AKT1 (v-akt murine thymoma viral oncogene homolog 1)

Review on AKT1 (v-akt murine thymoma viral oncogene homolog 1), with data on DNA, on the protein encoded, and where the gene is implicated

A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer.

Background An early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted. Case presentation We describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one. Conclusion This case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN-associated carcinogenesis

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder arising from T-cell progenitors. T-ALL accounts for 15% of newly diagnosed ALL cases in children and 25% in adults. Although the prognosis of T-ALL has improved, due to the use of polychemotherapy schemes, the outcome of relapsed/chemoresistant T-ALL cases is still poor. A signaling pathway that is frequently upregulated in T-ALL, is the phosphatidylinositol 3-kinase/Akt/mTOR network. To explore whether Akt could represent a target for therapeutic intervention in T-ALL, we evaluated the effects of the novel allosteric Akt inhibitor, MK-2206, on a panel of human T-ALL cell lines and primary cells from T-ALL patients. MK-2206 decreased T-ALL cell line viability by blocking leukemic cells in the G0/G1 phase of the cell cycle and inducing apoptosis. MK-2206 also induced autophagy, as demonstrated by an increase in the 14-kDa form of LC3A/B. Western blotting analysis documented a concentration-dependent dephosphorylation of Akt and its downstream targets, GSK-3a/b and FOXO3A, in response to MK-2206. MK-2206 was cytotoxic to primary T-ALL cells and induced apoptosis in a T-ALL patient cell subset (CD34þ/CD4/CD7), which is enriched in leukemia-initiating cells. Taken together, our findings indicate that Akt inhibition may represent a potential therapeutic strategy in T-ALL

Right pulmonary artery occlusion by an acute dissecting aneurysm of the ascending aorta

We describe the case of a 76-year old female who presented with a Type A aortic dissection requiring repair with an interposition graft and aortic valve replacement. Post-operatively she had clinical features and computerised tomographic images suggestive of a pulmonary embolus and died 24 hours later. The extremely rare finding of intramural thrombus occluding the right pulmonary artery was seen at post mortem

Thickening of the pulmonary artery wall in acute intramural hematoma of the ascending aorta

BACKGROUND: The occurrence of pulmonary artery obstruction in the course of acute aortic dissection is an unusual complication. The mechanism implicated is the rupture of the outer layer of the aorta and the subsequent hemorrhage into the adventitia of the pulmonary artery that causes its wall thickening and, at times, produces extrinsic obstruction of the vessel. There are no reports of this complication in acute intramural hematoma. CASE PRESENTATION: An 87-year-old woman was admitted to the hospital in shock after having had severe chest pain followed by syncope. An urgent transesophageal echocardiogram revealed the presence of acute intramural hematoma, no evidence of aortic dissection, severe pericardial effusion with cardiac tamponade, and periaortic hematoma that involved the pulmonary artery generating circumferential wall thickening of its trunk and right branch with no evidence of flow obstruction. Urgent surgery was performed but the patient died in the operating room. The post mortem examination, in the operating room, confirmed that there was an extensive hematoma around the aorta and beneath the adventitial layer of the pulmonary artery, with no evidence of flow obstruction. CONCLUSION: This is the first time that this rare complication is reported in the scenario of acute intramural hematoma and with the transesophageal echocardiogram as the diagnostic tool

The Second-Agent Effect: Communicative Gestures Increase the Likelihood of Perceiving a Second Agent

Background: Beyond providing cues about an agent’s intention, communicative actions convey information about the presence of a second agent towards whom the action is directed (second-agent information). In two psychophysical studies we investigated whether the perceptual system makes use of this information to infer the presence of a second agent when dealing with impoverished and/or noisy sensory input. Methodology/Principal Findings: Participants observed point-light displays of two agents (A and B) performing separate actions. In the Communicative condition, agent B’s action was performed in response to a communicative gesture by agent A. In the Individual condition, agent A’s communicative action was replaced with a non-communicative action. Participants performed a simultaneous masking yes-no task, in which they were asked to detect the presence of agent B. In Experiment 1, we investigated whether criterion c was lowered in the Communicative condition compared to the Individual condition, thus reflecting a variation in perceptual expectations. In Experiment 2, we manipulated the congruence between A’s communicative gesture and B’s response, to ascertain whether the lowering of c in the Communicative condition reflected a truly perceptual effect. Results demonstrate that information extracted from communicative gestures influences the concurrent processing of biological motion by prompting perception of a second agent (second-agent effect). Conclusions/Significance: We propose that this finding is best explained within a Bayesian framework, which gives

Marginal Level Dystrophin Expression Improves Clinical Outcome in a Strain of Dystrophin/Utrophin Double Knockout Mice

Inactivation of all utrophin isoforms in dystrophin-deficient mdx mice results in a strain of utrophin knockout mdx (uko/mdx) mice. Uko/mdx mice display severe clinical symptoms and die prematurely as in Duchenne muscular dystrophy (DMD) patients. Here we tested the hypothesis that marginal level dystrophin expression may improve the clinical outcome of uko/mdx mice. It is well established that mdx3cv (3cv) mice express a near-full length dystrophin protein at ∼5% of the normal level. We crossed utrophin-null mutation to the 3cv background. The resulting uko/3cv mice expressed the same level of dystrophin as 3cv mice but utrophin expression was completely eliminated. Surprisingly, uko/3cv mice showed a much milder phenotype. Compared to uko/mdx mice, uko/3cv mice had significantly higher body weight and stronger specific muscle force. Most importantly, uko/3cv outlived uko/mdx mice by several folds. Our results suggest that a threshold level dystrophin expression may provide vital clinical support in a severely affected DMD mouse model. This finding may hold clinical implications in developing novel DMD therapies

Magnetic resonance imaging of the erector spinae muscles in Duchenne muscular dystrophy: implication for scoliotic deformities

<p>Abstract</p> <p>Background</p> <p>In Duchenne muscular dystrophy (DMD), the muscular degeneration often leads to the development of scoliosis. Our objective was to investigate how anatomical changes in back muscles can lead to scoliosis. Muscular volume and the level of fat infiltration in those muscles were thus evaluated, in non-scoliotic, pre-scoliotic and scoliotic patients. The overlying skin thickness over the apex level of scoliotic deformations was also measured to facilitate the interpretation of electromyographic signals when recorded on the skin surface.</p> <p>Methods</p> <p>In 8 DMD patients and two healthy controls with no known muscular deficiencies, magnetic resonance imaging (MRI) was used to measure continuously at 3 mm intervals the distribution of the erector spinae (ES) muscle in the T8-L4 region as well as fat infiltration in the muscle and overlying skin thickness: four patients were non-scoliotic (NS), two were pre-scoliotic (PS, Cobb angle < 15°) and two were scoliotic (S, Cobb angle ≥ 15°). For each subject, 63 images 3 mm thick of the ES muscle were obtained in the T8-L4 region on both sides of the spine. The pixel dimension was 0.39 × 0.39 mm. With a commercial software, on each 12 bits image, the ES contour on the left and on the right sides of the spine were manually determined as well as those of its constituents i.e., the iliocostalis (IL), the longissimus (LO) and the spinalis (SP) muscles. Following this segmentation, the surfaces within the contours were determined, the muscles volume were obtained, the amount of fat infiltration inside each muscle was evaluated and the overlying skin thickness measured.</p> <p>Findings</p> <p>The volume of the ES muscle of our S and PS patients was found smaller on the convex side relative to the concave one by 5.3 ± 0.7% and 2.8 ± 0.2% respectively. For the 4 NS patients, the volume difference of this muscle between right and left sides was 2.1 ± 1.5% and for the 2 controls, it was 1.4 ± 1.2%. Fat infiltration for the S and the PS patients was larger on the convex side than on the concave one (4.4 ± 1.6% and 4.5 ± 0.7% respectively) and the difference was more important near the apex. Infiltration was more important in the lateral IL muscle than in the medial SP and it was always larger near L2 than at any other spinal level. Fat infiltration was much more important in the ES for the DMD patients (49.9% ± 1.6%) than for the two controls (2.6 ± 0.8%). As for the overlying skin thickness measured near the deformity of the patients, it was larger on the concave than on the convex side: 14.8 ± 6.1 vs 13.5 ± 5.7 mm for the S and 10.3 ± 6.3 vs 9.8 ± 5.6 mm for the PS.</p> <p>Interpretation</p> <p>In DMD patients, our results indicate that a larger replacement of muscles fibers by fat infiltration on one side of the spine is a factor that can lead to the development of scoliosis. Efforts to slow such an infiltration on the most affected side of the spine could thus be beneficial to those patients by delaying the apparition of the scoliotic deformation. In addition to anatomical considerations, results obtained from the same patients but in experiments dealing with electromyography recordings, point to differences in the muscular contraction mechanisms and/or of the neural input to back muscles. This is similar to the adolescent idiopathic scoliosis (AIS) where a role of the nervous system in the development of the deformation has also been suggested.</p