BMP-ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B-Cell Lymphoma.

EZH2 is the catalytic subunit of the histone methyltransferase Polycomb Repressive Complex 2 (PRC2), and its somatic activating mutations drive lymphoma, particularly the germinal center B-cell type. Although PRC2 inhibitors, such as tazemetostat, have demonstrated anti-lymphoma activity in patients, the clinical efficacy is not limited to EZH2-mutant lymphoma. In this study, Activin A Receptor Type 1 (ACVR1), a type I Bone Morphogenetic Protein (BMP) receptor, is identified as critical for the anti-lymphoma efficacy of PRC2 inhibitors through a whole-genome CRISPR screen. BMP6, BMP7, and ACVR1 are repressed by PRC2-mediated H3K27me3, and PRC2 inhibition upregulates their expression and signaling in cell and patient-derived xenograft models. Through BMP-ACVR1 signaling, PRC2 inhibitors robustly induced cell cycle arrest and B cell lineage differentiation in vivo. Remarkably, blocking ACVR1 signaling using an inhibitor or genetic depletion significantly compromised the in vitro and in vivo efficacy of PRC2 inhibitors. Furthermore, high levels of BMP6 and BMP7, along with ACVR1, are associated with longer survival in lymphoma patients, underscoring the clinical relevance of this study. Altogether, BMP-ACVR1 exhibits anti-lymphoma function and represents a critical PRC2-repressed pathway contributing to the efficacy of PRC2 inhibitors.

Targeting Rab-RILPL interactions as a strategy to downregulate pathogenic LRRK2 in Parkinson's disease.

Familial Parkinson's disease (PD) is frequently linked to multiple disease-causing mutations within Leucine-Rich Repeat Protein Kinase 2 (LRRK2), leading to aberrant kinase activity. Multiple pathogenic effects of enhanced LRRK2 activity have been identified, including loss of cilia and centrosomal cohesion defects. When phosphorylated by LRRK2, Rab8a and Rab10 bind to phospho-specific RILPL effector proteins. RILPL-mediated accumulation of pRabs proximal to the mother centriole is critical for initiating deficits in ciliogenesis and centrosome cohesion mediated by LRRK2. We hypothesized that Rab-derived phospho-mimics may serve to block phosphorylated Rab proteins from docking with RILPL in the context of hyperactive LRRK2 mutants. This would serve as an alternative strategy to downregulate pathogenic signaling mediated by LRRK2, rather than targeting LRRK2 kinase activity itself. To test this theory, we designed a series of constrained peptides mimicking phosphorylated Switch II derived from Rab8. These RILPL interacting peptides, termed RIP, were further shown to permeate cells. Further, several peptides were found to bind RILPL2 and restore ciliogenesis and centrosomal cohesion defects in cells expressing PD-associated mutant LRRK2. This research demonstrates the utility of constrained peptides as downstream inhibitors to target pathogenic LRRK2 activity and may provide an alternative approach to target specific pathways activated by LRRK2.

XB130 inhibits healing of diabetic skin ulcers through the PI3K/Akt signalling pathway.

BACKGROUND: Diabetic skin ulcers, a significant global healthcare burden, are mainly caused by the inhibition of cell proliferation and impaired angiogenesis. XB130 is an adaptor protein that regulates cell proliferation and migration. However, the role of XB130 in the development of diabetic skin ulcers remains unclear. AIM: To investigate whether XB130 can regulate the inhibition of proliferation and vascular damage induced by high glucose. Additionally, we aim to determine whether XB130 is involved in the healing process of diabetic skin ulcers, along with its molecular mechanisms. METHODS: We conducted RNA-sequencing analysis to identify the key genes involved in diabetic skin ulcers. We investigated the effects of XB130 on wound healing using histological analyses. In addition, we used reverse transcription-quantitative polymerase chain reaction, Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, immunofluorescence, wound healing, and tubule formation experiments to investigate their effects on cellular processes in human umbilical vein endothelial cells (HUVECs) stimulated with high glucose. Finally, we performed functional analysis to elucidate the molecular mechanisms underlying diabetic skin ulcers. RESULTS: RNA-sequencing analysis showed that the expression of XB130 was up-regulated in the tissues of diabetic skin ulcers. Knockdown of XB130 promoted the healing of skin wounds in mice, leading to an accelerated wound healing process and shortened wound healing time. At the cellular level, knockdown of XB130 alleviated high glucose-induced inhibition of cell proliferation and angiogenic impairment in HUVECs. Inhibition of the PI3K/Akt pathway removed the proliferative effects and endothelial protection mediated by XB130. CONCLUSION: The findings of this study indicated that the expression of XB130 is up-regulated in high glucose-stimulated diabetic skin ulcers and HUVECs. Knockdown of XB130 promotes cell proliferation and angiogenesis via the PI3K/Akt signalling pathway, which accelerates the healing of diabetic skin ulcers.

Emerging Treatments for Reactive Cutaneous Capillary Endothelial Proliferation.

Background: Reactive cutaneous capillary endothelial proliferation (RCCEP) is a common, burdensome adverse event that occurs in up to 88% of patients treated with camrelizumab. Without treatment, RCCEP is associated with social stigma and low quality of life. However, the optimal management of RCCEP remains inconclusive. Aims and Objectives: to elucidate the pathogenesis and clinical manifestations of RCCEP and systematically review the existing different therapeutic options for this dermatologic toxicity to encourage the selection of the most appropriate approaches for individual comprehensive management. Materials and Methods: As far as we know, we have systematically reviewed all cases complicated with RCCEP worldwide, and summarized the advantages and disadvantages of existing treatment methods. In addition, we report a successful case of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in a 61-year-old male Chinese patient who developed RCCEP after camrelizumab immunotherapy. Owing to the patient's advanced age, complicated medication history, and hyperalgesia, ALA-PDT was performed. The multiple lesions on his chest and buttocks showed rapid relief within 1 week of a single treatment session. Clinical recurrence was not observed within 6 months following treatment. Results: The current treatment of RCCEP is challenging and there is a lack of globally recommendations based on strict therapeutic regimens or clinical trials. Based on this case, we found that ALA-PDT is a safe and effective treatment option for RCCEP. This case also highlights the coexistence of several camrelizumab-induced dermatologic immune-related adverse events, which has never been reported before. Conclusion: New therapies for RCCEP have emerged in recent years. Dermatologists should raise better awareness of the complexity of drug eruption and the need for early diagnosis and medical intervention.

Trend analysis of mortality rates and causes of death in children under 5 years of age in Xuzhou, China from 2016 to 2020.

Objectives: To analyze the trends in mortality and causes of death among children under 5 years of age in Xuzhou, China between 2016 and 2020, in order to protect children's health and provide a basis for formulating child survival, development, and protection strategies. Methods: A population-based epidemiological study was conducted. Data were obtained from the Xuzhou Center for Disease Control Prevention. We input the data into the excel database and analyzed with SPSS20.0. Results: There were 1,949 children under 5 years of age died in Xuzhou, The number of deaths from 2016 to 2020 were 573 (29.40%), 577 (29.60%), 371 (19.04%), 334 (17.14%), and 94 (4.82%) respectively, mortality in children showed a downward trend. The number of deaths was relatively high in January (195 cases, 10.01%), February (190 cases, 9.75%), and May (180 cases, 9.24%), while was relatively small in July (147 cases, 7.54%), August (139 cases, 7.13%), and September (118 cases, 6.05%). The leading causes of death (COD) in children under 5 years of age were neonatal suffocation and hypoxia (323 cases, 16.57%). Pizhou (528 cases, 27.09%) showed the highest number of deaths in children under 5 years of age in China, and the Kaifa (25 cases, 1.28%) zone showed the lowest death toll. Conclusions: Our research suggested that the current strategies for reducing child mortality should prioritize the actions on neonatal deaths and conduct targeted interventions for the main cause.

TREM2 as a Potential Immune-Related Biomarker of Prognosis in Patients with Skin Cutaneous Melanoma Microenvironment.

Background: The skin cutaneous melanoma (SKCM) is a devastating form of skin cancer triggered by genetic and environmental factors, and the incidence of SKCM has rapidly increased in recent years. Immune infiltration of the tumor microenvironment is positively associated with overall survival in many tumors. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and a crucial signaling hub for multiple pathological pathways that mediate immunity. Although numerous evidences suggest a crucial role for TREM2 in tumorigenesis of some tumors, no systematic SKCM analysis of TREM2 is available. Mehods. The relationship between TREM2 expression and diagnostic and prognostic value of SKCM patients via using The Cancer Genome Atlas (TCGA) data. The expression level of TREM2 and clinical characteristic correlation in SKCM patients were assessed by the Wilcoxon rank sum test. The cox regression methods, Kaplan-Meier (KM), and log-rank test were used to assess the impact of TREM2 expression on the overall survival (OS). Furthermore, the Gene Set Enrichment Analysis (GSEA) and TIMER were performed to evaluate the enrichment pathways and potential functions and quantify the immune cell infiltration level for TREM2 expression. Results: The TREM2 in SKCM sample expression levels was significantly higher than in normal tissues. Moreover, this expression level of TREM2 was also associated with the BMI of SKCM patients. KM overall survival analysis and OS curve displayed that a high-level TREM2 expression was significantly correlated with a better SKCM prognosis of patients as compared with a low level of TREM2 expression. The GSEA analysis also revealed that TREM2 was associated with immune functions, such as neutrophil activation. Conclusion: TREM2 played a crucial role in SKCM, which might be a prognostic biomarker and correlated with immune infifiltrates in SKCM patients.

Amino porphyrin-peptide assemblies induce ribosome damage and cancer stem cell inhibition for an enhanced photodynamic therapy.

Cancer stem cells (CSCs) are the subpopulation of tumor cells with the properties of tumorigenesis, multilineage differentiation potential and self-renewal, which is the driving force of tumor recurrence and metastasis. However, targeting CSCs is still the main challenge in cancer therapy due to their rapid growth and fast mutation rate. Herein, we developed a simple strategy of photodynamic therapy (PDT) targeting CSCs, dependent on much more abundant ribosomes in CSCs. The interactions between positively charged nanoparticles with negatively charged nucleic acids architectures in cancer cells could lead ribosomes targeting as well as CSCs targeting. The co-assembly of simple amino porphyrin (m-TAPP) with short peptide (Fmoc-L3-OMe) formed nanoparticles (NPs) with good biocompatibility and photoactivity, became positively charged due to low pH value of tumour microenvironment, and efficiently accessed cancer cell ribosome, approached cancer cell nuclei, therefore enriched in the fast-amplifying CSCs. The inhibitive effect on CSCs by m-TAPP assemblies was verified by the significant reduction of CSCs markers CD44, CD133 and ribosome amount in cancer cells and tissues. Upon light irradiation, the NPs induced ROS generation to provoke destructive cancer cell ribosome damage and subsequent apoptosis to prevent tumor growth markedly. Based on the assemblies of small organic molecules, our study not only achieves ribosome degradation induced cancer cells apoptosis, but also indicates new possibility of performing CSCs targeting PDT.

BIOCHIP mosaic for the diagnosis of autoimmune bullous diseases in Chinese patients.

BACKGROUND: Autoimmune blistering diseases (AIBDs) are a group of fatal diseases with specific autoantibodies. BIOCHIP mosaic is a novel and all-in-one measure used for the rapid diagnosis of AIBDs. OBJECTIVES: To evaluate the diagnostic accuracy based on BIOCHIP mosaic (FA1501-1005-60) in Chinese patients with AIBDs. MATERIALS AND METHODS: Seventy-seven patients with AIBDs and 20 controls were enrolled. The BIOCHIP mosaic was performed using both serum and plasma samples. RESULTS: Based on BIOCHIP mosaic, the data from paired plasma and serum samples demonstrated a high degree of concordance (Cohen's kappa = 0.896-1.000) for autoantibodies against Dsg1, Dsg3, BP180-NC16A-4X, BP230gC, prickle-cell desmosomes, and pemphigoid antigens. Moreover, BIOCHIP mosaic also demonstrated a high degree of consistency for the detection rate of anti-Dsg1, Dsg3, plakins, BP180-NC16A-4X and non-collagenous domain of type VII collagen autoantibodies for the diagnosis of pemphigus foliaceus (77.3%), pemphigus vulgaris (88.6%), paraneoplastic pemphigus (100.0%), bullous pemphigoid (92.8%) and epidermolysis bullosa acquisita (99.0%), respectively. CONCLUSION: Using BIOCHIP mosaic, serum and plasma samples may be used interchangeably at 1/10 dilution. Overall, the BIOCHIP mosaic was shown to be a useful and accurate tool for the diagnosis of AIBDs.

Extremities of the N-terminus of envoplakin and C-terminus of its linker subdomain are major epitopes of paraneoplastic pemphigus.

BACKGROUND: Autoantibodies against N-terminal domains and linker subdomains of envoplakin (EVPL) and periplakin (PPL) were frequently detected in sera of paraneoplastic pemphigus(PNP) patients. OBJECTIVES: To further investigate finer epitopes of EVPL and PPL, and evaluate their associations with clinical aspects of PNP. METHODS: We produced 12 overlapping truncated fragments of these regions in Escherichia coli, and measured their reactivities to sera of 65 PNP patients and 50 healthy volunteers by enzyme-linked immunosorbent assays (ELISA). Then appropriate statistics were performed to evaluate the correlation between antibodies against different fragments and clinical information of patients. RESULTS: EVPL-N1 (aa1-141) and EVPL-L3 (aa1684-1784) were recognized by PNP sera at the same sensitivity of 75.38% (49/65) with specificities of 98% and 92%, respectively. Although neoplasm types were not associated with any fragment, the ELISA of these fragments and indirect immunofluorescence on rat bladder complemented each other in detecting PNP. Meanwhile, levels of autoantibodies against EVPL-N3 were elevated with PNP accompanied with bronchiolitis obliterans or presented with lichen planus-like lesions (P<0.05). No influence of autoantibodies against any fragments on prognosis of the patients was observed by Cox regression test, though antibodies against some fragments were higher in the dead patients. CONCLUSIONS: The study proved antigenic epitopes were mainly concentrated on EVPL-N1 and EVPL-L3 in PNP. Autoantibodies against EVPL-N3 might associate with those patients accompanied with bronchiolitis obliterans or presented with lichen planus-like lesions.

Association of conventional risk factors for cardiovascular disease with IMT in middle-aged and elderly Chinese.

To study the association between known risk factors for cardiovascular disease and intima-media thickness (IMT) in the carotid and popliteal arteries in middle-aged and elderly Chinese adults. 686 middle aged and elderly Chinese adults from the China Da Qing Diabetes Prevention Study who had full clinical, laboratory, ultrasound examination results were enrolled in the study. Common carotid artery (CCA) and popliteal artery (PA) IMT were obtained using high resolution ultrasound machine. Pearson's or Spearman's correlation analysis and logistic regression analysis were used to determine association between risk factors [age, gender, tobacco smoking, body mass index (BMI), diabetes mellitus (DM), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, total triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, glycosylated hemoglobin (HbA1c)] and CCA- or PA-IMT. The age range of the study population was 45-87 years, 384 of them (56 %) were women. The prevalence of high blood pressure and DM was 60.6 and 68.8 %, respectively. Participants in DM group tended to be older, had greater value for SBP, HbA1c and PA-IMT, but smaller value for DBP than those in control group. Smoke status, BMI, blood lipids and CCA-IMT were not statistically different between groups. Pearson's or Spearman's rank correlation analysis showed that CCA-IMT had a positive correlation with age, gender, DM, SBP, BMI and HbA1c, negative correlation with HDL-C. PA-IMT showed a positive correlation with age, gender and SBP. Univariate logistic regression analysis showed that elevation of age, SBP, BMI, HbA1c and having DM were significant predictors of CCA-IMT thickening, so was reduction of HDL-C. Risk factors that predicted significant thickening of PA-IMT were age, gender, tobacco smoking. After adjusted for age and gender, except HDL-C, the other four risk factors (SBP, BMI, HbA1c and having DM) that predicted CCA-IMT thickening remained significant; however none of the risk factors predicted PA-IMT thickening after adjusted for age and gender. The current results provide evidence that CCA-IMT is a superior marker for atherosclerosis compared with PA-IMT. Aggressive control of SBP, HbA1c and proper control of weight may postpone thickening of CCA-IMT.