The role of IGFBP-3 in tumor development and progression: enlightenment for diagnosis and treatment.

IGFBP-3 is aberrantly expressed in many tumor types, and its serum and tumor tissue levels provide auxiliary information for assessing the degree of tumor malignancy and patient prognosis, making it a potential therapeutic target for human malignancies and conferring it remarkable clinical value for determining patient prognosis. In this review, we provide a comprehensive overview of the aberrant expression, diverse biological effects, and clinical implications of IGFBP-3 in tumors and its role as a potential prognostic marker and therapeutic target for tumors. In addition, we summarize the signaling pathways through which IGFBP-3 exerts its effects. IGFBP-3 comprises an N-terminal, an intermediate region, and a C-terminal structural domain, each exerting different biological effects in several tumor cell types in an IGF-dependent/non-independent manner. IGFBP-3 shares an intricate relationship with the tumor microenvironment, thereby affecting tumor growth. Overall, IGFBP-3 is an essential regulatory factor that mediates tumor occurrence and progression. Gaining deeper insights into the fundamental characteristics of IGFBP-3 and its role in various tumor types will provide new perspectives and allow for the development of novel strategies for cancer diagnosis, treatment, and prognostic evaluation.

Spontaneous Rise of Hydrogen Microbubbles in Interfacial Gas Evolution Reaction.

Liquid organic hydrogen carrier is a promising option for the transport and storage of hydrogen as a clean energy source. This study examines the stability and behavior of organic drops immobilized on a substrate during an interfacial hydrogen-evolution reaction (HER) at the drop surface and its surrounding aqueous solution. Hydrogen microbubbles form within the drop and rise to the drop apex. The growth rate of the hydrogen in-drop bubble increases with the concentration of the reactant in the surrounding medium. The drop remains stable till the buoyancy acting on the in-drop bubble is large enough to overcome the capillary force and the external viscous drag. The bubble spontaneously rises and carries a portion drop liquid to the solution surface. These spontaneous rising in-drop bubbles are detected in measurements using a high-precision sensor placed on the upper surface of the aqueous solution, reversing the settling phase from phase separation in the reactive emulsion. The finding from this work provides new insights into the behaviors of drops and bubbles in many interfacial gas evolution reactions in clean technologies.

Clinical and ultrasound features of 46 children with suppurative osteoarthritis: experience from two centers.

OBJECTIVE: Diagnosing musculoskeletal infections in children is challenging. In recent years, with the advancement of ultrasound technology, high-resolution ultrasound has unique advantages for musculoskeletal children. The aim of this work is to summarize the ultrasonographic and clinical characteristics of children with pyogenic arthritis and osteomyelitis. This study provides a simpler and more effective diagnostic basis for clinical treatment. METHODS: Fifty children with osteomyelitis or arthritis were diagnosed via ultrasound, and the results of the ultrasound diagnosis were compared with those of magnetic resonance imaging and surgery. Clinical and ultrasound characteristics were also analyzed. RESULTS: Out of 50 patients, 46 were confirmed to have suppurative infection by surgical and microbiological examination. Among these 46 patients, 26 were diagnosed with osteomyelitis and 20 had arthritis. The manifestations of osteomyelitis were subperiosteal abscess (15 patients), bone destruction (17 patients), bone marrow abscess (9 patients), and adjacent joint abscess (13 patients). Osteomyelitis mostly affects the long bones of the limbs, femur and humerus (10 and 9 patients, respectively), followed by the ulna, radius, tibia and fibula (one patient each). The manifestations of arthritis were joint pus (20 patients) and joint capsule thickening (20 patients), and hip dislocation (8 patients). All the patients had arthritis involving the hip joint. CONCLUSION: Subperiosteal abscess, bone destruction, and joint abscess with dislocation are ultrasonographic features of pyogenic osteoarthritis. The findings of this work can improve the early diagnosis and differentiation of pyogenic osteoarthritis and provide a reliable basis for treatment.

Pickering emulsion stabilized by grass carp myofibrillar protein via one-step: Study on microstructure, processing stability and stabilization mechanism.

In this study, edible Pickering emulsions stabilized with GMP particles were prepared for the first time using low-value grass carp myofibrillar protein (GMP). To elucidate the emulsion formation mechanism, the grass carp myofibrillar protein particles were first characterized, and the results showed that the lyophilized GMP particles had an irregular polyhedral structure and were amphiphilic nanoparticles. The stability of GMP-based emulsions tended to stabilize with the increase of GMP concentration at an appropriate oil-to-water volume ratio, with a decrease in droplet particle size and an increase in water-holding capacity, storage stability, and rheological stability, whereas the phenomenon of droplet aggregation after storage appeared at 4.0% additive level. Therefore, appropriate concentrations of GMP at a certain oil-to-water volume ratio can stabilize Pickering emulsions, which have an important future as a potential food-grade active substance delivery carrier for biological applications.

Effect of Potentilla anserina L. powder on gel properties and volatile flavor characteristics of silver carp surimi.

BACKGROUND: Potentilla anserina L. is rich in various nutrients, active ingredients and unique flavor, comprising a natural nutrition and health food. However, its application in aquatic food has been rarely reported. Therefore, the effects of Potentilla anserina L. powder (PAP) on gel properties and volatile flavor profile of silver carp surimi were investigated. RESULTS: The gel strength and water-holding capacity of the surimi gels were significantly improved (P < 0.05), and the whiteness and cooking loss of all the samples decreased slightly with the increase in PAP content. The addition of PAP shortened the relaxation time (T2 ) of the surimi gels and converted some of the free water into immobile or bound water, which resulted in a better immobilization of water in the surimi. Scanning electron microscopy images demonstrated that the network of surimi gels with PAP added was denser and had a smoother surface compared to the control. Volatile components (VCs) analysis showed that 33 VCs were identified in the surimi gel samples with different additions of PAP, among which aldehydes, alcohols and esters were the major VCs, accounting for more than 50% of the VCs in the surimi gels. PAP addition reduced the fishy and rancid flavor compounds in surimi gels, such as 1-propanol, 1-octen-3-ol, etc., and promoted the production of aldehydes, alcohols, esters and other flavor substances. CONCLUSION: These results of the present study provide theoretical support for the investigation and development of new nutrient-health-flavored surimi products. © 2024 Society of Chemical Industry.

Ultrasound diagnosis of congenital Morgagni hernias: Ten years of experience at two Chinese centers.

BACKGROUND: Morgagni hernias are rare anomalies that are easily misdiagnosed or missed. AIM: To summarize the ultrasound (US) imaging characteristics of Morgagni hernias through a comparison of imaging and surgical results. METHODS: The records of children with Morgagni hernias who were hospitalized at two hospitals between January 2013 and November 2023 were retrospectively reviewed in terms of clinical findings, US features, and operative details. RESULTS: Between 2013 and 2023, we observed nine (five male and four female) children with Morgagni hernias. Upper abdominal scanning revealed a widening of the prehepatic space, with an abnormal channel extending from the xiphoid process to the right or left side of the thoracic cavity. The channel had intestinal duct and intestinal gas echoes. Hernia contents were found in the transverse colon (n = 6), the colon and small intestine (n = 2), and the colon and stomach (n = 1). Among the patients, seven had a right-sided lesion, two had a left-sided lesion, and all of them had hernial sacs. CONCLUSION: US imaging can accurately determine the location, extent, and content of Morgagni hernias. For suspected Morgagni hernias, we recommend performing sonographic screening first.

IGFBP3 induces PD-L1 expression to promote glioblastoma immune evasion.

BACKGROUND: Glioblastoma (GBM) characterized by immune escape is the most malignant primary brain tumors, which has strong immunosuppressive effect. Programmed death ligand-1 (PD-L1) is a recognized immunosuppressive member on the surface of tumor cells, and plays a crucial role in immune evasion of tumors. Actually, little is known about the regulation of PD-L1 expression in GBM. Insulin-like growth factor binding protein 3 (IGFBP3) is upregulated in GBM and is related to poor patient prognosis. However, it remains unclear whether IGFBP3 plays a role in the regulation of PD-L1 expression in GBM. METHODS: The role of IGFBP3 in the glioma immune microenvironment was investigated using the CIBERSORT algorithm. The correlation between IGFBP3 and PD-L1 expression was analyzed using TCGA and CGGA databases. QRT-PCR, immunoblotting and RNA-seq were used to examine the regulatory effect of IGFBP3 on PD-L1 expression. Co-culture assay, cell counting kit (CCK-8), qRT-PCR, ELISA and flow cytometry were performed to explore the function of IGFBP3 in inducing immunosuppression. The biological role of IGFBP3 was verified using immunohistochemical, immunofluorescence and mice orthotopic tumor model. RESULTS: In this study, we analyzed immune cells infiltration in gliomas and found that IGFBP3 may be associated with an immunosuppressive microenvironment. Then, by analyzing TCGA and CGGA databases, our results showed that IGFBP3 and PD-L1 expression were positively correlated in GBM patients, but not in LGG patients. In vitro experiments conducted on different GBM cell lines revealed that the overexpression of IGFBP3 led to an increase in PD-L1 expression, which was reversible upon knockdown IGFBP3. Mechanistically, IGFBP3 activated the JAK2/STAT3 signaling pathway, leading to an increase in PD-L1 expression. Additionally, co-culture experiments results showed IGFBP3 overexpression induced upregulation of PD-L1 expression promoted apoptosis in Jurkat cells, and this effect was blocked by IGFBP3 antibody and PDL-1 inhibitors. Importantly, in vivo experiments targeting IGFBP3 suppressed tumor growth and significantly prolonged the survival of mice. CONCLUSIONS: This research demonstrated IGFBP3 is a novel regulator for PD-L1 expression in GBM, and identified a new mechanism by which IGFBP3 regulates immune evasion through PD-L1, suggesting that IGFBP3 may be a potential novel target for GBM therapy.

Flexible Surface-Enhanced Raman Scattering Tape Based on Ag Nanostructured Substrate for On-Site Analyte Detection.

Surface-enhanced Raman scattering (SERS) has emerged as a powerful surface analytical technique that amplifies Raman scattering signals of molecules adsorbed onto metal nanostructured surfaces. The droplet reaction method has recently been employed to fabricate large-scale microring patterns of silver (Ag) nanostructures on rigid substrates, which enables sensitive detection within the ring area. However, these rigid substrates present limitations for direct on-site detection of analyte residues on irregular sample surfaces. There is a need to develop soft and flexible SERS substrates that can intimately conform to arbitrary surfaces. In this study, we presented a SERS substrate using flexible and adhesive tape as the supporting material. This SERS tape was fabricated by repeatedly transferring presynthesized Ag nanostructures from a rigid substrate to the tape. For a model compound adenine, our SERS tape exhibited a good linear response from 5 × 10-4 M to 5 × 10-5 M with a low limit of detection (LOD) of 5 × 10-7 M and displayed a SERS enhancement factor (EF) of 3.2 × 105. The relative standard deviation (RSD) of SERS intensity achieved was as low as 1.93%, indicating its outstanding uniformity. The as-prepared SERS tape was used for in situ detection of pesticide residue on an apple surface and dye residue on human hair. Leveraging the large surface area of Ag nanostructure patterns from the droplet reaction, the developed SERS tape demonstrates excellent performance in terms of sensitivity and uniformity. The successful detection of analyte residues on arbitrary surfaces of apple and human hair highlights the potential of this flexible SERS tape for real-world applications across various industries for enhanced diagnostic accuracy.

Effects of Ultrasonic Power on the Structure and Rheological Properties of Skin Collagen from Albacore (Thunnus alalunga).

The effects of ultrasonic power (0, 150, 300, 450, and 600 W) on the extraction yield and the structure and rheological properties of pepsin-soluble collagen (PSC) from albacore skin were investigated. Compared with the conventional pepsin extraction method, ultrasonic treatment (UPSC) significantly increased the extraction yield of collagen from albacore skin, with a maximum increase of 8.56%. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis revealed that peptides of low molecular weight were produced when the ultrasonic power exceeded 300 W. Meanwhile, secondary structure, tertiary structure, and X-ray diffraction analyses showed that the original triple helix structure of collagen was intact after the ultrasonic treatment. The collagen solutions extracted under different ultrasonic powers had significant effects on the dynamic frequency sweep, but a steady shear test suggested that the collagen extracted at 150 W had the best viscosity. These results indicate that an ultrasonic power between 150 and 300 W can improve not only the extraction yield of natural collagen, but also the rheological properties of the collagen solution without compromising the triple helix structure.

Ultrasonic treatment enhanced the binding capacity of volatile aldehydes and pearl mussel (Hyriopsis cumingii) muscle: Investigation of underlying mechanisms.

This study was aim to investigate the influencing mechanism of ultrasonic treatment on the interaction between volatile aldehydes and myosin. The results showed that when the mass concentration ratio of myosin to heptanal/hexanal was 1:0.3, ultrasonic treatment could enhance the binding capacity of myosin to heptanal/hexanal, especially the binding of myosin to hexanal. The entropy and enthalpy values of their interaction were negative, indicating that the interaction was mainly driven by hydrogen bond and van der Waals force. After ultrasonic treatment, the fluorescence wavelength of myosin-heptanal/hexanal complex was redshifted, the α-helix content was increased, while its roughness values, particle size and the polydispersity index were decreased. These demonstrated that ultrasonic treatment was conducive to myosin binding to heptanal/hexanal, thereby restraining the release of volatile flavor compounds from myosin, which could provide new insights for the regulation of volatile flavor compounds.

Determination of Trace Organic Contaminant Concentration via Machine Classification of Surface-Enhanced Raman Spectra.

Surface-enhanced Raman spectroscopy (SERS) has been well explored as a highly effective characterization technique that is capable of chemical pollutant detection and identification at very low concentrations. Machine learning has been previously used to identify compounds based on SERS spectral data. However, utilization of SERS to quantify concentrations, with or without machine learning, has been difficult due to the spectral intensity being sensitive to confounding factors such as the substrate parameters, orientation of the analyte, and sample preparation technique. Here, we demonstrate an approach for predicting the concentration of sample pollutants from SERS spectra using machine learning. Frequency domain transform methods, including the Fourier and Walsh-Hadamard transforms, are applied to spectral data sets of three analytes (rhodamine 6G, chlorpyrifos, and triclosan), which are then used to train machine learning algorithms. Using standard machine learning models, the concentration of the sample pollutants is predicted with >80% cross-validation accuracy from raw SERS data. A cross-validation accuracy of 85% was achieved using deep learning for a moderately sized data set (∼100 spectra), and 70-80% was achieved for small data sets (∼50 spectra). Performance can be maintained within this range even when combining various sample preparation techniques and environmental media interference. Additionally, as a spectral pretreatment, the Fourier and Hadamard transforms are shown to consistently improve prediction accuracy across multiple data sets. Finally, standard models were shown to accurately identify characteristic peaks of compounds via analysis of their importance scores, further verifying their predictive value.

Calcium Carbonate/Polydopamine Composite Nanoplatform Based on TGF-ß Blockade for Comfortable Cancer Immunotherapy.

Cancer pain seriously reduces the quality of life of cancer patients. However, most research about cancer focuses solely on inhibiting tumor growth, neglecting the issue of cancer pain. Therefore, the development of therapeutic agents with both tumor suppression and cancer pain relief is crucial to achieve human-centered treatment. Here, the work reports curcumin (CUR) and ropivacaine (Ropi) coincorporating CaCO3/PDA nanoparticles (CaPNMCUR+Ropi) that realized efficient tumor immunotherapy and cancer pain suppression. The therapeutic efficiency and mechanism are revealed in vitro and in vivo. The results indicate that CaPNMCUR+Ropi underwent tumor microenvironment-responsive degradation and realized rapid release of calcium ions, Ropi, and CUR. The excessive intracellular calcium triggered the apoptosis of tumor cells, and the transient pain caused by the tumor injection was relieved by Ropi. Simultaneously, CUR reduced the levels of immunosuppressive factor (TGF-ß) and inflammatory factor (IL-6, IL-1ß, and TNF-α) in the tumor microenvironment, thereby continuously augmenting the immune response and alleviating inflammatory pain of cancer animals. Meanwhile, the decrease of TGF-ß leads to the reduction of transient receptor potential vanilloid 1 (TRPV1) expression, thereby alleviating hyperalgesia and achieving long-lasting analgesic effects. The design of the nanosystem provides a novel idea for human-centered tumor treatment in the future.

A Tandem Regiospecific [3 + 2] Annulation/Ring Cleavage Reaction for the Synthesis of ß-Ketoenamides.

A series of ß-ketoenamines was synthesized from various phenacyl sulfoxides bearing 1-methyl-1H-tetrazole and oximes in moderate to excellent yields. The proposed mechanism involved the generation of α-sulfines from sulfoxides through thermolytic elimination, regiospecific formal [3 + 2] annulations, and elimination of SO2. This protocol provides convenient access to a variety of synthetically valuable N-unprotected ß-enaminones with absolute Z selectivity.

Pelvic Floor Peritoneum Closure Reduces Severe Postoperative Complications in Rectal Cancer Patients After Laparoscopic Anterior Rectal Resection.

BACKGROUND: Laparoscopic anterior rectal resection (LAR) is a commonly performed surgery for rectal cancer patients. Pelvic floor peritoneum closure (PC), a vital procedure in conventional anterior rectal resection, is not routinely performed in LAR. STUDY DESIGN: A total of 1118 consecutive patients with rectal cancer receiving LAR were included in this retrospective study. Patients were allocated into the PC group and the non-PC group. The occurrence of postoperative complications was compared between the 2 groups. Influential factors in anastomotic leakage (AL) were explored using univariate and multivariate logistic regression. RESULTS: There was no difference between the groups in terms of baseline characteristics. The occurrence of postoperative complications was similar between the groups. The PC group had significantly shorter postoperative hospitalization and longer operation duration compared with the non-PC group. The occurrences of Clavien-Dindo (CD) III-IV complications, CD III-IV AL, and reoperation were significantly lower in the PC group than the non-PC group. PC and a protective ileostomy were independent protective factors for CD III-IV AL. CONCLUSION: PC could reduce the occurrence of CD III-IV complications, especially CD III-IV AL, and the rate of secondary surgery, especially in patients with a lower body mass index and patients who did not receive protective ileostomies.

Launching a Drop via Interplay of Buoyancy and Stick-Jump Dissolution.

According to Archimedes' principle, a submerged object with a density lower than that of aqueous acid solution is more buoyant than a smaller one. In this work, a remarkable phenomenon is reported wherein a dissolving drop on a substrate rises in the water only after it has diminished to a much smaller size, though the buoyancy is smaller. The drop consisting of a polymer solution reacts with the acid in the surrounding, yielding a water-soluble product. During drop dissolution, water-rich microdroplets form within the drop, merging with the external aqueous phase along the drop-substrate boundary. Two key elements determine the drop rise dynamics. The first is the stick-jump behavior during drop dissolution. The second is that buoyancy exerts a strong enough force on the drop at an Archimedean number greater than 1, while the stick-jump behavior is ongoing. The time of the drop rise is controlled by the initial size and the reaction rate of the drop. This novel mechanism for programmable drop rise may be beneficial for many future applications, such as microfluidics, microrobotics, and device engineering where the spontaneous drop detachment may be utilized to trigger a cascade of events in a dense medium.

Jahn-Teller Distortions Induced by in situ Li Migration in λ-MnO2 for Boosting Electrocatalytic Nitrogen Fixation.

Lithium-mediated electrochemical nitrogen reduction reaction (Li-NRR) completely eschews the competitive hydrogen evolution reaction (HER) occurred in aqueous system, whereas the continuous deposition of lithium readily blocks the active sites and further reduces the reaction kinetics. Herein, we propose an innovative in situ Li migration strategy to realize that Li substitutes Mn sites in λ-MnO2 instead of evolving into the dead Li. Comprehensive characterizations corroborate that the intercalation of Li+ at high voltage breaks the structural integrity of MnO6 octahedron and further triggers unique Jahn-Teller distortions, which promotes the spin state regulation of Mn sites to generate the ameliorative eg orbital configuration and accelerates N≡N bond cleavage via eg -σ and eg -π* interaction. To this end, the resulted cationic disordered LiMnO4 delivers the recorded highest NH3 yield rate of 220 µg h-1 cm-2 and a Faradaic efficiency (FE) 83.80 % in organic electrolyte.

Long-term outcomes of single-incision plus one-port laparoscopic surgery versus conventional laparoscopic surgery for rectosigmoid cancer: a randomized controlled trial.

BACKGROUND: Though our previous study has demonstrated that the single-incision plus one-port laparoscopic surgery (SILS + 1) is safe and feasible for sigmoid colon and upper rectal cancer and has better short-term outcomes compared with conventional laparoscopic surgery (CLS), the long-term outcomes of SILS + 1 remains uncertain and are needed to evaluated by an RCT. METHODS: Patients with clinical stage T1-4aN0-2M0 rectosigmoid cancer were enrolled. The participants were randomly assigned to either SILS + 1 (n = 99) or CLS (n = 99). The 3-year DFS, 5-year OS, and recurrence patterns were analyzed. RESULTS: Between April 2014 and July 2016, 198 patients were randomly assigned to either the SILS + 1 group (n = 99) or CLS group (n = 99). The median follow-up in the SILS + 1 group was 64.0 months and in CLS group was 65.0 months. The 3-year DFS was 87.8% (95% CI, 81.6-94.8%) in SILS + 1 group and 86.9% (95% CI, 81.3-94.5%) in CLS group (hazard ratio: 1.09 (95% CI, 0.48-2.47; P = 0.84)). The 5-year OS was 86.7% (95% CI,79.6-93.8%) in the SILS + 1 group and 80.5% (95% CI,72.5-88.5%) in the CLS group (hazard ratio: 1.53 (95% CI, 0.74-3.18; P = 0.25)). There were no significant differences in the recurrence patterns between the two groups. CONCLUSIONS: We found no significant difference in 3-year DFS and 5-year OS of patients with sigmoid colon and upper rectal cancer treated with SILS + 1 vs. CLS. SILS + 1 is noninferior to CLS when performed by expert surgeons. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02117557 (registered on 21/04/2014).

Asphaltene-Derived Graphene Quantum Dots for Controllable Coatings on Glass, Fabrics, and Aerogels.

Graphene quantum dots (GQDs) derived from natural asphaltene byproducts can produce controlled hydrophobic or hydrophilic interfaces on glass, fabrics, and aerogels. A set of facile solvent extraction methods were used to isolate and chemically prepare materials with different surface functionalities from a commercially derived asphaltene precursor. The organic-soluble fraction was used to create hydrophobic and water-repellent surfaces on glass and cotton fabrics. The GQD solutions could also penetrate the pores of a silica aerogel, rendering it hydrophobic. Alternatively, by extracting the more polar fraction of the GQDs and oxidizing their surfaces, we also demonstrate strongly hydrophilic coatings. This work shows that naturally abundant GQD-containing materials can produce interfaces with the desired wettability properties through a straightforward tuning of the solvent extraction procedure. Owing to their natural abundance, low toxicity, and strong fluorescence, asphaltene-derived GQDs could thus be applied, in bulk, toward a wide range of tunable surface coatings. This approach, moreover, uses an important large-scale hydrocarbon waste material, thereby offering a sustainable alternative to the disposal of asphaltene wastes.

Short-term and long-term outcomes of single-incision plus one-port laparoscopic surgery for colorectal cancer: a propensity-matched cohort study with conventional laparoscopic surgery.

BACKGROUND: Single-incision plus one-port laparoscopic surgery (SILS + 1) has been demonstrated to be minimally invasive while possessing better cosmesis and less pain compared with conventional laparoscopic surgery (CLS). However, SILS + 1 as an alternative to CLS for colorectal cancer is still controversial. METHODS: A total of 1071 patients who underwent curative laparoscopic surgery for colon cancer between 2015 and 2018 were included. Of these patients, 258 SILS + 1 cases and 516 CLS cases were analyzed using propensity score matching. The baseline characteristics, surgical outcomes, pathologic findings and recovery course, morbidity and mortality within postoperative 30 days and 3-year disease-free and overall survival were compared. RESULTS: Baseline characteristics were balanced between the groups. The mean operating time was significantly shorter in SILS + 1 group, with less estimated blood loss. Tumor size, tumor differentiation, number of harvested lymph nodes, resection margin and pathologic T, N, TNM stage was similar between the groups. There was no significant difference in overall perioperative complications. Uni- and multivariate analyses revealed that SILS + 1 was not a risk factor for complications. Postoperatively, SILS + 1 group showed faster recovery than CLS group in terms of ambulation, bowel function, oral intake and discharge. The 3-year disease-free survival rates of SILS + 1 and CLS groups were 90.1% and 87.3%(p = 0.59), respectively and the 3-year overall survival rates were 93.3% vs. 89.8%(p = 0.172). DISCUSSION: Our study revealed that SILS + 1 is safe, feasible, oncologically efficient, and may be considered as a surgical option for selected patients with colorectal cancer.

Decoding the deactivation mechanism of R192W mutation of ZAP-70 using molecular dynamics simulations and binding free energy calculations.

CONTEXT: ZAP-70 (zeta-chain-associated protein of 70 kDa), serving as a critical regulator for T cell antigen receptor signaling, represents an attractive therapeutic target for autoimmunity disease. How the mechanistical mechanism of ZAP-70 to a human autoimmune syndrome-associated R192W mutation remains unclear. The results indicated that the R192W mutation of ZAP-70 clearly affected the conformational flexibility of the N-terminal ITAM-Y2P. Structural analysis unveiled that the R192W mutation of ZAP-70 caused the exposure of the N-terminal ITAM-Y2P to the solvent. MM-GBSA binding free energy calculations exhibited that the R192W mutation decreased the binding affinity of ITAM-Y2P to the ZAP-70 mutant. Residue-based free energy decomposition further revealed that the protein-peptide interaction networks involving electrostatic interactions provide significant contributions for complex formation. The energy unfavorable residues include Arg43, Arg192, Tyr240, and Lys244 from ZAP-70 and Asn301, Leu303, pY304, and pY315 from ITAM-Y2P in the R192W mutant. Our obtained results may help the understanding of the deactivation mechanism of ZAP-70 induced by the R192W mutation. METHODS: In the work, multiple replica molecular dynamics simulations and molecular mechanics-generalized Born surface area (MM-GBSA) method were performed to reveal the doubly phosphorylated ITAMs (ITAM-Y2P)-mediated deactivation mechanism of ZAP-70 induced by the R192W mutation.