Co-targeting bromodomain and extra-terminal proteins and MCL1 induces synergistic cell death in melanoma

The treatment of melanoma has been markedly improved by the introduction of targeted therapies and checkpoint blockade immunotherapy. Unfortunately, resistance to these therapies remains a limitation. Novel anticancer therapeutics targeting the MCL1 anti-apoptotic protein have shown impressive responses in haematological cancers but are yet to be evaluated in melanoma. To assess the sensitivity of melanoma to new MCL1 inhibitors, we measured the response of 51 melanoma cell lines to the novel MCL1 inhibitor, S63845. Additionally, we assessed combination of this drug with inhibitors of the bromodomain and extra-terminal (BET) protein family of epigenetic readers, which we postulated would assist MCL1 inhibition by downregulating anti-apoptotic targets regulated by NF-kB such as BCLXL, BCL2A1 and XIAP, and by upregulating pro-apoptotic proteins including BIM and NOXA. Only 14% of melanoma cell lines showed sensitivity to S63845, however, combination of S63845 and I-BET151 induced highly synergistic apoptotic cell death in all melanoma lines tested and in an in vivo xenograft model. Cell death was dependent on caspases and BAX/BAK. Although the combination of drugs increased the BH3-only protein, BIM, and downregulated anti-apoptotic proteins such as BCL2A1, the importance of these proteins in inducing cell death varied between cell lines. ABT-199 or ABT-263 inhibitors against BCL2 or BCL2 and BCLXL, respectively, induced further cell death when combined with S63845 and I-BET151. The combination of MCL1 and BET inhibition appears to be a promising therapeutic approach for metastatic melanoma, and presents opportunities to add further BCL2 family inhibitors to overcome treatment resistance.     

Peripheral pulmonary artery aneurysm in a patient with limited respiratory reserve: controlled resection using cardiopulmonary bypass

Pulmonary artery aneurysms are rare lesions for which operative management is not frequently undertaken. When operation is indicated, central lesions involving the pulmonary trunk, right main pulmonary artery, or left main pulmonary artery are repaired using cardiopulmonary bypass. Peripheral aneurysms in segmental intrapulmonary arteries have been managed most frequently by lobectomy, but occasionally by aneurysmectomy and pulmonary arterial repair. We used cardiopulmonary bypass for peripheral pulmonary aneurysmectomy in a patient with limited respiratory reserve because he had undergone prior contralateral bilobectomy; this allowed controlled resection while preserving a maximal amount of pulmonary parenchyma.     

Asymptomatic HIV infection does not cause EEG abnormalities: results from the Multicenter AIDS Cohort Study (MACS)

We conducted EEG testing in 200 asymptomatic homosexual men, half of whom were HIV seropositive. We chose to include half of the subjects because they were rated as impaired on a neuropsychological screening test. We used both traditional visual EEG interpretation and quantitative EEG analysis. Abnormal EEGs and borderline degrees of EEG slowing occurred in 32% of these men. These EEG changes were not related to HIV serostatus. EEG changes did correlate with the impaired neuropsychological test performance. Clinicians faced with abnormal EEG results or borderline EEG slowing in an asymptomatic HIV-seropositive patient should not attribute the EEG change to effects of the serostatus itself but should look for other causes.     

Spatial learning deficits in adult children of alcoholic parents

This study investigated whether the visuospatial deficits displayed by chronic alcoholics are present in persons at risk for alcoholism. Participants were 34 matched social drinkers, half of whom were children of alcoholic parents and half of whom had no family alcoholism history. Ss with a family history of alcoholism displayed visuospatial learning that was significantly poorer than that displayed by Ss with no family alcoholism history. The learning patterns displayed by those with a family alcoholism history were similar to those displayed by previously studied detoxified alcoholics and young children of alcoholics using a similar learning task. Data suggest that visuospatial learning deficits may reflect an antecedent to rather than a consequence of chronic alcohol abuse.     

Investigation of a whole-body receiver coil operating at liquid nitrogen temperatures

This communication describes the design and application of a receiver coil operating at liquid nitrogen temperature and intended as a surface coil in a whole-body imager. Its particular application is seen as the external receiver for parasitic internal or implanted detectors.     

The role of sentinel node biopsy in the management of melanocytic lesions of uncertain malignant potential (MUMP).

Melanocytic lesions of uncertain malignant potential (MUMP) is a term which is useful in identifying melanocytic tumours where the distinction between benign and malignant is a histological problem. Sentinel node biopsy is recognised to provide unmatched prognostic information in melanoma patients, but has recently been advocated for diagnostic purposes in MUMP. We present the case of a seven-year-old girl who presented with a six-month history of a changing pigmented lesion on her left upper arm. Excision biopsy not only showed a melanocytic lesion with some spitzoid features but also marked atypia making it appropriate to use the term MUMP. Sentinel node biopsy was undertaken. This case demonstrates that sentinel node biopsy can be performed safely in children. Given the low morbidity of the procedure we advocate that this technique should be considered in this difficult diagnostic situation to further the management of these patients.