Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome.
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ABSTRACT:
SUBMITTER: Ours CA
PROVIDER: S-EPMC8751418 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A 20-yr-old man with Proteus syndrome (PS) and somatic mosaicism of the AKT1 c.49G > A p.(E17K) variant had asymmetric overgrowth of the right frontal and facial bones, asymmetric spinal overgrowth with thoracolumbar scoliosis, dilatation of the inferior vena cava, testicular cystadenoma, bilateral knee deformities, macrodactyly, and apparent intellectual disability. Miransertib (ARQ 092) is an oral, allosteric, selective pan-AKT inhibitor initially developed for cancer therapeutics, now being evaluated for the treatment of PS. After baseline evaluation, the patient started unblinded treatment of 10 mg oral miransertib daily (∼5 mg/m2/day), escalated to 30 mg daily (∼15 mg/m2/day), and then to 50 mg daily (∼25 mg/m2/day) after 3 mo of treatment. Adverse events included dry mouth, one episode of gingivostomatitis, and loose, painful dentition due to preexisting periodontal disease, all of which resolved spontaneously. After 11 mo of treatment, the patient reported improved general well-being, increased mobility of the ankle, spine, and hands, a subjective decrease in size of the right facial bone overgrowth, and reduced areas of cerebriform connective tissue nevi on the soles. Whole-body MRI findings were stable without apparent disease progression. We conclude that 1 yr of treatment with miransertib was beneficial in this case.
| S-EPMC6996520 | biostudies-literature
Project description:Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m2/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform connective tissue nevus and a reduction in pain in children. We conclude that 5 mg/m2/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.
| S-EPMC6407523 | biostudies-literature
Project description:Leishmaniasis is amongst the most important neglected diseases, afflicting more than 12 million people in 88 countries. There is an urgent need for safe orally bioavailable and cost-effective drugs for the treatment of leishmaniasis. It has recently been shown that Leishmania activates host macrophage serine/threonine kinase Akt, to promote survival of both parasites and infected cells. Here, we sought to evaluate a compound, Miransertib (ARQ 092), an orally bioavailable and selective allosteric Akt inhibitor currently in clinical trials for patients with PI3K/Akt-driven tumors or Proteus syndrome. Miransertib was tested against Leishmania donovani and Leishmania amazonensis, causative agents of visceral and cutaneous leishmaniasis, respectively. Cultured promastigotes were susceptible to Miransertib. In addition, Miransertib was markedly effective against intracellular amastigotes of L. donovani or L. amazonensis-infected macrophages. Miransertib also enhanced mTOR dependent autophagy in Leishmania-infected macrophages, which may represent one mechanism of Miransertib-mediated killing of intracellular Leishmania. Whereas parasite clearance in the spleen of mice infected with L. donovani and treated with Miransertib was comparable to that when treated with miltefosine, Miransertib caused a greater reduction in the parasite load in the liver. In the cutaneous leishmaniasis infection model, lesions were reduced by 40% as compared to mock treated mice. Together, these results provide direct evidence to support the conclusion that Miransertib is an excellent lead compound for the development of a new oral drug therapy for visceral and cutaneous leishmaniasis.
| S-EPMC6219794 | biostudies-literature
Project description:INTRODUCTION: Faculty assessment of students' professionalism is often based upon sporadic exposure to students. Peers are in a unique position to provide valid judgments of these behaviors. AIMS: (1) To learn if peer assessments of professional conduct correlate with traditional performance measures; (2) to determine if peer assessments of professionalism influence the designation of honors, and (3) to explore student and faculty opinions regarding peer assessment. SETTING: Internal Medicine Clerkship at Southern Illinois University. PROGRAM DESCRIPTION: Since 2001 anonymous student peer assessments of professionalism have been used in assigning clerkship grades. PROGRAM EVALUATION: Peer assessments of professionalism had weak, though significant, correlations with faculty ratings (r = 0.29), performance on the NBME subject test (r = 0.28), and performance on a cumulative performance assessment (r = 0.30), and did not change the total number of honors awarded. A majority of students (71%) felt comfortable evaluating their peers, and 77% would keep the peer evaluation procedure in place. A majority of faculty (83%) indicated that peer assessments added valuable information. DISCUSSION: Peer assessments of professional conduct have little correlation with other performance measures, are more likely to have a positive influence on final clerkship grades, and have little impact on awarding honors.
| S-EPMC2686767 | biostudies-other
Project description:IntroductionWhipple procedure is one of the major surgeries performed in tertiary care centers. Once considered a high mortality procedure is now being practicing with mortality declining to less than 5%. This study describes our five-year experience of the Whipple procedure in terms of preoperative, operative, and postoperative parameters of patients undergoing surgery in a local tertiary care setting.Material and methodsThis was a non-randomized interventional study that was conducted at the Surgical Department of Services Hospital Lahore from January 2014 to December 2018. A total of 57 Whipple procedures were performed during this period. Demographic data, presenting symptoms, physical signs, past medical history, preoperative stenting details, intra-operative duration of surgery, postoperative course and complications, pathology, and causes of postoperative death were collected on a pre-designed questionnaire. Data were entered and analyzed by using SPSS 22 (IBM Corp., Armonk, USA).ResultsOut of 57 patients, 19 were females and 38 were males. The mean age of patients was 53±05 years. The most common presenting symptom was jaundice 39 (68.4%), followed by abdominal pain 32 (56.1%). The mean size of the tumor on CT-scan was 2.8±1.4 cm, the mean operation time was 315±38.3 min, mean blood loss during surgery was 500±130 ml, and mean hospital stay was 10±6 days. The major postoperative complication was the pancreatic fistula (12%). Twenty-one out of 39 patients presented with jaundice had undergone preoperative biliary stenting by endoscopic retrograde biliary stenting. The most common histological diagnosis was adenocarcinoma of pancreas 19 (33.3%). Out of 57 patients, nine (15.8%) patients expired in the first 30 days and the most frequent cause of mortality was septic shock.ConclusionIn this study, the most common presentation of patients undergoing Whipple procedure was obstructive jaundice, the most frequent operative complication was pancreatic fistula, and the most prevalent histopathology was carcinoma of the pancreas. Perioperative parameters such as mean operative time, mean blood loss during surgery, and mean length of hospital stay were comparable with other studies. However, mortality in this study was slightly higher. It can be concluded that with meticulous surgical technique, securing hemostasis strictly and standard critical care postoperatively can decrease morbidity and mortality after the Whipple procedure.
| S-EPMC7733773 | biostudies-literature
Project description:microRNAs(miRNAs) play critical regulatory roles mainly through cleaving targeted mRNAs or repressing gene translation during plant developments. Grapevine is amongst the most economically important fruit crops with whole genome available, and the study on grapevine miRNAs (Vv-miRNAs) have also been emphasized. However, the regulation mode of Vv-miRNAs on their target mRNAs during grapevine development has not been studied well, especially on a transcriptome-wide level. Here, six small RNA (sRNA) and mRNA libraries from various grapevine tissues were constructed for Illumina and Degradome sequencing. Subsequently, the spatiotemporal variation in the Vv-miRNAs’ regulation on their target genes was systematically analyzed. Totally, 242 known and 132 novel Vv-miRNAs were identified, and 193 target mRNAs including 103 for known and 90 for novel miRNAs were validated in one or more of tissues examined. The interesting finding was that over 50% of novel miRNAs were expressed exclusively in flowers or berries where they had tissue-specific cleavage roles on their target genes, especially, the breadth of their cleavage sites in flower tissues. Moreover, six novel miRNAs in berries were found to response to exogenous gibberellin (GA) and/or ethylene by real time RT-PCR (qRT-PCR) analysis, confirming their regulatory functions during berry development. Other finding was that about 93.6% of the known miRNAs possessed the high conservation in various tissues where their expression levels exhibited some dynamic variations during grapevine development. Significantly, it was found the phenomena that some Vv-miRNA families exist one key member that act as the main regulator of their target genes during grapevine development.
2021-08-24 | GSE182618 | GEO
Project description:AIMS:Penumbral selection is best-evidence practice for thrombectomy in the 6-24 hour window. Moreover, it helps to identify the best responders to thrombolysis. Multimodal computed tomography (mCT) at the primary centre-including noncontrast CT, CT perfusion, and CT angiography-may enhance reperfusion therapy decision-making. We developed a network with five spoke primary stroke sites and assessed safety, feasibility, and influence of mCT in rural hospitals on decision-making for thrombolysis. METHODS:Consecutive patients assessed via telemedicine from April 2013 to June 2018. Clinical outcomes were measured, and decision-making compared using theoretical models for reperfusion therapy applied without mCT guidance. Symptomatic intracranial hemorrhage (sICH) was assessed according to Safe Implementation of Treatments in Stroke Thrombolysis Registry criteria. RESULTS:A total of 334 patients were assessed, 240 received mCT, 58 were thrombolysed (24.2%). The mean age of thrombolysed patients was 70 years, median baseline National Institutes of Health Stroke Scale was 10 (IQR 7-18) and 23 (39.7%) had a large vessel occlusion. 1.7% had sICH and 3.5% parenchymal hematoma. Three months poststroke, 55% were independent, compared with 70% in the non-thrombolysed group. CONCLUSION:Implementation of CTP in rural centers was feasible and led to high thrombolysis rates with low rates of sICH.
| S-EPMC7052799 | biostudies-literature
Project description:A large body of work has focused on children's ability to attribute mental states to other people, and whether these abilities are influenced by the extent and nature of children's social interactions. However, it remains largely unknown which developmental factors shape children's ability to influence the mental states of others. Building on the suggestion that collaborative experiences early in life might be crucial for the emergence of mental coordination abilities, here we assess the relative contribution of social exposure to familial and non-familial agents on children's communicative adjustments to their mental model of an addressee ('audience design'). During an online interactive game, five-year-olds spontaneously organized their non-verbal communicative behaviors according to their beliefs about an interlocutor. The magnitude of these communicative adjustments was predicted by the time spent at daycare, from birth until four years of age, over and above effects of familial social environment. These results suggest that the degree of non-familial social interaction early in life modulates the influence that children's beliefs have on their referential communicative behavior.
| S-EPMC3757022 | biostudies-literature
Project description:Clinical laboratories have adopted next generation sequencing (NGS) as a gold standard for the diagnosis of hereditary disorders because of its analytic accuracy, high throughput, and potential for cost-effectiveness. We describe the implementation of a single broad-based NGS sequencing assay to meet the genetic testing needs at the University of Minnesota. A single hybrid capture library preparation was used for each test ordered, data was informatically blinded to clinically-ordered genes, and identified variants were reviewed and classified by genetic counselors and molecular pathologists. We performed 2509 sequencing tests from August 2012 till December 2017. The diagnostic yield has remained steady at 25%, but the number of variants of uncertain significance (VUS) included in a patient report decreased over time with 50% of the patient reports including at least one VUS in 2012 and only 22% of the patient reports reporting a VUS in 2017 (p = .002). Among the various clinical specialties, the diagnostic yield was highest in dermatology (60% diagnostic yield) and ophthalmology (42% diagnostic yield) while the diagnostic yield was lowest in gastrointestinal diseases and pulmonary diseases (10% detection yield in both specialties). Deletion/duplication analysis was also implemented in a subset of panels ordered, with 9% of samples having a diagnostic finding using the deletion/duplication analysis. We have demonstrated the feasibility of this broad-based NGS platform to meet the needs of our academic institution by aggregating a sufficient sample volume from many individually rare tests and providing a flexible ordering for custom, patient-specific panels.
| S-EPMC6403447 | biostudies-other
Project description:IntroductionEculizumab has transformed outcomes for patients with atypical hemolytic uremic syndrome (aHUS). Its efficacy and safety profile was well characterized in the clinical trial program. The long-term safety profile was not previously assessed or compared against nontreated patients in an observational registry setting.MethodsThe Global aHUS Registry recruits patients with clinical diagnoses of aHUS. This analysis includes baseline characteristics and targeted safety events from adult and pediatric patients who were "ever treated" versus "never treated" with eculizumab in the first 5 years of the registry, through January 26, 2017.ResultsOverall, 1321 patients (adult, n = 842; pediatric, n = 479; ever treated, n = 865; never treated, n = 456) were enrolled. A higher proportion of ever-treated versus never-treated adult and pediatric patients had renal, cardiovascular, pulmonary, central nervous system, gastrointestinal symptoms, and hepatic impairment. No differences in safety event rates between ever-treated and never-treated patients were observed, except serious infections in pediatric patients (5.15 versus 1.12 events/100 patient-years for ever- and never-treated patients, respectively). Deaths were more frequent in adult (4.7% and 9.9% of ever- and never-treated patients) compared with pediatric patients (1.8% of ever-treated patients; no deaths in never-treated patients).Three meningococcal infections were reported in ever-treated patients; 1 infection led to a fatal outcome.ConclusionIn this large observational dataset covering 5 years of registry enrollment, no new safety concerns were identified for adult or pediatric eculizumab-treated patients with aHUS, confirming a positive benefit-risk profile in a real-world setting.
| S-EPMC6933459 | biostudies-literature