Safety and benefit of modified mesohepatectomy in the treatment of bilobar involvement congenital biliary dilatation.

BACKGROUND: The diseased bile duct in bilobar congenital biliary dilatation is extensive and often requires major hepatectomy or liver transplantation associated with a higher risk. We aimed to evaluate the safety and benefit of modified mesohepatectomy, in comparison with trisectionectomy, to treat bilobar congenital biliary dilatation. METHODS: This study included 28 patients with type IV and V bilobar congenital biliary dilatation. An innovative mesohepatectomy comprising the hepatectomy technique beyond the P/U point and bile duct shaping was applied to 14 patients to address the extensively diseased bile duct and difficulty in hepaticojejunostomy. Another 14 patients received trisectionectomy. The perioperative and long-term outcomes of these patients were compared. RESULTS: The ratio of residual liver volume to standard liver volume in the mesohepatectomy group was higher (78.68% vs. 40.90%, p = 0.005), while the resection rate of the liver parenchyma was lower (28.25% vs. 63.97%, p = 0.000), than that in trisectionectomy group. The mesohepatectomy group had a lower severe complication (>Clavein III, 0% vs. 57.70%, p = 0.019) and incidence of posthepatectomy liver failure (7.14% vs. 42.86%, p = 0.038). No significant difference was observed in blood loss and bile leakage (p > 0.05). All the patients in the mesohepatectomy group achieved optimal results in the long-term follow-up. CONCLUSIONS: mesohepatectomy provides an efficient treatment option for bilobar congenital biliary dilatation and can achieve radical resection, retain more liver parenchyma, and reduce the difficulty of hepaticojejunostomy, especially for patients that are not eligible for major hepatectomy and liver transplantation.

Predicting the outcomes of hepatocellular carcinoma downstaging with the use of clinical and radiomics features.

BACKGROUND: Downstaging of hepatocellular carcinoma (HCC) makes it possible for patients beyond the criteria to have the chance of liver transplantation (LT) and improved outcomes. Thus, a procedure to predict the prognosis of the treatment is an urgent requisite. The present study aimed to construct a comprehensive framework with clinical information and radiomics features to accurately predict the prognosis of downstaging treatment. METHODS: Specifically, three-dimensional (3D) tumor segmentation from contrast-enhanced computed tomography (CT) is employed to extract spatial information of the lesions. Then, the radiomics features within the segmented region are calculated. Combining radiomics features and clinical data prompts the development of feature selection to enhance the robustness and generalizability of the model. Finally, we adopt the support vector machine (SVM) algorithm to establish a classification model for predicting HCC downstaging outcomes. RESULTS: Herein, a comparative study was conducted on three different models: a radiomics features-based model (R model), a clinical features-based model (C model), and a joint radiomics clinical features-based model (R-C model). The average accuracy of the three models was 0.712, 0.792, and 0.844, and the average area under the receiver-operating characteristic (AUROC) of the three models was 0.775, 0.804, and 0.877, respectively. CONCLUSIONS: The novel and practical R-C model accurately predicted the downstaging outcomes, which could be utilized to guide the HCC downstaging toward LT treatment.

"RESET" Effect: Random Extending Sequences Enhance the Trans-Cleavage Activity of CRISPR/Cas12a.

The trans-cleavage activity of CRISPR/Cas12a has been widely used in biosensing applications. However, the lack of exploration on the fundamental properties of CRISPR/Cas12a not only discourages further in-depth studies of the CRISPR/Cas12a system but also limits the design space of CRISPR/Cas12a-based applications. Herein, a "RESET" effect (random extending sequences enhance trans-cleavage activity) is discovered for the activation of CRISPR/Cas12a trans-cleavage activity. That is, a single-stranded DNA, which is too short to work as the activator, can efficiently activate CRISPR/Cas12a after being extended a random sequence from its 3'-end, even when the random sequence folds into secondary structures. The finding of the "RESET" effect enriches the CRISPR/Cas12a-based sensing strategies. Based on this effect, two CRISPR/Cas12a-based biosensors are designed for the sensitive and specific detection of two biologically important enzymes.

Patterns of Caudate Lobe Invasion of Hilar Cholangiocarcinoma: A Panoramic Histologic Study of Liver.

BACKGROUND: At present, caudate lobectomy (CL) in hilar cholangiocarcinoma (HCCA) was controversial. Our study was designed to investigate the features of caudate lobe invasion (CLI) by whole-mount histologic large sections (WHLS). METHODS: A total of 46 HCCA patients underwent hemihepatectomy or trisectionectomy combined with CL were included. Serial WHLS (120 mm × 100 mm) were collected, and the relationship between caudate lobe and tumor was retained to determine the incidence of CLI. Hematoxylin and eosin (HE) and immunohistochemical (IHC) staining were completed to further explore the pathway of CLI. RESULTS: The whole region of the Glisson system in caudate lobe and hilar area can be clearly displayed by WHLS, and 32 (32/46 69.6%) patients were identified with CLI. There were three different pathways of CLI with panoramic IHC staining. The most common pathway is through the fibrous connective tissue along Glisson system (20/32 62.5%, without carcinoma in bile ducts). The Bismuth type, tumor size, vascular invasion, pathological type, and hepatic invasion were related to the CLI (p < 0.05). CONCLUSIONS: The incidence and distribution of CLI provided histologic evidence for CL in HCCA. Based on the invasion pathway, it is necessary to assess the fibrous connective tissue in Glisson system of caudate lobe in pathological research and practice.

Particle electrode materials dependent tetrabromobisphenol A degradation in three-dimensional biofilm electrode reactors.

The completely biological degradation of Tetrabromobisphenol A (TBBPA) contaminant is challenging. Bio-electrochemical systems are efficient to promote electrons transfer between microbes and pollutants to improve the degradation of refractory contaminants. In particular, three-dimensional biofilm electrode reactors (3DBERs), integrating the biofilm with particle electrodes, represent a novel bio-electrochemical technology with superior treatment performances. In this study, the electroactive biofilm is cultured and acclimated on two types of particle electrodes, granular activated carbon (GAC) and granular zeolite (GZ), to degrade the target pollutant TBBPA in 3DBERs. Compared to GZ, GAC materials are more favorable for biofilm formation in terms of high specific surface area and good conductivity. The genus of Thauera is efficiently enriched on both GAC and GZ particles, whose growth is promoted by the electricity. By applying 5 V voltage, TBBPA can be removed by over 95% in 120 min whether packing GAC or GZ particle electrodes in 3DBERs. The synergy of electricity and biofilm in TBBPA degradation was more significant in GAC packed 3DBER, because the improved microbial activity by electrical stimulation accelerates debromination rate and hence the decomposition of TBBPA. Applying electricity also promotes TBBPA degradation in GZ packed 3DBER mainly due to the enhanced electrochemical effects. Roles of particle electrode materials in TBBPA removal are distinguished in this work, bringing new insights into refractory wastewater treatment by 3DBERs.

Laparoscopic versus open surgery for pheochromocytoma: a meta-analysis.

BACKGROUND: Surgical resection is the main treatment for pheochromocytoma (PHEO). Although open surgery (OS) has been shown to be safe and feasible, the safety and efficacy of laparoscopic surgery (LS) for PHEO remain controversial due to the uncertain effects of pneumoperitoneum on haemodynamics and the complexity of the tumour itself. This study was performed to compare the treatment outcomes of OS with those of LS for patients with PHEO. METHODS: A systematic search through November 11, 2019, was conducted. All studies comparing outcomes of LS and OS for PHEO were included according to eligibility criteria. This meta-analysis was conducted using Review Manager Software, version 5.3, and STATA software, version 12.0. The quality of the included studies was assessed using the Newcastle-Ottawa scale. RESULTS: Fourteen studies involving 626 patients were included in this meta-analysis. LS was associated with lower rates of intraoperative haemodynamic instability (IHD) [odds ratio (OR) = 0.61, 95% CI: 0.37 to 1.00, P = 0.05], less intraoperative blood loss [weighted mean difference (WMD) = - 115.27 ml, 95% confidence interval (CI): - 128.54 to - 101.99, P < 0.00001], lower blood transfusion rates [OR = 0.33, 95% CI: 0.21 to 0.52, P < 0.00001], earlier ambulation (WMD = - 1.57 d, 95% CI: - 1.97 to - 1.16, P < 0.00001) and food intake (WMD = - 0.98 d, 95% CI: - 1.36 to - 0.59, P < 0.00001), shorter drainage tube indwelling time (WMD = - 0.51 d, 95% CI: - 0.96 to - 0.07, P = 0.02) and postoperative stay (WMD = - 3.17 d, 95% CI: - 4.76 to - 1.58, P < 0.0001), and lower overall complication rates (OR = 0.56, 95% CI: 0.35 to 0.88, P = 0.01). However, no significant differences in operative time, postoperative blood pressure control, rates of severe complications, postoperative hypotension or cardiovascular disease (CVD) were found between the two groups. CONCLUSIONS: LS is safe and effective for PHEO resection. Compared with OS, LS caused less IHD, providing an equal chance to cure hypertension while also yielding a faster and better postoperative recovery.

Optimizing Texture Retrieving Model for Multimodal MR Image-Based Support Vector Machine for Classifying Glioma.

BACKGROUND: Accurate glioma grading plays an important role in patient treatment. PURPOSE: To investigate the influence of varied texture retrieving models on the efficacy of grading glioma with support vector machine (SVM). STUDY TYPE: Retrospective. POPULATION: In all, 117 glioma patients including 25, 29, and 63 grade II, III, and IV gliomas, respectively, based on WHO 2007. FIELD STRENGTH/SEQUENCE: 3.0T MRI/ T1 WI, T2 fluid-attenuated inversion recovery, contrast enhanced T1 , arterial spinal labeling, diffusion-weighted imaging (0, 30, 50, 100, 200, 300, 500, 800, 1000, 1500, 2000, 3000, and 3500 sec/mm2 ), and dynamic contrast-enhanced. ASSESSMENT: Texture attributes from 30 parametric maps were retrieved using four models, including Global, gray-level co-occurrence matrix (GLCM), gray-level run-length matrix (GLRLM), and gray-level size-zone matrix (GLSZM). Attributes derived from varied models were input into radial basis function SVM (RBF-SVM) combined with attribute selection using SVM-recursive feature elimination (SVM-RFE). The SVM model was trained and established with 80% randomly selected data of each category using 10-fold crossvalidation. The model performance was further tested using the remaining 20% data. STATISTICAL TESTS: Ten-fold crossvalidation was used to validate the model performance. RESULTS: Based on 30 parametric maps, 90, 240, 390, or 390 texture attributes were retrieved using the Global, GLCM, GLRLM, or GLSZM model, respectively. SVM-RFE was able to reduce attribute redundancy as well as improve RBF-SVM performance. Training data were oversampled by applying the Synthetic Minority Oversampling Technique (SMOTE) method to overcome the data imbalance problem; test results were able to further demonstrate the classifying performance of the final models. GLSZM using gray-level 64 was the optimal model to retrieve powerful image texture attributes to produce enough classifying power with an accuracy / area under the curve of 0.760/0.867 for the training and 0.875/0.971 for the independent test. Fifteen attributes were selected with SVM-RFE to provide comparable classifying efficacy. DATA CONCLUSION: When using image textures-based SVM classification of gliomas, the GLSZM model in combination with gray-level 64 and attribute selection may be an optimized solution. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1263-1274.

Preliminary Assignment of Protonated and Deprotonated Homocitrates in Extracted FeMo-Cofactors by Comparisons with Molybdenum(IV) Lactates and Oxidovanadium Glycolates.

A similar pair of protonated and deprotonated mononuclear oxidovanadium glycolates [VO(Hglyc)(phen)(H2O)]Cl·2H2O (1) and [VO(glyc)(bpy)(H2O)] (2) and a mixed-(de)protonated oxidovanadium triglycolate (NH4)2[VO(Hglyc)2(glyc)]·H2O (3) were isolated and examined. The ≡C-O(H) (≡C-OH or ≡C-O) groups coordinated to vanadium were spectroscopically and structurally identified. The glycolate in 1 features a bidentate chelation through protonated α-hydroxy and α-carboxy groups, whereas the glycolate in 2 coordinates through deprotonated α-alkoxy and α-carboxy groups. The glycolates in 3 coordinate to vanadium through α-alkoxy or α-hydroxy and α-carboxy groups and thus have both protonated ≡C-OH and deprotonated ≡C-O bonds simultaneously. Structural investigations revealed that the longer protonated V-Oα-hydroxy bonds [2.234(2) Å and 2.244(2) Å] in 1 and 3 are close to those of FeV-cofactor (FeV-co) 2.17 Å1 (FeMo-co 2.17 Å2), while deprotonated V-Oα-alkoxy bonds [2, 1.930(2); 3, 1.927(2) Å] were obviously shorter. This shows a similar elongated trend as the Mo-O distances in the previously reported deprotonated vs protonated molybdenum lactates (Wang, S. Y. et al. Dalton Trans. 2018, 47, 7412-7421) and these vanadium and molybdenum complexes have the same local V/Mo-homocitrate structures as those of FeV/Mo-cos of nitrogenases. The IR spectra of these oxidovanadium and the previously synthesized molybdenum complexes including different substituted ≡C-O(H) model compounds show red-shifts for ≡C-OH vs ≡C-O alternation, which further assign the two IR bands of extracted FeMo-co at 1084 and 1031 cm-1 to ≡C-O and ≡C-OH vibrations, respectively. Although the structural data or IR spectra for some of the previously synthesized Mo/V complexes and extracted FeMo-co were measured earlier, this is the first time that the ≡C-O(H) coordinated peaks are assigned. The overall structural and IR results well suggest the coexistence of homocitrates coordinated with α-alkoxy (deprotonated) and α-hydroxy (protonated) groups in the extracted FeMo-co.

Antitumor effect of axitinib combined with dopamine and PK-PD modeling in the treatment of human breast cancer xenograft.

Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX's efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA. The results showed that AX up-regulated the expression of breast CSC (BCSC) markers (CD44+/CD24-/low) in vivo, and DA significantly synergized the inhibitory effect on tumor growth by deducting the BCSC frequency. The PK-PD model quantitatively confirmed the synergistic interaction with the parameter estimate of interaction factor ψ 2.43. The dose regimen was optimized as 60 mg/kg AX i.g. b.i.d. combined with 50 mg/kg DA i.p. q3d in the simulation study on the basis of the PK-PD model. The model where DA synergistically enhances the effect of AX in an all-or-none manner provides a possible solution in modeling the agents like DA. Moreover, the outcome of AX and DA combination therapy in MCF-7/ADR breast cancer provided further insight of co-administering DA in the treatment of the possible CSC-causing AX-resisting breast cancer. And this combination therapy has the prospect of clinical translation.

Evaluation for Bearing Wear States Based on Online Oil Multi-Parameters Monitoring.

As bearings are critical components of a mechanical system, it is important to characterize their wear states and evaluate health conditions. In this paper, a novel approach for analyzing the relationship between online oil multi-parameter monitoring samples and bearing wear states has been proposed based on an improved gray k-means clustering model (G-KCM). First, an online monitoring system with multiple sensors for bearings is established, obtaining oil multi-parameter data and vibration signals for bearings through the whole lifetime. Secondly, a gray correlation degree distance matrix is generated using a gray correlation model (GCM) to express the relationship of oil monitoring samples at different times and then a KCM is applied to cluster the matrix. Analysis and experimental results show that there is an obvious correspondence that state changing coincides basically in time between the lubricants' multi-parameters and the bearings' wear states. It also has shown that online oil samples with multi-parameters have early wear failure prediction ability for bearings superior to vibration signals. It is expected to realize online oil monitoring and evaluation for bearing health condition and to provide a novel approach for early identification of bearing-related failure modes.

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer.

Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg-1·d-1) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg-1·d-1) and DEX (8 mg·kg-1·d-1) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.

Factors related to fatigue in Chinese patients with end-stage renal disease receiving maintenance hemodialysis: a multi-center cross-sectional study.

BACKGROUD: Fatigue is considered as a common symptom in patients with end-stage renal disease (ESRD) and can significantly decrease patients' quality of life. This study aimed to assess fatigue in hemodialysis patients and to investigate risk factors of fatigue in Chinese patients receiving maintenance hemodialysis (MHD) in China. METHODS: Eligible patients completed questionnaires including demographic information, a Chinese version of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), the Family APGAR Index (APGAR), the medical outcomes study health status-Social Functioning subscale (SF-36,SocF), and the Pittsburgh sleep quality index (PSQI). Laboratory parameters were abstracted by medical records review. The multiple linear regression model was used to relate parameters with the FACIT-Fatigue score. RESULTS: A total of 345 MHD patients (216 men and 129 women, age 55.6 ± 12.8) were recruited in this study. The score of FACIT-Fatigue was 39 (Interquartile Range, 31-44). Fatigue was correlated with PSQI scores (p < 0.001), SocF scores (p < 0.001), comorbidity (p = 0.006), exercise time <1 hour per day (p = 0.003), adequacy of dialysis (Kt/V) < 1.2 (p = 0.016), APGAR scores (p = 0.014), and high Scr (p = 0.043). CONCLUSIONS: Fatigue is related to sleep disturbance, social and family functioning, taking physical exercise time, comorbidity condition, Kt/V and serum creatinine level in Chinese MHD patients. Future studies and interventions should focus on developing strategies and improving the quality of life in patients by addressing these significant contributing factors.

Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208.

AIM: Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo. METHODS: The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg·kg(-1)·d(-1)) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses. RESULTS: Treatment with TM208 (10, 15 and 20 µmol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208-induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo. CONCLUSION: The induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer.

Hydrogen Therapy Reduces Oxidative Stress-associated Risks Following Acute and Chronic Exposure to High-altitude Environment.

Low pressure, low oxygen concentration, and intense ultraviolet (UV) radiation in high-altitude environments, can cause oxidative stress which can trigger mountain sickness. A recent study demonstrated that hydrogen gas with a good permeability in biological membranes can treat various disorders by exerting its selective anti-oxidation and anti-inflammatory effects, indicating that hydrogen therapy plays a role in scavenging free radicals and in balancing oxidation and anti-oxidation systems of cells. Therefore, we hypothesize that inhaling low-dose hydrogen or drinking hydrogen-saturated water is a novel and simple method to prevent and treat oxidative stress injury caused by low pressure, low oxygen concentration and intense UV radiation in plateaus, thus reducing the risk of mountain sickness.

Dopamine D1 receptor activation induces dehydroepiandrosterone sulfotransferase (SULT2A1) in HepG2 cells.

AIM: Dopamine receptors are present in the nervous system and also widely distributed in the periphery. The aim of this study was to investigate the role of D1 subtype dopamine receptors (DRD1) in the regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) in HepG2 cells. METHODS: HepG2 cells were treated with DRD1 agonists with or without DRD1 antagonist for 9 d. DRD1 and SULT2A1 mRNA expression, protein expression, and SULT2A1 activity were detected using RT-PCR, Western blotting and HPLC, respectively. The level of cAMP was measured using a commercial kit. RESULTS: All the 5 DR subtypes (DRD1-DRD5) were found to be expressed in HepG2 cells. Treatment of HepG2 cells with the specific DRD1 agonists SKF82958 (2.5 µmol/L) or SKF38393 (5 and 50 µmol/L) significantly increased the mRNA and protein expression of both DRD1 and SULT2A1, and increased SULT2A1 activity and cAMP levels. These effects were partially blocked by co-treatment with the specific DRD1 antagonist SCH23390 (2.5 µmol/L). In addition, transfection of HepG2 cells with DRD1-specific siRNAs decreased DRD1 mRNA expression by 40%, which resulted in the reduction of SULT2A1 mRNA expression by 60%, protein expression by 40%, and enzyme activity by 20%. CONCLUSION: DRD1 activation upregulates DRD1 and SULT2A1 expression and SULT2A1 activity in HepG2 cells, suggesting that the DRD1 subtype may be involved in the metabolism of drugs and xenobiotics through regulating SULT2A1.

Inhibition of EGFR autophosphorylation plays an important role in the anti-breast cancer efficacy of the dithiocarbamate derivative TM208.

AIM: To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacokinetic characteristics of TM208 in human breast cancer xenograft mice. METHODS: Human breast cancer MCF-7 and MDA-MB-231 cells were treated with TM208 or a positive control drug tamoxifen. Cell proliferation was examined using SRB and colony formation assays. Cell apoptosis was analyzed with Annexin V-FITC/PI staining assay. Protein expression was examined with Western blot, ELISA and immunohistochemical analyses. MCF-7 breast cancer xenograft nude mice were orally administered TM208 (50 or 150 mg·kg(-1)·d(-1)) or tamoxifen (50 mg·kg(-1)·d(-1)) for 18 d. On d 19, the tumors were collected for analyses. Blood samples were collected from the mice treated with the high dose of TM208, and plasma concentrations of TM208 were measured using LC-MS/MS. RESULTS: Treatment of MCF-7 and MDA-MB-231 cells with TM208 dose-dependently inhibited the cell proliferation and colony formation in vitro (the IC50 values were 36.38 ± 3.77 and 18.13 ± 0.76 µmol/L, respectively). TM208 (20-150 µmol/L) dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-dependently reduced the tumor growth, but did not result in the accumulation of TM208 or weight loss. TM208 dose-dependently inhibited the phosphorylation of EGFR and ERK1/2 in both the breast cancer cells in vitro as well as in the MCF-7 xenograft tumor. CONCLUSION: Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.

Melittin analog p5RHH enhances recombinant adeno-associated virus transduction efficiency.

OBJECTIVE: Melittin and its derivative have been developed to support effective gene delivery systems. Their ability to facilitate endosomal release enhances the delivery of nanoparticle-based gene therapy. Nevertheless, its potential application in the context of viral vectors has not received much attention. Therefore, we would like to optimize the rAAV vector by Melittin analog to improve the transduction efficiency of rAAV in liver cancer cells and explore the mechanism of Melittin analog on rAAV. METHODS: Various melittin-derived peptides were inserted into loop VIII of the capsid protein in recombinant adeno-associated virus vectors. These vectors carrying either gfp or fluc genes were subjected to quantitative polymerase chain reaction assays and transduction assays in human embryonic kidney 293 (HEK293T) cells to investigate the efficiency of vector production and gene delivery. In addition, the ability of a specific p5RHH-rAAV vector to deliver genes was examined through in vitro transduction of different cultured cells and in vivo tail vein administration to C57BL/6 mice. Finally, the intricate details of the vector-mediated transduction mechanisms were explored by using pharmacological inhibitors of every stage of the rAAV2 intracellular life cycle. RESULTS: A total of 76 melittin-related peptides were identified from existing literature. Among them, CMA-3, p5RHH and aAR3 were found to significantly inhibit transduction of rAAV2 vector crude lysate. The p5RHH-rAAV2 vectors efficiently transduced not only rAAV-potent cell lines but also cell lines previously considered resistant to rAAV. Mechanistically, bafilomycin A1, a vacuolar endosome acidification inhibitor, completely inhibited the transgene expression mediated by the p5RHH-rAAV2 vectors. Most importantly, p5RHH-rAAV8 vectors also increased hepatic transduction in vivo in C57BL/6 mice. CONCLUSION: The incorporation of melittin analogs into the rAAV capsids results in a significant improvement in rAAV-mediated transgene expression. While further modifications remain an area of interest, our studies have substantially broadened the pharmacological prospects of melittin in the context of viral vector-mediated gene delivery. Please cite this article as: Meng J, He Y, Yang H, Zhou L, Wang S, Feng X, Al-shargi OY, Yu X, Zhu L, Ling, C. Melittin analog p5RHH enhances recombinant adeno-associated virus transduction efficiency. J Integr Med. 2024; 22(1): 72-82.

Stratifying risk of failure to achieve textbook outcomes among patients undergoing hepatectomy for hepatocellular carcinoma: A multicenter score validation study.

BACKGROUND AND AIMS: The concept of textbook outcomes (TOs) has gained increased attention as a critical metric to assess the quality and success of outcomes following complex surgery. A simple yet effective scoring system was developed and validated to predict risk of not achieving textbook outcomes (non-TOs) following hepatectomy for hepatocellular carcinoma (HCC). METHODS: Using a multicenter prospectively collected database, risk factors associated with non-TO among patients who underwent hepatectomy for HCC were identified. A predictive scoring system based on factors identified from multivariate regression analysis was used to risk stratify patients relative to non-TO. The score was developed using 70 % of the overall cohort and validated in the remaining 30 %. RESULTS: Among 3681 patients, 1458 (39.6 %) failied to experience a TO. Based on the derivation cohort, obesity, American Society of Anaesthesiologists score(ASA score), Child-Pugh grade, tumor size, and extent of hepatectomy were identified as independent predictors of non-TO. The scoring system ranged from 0 to 10 points. Patients were categorized into low (0-3 points), intermediate (4-6 points), and high risk (7-10 points) of non-TO. In the validation cohort, the predicted risk of developing non-TOs was 39.0 %, which closely matched the observed risk of 39.9 %. There were no differences among the predicted and observed risks within the different risk categories. CONCLUSIONS: A novel scoring system was able to predict risk of non-TO accurately following hepatectomy for HCC. The score may enable early identification of individuals at risk of adverse outcomes and inform surgical decision-making, and quality improvement initiatives.