Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in ~65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K γ-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3Kγ-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner

Three-Dimensional Handheld Scanning to Quantify Head-Shape Changes in Spring-Assisted Surgery for Sagittal Craniosynostosis

Three-dimensional (3D) imaging is an important tool for diagnostics, surgical planning, and evaluation of surgical outcomes in craniofacial procedures. Gold standard for acquiring 3D imaging is computed tomography that entails ionizing radiations and, in young children, a general anaesthesia. Three-dimensional photographic imaging is an alternative method to assess patients who have undergone calvarial reconstructive surgery. The aim of this study was to assess the utility of 3D handheld scanning photography in a cohort of patients who underwent spring-assisted correction surgery for scaphocephaly. Pre- and postoperative 3D scans acquired in theater and at the 3-week follow-up in clinic were postprocessed for 9 patients. Cephalic index (CI), head circumference, volume, sagittal length, and coronal width over the head at pre-op, post-op, and follow-up were measured from the 3D scans. Cephalic index from 3D scans was compared with measurements from planar x-rays. Statistical shape modeling (SSM) was used to calculate the 3D mean anatomical head shape of the 9 patients at the pre-op, post-op, and follow-up. No significant differences were observed in the CI between 3D and x-ray. Cephalic index, volume, and coronal width increased significantly over time. Mean shapes from SSM visualized the overall and regional 3D changes due to the expansion of the springs in situ. Three-dimensional handheld scanning followed by SSM proved to be an efficacious and practical method to evaluate 3D shape outcomes after spring-assisted cranioplasty in individual patients and the population

Co-occurrence of the bla(VIM-1) and bla(SHV-12) genes on an IncHI2 plasmid of an Escherichia coli isolate recovered from German livestock

The dissemination of carbapenemase-producing Enterobacterales (CPE) is an important public health issue. The number of human CPE isolates has been steadily increasing during recent years, worldwide. Despite the fact that carbapenems are not licensed for use in veterinary medicine, increasing numbers of CPE from the veterinary sector have been reported. The transmission of CPE between pets/livestock and exposed humans as well as via food has been demonstrated. In this study, a detailed characterization of a carbapenem-resistant porcine Escherichia coli co-harbouring blaVIM-1, blaSHV-12 and blaACC-1 genes, along with other resistance genes, is provided

Design and manufacturing of a patient-specific nasal implant for congenital arhinia: Case report

Arhinia (congenital absence of the nose) is a congenital rare disease, which has been reported in less than 60 cases in the literature. It consists of the absence of external nose, nasal cavities and olfactory apparatus and is generally associated with midline defects, microphthalmia, blepharophimosis and hypotelorism. Aesthetic problems as well as associated functional anomalies can potentially impact on the development and interpersonal relationships of the child at a later stage in life. Arhinia requires extensive management in early life in order to ensure airway patency and protection by means of tracheostomy, and to allow adequate pharyngeal and feeding function to the child. Aesthetic issues are managed with reconstructive surgery or an external prosthesis. There is no previous description in Literature of internal prosthetic devices used to sequentially shape soft tissues in complex reconstruction. We present an example of design and manufacturing of a bespoke nose implant produced by means of 3D printing and directly assessed on-table by means of 3D surface scanning

Quantifying the effect of corrective surgery for trigonocephaly: A non-invasive, non-ionizing method using three-dimensional handheld scanning and statistical shape modelling

Trigonocephaly in patients with metopic synostosis is corrected by fronto-orbital remodelling (FOR). The aim of this study was to quantitatively assess aesthetic outcomes of FOR by capturing 3D forehead scans of metopic patients pre- and post-operatively and comparing them with controls. Ten single-suture metopic patients undergoing FOR and 15 age-matched non-craniosynostotic controls were recruited at Great Ormond Street Hospital for Children (UK). Scans were acquired with a three-dimensional (3D) handheld camera and post-processed combining 3D imaging software. 3D scans were first used for cephalometric measurements. Statistical shape modelling was then used to compute the 3D mean head shapes of the three groups (FOR pre-op, post-op and controls). Head shape variations were described via principal component analysis (PCA). Cephalometric measurements showed that FOR significantly increased the forehead volume and improved trigonocephaly. This improvement was supported visually by pre- and post-operative computed mean 3D shapes and numerically by PCA (p < 0.001). Compared with controls, post-operative scans showed flatter foreheads (p < 0.001). In conclusion, 3D scanning followed by 3D statistical shape modelling enabled the 3D comparison of forehead shapes of metopic patients and non-craniosynostotic controls, and demonstrated that the adopted FOR technique was successful in correcting bitemporal narrowing but overcorrected the rounding of the forehead

Antimicrobial use and antimicrobial resistance in broiler farms in peri-urban Wakiso, Uganda

Objective: A cross sectional study was carried out to 1) describe the antimicrobial use patterns among poultry farmers in Wakiso 2) establish resistant profiles of Salmonella, E. coli and Enterococci among poultry farms in Wakiso. Methods: A cross sectional study in Wakiso district was carried out in October and November 2021 for a period of 6 weeks. A semi structured questionnaire was used to collect data on antimicrobial use on the farms. Boot sock sampling was used to collect samples from the whole poultry house. A composite sample of faecal material was also collected from the poultry house. The information on antimicrobial use is being analyzed for descriptive statistics. The faecal samples were cultured in the laboratory for Isolation of Salmonella, E. coli and Enterococci. The Isolates will further be tested to establish their resistant profiles. The composite sample was used to quantify resistant coliforms against cefotaxime and colistin Results: A total of 200 poultry farms in Wakiso were visited, 211 boot sock samples and 211 composite samples were collected. 29.85% of the respondents were male while 70.15% were female.37.38% had attained secondary level of education. There was observed widespread use of antimicrobials on the farms for treatment of different conditions as well as prevention of disease. The most used groups of antibiotics were, Penicillins, Tetracyclines and Aminoglycosides while Sulphonamides were the least used. From the laboratory analysis, out of the 211 samples collected, Salmonella was isolated at a rate of 8.5%, E. coli at 77.3% and Enterococcus at 62.6%. Resistant coliforms to cefotaxime (5I.7%) and colistin (45.5%) were also identified. Conclusion: There are indications of resistant coliforms among poultry farms in Wakiso. This is attributed to the observed continuous use of antibiotics on the poultry farms. There is need to improve antimicrobial use among farmers. Proper diagnosis of conditions is one possible way that will reduce the use of different antibiotics at farm level