DDX3X loss is an adverse prognostic marker in diffuse large B-cell lymphoma and is associated with chemoresistance in aggressive non-Hodgkin lymphoma subtypes.

Funder: addenbrooke's charitable trust, cambridge university hospital

Suggested Rationale for Prevention and Treatment of Glucocorticoid-Induced Bone Loss in Dermatologic Patients

Glucocorticoid-induced bone loss is the most predictable and debilitating complication of prolonged administration of systemic corticosteroids. It has been shown that patients treated with glucocorticoids have an increased risk of osteoporotic fractures, resulting in marked morbidity, particularly in elderly individuals. Studies on the effect of glucocorticoids on bone density and the efficacy of treatment regimens (namely, bisphosphonates and calcitonin) for preventing bone loss have been mainly on patients with asthma and rheumatologic diseases. However, no long-term studies have been done on the impact of prolonged corticosteroid treatment in dermatologic patients. The purpose of this review is to raise awareness about osteoporosis and new preventive measures among the dermatologists treating patients with glucocorticoids at high doses and for long periods. We summarize the assessment methods used to evaluate this condition, examine the results of clinical trials of drugs, and suggest a practical approach to managing corticosteroid osteoporosis in dermatologic patients based on data collected from published articles.--

Overexpression of CDC42SE1 in A431 Cells Reduced Cell Proliferation by Inhibiting the Akt Pathway

Cell division cycle 42 (CDC42), a small Rho GTPase, plays a critical role in many cellular processes, including cell proliferation and survival. CDC42 interacts with the CRIB (Cdc42- and Rac-interactive binding) domain of CDC42SE1, a small effector protein of 9 kDa. We found that the expression of CDC42SE1 was reduced in human skin cancer samples relative to matched perilesional control. Exogenous expression of CDC42SE1 but not CDC42SE1H38A (mutation within CRIB domain) in A431 cells (A431SE1, A431SE1-H38A) reduced cell proliferation. Antibody microarray analysis of A431Ctrl and A431SE1 lysate suggested that reduced A431SE1 cells proliferation was due to inhibition of Akt pathway, which was confirmed by the reduced P-Akt and P-mTOR levels in A431SE1 cells compared to A431Ctrl cells. This suggests that CDC42SE1 modulates the CDC42-mediated Akt pathway by competing with other effector proteins to bind CDC42. A431SE1 cells formed smaller colonies in soft agar compared to A431Ctrl and A431SE1-H38A cells. These findings correlate with nude mice xenograft assays, where A431SE1 cells formed tumors with significantly-reduced volume compared to the tumors formed by A431Ctrl cells. Our results suggest that CDC42SE1 is downregulated in skin cancer to promote tumorigenesis, and thus CDC42SE1 might be an important marker of skin cancer progression

N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP

Neural Wiskott-Aldrich Syndrome Protein (N-WASP) regulates actin cytoskeleton remodeling. It has been known that reduced N-WASP expression in breast and colorectal cancers is associated with poor prognosis. Here, we found reduced N-WASP expression in squamous cell carcinoma (SCC) patient samples. The SCC cell line HSC-5 with reduced N-WASP expression was used to generate HSC-5CN (control) and HSC-5NW (N-WASP overexpression) cells. HSC-5NW cells had reduced cell proliferation and migration compared to HSC-5CN cells. HSC-5NW cells had increased phospho-ERK2 (extracellular signal-regulated kinase 2), phosphorylated Forkhead box protein class O1 (FOXO1) and reduced nuclear FOXO1 staining compared to HSC-5CN cells. Proteasome inhibition stabilized total FOXO1, however, not nuclear staining, suggesting that FOXO1 could be degraded in the cytoplasm. Inhibition of ERK2 enhanced nuclear FOXO1 levels and restored cell proliferation and migration of HSC-5NW to those of HSC-5CN cells, suggesting that ERK2 regulates FOXO1 activity. The expression of thioredoxin-interacting protein (TXNIP), a FOXO1 target that inhibits thioredoxin and glucose uptake, was higher in HSC-5NW cells than in HSC-5CN cells. Knockdown of TXNIP in HSC-5NW cells restored cell proliferation and migration to those of HSC-5CN cells. Thus, we propose that N-WASP regulates cell proliferation and migration via an N-WASP-ERK2-FOXO1-TXNIP pathway.Ministry of Education (MOE)Published versionThis work was supported by the Academic Research Fund Tier 2 (MOE 2013-T2-2-031) and Academic Research Fund Tier 1 (MOE) RG31/20 and RG154/17 grants from the Ministry of Education of Singapore

Prevention of glucocorticoid-induced osteoporosis in immunobullous diseases with alendronate: a randomized, double-blind, placebo-controlled study

To evaluate the efficacy and safety of oral alendronate sodium therapy once daily in preventing glucocorticoid-induced bone loss in patients with immunobullous skin diseases treated with long-term glucocorticoid therapy. A 12-month randomized, double-blind, placebo-controlled trial. A tertiary referral dermatology center in Singapore. Patients newly diagnosed as having an immunobullous disease and deemed to require at least 6 months of systemic glucocorticoid therapy. The patients were randomized to receive either oral alendronate sodium (10 mg/d) or a matching placebo for 12 months. All patients also received concurrent calcium with vitamin D, 2 tablets daily. Percent change in bone mineral density (BMD) at the lumbar spine and the femoral neck at 12 months. A total of 29 patients (alendronate [n = 15], placebo [n = 14]) were evaluated. The percent change in BMD in the alendronate group was +3.7% and +3.5% at the lumbar spine and the femoral neck, respectively, whereas in the placebo group, it was -1.4% and -0.7% at the lumbar spine and the femoral neck, respectively. The increase in BMD observed in the alendronate group compared with the placebo group was statistically significant at both the lumbar spine (P = .01) and the femoral neck (P = .01). There was also a statistically significant decrease in serum heat-labile alkaline phosphatase levels after 12 months (-32.6%, P < .01) in the alendronate group but not in the placebo group. Adverse events were generally minor, and the frequency of occurrence did not differ significantly between both treatment groups (P = .59). There were statistically significant increases in BMD at both the lumbar spine (P = .01) and the femoral neck (P = .01) with alendronate therapy. It is imperative to use bisphophonate therapy in patients with immunobullous disorders who are receiving oral corticosteroids because it largely prevents the morbidity associated with low BMD

DDX3X loss is an adverse prognostic marker in diffuse large B-cell lymphoma and is associated with chemoresistance in aggressive non-Hodgkin lymphoma subtypes

10.1186/s12943-021-01437-0MOLECULAR CANCER20

Genome-wide association study of B cell non-Hodgkin lymphoma identifies 3q27 as a susceptibility locus in the Chinese population

10.1038/ng.2666Nature Genetics457804-807NGEN