Histone acetyltransferase P300 deficiency promotes ferroptosis of vascular smooth muscle cells by activating the HIF-1α/HMOX1 axis.

BACKGROUND: E1A-associated 300-kDa protein (P300), an endogenous histone acetyltransferase, contributes to modifications of the chromatin landscape of genes involved in multiple cardiovascular diseases. Ferroptosis of vascular smooth muscle cells (VSMCs) is a novel pathological mechanism of aortic dissection. However, whether P300 regulates VSMC ferroptosis remains unknown. METHODS: Cystine deprivation (CD) and imidazole ketone erastin (IKE) were used to induce VSMC ferroptosis. Two different knockdown plasmids targeting P300 and A-485 (a specific inhibitor of P300) were used to investigate the function of P300 in the ferroptosis of human aortic smooth muscle cells (HASMCs). Cell counting kit-8, lactate dehydrogenase and flow cytometry with propidium iodide staining were performed to assess the cell viability and death under the treatment of CD and IKE. BODIPY-C11 assay, immunofluorescence staining of 4-hydroxynonenal and malondialdehyde assay were conducted to detect the level of lipid peroxidation. Furthermore, co-immunoprecipitation was utilized to explore the interaction between P300 and HIF-1α, HIF-1α and P53. RESULTS: Compared with normal control, the protein level of P300 was significantly decreased in HASMCs treated with CD and IKE, which was largely nullified by the ferroptosis inhibitor ferrostatin-1 but not by the autophagy inhibitor or apoptosis inhibitor. Knockdown of P300 by short-hairpin RNA or inhibition of P300 activity by A-485 promoted CD- and IKE-induced HASMC ferroptosis, as evidenced by a reduction in cell viability and aggravation of lipid peroxidation of HASMCs. Furthermore, we found that hypoxia-inducible factor-1α (HIF-1α)/heme oxygenase 1 (HMOX1) pathway was responsible for the impacts of P300 on ferroptosis of HASMCs. The results of co-immunoprecipitation demonstrated that P300 and P53 competitively bound HIF-1α to regulate the expression of HMOX1. Under normal conditions, P300 interacted with HIF-1α to inhibit HMOX1 expression, while reduced expression of P300 induced by ferroptosis inducers would favor HIF-1α binding to P53 to trigger HMOX1 overexpression. Furthermore, the aggravated effects of P300 knockdown on HASMC ferroptosis were largely nullified by HIF-1α knockdown or the HIF-1α inhibitor BAY87-2243. CONCLUSION: Thus, our results revealed that P300 deficiency or inactivation facilitated CD- and IKE-induced VSMC ferroptosis by activating the HIF-1α/HMOX1 axis, which may contribute to the development of diseases related to VSMC ferroptosis.

[Analysis of Long-Term Prognostic Factors Based on Nutritional Status in Patients with Multiple Myeloma].

OBJECTIVE: To explore the prognostic factors of patients with multiple myeloma (MM) based on nutritional status. METHODS: The Controlling Nutritional Status (CONUT) score and clinical parameters at diagnosis of 203 newly diagnosed MM patients hospitalized in the department of hematology, Wuxi People's Hospital from January 1, 2007 to June 30, 2019 were analyzed retrospectively. The best cut-off value was determined by ROC curve, and the patients were divided into high CONUT group (>6.5 points) and low CONUT group (≤6.5 points); through COX regression multivariate analysis of overall survival (OS) time, CONUT, ISS stage, LDH and treatment response were selected for multiparameter prognostic stratification. RESULTS: The OS of MM patients in high CONUT group was shorter. The low-risk group (≤2 points) of the multiparameter risk stratification had longer OS time and progression-free survival (PFS) time compared with the high-risk group (>2 points), and it was also effective for different age or karyotype subgroups, new drug groups containing bortezomib and transplant-ineligible subgroup. CONCLUSION: The risk stratification of MM patients based on CONUT, ISS stage, LDH and treatment response is worthy of clinical application.

Impact of Extended Treatment Interval on the Prognosis of Multiple Myeloma Patients: A Retrospective Study.

INTRODUCTION: Recently, treatment with proteasome inhibitors and immunomodulators has improved the prognosis of multiple myeloma (MM). However, in a complex real-world situation, the patient's ability to undergo regular and timely treatment as prescribed in clinical trials has not been studied, as well as the impact of extended treatment intervals due to different reasons. This study aimed to evaluate the treatment interval and clinical characteristics of 122 patients with primary myeloma in our hospital and explore the prognostic effects of different treatment intervals. METHODS: In total, 122 patients with MM were analyzed retrospectively in our hospital from January 2007 to June 2018. The clinical and laboratory data (such as age, International Staging System [ISS] stage, chromosome, etc.) and subsequent treatment intervals were analyzed. The Cox proportional hazard regression model was used for univariate and multivariate analyses of overall survival (OS) and progression-free survival. The Kaplan-Meier method was used in survival analysis, and the log-rank test was used to test survival difference. p < 0.05 was considered to indicate statistical significance. RESULTS: We found that prolonging the interval treatments (>28 days) shortened the OS in the younger and high-risk subgroups. On the contrary, the OS of the older and low-risk subgroups was not shortened. OS was also shortened in patients who were suitable for transplantation but did not receive a transplant. Univariate and multivariate analyses showed that extension of treatment interval was a risk factor for OS shortening. In addition, prolonged treatment interval was due to iatrogenic and family reasons. CONCLUSION: Extended treatment interval is unfavorable in young and high-risk MM patients and those suitable for transplantation but who did not receive a transplant. However, it has a faint impact on the elderly and low-risk subgroups.

[Long-Term Retrospective Analysis of Prognostic Factors in Patients with Newly Diagnosed Multiple Myeloma without Hematopoietic Stem Cell Transplantation].

OBJECTIVE: To retrospectively analyze the cases of multiple myeloma treated with chemotherapeatic regimens based on thalidomide, and to investigate the factors affecting MM patients treated using chemotherapeutic regimens with or without bortezomib. METHODS: The clinical, laboratorial and survival data of 200 patients with newly diagnosed MM from October 2007 to December 2015 were collected, and the correlation of clinical and laboratorial indicators with the clinical characteristics and prognosis of MM patients was analyzed by using χ2 test, COX regression analysis, Kaplan-Meier method and Log-rank test. RESULTS: Multivariable analysis showed that age (≥65 years old), ISS staging (Ⅲ), complex karyotypes and no-complete remission were the independent prognostic factors for OS in bortezomib-treated group, while the ß2-MG (≥8.95 mg/L), no-complete remission were the independent prognostic factros for OS in traditional therapy group. In addition, the MPI-1 myeloma prognostic index 1, consisted of age, complex karyotypes and complete remission in bortezomib-treated group, and MPI-2 consisted of ß2-MG (≥8.95 mg/L), complex karyotypes, complete remission in traditional therapy group were suitable for evaluating the pregnosis of MM patients treated with regimens contiaining bortezomib and traditional chemotherapentic regimans. CONCLUSION: The differences of prognostic factors exist in MM patients treated with different chemotherapeutic regimens, moreover, the patients with comples karyotypes and no-complete remisson have poor prognosis. The MPI as more simple and easy clinical parameter, may be come an useful and complemental method for evaluation of prognosis except ISS and R-ISS.

[Prognostic Value of Red Blood Cell Distribution Width in Senile Potients with Non-trans planted Multiple Myeloma].

OBJECTIVE: To investigate the prognostic value of red blood cell distribution width (RDW) in senile patients with non-transplanted multiple myeloma (MM). METHODS: The RDW and clinical parameters such as ß-2 microglobulin, creatiain, LDH and so on at diagnosis of 99 newly diagnosed senile MM patients were analysed retrospectively. The 99 patients were treated with chemotherapeutic regimens with or without bertezomib. The patients were divided into 2 groups: high (≥17.95%) and low (<17.95%) RDW groups according to ROC curve, then the prognosis of patients was compared between high and low RDW groups. RESULTS: The levels of hemoglobin and C-reactive protein in high RDW group were lower than those in low RDW group, while the ratio of myeloma cells in high RDW group was higher than that in low RDW group. The unvariate and multivariate analyses in patients trented with chemotherapeutic regimen without bertezomib showed that the overall survival (OS) and progress free survival (PFS) time were shorter, while the high RDW group demonstrated the showter PFS in patients treated with chemotherapeutic regimen including bortezomib. CONCLUSION: he RDW as a simple and easly available biomarker, suggests unfavorable prognosis for senile patients with non-transplanted MM; however the prognosis shows a certain difference on the basis of different chemotherapeutic regimens.

Association of CD117 and HLA-DR expression with shorter overall survival and/or progression-free survival in patients with multiple myeloma treated with bortezomib and thalidomide combination treatment without transplantation.

Certain immunophenotypes in multiple myeloma (MM), including CD56 and CD117, have been reported to be associated with overall survival (OS). However, previous reports have ignored the impact of different treatment regimens and the long-term prognostic value of immunophenotyping in MM when treated with novel agents, including thalidomide and bortezomib, in the absence of transplantation for autologous stem cell transplantation and allo-hematopoietic stem cell transplantation. To further understand the long-term prognostic value of immunophenotyping in MM, when treated with bortezomib combined with thalidomide-based regimens without transplantation, 80 patients who were newly diagnosed between January 2007 and December 2015, were analyzed retrospectively. In contrast to previous studies, no significant survival time difference was observed between CD56+/CD117+ and CD56-/CD117- groups. Multivariate analysis suggested that human leukocyte antigen-antigen D-related (HLA-DR)+ was independently associated with shorter OS and progression-free survival (PFS), while CD117+ was an independent prognostic factor for decreased PFS. In addition, the myeloma prognostic index (MPI), defined by HLA-DR+, age ≥65 years and international staging system stage III, was suitable for risk stratification of patients treated with novel agents for OS and PFS. The results of the current study suggested that HLA-DR+ patients had a shorter OS and PFS and CD117+ patients had shorter PFS. HLA-DR+ or CD117+ was sufficient to affect survival. Evaluating these markers may reveal valuable prognostic factors for MM in patients receiving bortezomib combined with thalidomide-based regimens without autologous stem cell transplantation and allo-hematopoietic stem cell transplantation). MPI may describe an accessible tool to predict the prognosis of patients with MM.

Extramammary Paget's disease resistant to surgery and imiquimod monotherapy but responsive to imiquimod combination topical chemotherapy with 5-fluorouracil and retinoic acid: a case report.

Extramammary Paget's disease (EMPD) is an uncommon skin neoplasm that usually affects the elderly population and occurs in the genital, anorectal, or axillary areas. The recommended treatment of EMPD involves surgical excision, including Mohs micrographic surgery; however, surgery is associated with a high rate of recurrence. There have been reports of successful treatment of recurrence with monochemotherapy involving topical imiquimod 5% cream. We report a case of EMPD recurrence after surgery that was resistant to imiquimod monotherapy but that completely resolved after imiquimod was combined with topical 5-fluorouracil (5-FU) and retinoic acid. To our knowledge, this is the first reported case of imiquimod combination therapy with 5-FU and retinoic acid for the treatment of recurrent EMPD.