MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks.

BACKGROUND: Patients with deleterious variants in MYSM1 have an immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity. MYSM1 is a histone deubiquitinase with established activity in regulating gene expression. MYSM1 also localizes to sites of DNA injury but its function in cellular responses to DNA breaks has not been elucidated. OBJECTIVES: This study sought to determine the activity of MYSM1 in regulating DNA damage responses (DDRs) to DNA double-stranded breaks (DSBs) generated during immunoglobulin receptor gene (Ig) recombination and by ionizing radiation. METHODS: MYSM1-deficient pre- and non-B cells were used to determine the role of MYSM1 in DSB generation, DSB repair, and termination of DDRs. RESULTS: Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression. Radiosensitivity testing in patient's peripheral blood lymphocytes showed constitutive γH2AX, a marker of DNA damage, in B cells in the absence of irradiation, suggesting a role for MYSM1 in response to DSBs generated during Ig recombination. Suppression of MYSM1 in pre-B cells did not alter generation or repair of Ig DSBs. Rather, loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling. Loss of MYSM1 also led to protracted DDRs in U2OS cells with irradiation induced DSBs. CONCLUSIONS: MYSM1 regulates termination of DNA damage responses but does not function in DNA break generation and repair.

Transforming growth factor Beta 3 is required for excisional wound repair in vivo.

Wound healing is a complex process that relies on proper levels of cytokines and growth factors to successfully repair the tissue. Of particular interest are the members of the transforming growth factor family. There are three TGF-ß isoforms-TGF- ß 1, 2, and 3, each isoform showing a unique expression pattern, suggesting that they each play a distinct function during development and repair. Previous studies reported an exclusive role for TGF-ß 3 in orofacial development and a potent anti-scarring effect. However, the role of TGF- ß 3 in excisional wound healing and keratinocyte migration remains poorly understood. We tested the effect of TGF-ß 3 levels on excisional cutaneous wounds in the adult mouse by directly injecting recombinant TGF-ß 3 or neutralizing antibody against TGF-ß 3 (NAB) in the wounds. Our results demonstrate that TGF-ß 3 does not promote epithelialization. However, TGF-ß 3 is necessary for wound closure as wounds injected with neutralizing antibody against TGF-ß 3 showed increased epidermal volume and proliferation in conjunction with a delay in keratinocyte migration. Wild type keratinocytes treated with NAB and Tgfb3-deficient keratinocytes closed an in vitro scratch wound with no delay, suggesting that our in vivo observations likely result from a paracrine effect.

Autopsy after traumatic death--a shifting paradigm.

OBJECTIVE: The role of autopsy in evaluating missed injury after traumatic death is well established and discussed in the literature. The frequency of incidental findings in trauma patients has not been reported. We believe that incidental findings are under recognized and reported by trauma surgeons. PATIENTS AND METHODS: This prospective, descriptive, cohort study was conducted at a Level 1 trauma center in a rural state. Four hundred ninety-six deaths over a 4-y period were identified from the trauma registry. Two hundred four complete autopsies were available for review. One thousand eighteen traumatic diagnoses were identified from 204 autopsies and corresponding medical records by trauma surgeons blinded to patient identity. The surgeons recorded missed diagnoses, incidental diagnoses identified at autopsy, and diagnoses known at the time of death confirmed by autopsy. RESULTS: The surgeons had a κ-score of 0.82-0.84. Forty-two patients (21% of patients) had 68 severe missed injuries; 67 patients (33% of patients) had 94 minor missed injuries. Twenty-eight patients (14%) had significant incidental findings including premature atherosclerosis, multiple endocrine neoplasia, tuberculosis, and others. CONCLUSIONS: The autopsy after traumatic death is more than a mechanism of quality control and teaching. A high proportion of patients will have incidental findings important to family members, and have public health importance. Systems need to be developed to review autopsy results with attention to identifying and communicating incidental findings. Given the incidence of significant missed injuries and incidental findings, the autopsy continues to have an important role in health care.