A novel Iowa–Mayo validated composite risk assessment tool for allogeneic stem cell transplantation survival outcome prediction

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematologic conditions and is associated with considerable morbidity and mortality. Therefore, prognostic tools are essential to navigate the complex patient, disease, donor, and transplant characteristics that differentially influence outcomes. We developed a novel, comprehensive composite prognostic tool. Using a lasso-penalized Cox regression model (n = 273), performance status, HCT-CI, refined disease-risk index (rDRI), donor and recipient CMV status, and donor age were identified as predictors of disease-free survival (DFS). The results for overall survival (OS) were similar except for recipient CMV status not being included in the model. Models were validated in an external dataset (n = 378) and resulted in a c-statistic of 0.61 and 0.62 for DFS and OS, respectively. Importantly, this tool incorporates donor age as a variable, which has an important role in HSCT outcomes. This needs to be further studied in prospective models. An easy-to-use and a web-based nomogram can be accessed here: https://allohsctsurvivalcalc.iowa.uiowa.edu/.Subject terms: Chemotherapy, Stem-cell therapies     

Exploration of CH⋯F & CF⋯H mediated supramolecular arrangements into fluorinated terphenyls and theoretical prediction of their third-order nonlinear optical response

In the present study, three novel fluorinated terphenyl compounds i.e., 2′,4,4′′,5′-tetrafluoro-1,1'':4′,1′′-terphenyl (1), 2′,5′-difluoro-1,1'':4′,1′′-terphenyl (2) and 2′,5′-difluro-4,4′′-diphenoxy-1,1:4′,1′′-terphenyl (3) have been synthesized by Suzuki Miyaura method. Single crystal XRD study reveals ð-ð stacking stabilization in molecular packing along with F⋯H and F⋯C interactions. This computational quantum chemical exploration was also done by using density functional theory (DFT) methods. The comparison of experimental (SC-XRD) and theoretical (DFT) investigations on structural parameters have been reported which shows reasonable agreements. Hirshfeld surface analysis explores the strength of intermolecular interactions present in the synthesized compounds. A substantial computational analysis of synthesized compounds is done for their optoelectronic and third-order nonlinear optical properties. The third-order NLO study was performed at M06/6-311G* level of theory. A comparative analysis of third-order polarizability of studied compounds is done with that of para-nitroaniline (p-NA) molecule which is often considered as a prototype NLO molecule. The third-order NLO analysis results suggest that all investigated compounds 1, 2 and 3 have significant potential as efficient third-order NLO molecules as compared to p-NA. The studied compounds 1, 2 and 3 possess about 13.7 times, 5.2 times and 5.17 times larger third-order polarizability amplitudes than that of p-NA (25.45 × 10⁻³⁶ esu) as calculated at same M06/6-311G* levels of theory. Time-dependent density functional theory (TD-DFT) calculations are performed for electronic excitation energies and their oscillator strengths. The studies of frontier molecular orbitals (FMO) analysis, total and partial density of states (DOS) were performed to investigate the intramolecular charge transfer (ICT) process in the entitled compounds.

Three novel fluorinated terphenyls were synthesized by a Suzuki Miyaura method. DFT and TDDFT were performed to explore FMO, DOS analysis and third-order NLO properties. This may provide new ways to utilise fluorinated terphenyl compounds as advanced functional materials.     

Objective predictors of ‘early tolerance’ to ventral intermediate nucleus of thalamus deep brain stimulation in essential tremor patients

Objective

To identify pre-operative clinical and computerized spiral analysis characteristics that may help ascertain which patients with Essential Tremor (ET) will exhibit ‘early tolerance’ to ventral intermediate nucleus of thalamus (Vim) deep brain stimulation (DBS).

The success of sleeve gastrectomy in the management of metabolic syndrome and obesity

The rapid reversal of diabetes,hypertension,hyperlipidaemia and obesity by surgical means has challenged accepted doctrines regarding the management of metabolic syndrome.Sleeve gastrectomy,which developed initially as a preparatory procedure for biliopancreatic diversion with duodenal switch,has seen an exponential rise in popularity as an effective lone laparoscopic bariatric procedure.Superior excess weight loss,a low complication rate,and excellent food tolerance,combined with a short hospital stay,have made this the procedure of choice for patients and surgeons across the globe.High volume centres nurture the ongoing development of experienced and specialized teams,pathways and regimens.Optimum surgical outcomes allow minimization of metabolic syndrome,reducing cardiovascular and cerebrovascular risk.     

Effects of FSW Tool Plunge Depth on Properties of an Al-Mg-Si Alloy T-Joint: Thermomechanical Modeling and Experimental Evaluation

One of the main challenging issues in friction stir welding (FSW) of stiffened structures is maximizing skin and flange mixing. Among the various parameters in FSW that can affect the quality of mixing between skin and flange is tool plunge depth (TPD). In this research, the effects of TPD during FSW of an Al-Mg-Si alloy T-joint are investigated. The computational fluid dynamics (CFD) method can help understand TPD effects on FSW of the T-joint structure. For this reason, the CFD method is employed in the simulation of heat generation, heat distribution, material flow, and defect formation during welding processes at various TPD. CFD is a powerful method that can simulate phenomena during the mixing of flange and skin that are hard to assess experimentally. For the evaluation of FSW joints, macrostructure visualization is carried out. Simulation results showed that at higher TPD, more frictional heat is generated and causes the formation of a bigger stir zone. The temperature distribution is antisymmetric to the welding line, and the concentration of heat on the advancing side (AS) is more than the retreating side (RS). Simulation results from viscosity changes and material velocity study on the stir zone indicated that the possibility of the formation of a tunnel defect on the skin–flange interface at the RS is very high. Material flow and defect formation are very sensitive to TPD. Low TPD creates internal defects with incomplete mixing of skin and flange, and high TPD forms surface flash. Higher TPD increases frictional heat and axial force that diminish the mixing of skin and flange in this joint. The optimum TPD was selected due to the best materials flow and final mechanical properties of joints.     

The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells

Resistance against first and second generation (irreversible) ErbB inhibitors is an unsolved problem in clinical oncology. The purpose of this study was to examine the effects of the irreversible ErbB inhibitors pelitinib and canertinib on growth of breast and ovarian cancer cells. Although in vitro growth-inhibitory effects of both drugs exceeded by far the effects of all reversible ErbB blockers tested (lapatinib, erlotinib, and gefitinib), complete growth inhibition was usually not reached. To define the mechanism of resistance, we examined downstream signaling pathways in drug-exposed cells by Western blot analysis. Although ErbB phosphorylation was reduced by pelitinib and canertinib, activation of the AKT/mTOR pathway remained essentially unaltered in drug-resistant cells. Correspondingly, transfection of tumor cells with constitutively activated AKT was found to promote resistance against all ErbB inhibitors tested, whereas dominant negative AKT reinstalled sensitivity in drug-resistant cells. In a next step, we applied PI3K/AKT/mTOR blockers including the dual PI3K/mTOR kinase inhibitor NVP-BEZ235. These agents were found to cooperate with pelitinib and canertinib in producing in vitro growth inhibition in cancer cells resistant against ErbB-targeting drugs. In conclusion, our data show that ErbB drug-refractory activation of the PI3K/AKT/mTOR pathway plays a crucial role in resistance against classical and second-generation irreversible ErbB inhibitors, and NVP-BEZ235 can override this form of resistance against pelitinib and canertinib.     

Gut microbiome in acute pancreatitis: A review based on current literature

The gut microbiome is a complex microbial community, recognized for its potential role in physiology, health, and disease. The available evidence supports the role of gut dysbiosis in pancreatic disorders, including acute pancreatitis (AP). In AP, the presence of gut barrier damage resulting in increased mucosal permeability may lead to translocation of intestinal bacteria, necrosis of pancreatic and peripancreatic tissue, and infection, often accompanied by multiple organ dysfunction syndrome. Preserving gut microbial homeostasis may reduce the systemic effects of AP. A growing body of evidence suggests the possible involvement of the gut microbiome in various pancreatic diseases, including AP. This review discusses the possible role of the gut microbiome in AP. It highlights AP treatment and supplementation with prebiotics, synbiotics, and probiotics to maintain gastrointestinal microbial balance and effectively reduce hospitalization, morbidity and mortality in an early phase. It also addresses novel therapeutic areas in the gut microbiome, personalized treatment, and provides a roadmap of human microbial contributions to AP that have potential clinical benefit.