Enhancing antitumor efficacy of NIR-I region zinc phthalocyanine@upconversion nanoparticle through lysosomal escape and mitochondria targeting.

Accurately visualizing the intracellular trafficking of upconversion nanoparticles (UCNPs) loaded with phthalocyanines and achieving precise photodynamic therapy (PDT) using near-infrared (NIR) laser irradiation still present challenges. In this study, a novel NIR laser-triggered upconversion luminescence (UCL) imaging-guided nanoparticle called FA@TPA-NH-ZnPc@UCNPs (FTU) was developed for PDT. FTU consisted of UCNPs, folic acid (FA), and triphenylamino-phenylaniline zinc phthalocyanine (TPA-NH-ZnPc). Notably, TPA-NH-ZnPc showcases aggregation-induced emission (AIE) characteristic and NIR absorption properties at 741 nm, synthesized initially via molybdenum-catalyzed condensation reaction. The UCL emitted by FTU enable real-time visualization of their subcellular localization and intracellular trafficking within ovarian cancer HO-8910 cells. Fluorescence images revealed that FTU managed to escape from lysosomes due to the "proton sponge" effect of TPA-NH-ZnPc. The FA ligands on the surface of FTU further directed their transport and accumulation within mitochondria. When excited by a 980 nm laser, FTU exhibited UCL and activated TPA-NH-ZnPc, consequently generating cytotoxic singlet oxygen (1O2), disrupted mitochondrial function and induced apoptosis in cancer cells, which demonstrated great potential for tumor ablation.

Unveiling the Synergy of Architecture and Anion Vacancy on Bi2Te3-x@NPCNFs for Fast and Stable Potassium Ion Storage.

Large volume strain and slow kinetics are the main obstacles to the application of high-specific-capacity alloy-type metal tellurides in potassium-ion storage systems. Herein, Bi2Te3-x nanocrystals with abundant Te-vacancies embedded in nitrogen-doped porous carbon nanofibers (Bi2Te3-x@NPCNFs) are proposed to address these challenges. In particular, a hierarchical porous fiber structure can be achieved by the polyvinylpyrrolidone-etching method and is conducive to increasing the Te-vacancy concentration. The unique porous structure together with defect engineering modulates the potassium storage mechanism of Bi2Te3, suppresses structural distortion, and accelerates K+ diffusion capacity. The meticulously designed Bi2Te3-x@NPCNFs electrode exhibits ultrastable cycling stability (over 3500 stable cycles at 1.0 A g-1 with a capacity degradation of only 0.01% per cycle) and outstanding rate capability (109.5 mAh g-1 at 2.0 A g-1). Furthermore, the systematic ex situ characterization confirms that the Bi2Te3-x@NPCNFs electrode undergoes an "intercalation-conversion-step alloying" mechanism for potassium storage. Kinetic analysis and density functional theory calculations reveal the excellent pseudocapacitive performance, attractive K+ adsorption, and fast K+ diffusion ability of the Bi2Te3-x@NPCNFs electrode, which is essential for fast potassium-ion storage. Impressively, the assembled Bi2Te3-x@NPCNFs//activated-carbon potassium-ion hybrid capacitors achieve considerable energy/power density (energy density up to 112 Wh kg-1 at a power density of 1000 W kg-1) and excellent cycling stability (1600 cycles at 10.0 A g-1), indicating their potential practical applications.

Application of Mid-Pancreatectomy with End-to-End Anastomosis in Pancreatic Benign Tumors.

Mid-pancreatectomy combined with end-to-end anastomosis is a surgical procedure used to treat benign pancreatic tumors. It involves removing the tumor from the middle section of the pancreas and connecting the proximal and distal ends through an anastomosis. The traditional surgical approach for resecting the middle segment of the pancreas involves closing the proximal pancreas and creating a Roux-en-Y anastomosis with the jejunum. However, this approach carries a double risk of pancreatic stump fistula and pancreatico enteric anastomotic leak postoperatively. In this paper, a new procedure is described where stent tubes were placed into the proximal and distal sides of the pancreatic ducts after ensuring sufficient freedom from the proximal distal pancreas. The pancreatic parenchyma was then sutured continuously under direct vision to achieve pancreatic end-to-end anastomosis. This procedure helps preserve pancreatic function, reducing the risk of postoperative pancreatic insufficiency. However, due to the complexity and risks involved, thorough evaluation and preparation are necessary before surgery. We carefully assess the patient's history, serology, and imaging results to determine the feasibility and effectiveness of the procedure. During surgery, we consider the use of a suitable pancreatic duct stent to ensure the flow of pancreatic juice into the intestine through physiological pathways. Our goal is to remove the tumor while preserving as much normal pancreatic tissue as possible for the anastomosis. After the operation, it is crucial to monitor the patient's pancreatic function, paying close attention to blood glucose levels, drainage fluid volume, and amylase value of the pancreatic anastomosis. During the postoperative follow-up visit, the patient's pancreatic function was assessed, and there was no significant change in quality of life compared to before the surgery. This indicates that mid-pancreatectomy combined with end-to-end anastomosis is a safe and effective procedure for treating pancreatic benign neoplasms.

Efficient Polytelluride Anchoring for Ultralong-Life Potassium Storage: Combined Physical Barrier and Chemisorption in Nanogrid-in-Nanofiber.

Metal tellurides (MTes) are highly attractive as promising anodes for high-performance potassium-ion batteries. The capacity attenuation of most reported MTe anodes is attributed to their poor electrical conductivity and large volume variation. The evolution mechanisms, dissolution properties, and corresponding manipulation strategies of intermediates (K-polytellurides, K-pTex) are rarely mentioned. Herein, we propose a novel structural engineering strategy to confine ultrafine CoTe2 nanodots in hierarchical nanogrid-in-nanofiber carbon substrates (CoTe2@NC@NSPCNFs) for smooth immobilization of K-pTex and highly reversible conversion of CoTe2 by manipulating the intense electrochemical reaction process. Various in situ/ex situ techniques and density functional theory calculations have been performed to clarify the formation, transformation, and dissolution of K-pTex (K5Te3 and K2Te), as well as verifying the robust physical barrier and the strong chemisorption of K5Te3 and K2Te on S, N co-doped dual-type carbon substrates. Additionally, the hierarchical nanogrid-in-nanofiber nanostructure increases the chemical anchoring sites for K-pTex, provides sufficient volume buffer space, and constructs highly interconnected conductive microcircuits, further propelling the battery reaction to new heights (3500 cycles at 2.0 A g-1). Furthermore, the full cells further demonstrate the potential for practical applications. This work provides new insights into manipulating K-pTex in the design of ultralong-cycling MTe anodes for advanced PIBs.

LRP4-related signalling pathways and their regulatory role in neurological diseases.

The mechanism of action of low-density lipoprotein receptor related protein 4 (LRP4) is mediated largely via the Agrin-LRP4-MuSK signalling pathway in the nervous system. LRP4 contributes to the development of synapses in the peripheral nervous system (PNS). It interacts with signalling molecules such as the amyloid beta-protein precursor (APP) and the wingless type protein (Wnt). Its mechanisms of action are complex and mediated via interaction between the pre-synaptic motor neuron and post-synaptic muscle cell in the PNS, which enhances the development of the neuromuscular junction (NMJ). LRP4 may function differently in the central nervous system (CNS) than in the PNS, where it regulates ATP and glutamate release via astrocytes. It mayaffect the growth and development of the CNS by controlling the energy metabolism. LRP4 interacts with Agrin to maintain dendrite growth and density in the CNS. The goal of this article is to review the current studies involving relevant LRP4 signaling pathways in the nervous system. The review also discusses the clinical and etiological roles of LRP4 in neurological illnesses, such as myasthenia gravis, Alzheimer's disease and epilepsy. In this review, we provide a theoretical foundation for the pathogenesis and therapeutic application of LRP4 in neurologic diseases.

The neutrophil-to-lymphocyte ratio and lactate dehydrogenase combined in predicting liver metastasis and prognosis of colorectal cancer.

Background: The neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level are inflammatory markers related to tumor growth and metabolism. This study investigated the value of preoperative NLR, LDH and the combination of NLR and LDH (NLR-LDH) for predicting colorectal cancer liver metastasis (CRLM) and tumor prognosis in the early stages of colorectal cancer (CRC). Materials and methods: Three hundred patients undergoing CRC resection were included. Logistic regression analysis was used to estimate the correlation between CRLM time and inflammatory markers, and Kaplan-Meier survival and Cox regression analyses were used to estimate overall survival (OS). Forest plots were prepared based on the multivariate Cox analysis model and evaluated by receiver operating characteristic (ROC) curve analysis. Results: The NLR cut-off value was 2.071 according to the ROC curve. The multivariate analysis showed that the elevated LDH level and a high NLR-LDH level were independent predictors of synchronous CRLM and OS (p < 0.05). The combination of a high NLR and elevated LDH and NLR-LDH levels suggested a poor prognosis and a significantly shorter median survival time than a low NLR and low levels of LDH and NLR-LDH. The ROC curve analysis results illustrated that the predictive value of the NLR-LDH score for synchronous CRLM [area under the curve (AUC) = 0.623, p < 0.001] and OS (AUC = 0.614, p = 0.001) was superior to that of the NLR or LDH score used alone. Conclusion: LDH and NLR-LDH are reliable, easy-to-use, independent biomarkers for predicting synchronous or metachronous CRLM and OS in CRC patients. The NLR is an important monitoring index for CRLM. Preoperative NLR, LDH and NLR-LDH may help to guide the use of therapeutic strategies and cancer surveillance.

Efficient-Lightweight YOLO: Improving Small Object Detection in YOLO for Aerial Images.

The most significant technical challenges of current aerial image object-detection tasks are the extremely low accuracy for detecting small objects that are densely distributed within a scene and the lack of semantic information. Moreover, existing detectors with large parameter scales are unsuitable for aerial image object-detection scenarios oriented toward low-end GPUs. To address this technical challenge, we propose efficient-lightweight You Only Look Once (EL-YOLO), an innovative model that overcomes the limitations of existing detectors and low-end GPU orientation. EL-YOLO surpasses the baseline models in three key areas. Firstly, we design and scrutinize three model architectures to intensify the model's focus on small objects and identify the most effective network structure. Secondly, we design efficient spatial pyramid pooling (ESPP) to augment the representation of small-object features in aerial images. Lastly, we introduce the alpha-complete intersection over union (α-CIoU) loss function to tackle the imbalance between positive and negative samples in aerial images. Our proposed EL-YOLO method demonstrates a strong generalization and robustness for the small-object detection problem in aerial images. The experimental results show that, with the model parameters maintained below 10 M while the input image size was unified at 640 × 640 pixels, the APS of the EL-YOLOv5 reached 10.8% and 10.7% and enhanced the APs by 1.9% and 2.2% compared to YOLOv5 on two challenging aerial image datasets, DIOR and VisDrone, respectively.

Nursing management of treatment-related venous thromboembolism in patients with multiple myeloma.

Objectives: Venous thromboembolism (VTE) is a common complication among patients with newly diagnosed multiple myeloma (NDMM). Therefore, this study aimed to analyze the incidence and risk factors associated with VTE in the current era of thromboprophylaxis and to propose appropriate nursing measures. Methods: A total of 1,539 NDMM patients were retrospectively analyzed. All patients underwent VTE risk assessment and received aspirin or low molecular weight heparin (LMWH) to prevent thrombosis, followed by appropriate care based on their individual thrombosis risk. The incidence of VTE and its related risk factors were then analyzed. Results: All patients received at least four cycles of therapy containing immunomodulators (IMiDs) and/or proteasome inhibitors (PIs). We assigned 371 patients (24.1%) to the moderate-risk thrombosis group, who received daily aspirin (75 mg) for thrombosis prevention and 1,168 patients (75.9%) to the high-risk group, who received daily low molecular weight heparin (3,000 IU) for thrombosis prevention two times a day. Among all the patients, 53 (3.4%) experienced lower extremity venous thromboembolism events, with three of those patients experiencing a concurrent pulmonary embolism. A multivariate analysis indicated that bed rest lasting more than 2 months and plasma cells of ≥60% were independent factors associated with thrombosis. Conclusion: More effective risk assessment models are needed to predict thrombosis accurately. In addition, nurses involved in the treatment and management of thrombosis should continually engage in professional development to enhance their knowledge and skills.

Hand-sewn esophagojejunostomy in transthoracic single-port assisted laparoscopic esophagogastrectomy for Siewert type II adenocarcinoma of the esophagogastric junction with esophageal invasion > 3 cm.

BACKGROUND: An optimal method for digestive tract reconstruction (DTR) in laparoscopic radical resection of Siewert type II adenocarcinoma of esophagogastric junction (AEG) has not yet been standardized. The aim of this study was to evaluate the safety and feasibility of a hand-sewn esophagojejunostomy (EJ) technique during transthoracic single-port assisted laparoscopic esophagogastrectomy (TSLE) for Siewert type II AEG with esophageal invasion > 3 cm. METHODS: The perioperative clinical data and short-term outcomes for patients who underwent TSLE using hand-sewn EJ for Siewert type II AEG with esophageal invasion > 3 cm between March 2019 and April 2022 have been retrospectively reviewed. RESULTS: A total of 25 patients were eligible. All 25 patients were successfully operated. None was converted to open surgery or mortality. 84.00% of patients were male and 16.00% were female. The mean age, body mass index (BMI), and the American Society of Anesthesiologists (ASA) score were 67.88 ± 8.10 years, 21.30 ± 2.80 kg/m2, and 2.08, respectively. The average incorporated operative and hand-sewn EJ procedural times were 274.92 ± 57.46 and 23.36 ± 3.00 min, respectively. The length of extracorporeal esophageal involvement and proximal margin was 3.31 ± 0.26 cm and 3.12 ± 0.12 cm, respectively. The average time for the first oral feeding and hospital stay were 6 (3-14) and 7 (3-18) days, respectively. Two patients (8.00%) developed postoperative grade IIIa complications according to the Clavien-Dindo classification, including 1 case of pleural effusion and 1 case of anastomotic leakage, both of whom were cured by puncture drainage. CONCLUSION: Hand-sewn EJ in TSLE is safe and feasible for Siewert type II AEG. This method can ensure safe proximal margins and could be a good option with an advanced endoscopic suture technique for type II tumor with esophageal invasion > 3 cm.

Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of Novel C-17 Amine Derivatives Based on GSK3640254 as HIV-1 Maturation Inhibitors with Broad Spectrum Activity.

An investigation of the structure-activity relationships of a series of HIV-1 maturation inhibitors (MIs) based on GSK3640254 (4) was conducted by incorporating novel C-17 amine substituents to reduce the overall basicity of the resultant analogues. We found that replacement of the distal amine on the C-17 sidechain present in 4 with a tertiary alcohol in combination with either a heterocyclic ring system or a cyclohexyl ring substituted with polar groups provided potent wild-type HIV-1 MIs that also retained excellent potency against a T332S/V362I/prR41G variant, a laboratory strain that served as a surrogate to assess HIV-1 polymorphic virus coverage. Compound 26 exhibited broad-spectrum HIV-1 activity against an expanded panel of clinically relevant Gag polymorphic viruses and had the most desirable overall profile in this series of compounds. In pharmacokinetic studies, 26 had low clearance and exhibited 24 and 31% oral bioavailability in rats and dogs, respectively.

Maintaining Breastfeeding During the Treatment of Breast Abscesses Is Not Contraindicated.

Background: World Health Organization guidelines recommend maintaining breastfeeding if a woman develops breast abscess, because of benefits to her recovery and the infant's health. However, clinical staff recommend weaning to promote faster recovery from the abscess. The purpose of this study was to determine whether maintaining breastfeeding after development of a breast abscess has any influence on the resolution of the breast abscess. Methods: The records of 212 patients who were breastfeeding and developed breast abscess treated at Guangzhou Women and Children's Medical Center from January 2018 to December 2019 were retrospectively reviewed. Patients were divided into two groups: those who maintained breastfeeding (study group) and those who stopped breastfeeding (control group). Results: There were 139 patients in study group and 73 patients in the control group. Baseline characteristics were similar between the two groups. The time to cure in the study group and in the control group was 7.20 ± 2.21 days and 7.01 ± 2.39 days, respectively (t = 0.579, p = 0.563). Common complications were milk fistula and galactocele, and the frequency of both was similar between the two groups (milk fistula: 7.9% versus 8.2%, respectively; χ2 = 0.006, p = 0.938; galactocele: 8.6% versus 9.6%, respectively; χ2 = 0.054, p = 0.817). There was no significant difference in the recurrence rates between the two groups (5.0% versus 2.7%; χ2 = 0.184, p = 0.668). Conclusion: Maintaining breastfeeding during treatment of breast abscess does not affect the outcome of treatment provided, on condition that the abscess is treated appropriately.

Whether the infracardiac bursa protect right pleura during laparoscopic radical operation of Siewert type II adenocarcinoma of esophagogastric junction?

BACKGROUND: Transthoracic single-port assisted laparoscopic five-step maneuver inferior mediastinal lymphadenectomy for Siewert type II adenocarcinoma of esophagogastric junction (AEG) has superiority in lower mediastinal lymph nodes dissection and digestive tract reconstruction. However, the right pleura was probably ruptured in this surgical technique. The aim of this study was to explore whether the infracardiac bursa (ICB) exposed could protect right pleura. METHODS: We retrospectively collected and evaluated the clinical and pathological data of patients who underwent five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymphadenectomy for Siewert II AEG at Guangdong Provincial Hospital of Chinese Medicine between May 2017 and February 2022. RESULTS: A total of 49 patients were eligible, including 31 patients in ICB exposed group (group A) and 18 patients in ICB unexposed group (group B). There were no statistically significant differences in baseline characteristics between the two groups. 4 patients (12.9%) had right pleura rupture in group A, while 14 patients (77.8%) in group B, and the difference was statistically significant (p < 0.001). Compared with group B, the extubation time of endotracheal intubation (10.0 (6.0 ~ 12.0) vs. 13.0 (8.0 ~ 15.0) min, p = 0.003) and thoracic drainage tube stay (6.0 (5.0 ~ 7.0) vs. 8.0 (6.0 ~ 10.5) days, p = 0.041) were significantly shorted in the group A. The drainage volume of thorax (351.61 ± 125.00 vs. 418.61 ± 207.86 mL, p = 0.146) was non-significant less and the rate of complications (3.2% vs. 11.1%, p = 0.074) was non-significant lower in group A compared with group B. The postoperative hospital stay (9.0 (8.0,13.0) vs. 9.0 (8.0,12.0) days, p = 0.983) were similar in two groups. No serious adverse event occurred in any patient. CONCLUSIONS: The ICB exposed could protect the right pleura and may promote postoperative recovery, which may be used as an anatomical marker in inferior mediastinal lymphadenectomy.

The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation.

GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH2F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.

Discovery of Non-Nucleotide Small-Molecule STING Agonists via Chemotype Hybridization.

The identification of agonists of the stimulator of interferon genes (STING) pathway has been an area of intense research due to their potential to enhance innate immune response and tumor immunogenicity in the context of immuno-oncology therapy. Initial efforts to identify STING agonists focused on the modification of 2',3'-cGAMP (1) (an endogenous STING activator ligand) and other closely related cyclic dinucleotides (CDNs). While these efforts have successfully identified novel CDNs that have progressed into the clinic, their utility is currently limited to patients with solid tumors that STING agonists can be delivered to intratumorally. Herein, we report the discovery of a unique class of non-nucleotide small-molecule STING agonists that demonstrate antitumor activity when dosed intratumorally in a syngeneic mouse model.

Mitofusin-2 Restrains Hepatic Stellate Cells' Proliferation via PI3K/Akt Signaling Pathway and Inhibits Liver Fibrosis in Rats.

The mitochondrial GTPase mitofusin-2 (MFN2) gene can suppress the cell cycle and regulate cell proliferation in a number of cell types. However, its function in hepatic fibrosis remains largely unexplored. We attempted to understand the mechanism of MFN2 in hepatic stellate cell (HSC) proliferation and the development of hepatic fibrosis. Rat HSC-T6 HSC were cultured and transfected by adenovirus- (Ad-) Mfn2 or its negative control (NC) vector (Ad-green fluorescent protein (GFP)); a rat liver cirrhosis model was established via subcutaneous injection with carbon tetrachloride (CCl4). Seventy-two rats were randomly divided into four groups: CCl4, Mfn2, GFP, and NC. Ad-Mfn2 or Ad-GFP was transfected into the circulation via intravenous injection at day 1, 14, 28, 42, or 56 after the first injection of CCl4 in the Mfn2/GFP groups. Biomarkers related to HSC proliferation and the development of hepatic fibrosis were detected using western blotting, hematoxylin-eosin and Masson staining, and immunohistochemistry. In vitro, Mfn2 interfered specifically with platelet-derived growth factor- (PDGF-) induced signaling pathway (phosphatidylinositol 3-kinase- (PI3K-) AKT), inhibiting HSC-T6 cell activation and proliferation. During the process of hepatic fibrosis in vivo, extracellular collagen deposition and the expression of fibrosis-related proteins increased progressively, while Mfn2 expression decreased gradually. Upregulating Mfn2 expression at the early stage of fibrosis impeded the process, triggered the downregulation of type I collagen, and antagonized the formation of factors associated with liver fibrosis. Mfn2 suppresses HSC proliferation and activation and exhibits antifibrotic potential in early-stage hepatic fibrosis. Therefore, it may represent a significant therapeutic target for eradicating hepatic fibrosis.

Dynamic Nomogram for Predicting Lateral Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma.

OBJECTIVE: To establish a dynamic nomogram based on preoperative clinical data for prediction of lateral lymph node metastasis (LLNM) of papillary thyroid carcinoma. STUDY DESIGN: Retrospective study. SETTING: The Sixth Affiliated Hospital of Sun Yat-Sen University. METHODS: The data of 477 patients from 2 centers formed the training group and validation group and were retrospectively reviewed. Preoperative clinical factors influencing LLNM were identified by univariable and multivariable analysis and were to construct a predictive dynamic nomogram for LLNM. Receiver operating characteristic analysis and calibration curves were used to evaluate the predictive power of the nomogram. RESULTS: The following were identified as independent risk factors for LLNM: male sex (odds ratio [OR] = 4.6, P = .04), tumor size ≥10.5 mm (OR = 7.9, P = .008), thyroid nodules (OR = 6.1, P = .013), irregular tumor shape (OR = 24.6, P = .001), rich lymph node vascularity (OR = 9.7, P = .004), and lymph node location. The dynamic nomogram constructed with these factors is available at https://zxh1119.shinyapps.io/DynNomapp/. The nomogram showed good performance, with an area under the curve of 0.956 (95% CI, 0.925-0.986), a sensitivity of 0.87, and a specificity of 0.91, if high-risk patients were defined as those with a predicted probability ≥0.3 or total score ≥200. The nomogram performed well in the external validation cohort (area under the curve, 0.915; 95% CI, 0.862-0.967). CONCLUSIONS: The dynamic nomogram for preoperative prediction of LLNM in papillary thyroid carcinoma can help surgeons identify high-risk patients and develop individualized treatment plans.

GSK3640254 Is a Novel HIV-1 Maturation Inhibitor with an Optimized Virology Profile.

HIV-1 maturation inhibitors (MIs) offer a novel mechanism of action and potential for use in HIV-1 treatment. Prior MIs displayed clinical efficacy but were associated with the emergence of resistance and some gastrointestinal tolerability events. Treatment with the potentially safer next-generation MI GSK3640254 (GSK'254) resulted in up to a 2-log10 viral load reduction in a phase IIa proof-of-concept study. In vitro experiments have defined the antiviral and resistance profiles for GSK'254. The compound displayed strong antiviral activity against a library of subtype B and C chimeric viruses containing Gag polymorphisms and site-directed mutants previously shown to affect potency of earlier-generation MIs, with a mean protein-binding adjusted 90% effective concentration (EC90) of 33 nM. Furthermore, GSK'254 exhibited robust antiviral activity against a panel of HIV-1 clinical isolates, with a mean EC50 of 9 nM. Mechanistic studies established that bound GSK'254 dissociated on average 7.1-fold more slowly from wild-type Gag virus-like particles (VLPs) than a previous-generation MI. In resistance studies, the previously identified A364V Gag region mutation was selected under MI pressure in cell culture and during the phase IIa clinical study. As expected, GSK'254 inhibited cleavage of p25 in a range of polymorphic HIV-1 Gag VLPs. Virus-like particles containing the A364V mutation exhibited a p25 cleavage rate 9.3 times higher than wild-type particles, providing a possible mechanism for MI resistance. The findings demonstrate that GSK'254 potently inhibits a broad range of HIV-1 strains expressing Gag polymorphisms.

The prognostic value of preoperative serum lactate dehydrogenase levels in patients underwent curative-intent hepatectomy for colorectal liver metastases: A two-center cohort study.

BACKGROUND: The prognostic value of lactate dehydrogenase (LDH) in colorectal cancer patients has remained inconsistent between nonmetastatic and metastatic settings. So far, very few studies have included LDH in the prognostic analysis of curative-intent surgery for colorectal liver metastases (CRLM). PATIENTS AND METHODS: Five hundred and eighty consecutive metastatic colorectal cancer patients who underwent curative-intent CRLM resection from Sun Yat-sen University Cancer Center (434 patients) and Sun Yat-sen University Sixth Affiliated Hospital (146 patients) in 2000-2019 were retrospectively collected. Overall survival (OS) was the primary end point. Cox regression model was performed to identify the prognostic values of preoperative serum LDH levels and other clinicopathology variables. A modification of the established Fong CRS scoring system comprising LDH was developed within this Chinese population. RESULTS: At the median follow-up time of 60.5 months, median OS was 59.5 months in the pooled cohort. In the multivariate analysis, preoperative LDH >upper limit of normal (250 U/L) was the strongest independent prognostic factor for OS (HR 1.73, 95% confidence interval [CI], 1.22-2.44; p < 0.001). Patients with elevated LDH levels showed impaired OS than patients with normal LDH levels (27.6 months vs. 68.8 months). Five-year survival rates were 53.7% and 22.5% in the LDH-normal group and LDH-high group, respectively. Similar results were also confirmed in each cohort. In the subgroup analysis, LDH could distinguish the survival regardless of most established prognostic factors (number and size of CRLM, surgical margin, extrahepatic metastases, CEA, and CA19-9 levels, etc.). Integrating LDH into the Fong score contributed to an improvement in the predictive value. CONCLUSION: Our study implicates serum LDH as a reliable and independent laboratory biomarker to predict the clinical outcome of curative-intent surgery for CRLM. Composite of LDH and Fong score is a potential stratification tool for CRLM resection. Prospective, international studies are needed to validate these results across diverse populations.

Erratum.

Overexpression of the tumor necrosis factor receptor-associated factor 4 (TRAF4) has been detected in many cancer types and is considered to foster tumor progression. However, the role of TRAF4 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that TRAF4 was highly expressed in HCC cell lines and HCC tissues compared with normal liver cell lines and adjacent noncancerous tissues. TRAF4 overexpression in HCC tissues was correlated with tumor quantity and vascular invasion. In vitro studies showed that TRAF4 was associated with HCC cell migration and invasion. An in vivo study verified that TRAF4 overexpression facilitated metastasis in nude mice. In addition, overexpressed TRAF4 promoted the phosphorylation of Akt and induced Slug overexpression, leading to downregulated E-cadherin and upregulated vimentin, while silencing TRAF4 moderated the phosphorylation of Akt and repressed the expression of Slug, which resulted in upregulated E-cadherin and downregulated vimentin. These effects were inversed after pretreatment of the PI3K/Akt inhibitor LY294002 or overexpression of constitutively active Akt1. Our study demonstrated that TRAF4 was involved in promoting HCC cell migration and invasion. The process was induced by the EMT through activation of the PI3K/Akt signaling pathway.

Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors.

The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with raltegravir and elvitegravir.