Comparison of the cachexia index based on hand-grip strength (H-CXI) with the original CXI for the prediction of cancer cachexia and prognosis in patients who underwent radical colectomy for colorectal cancer.

Background and aims: The cachexia index (CXI) is a novel biomarker for estimating cancer cachexia. The cachexia index based on hand-grip strength (H-CXI) has been recently developed as a simple proxy for CXI. The present study aims to compare both the H-CXI and CXI for the prediction of cancer cachexia and postoperative outcomes in patients who underwent radical colectomy for colorectal cancer. Methods: Patients who underwent radical operations for colorectal cancer were included in this study. Cancer cachexia was diagnosed according to the international consensus outlined by Fearon et al. The cachexia index (CXI) was calculated as [skeletal muscle index (SMI) × serum albumin/neutrophil-to-lymphocyte ratio (NLR)]. The H-CXI was calculated as [hand-grip strength (HGS)/height2 × serum albumin/NLR]. The SMI was measured based on the preoperative CT images at the third lumbar vertebra (L3) level. HGS was measured before surgery. Results: From July 2014 to May 2021, a total of 1,411 patients were included in the present study, of whom 361 (25.6%) were identified as having cancer cachexia. Patients with cachexia had a lower CXI (p < 0.001) and lower H-CXI (p < 0.001) than those without cachexia. A low CXI but not low H-CXI independently predicted cancer cachexia in the multivariate analysis (OR 1.448, p = 0.024). Both a low CXI (HR 1.476, p < 0.001 for OS; HR 1.611, p < 0.001 for DFS) and low H-CXI (HR 1.369, p = 0.007 for OS; HR 1.642, p < 0.001 for DFS) were independent predictors for overall survival (OS) and disease-free survival (DFS) after adjusting for the same covariates. A low H-CXI but not low CXI was an independent risk factor for postoperative complications (OR 1.337, p = 0.044). No significant association was found between cancer cachexia and postoperative complications. Conclusion: The CXI and H-CXI exhibited better prognostic value than cancer cachexia for the prediction of postoperative outcomes in patients who underwent radical colectomy for colorectal cancer. The H-CXI was a superior index over the CXI in predicting short-term clinical outcomes, whereas the CXI demonstrated a closer correlation with Fearon's criteria for cancer cachexia. Ideal tools for the assessment of cancer cachexia should incorporate not only weight loss but also muscle mass, physical function, and inflammatory state.

Sarcopenia predicts postoperative complications and survival in colorectal cancer patients with GLIM-defined malnutrition: Analysis from a prospective cohort study.

OBJECTIVE: To investigate whether sarcopenia could predict postoperative outcomes in patients with colorectal cancer with Global Leadership Initiative on Malnutrition (GLIM)-defined malnutrition. METHODS: Clinical data of patients who underwent radical resection for colorectal cancer were prospectively collected. Sarcopenia was diagnosed by the combination of low handgrip strength and low muscle quantity or quality as measured by abdominal computed tomography (CT) images. Logistic regression analysis and Cox proportional hazards regression analysis were performed to identify independent predictors for postoperative complications and survival, respectively. RESULTS: A total of 310 patients with colorectal cancer with GLIM-defined malnutrition were included, of which 145 (46.77%) were identified with sarcopenia. Malnutritional patients with sarcopenia had significantly higher incidences of total complications (34.5% versus 15.8%), severe complications (9.7% versus 1.8%), longer lengths of postoperative hospital stay (median, 14 days versus 12 days), and more costs (median, 56,257 RMB versus 49,024 RMB) than those without sarcopenia. Sarcopenia was an independent predictive factor for postoperative complications (OR 2.531, 95% CI 1.451-4.415), overall survival (HR 1.519, 95% CI 1.026-2.248), and disease-free survival (HR 1.847, 95% CI 1.324-2.576). Patients with severe sarcopenia had a higher incidence of severe complications but not total complications or survival than those with not-severe sarcopenia. Moreover, the predictive value of sarcopenia for postoperative complications was attributed to muscle strength and quality but not muscle quantity. CONCLUSION: Sarcopenia predicts postoperative complications and survival in patients with colorectal cancer with GLIM-defined malnutrition. Preoperative assessment of sarcopenia is still necessary when nutritional assessment has been well performed.

Activating mutations drive human MEK1 kinase using a gear-shifting mechanism.

There is an unmet need to classify cancer-promoting kinase mutations in a mechanistically cognizant way. The challenge is to understand how mutations stabilize different kinase configurations to alter function, and how this influences pathogenic potential of the kinase and its responses to therapeutic inhibitors. This goal is made more challenging by the complexity of the mutational landscape of diseases, and is further compounded by the conformational plasticity of each variant where multiple conformations coexist. We focus here on the human MEK1 kinase, a vital component of the RAS/MAPK pathway in which mutations cause cancers and developmental disorders called RASopathies. We sought to explore how these mutations alter the human MEK1 kinase at atomic resolution by utilizing enhanced sampling simulations and free energy calculations. We computationally mapped the different conformational stabilities of individual mutated systems by delineating the free energy landscapes, and showed how this relates directly to experimentally quantified developmental transformation potentials of the mutations. We conclude that mutations leverage variations in the hydrogen bonding network associated with the conformational plasticity to progressively stabilize the active-like conformational state of the kinase while destabilizing the inactive-like state. The mutations alter residue-level internal molecular correlations by differentially prioritizing different conformational states, delineating the various modes of MEK1 activation reminiscent of a gear-shifting mechanism. We define the molecular basis of conversion of this kinase from its inactive to its active state, connecting structure, dynamics, and function by delineating the energy landscape and conformational plasticity, thus augmenting our understanding of MEK1 regulation.

Retrograde branched extension limb assembling stent of pararenal abdominal aortic aneurysm: A longitudinal hemodynamic analysis for stent graft migration.

PURPOSE: Pararenal abdominal aortic aneurysms (PRAAAs) are a life-threatening disease, and hemodynamic analysis may provide greater insight into the effectiveness and long-term outcomes of endovascular aneurysm repair (EVAR). However, the lack of patient-specific boundary conditions on the periphery compromises the accuracy. Windkessel (WK) boundary conditions coupled to hemodynamic follow-up models of a PRAAA patient, aims to provide insights into the link between hemodynamics and poor prognosis. METHOD: One PRAAA patient underwent EVAR and reintervention after one branch of stent-graft (SG) had migrated. Totally five computational follow-up models were studied. Patient-specific flow data acquired via ultrasound were used to define the boundary conditions in the ascending aorta and the following three branches. Coupled zero-dimensional WK models representing the distal vasculature were used to define the outlet boundary conditions under the abdomen. RESULTS: Flow divisions of the main SG branches were 40.7% and 24.7%, respectively. Time-averaged wall shear stress and oscillatory shear index (OSI) increased at the junction connected the SG branch and the stent leading to the right common iliac artery (RCIA) where the stent migrated. The OSI and relative residence time (RRT) value in superior mesenteric artery increased notably after the migration, the RRT continuously increased following the reintervention. CONCLUSION: Unbalanced flow, resulting in locally high-speed flow, high WSS and OSI might significantly affect stent stability. Results suggest that diameters and interconnection design of stents in complex cases should take the flow division into consideration and computational simulations might be considered as a tool for intervention protocol design.

Chiral phosphoric acid catalyzed enantioselective N-alkylation of indoles with in situ generated cyclic N-acyl ketimines.

A chiral SPINOL derived phosphoric acid-catalyzed asymmetric N-alkylation reaction of indoles with cyclic α-diaryl-substituted N-acyl imines, which are generated in situ from 3-aryl 3-hydroxyisoindolinones, has been demonstrated. The transformation proceeds smoothly with a broad range of indoles and isoindolinone alcohols. A variety of indole derived N-alkylated tetrasubstituted chiral aminals were afforded in moderate to good yields (50-79%) with excellent enantioselectivities (up to 98% ee).

Construction of tetrahydropyranoquinoline derivatives via an asymmetric organocatalytic aza-Michael-IED/HAD cascade reaction.

Chiral functionalized tetrahydroquinolines and pyranoquinolines with multiple stereogenic centres have emerged as attractive structures for derivatizing bioactive complex molecules. Herein, we develop a novel, facile organocatalytic asymmetric aza-Michael-IED/HAD cascade reaction of (E)-ethyl 4-(2-(4-methylphenylsulfon amido)phenyl)-2-oxobut-3-enoate and enals. This method enables a convenient, powerful, and atom-economical access to various desired tetrahydropyranoquinoline derivatives with control of four stereogenic centres in good yields (up to 88%) with excellent diastereo- and enantioselectivities (up to >99 : 1 dr and >99% ee, respectively).

Synthesis of Cyano-Containing Phenanthridine Derivatives via Catalyst-, Base-, and Oxidant-Free Direct Cyanoalkylarylation of Isocyanides.

An efficient catalyst-, base-, and oxidant-free direct cyanoalkylarylation of isocyanides with AIBN has been developed under mild conditions. This strategy provides an elusive and rapid access to a wide range of cyano-containing phenanthridine derivatives in good yields via a one-pot alkylation/cyclization radical-cascade process. The mild reaction conditions together with no need of any catalyst, base, or oxidant make this protocol environmentally benign and practical.