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.     

Morphometrics for cephalometric diagnosis.

This article demonstrates morphometric methods by applying them to an orthodontic sample. A total of 150 pretreatment cephalograms of consecutive patients (84 female, 66 male) were traced and digitized. Fifteen points were used for the analysis. The tracings were superimposed by the Procrustes method, and shape variability was assessed by principal component analysis. Approximately 70% of the total sample variability was incorporated in the first 5 principal components. The most significant principal component, accounting for 29% of shape variability, was the divergence of skeletal pattern; the second principal component, accounting for 20% of shape variability, was the anteroposterior maxillary relationship. It is recommended that Procrustes superimposition and principal component analysis be incorporated into routine cephalometric analysis for more valid and comprehensive shape assessment.     

Effects of tracheal extubation on coronary blood flow,myocardial metabolism and systemic haemodynamic responses

Global coronary blood flow and metabolism were measured in seven patients on the first postoperative day following coronary revascularization to test the hypothesis that tracheal extubation produces adverse haemodynamic responses akin to those observed during tracheal intubation. Regional coronary flow and metabolic measurements were made in five of the seven patients. Extubation from a continuous positive airway pressure (CPAP) of 5 cm H₂O was associated with a statistically significant rise in cardiac index from 3.44 ± 0.23 L · min^-1 · m^-2 to 3.73 ± 0.15L·min^-1 ·m^-2 related to an increase in stroke index, without significant changes in heart rate, mean arterial and pulmonary capillary wedge pressure. Consequently the changes in myocardial oxygen consumption (8.52 ± 0.55 to 8.85 ± 0.93 ml · min^-1) and coronary blood flow (172 ± 18 to 179 ± 17 ml·min^-1) were less prominent than those reported during intubation, where substantial rises in myocardial oxygen consumption and coronary flow occurred. Two patients experienced cardiac lactate production but there were no changes in systemic or coronary haemodynamics, nor were there clinical or electrocardiographic signs of ischaemia. We conclude that extubation does not appear to be associated with adverse systemic or coronary haemodynamic responses in patients following coronary bypass grafting. However, the revascularized myocardium may remain vulnerable to anaerobic metabolism in the immediate postoperative period. Pour savoir si comme ľintubation, ľextubation de la trachée provoque des perturbations hémodynamiques, on a mesuré le métabolisme et la circulation coronarienne globale chez sept patients, au lendemain ďun pontage aorto-coronarien. On a aussi calculé les valeurs régionales de ces mêmes variables pour cinq ďentre eux. Ľindex cardiaque de 3.44 ± 0.23 L · min^-1 · m^-2 sous pression positive en respiration spontanée (CPAP) de 5 cm. H₂O s’est élevé à 3.73 ± 0.15 L · min^-1 · m^-2 post-extubation avec une augmentation significative du volume ďéjection. La fréquence cardiaque et les pressions artérielles moyennes et capillaires pulmonaires n’ont pas changé. Ainsi ľaugmentation de la consommation ďoxygène du myocarde de 8.52 ± 0.55 à 8.85 ± 0.93 ml · min^-1 et celle du flot coronarien de 172 ± 18 à 179 ± 17 ml · min^-1 ont été moindres que celles, importantes, déjà observées lors de ľintubation. On a noté chez deux patients une production de lactate par le myocarde, sans changement de ľhémodynamic systémique et coronarienne non plus que de signe clinique ou électrocardiographique ďischémie. Donc, après un pontage coronarien, ľextubation ne semble pas causer ďeffet néfaste sur les circulations systémique et coronarienne, toutefois, le myocarde revascularisé peut demeurer sensible au métabolisme anaérobique.     

Arthroscopic treatment of synovial chondromatosis of the ankle

A 34-year-old male soccer player with chronic right ankle dysfunction and a history of repeated ankle joint injuries is presented. Imaging studies revealed synovial chondromatosis of the ankle joint. Arthroscopic partial synovectomy was performed and more than 20 loose bodies were excised. Four months postoperatively the patient was asymptomatic and has returned to his previous level of sport activities. At the latest follow-up, 2 years after the initial diagnosis there is no local recurrence of the disease. Arthroscopy is a minimal invasive surgical technique, with satisfactory results in the treatment of synovial chondromatosis of the ankle joint.     

Treatment of chronic sialadenitis by intraductal penicillin or saline.

PURPOSE: We sought to describe the treatment of chronic sialadenitis by intraductal penicillin or saline. PATIENTS AND METHODS: The study group consisted of 32 males and 23 females with chronic submandibular sialadenitis aged 12 to 65 years and 16 males and 11 females with chronic parotitis aged 8 to 65 years who were treated by intraductal instillation of penicillin or saline. RESULTS: In the patients with submandibular sialadenitis, 44 patients treated with penicillin and 11 treated with saline became symptom free; symptoms recurred in 3 treated with penicillin, of whom 2 became symptom free after further instillations and 1 after removal of a sialolith at the ductal orifice; and follow-up of 22 patients verified that 18 treated with penicillin and 4 with saline had been symptom free for 1 to 15 years and 1 to 3 years, respectively. In the patients with parotitis, 18 patients treated with penicillin, 8 treated with saline, and 1 treated with both became symptom free; symptoms recurred in 1 treated with penicillin and 1 with saline, both of whom became symptom free after further instillations; and follow-up of 15 patients verified that 11 treated with penicillin, 3 with saline, and 1 with both had been symptom free for 1 to 14 years, 2 to 12 years, and 3 years, respectively. CONCLUSION: The intraductal instillation of penicillin or saline is a simple and surprisingly successful technique for the treatment of chronic sialadenitis.     

Oral tuberculosis associated with a treatment with anti-rheumatic drugs

BACKGROUND: The use of immunosuppressive medication is a dominant risk factor for infection in patients with rheumatoid arthritis (RA). Methotrexate (MTX) is one of the traditional disease-modifying antirheumatic drugs. Adalimumab [a human anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody] represent an important advance in the treatment of RA and has been recently come in use. TNF-alpha plays a role in the host defense against Mycobacterium tuberculosis and notably in granuloma formation. Infections occur at a high rate among those who use one or the combination of the two medications. METHOD: We examined a female patient that was referred to our department for evaluation and treatment of a granular lesion on the soft palate and uvula, complaining of mild dysphagia. The patient was treated for 4 months with MTX and adalimumab for RA before the oral lesion appeared. RESULTS: The histopathological examination of a specimen of the oral lesion, taken by biopsy, showed a chronic inflammation characterized by tuberculous granulomas. Polymerase chain reaction test and culture of a new specimen was positive for M. tuberculosis. CONCLUSIONS: The therapeutic use of MTX or/and adalimumab for the treatment of RA or few others diseases, can cause oral tuberculosis.     

Effects of Dopexamine on Lipid Peroxidation During Aortic Surgery in Pigs: Comparison with Dopamine

OBJECTIVE: We investigated the dose-related effect of dopexamine and dopamine on free radical production and lipid peroxidation estimated by MDA measurements in an ischaemia-reperfusion model of supraceliac aortic repair. DESIGN: Prospective, randomized, blinded experimental study. MATERIALS: Twenty-five healthy pigs. METHODS: All experiments were performed under general endotracheal anaesthesia. Supraceliac aortic cross clamping was performed in all pigs. The pigs were randomly assigned into five groups (n=5 in each group) and received a continuous intravenous infusion of normal saline (CTL), dopamine 2 microg kg(-1)min(-1) (dopa 2), dopamine 8 microg kg(-1)min(-1) (dopa 8), dopexamine 2 microg kg(-1)min(-1) (dopex 2), dopexamine 8 microg kg(-1)min(-1) (dopex 8). Cardiac output, mean arterial pressure, arterial blood gas analysis and blood sampling for plasma MDA measurements (to reveal lipid peroxidation) were recorded after induction of anaesthesia (baseline), 60 and 120 min after cross-clamping of aorta (ischaemia phase), and 60 and 120 min after restoration of flow (reperfusion phase). RESULTS: Dopexamine and dopamine at 8 microgkg(-1)min(-1) reduced MDA at 60 and 120 min after reperfusion. CONCLUSION: Dopexamine seems superior to dopamine in reducing oxygen free radicals and subsequent lipid peroxidation during reperfusion after supraceliac aortic cross clamping in pigs.     

Expression of CEA, CA-125 and SCC antigen by biological fluids associated with pregnancy.

Carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125) and squamous cell carcinoma (SCC) antigen were measured in 56 full-termed pregnancies by enzyme-immunoassays (EIA-MEIA). The measurements were done in maternal serum (MS), umbilical cord blood (UCB) and amniotic fluid (AF) samples, during delivery. Very high antigen levels were found in AF samples (median: CEA = 124 ng/ml; CA-125 = 710 U/ml; SCC = 710 ng/ml) compared to UCB and MS. CEA and SCC showed significantly lower values in MS (0.6 and 1.7 ng/ml, respectively) than in UCB (1.6 ng/ml, P = 7.7 x 10(-9); 3.55 ng/ml, P = 6.5 x 10(-6), respectively), while CA-125 had significantly higher values in MS (6 U/ml) than in UCB (0.0 U/ml, P = 17 x 10(-6); Wilcoxon paired test). All CEA values in MS were below cut-off (less than or equal to 5 ng/ml), while 10% of CA-125 and 30% of SCC values were above cut-off (less than or equal to 35 U/ml and less than or equal to 2.5 ng/ml, respectively). Amniotic fluid CEA with meconium had higher values (P = 0.0002), while the highest CA-125 values in AF samples were found in primiparae (P = 0.02). Moreover SCC in AF samples from vaginal delivered pregnancies showed significantly higher values, compared to those from cesarean section (P = 4.2 x 10(-7); Mann-Whitney U-test). Thus, our findings suggest that pregnancy has an influence on maternal serum SCC and CA-125 values, while CEA is independent of gestation and seems to conserve its diagnostic value during pregnancy as well.