Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination With Fulvestrant in Patients With AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.

PURPOSE:The activating mutation AKT1 E17K occurs in ~7% of ER+ metastatic breast cancer (MBC). We report, from a multipart, first-in-human, Phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of AKT1 E17K-mutant ER+ MBC patients. PATIENTS AND METHODS:Patients with an AKT1 E17K mutation, detected by local (NGS) or central (plasma-based BEAMing) testing, received capivasertib 480 mg bid, 4 days on, 3 days off, weekly or 400 mg bid combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS) and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort. RESULTS:From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although this latter group may have had more aggressive disease at baseline. AKT1 E17K mutations were detectable in plasma by BEAMing (95%, 41/43), ddPCR (80%, 33/41) and NGS (76%, 31/41). A 50% decrease in AKT1 E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy (most frequent grade ≥3 adverse events: rash [9% vs 20%], hyperglycemia [5% vs 30%], diarrhea [5% vs 10%]). CONCLUSIONS:Capivasertib demonstrated clinically meaningful activity in heavily pretreated AKT1 E17K-mutant ER+ MBC patients, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination

Management of patients with biliary sphincter of Oddi disorder without sphincter of Oddi manometry

<p>Abstract</p> <p>Background</p> <p>The paucity of controlled data for the treatment of most biliary sphincter of Oddi disorder (SOD) types and the incomplete response to therapy seen in clinical practice and several trials has generated controversy as to the best course of management of these patients. In this observational study we aimed to assess the outcome of patients with biliary SOD managed without sphincter of Oddi manometry.</p> <p>Methods</p> <p>Fifty-nine patients with biliary SOD (14% type I, 51% type II, 35% type III) were prospectively enrolled. All patients with a dilated common bile duct were offered endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy whereas all others were offered medical treatment alone. Patients were followed up for a median of 15 months and were assessed clinically for response to treatment.</p> <p>Results</p> <p>At follow-up 15.3% of patients reported complete symptom resolution, 59.3% improvement, 22% unchanged symptoms, and 3.4% deterioration. Fifty-one percent experienced symptom resolution/improvement on medical treatment only, 12% after sphincterotomy, and 10% after both medical treatment/sphincterotomy. Twenty percent experienced at least one recurrence of symptoms after initial response to medical and/or endoscopic treatment. Fifty ERCP procedures were performed in 24 patients with an 18% complication rate (16% post-ERCP pancreatitis). The majority of complications occurred in the first ERCP these patients had. Most complications were mild and treated conservatively. Age, gender, comorbidity, SOD type, dilated common bile duct, presence of intact gallbladder, or opiate use were not related to the effect of treatment at the end of follow-up (p > 0.05 for all).</p> <p>Conclusions</p> <p>Patients with biliary SOD may be managed with a combination of endoscopic sphincterotomy (performed in those with dilated common bile duct) and medical therapy without manometry. The results of this approach with regards to symptomatic relief and ERCP complication rate are comparable to those previously published in the literature in cohorts of patients assessed by manometry.</p

A CLASP-modulated cell edge barrier mechanism drives cell-wide cortical microtubule organization in Arabidopsis

It is well known that the parallel order of microtubules in the plant cell cortex defines the direction of cell expansion, yet it remains unclear how microtubule orientation is controlled, especially on a cell-wide basis. Here we show through 4D imaging and computational modelling that plant cell polyhedral geometry provides spatial input that determines array orientation and heterogeneity. Microtubules depolymerize when encountering sharp cell edges head-on, whereas those oriented parallel to those sharp edges remain. Edge-induced microtubule depolymerization, however, is overcome by the microtubule-associated protein CLASP, which accumulates at specific cell edges, enables microtubule growth around sharp edges and promotes formation of microtubule bundles that span adjacent cell faces. By computationally modelling dynamic 'microtubules on a cube' with edges differentially permissive to microtubule passage, we show that the CLASP-edge complex is a 'tuneable' microtubule organizer, with the inherent flexibility to generate the numerous cortical array patterns observed in nature

Diet and food strategies in a southern al-Andalusian urban environment during Caliphal period, ecija, Sevilla

The Iberian medieval period is unique in European history due to the widespread socio-cultural changes that took place after the arrival of Arabs, Berbers and Islam in 711 AD. Recently, isotopic research has been insightful on dietary shifts, status, resource availability and the impact of environment. However, there is no published isotopic research exploring these factors in southern Iberian populations, and as the history of this area differs to the northern regions, this leaves a significant lacuna in our knowledge. This research fills this gap via isotopic analysis of human (n = 66) and faunal (n = 13) samples from the 9th to the 13th century Écija, a town renowned for high temperatures and salinity. Stable carbon (δ13C) and nitrogen (δ15N) isotopes were assessed from rib collagen, while carbon (δ13C) values were derived from enamel apatite. Human diet is consistent with C3 plant consumption with a very minor contribution of C4 plants, an interesting feature considering the suitability of Écija to C4 cereal production. δ15N values vary among adults, which may suggest variable animal protein consumption or isotopic variation within animal species due to differences in foddering. Consideration of δ13C collagen and apatite values together may indicate sugarcane consumption, while moderate δ15N values do not suggest a strong aridity or salinity effect. Comparison with other Iberian groups shows similarities relating to time and location rather than by religion, although more multi-isotopic studies combined with zooarchaeology and botany may reveal subtle differences unobservable in carbon and nitrogen collagen studies alone.OLC is funded by Plan Galego I2C mod.B (ED481D 2017/014). The research was partially funded by the projects “Galician Paleodiet” and by Consiliencia network (ED 431D2017/08) Xunta de GaliciaS

Brain type carnosinase in dementia: a pilot study

Research articl

Geographical gradient of the <em>eIF4E</em> alleles conferring resistance to potyviruses in pea (<em>Pisum</em>) germplasm

<div><p>Background</p><p>The eukaryotic translation initiation factor 4E was shown to be involved in resistance against several potyviruses in plants, including pea. We combined our knowledge of pea germplasm diversity with that of the <i>eIF4E</i> gene to identify novel genetic diversity.</p><p>Methodology/Principal findings</p><p>Germplasm of 2803 pea accessions was screened for <i>eIF4E</i> intron 3 length polymorphism, resulting in the detection of four <i>eIF4E^A-B-C-S</i> variants, whose distribution was geographically structured. The <i>eIF4E^A</i> variant conferring resistance to the P1 PSbMV pathotype was found in 53 accessions (1.9%), of which 15 were landraces from India, Afghanistan, Nepal, and 7 were from Ethiopia. A newly discovered variant, <i>eIF4E^B</i>, was present in 328 accessions (11.7%) from Ethiopia (29%), Afghanistan (23%), India (20%), Israel (25%) and China (39%). The <i>eIF4E^C</i> variant was detected in 91 accessions (3.2% of total) from India (20%), Afghanistan (33%), the Iberian Peninsula (22%) and the Balkans (9.3%). The <i>eIF4E^S</i> variant for susceptibility predominated as the wild type. Sequencing of 73 samples, identified 34 alleles at the whole gene, 26 at cDNA and 19 protein variants, respectively. Fifteen alleles were virologically tested and 9 alleles (<i>eIF4E^{A-1-2-3-4-5-6-7}</i>, <i>eIF4E^B-1</i>, <i>eIF4E^C-2</i>) conferred resistance to the P1 PSbMV pathotype.</p><p>Conclusions/Significance</p><p>This work identified novel <i>eIF4E</i> alleles within geographically structured pea germplasm and indicated their independent evolution from the susceptible <i>eIF4E^S1</i> allele. Despite high variation present in wild <i>Pisum</i> accessions, none of them possessed resistance alleles, supporting a hypothesis of distinct mode of evolution of resistance in wild as opposed to crop species. The Highlands of Central Asia, the northern regions of the Indian subcontinent, Eastern Africa and China were identified as important centers of pea diversity that correspond with the diversity of the pathogen. The series of alleles identified in this study provides the basis to study the co-evolution of potyviruses and the pea host.</p></div

AKT Inhibition in Solid Tumors With AKT1 Mutations.

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363