. Production of the proinflammatory cytokine IL-6 and TRIF relevant chemokine MCP-1 was significantly increased early after bone marrow transplantation. In vivo specific depletion of macrophages or NK innate immune cells in combination with anti-CD154/rapamycin resulted in additive-enhanced allogeneic engraftment. The requirement for irradiation was completely eliminated when both macrophages and NK cells were depleted in combination with anti-CD154/rapamycin to target T- and B-cells, supporting the hypothesis that two barriers involving innate and adaptive immunity exist in mediating the rejection of allogeneic BMCs. In summary, our results clearly demonstrate a previously unappreciated role for innate immunity in BMC allorejection via signaling through a unique MyD88-independent TLR4/TRIF mechanism. These findings may have direct clinical impact on strategies for conditioning recipients for stem cell transplantation.