-
1.
Molecular dynamics simulations support a preference of cyclotide kalata B1 for phosphatidylethanolamine phospholipids.
Roseli, RB, Huang, YH, Henriques, ST, Kaas, Q, Craik, DJ
Biochimica et biophysica acta. Biomembranes. 2024;(3):184268
Abstract
Kalata B1 (kB1), a naturally occurring cyclotide has been shown experimentally to bind lipid membranes that contain phosphatidylethanolamine (PE) phospholipids. Here, molecular dynamics simulations were used to explore its interaction with two phospholipids, palmitoyloleoylphosphatidylethanolamine (POPE), palmitoyloleoylphosphatidylcholine (POPC), and a heterogeneous membrane comprising POPC/POPE (90:10), to understand the basis for the selectivity of kB1 towards PE phospholipids. The simulations showed that in the presence of only 10 % POPE lipid, kB1 forms a stable binding complex with membrane bilayers. An ionic interaction between the E7 carboxylate group of kB1 and the ammonium group of PE headgroups consistently initiates binding of kB1 to the membrane. Additionally, stable noncovalent interactions such as hydrogen bonding (E7, T8, V10, G11, T13 and N15), cation-π (W23), and CH-π (W23) interactions between specific residues of kB1 and the lipid membrane play an important role in stabilizing the binding. These findings are consistent with a structure-activity relationship study on kB1 where lysine mutagenesis on the bioactive and hydrophobic faces of the peptide abolished membrane-dependent bioactivities. In summary, our simulations suggest the importance of residue E7 (in the bioactive face) in enabling kB1 to recognize and bind selectively to PE-containing phospholipids bilayers through ionic and hydrogen bonding interactions, and of W23 (in the hydrophobic face) for the association and insertion of kB1 into the lipid bilayer through cation-π and CH-π interactions. Overall, this work enhances our understanding of the molecular basis of the membrane binding and bioactivity of this prototypic cyclotide.
-
2.
Response and adaptation of rhizosphere microbiome to organic pollutants with enriching pollutant-degraders and genes for bioremediation: A critical review.
Lü, H, Tang, GX, Huang, YH, Mo, CH, Zhao, HM, Xiang, L, Li, YW, Li, H, Cai, QY, Li, QX
The Science of the total environment. 2024;:169425
Abstract
Phytoremediation largely involves microbial degradation of organic pollutants in rhizosphere for removing organic pollutants like polycyclic aromatic hydrocarbons, phthalates and polychlorinated biphenyls. Microbial community in rhizosphere experiences complex processes of response-adaptation-feedback up on exposure to organic pollutants. This review summarizes recent research on the response and adaptation of rhizosphere microbial community to the stress of organic pollutants, and discusses the enrichment of the pollutant-degrading microbial community and genes in the rhizosphere for promoting bioremediation. Soil pollution by organic contaminants often reduces the diversity of rhizosphere microbial community, and changes its functions. Responses vary among rhizosphere microbiomes up on different classes of organic pollutants (including co-contamination with heavy metals), plant species, root-associated niches (e.g., rhizosphere, rhizoplane and endosphere), geographical location and soil properties. Soil pollution can deplete some sensitive microbial taxa and enrich some tolerant microbial taxa in rhizosphere. Furthermore, rhizosphere enriches pollutant-degrading microbial community and functional genes including different gene clusters responsible for biodegradation of organic pollutants and their intermediates, which improve the adaptation of microbiome and enhance the remediation efficiency of the polluted soil. The knowledge gaps and future research challenges are highlighted on rhizosphere microbiome in response-adaptation-feedback processes to organic pollution and rhizoremediation. This review will hopefully update understanding on response-adaptation-feedback processes of rhizosphere microbiomes and rhizoremediation for the soil with organic pollutants.
-
3.
Life satisfaction components and all-cause and cause-specific mortality: A large prospective cohort study.
Lin, TF, Zhao, ZY, Yuan, CZ, Huang, YH, Liu, D, Li, FX, Jiang, YW, Li, BL, Wei, C, Sha, F, et al
Journal of affective disorders. 2024;:916-925
Abstract
BACKGROUND Which life satisfaction components could be a target of positive psychological interventions for longevity is largely unknown. We aimed to investigate association of the composite measure of life satisfaction and its individual components with mortality. METHODS This cohort study included UK Biobank participants who responded to questions concerning five components of life satisfaction at baseline. We generated a composite score representing overall life satisfaction, ranging from 0 (lowest) to 5 (highest). The outcomes were all-cause and cause-specific mortality. We used multivariable Cox regression to estimate hazard ratios (HR) for the associations of interest. RESULTS Among 165,842 eligible participants, 12,261 all-cause deaths were observed over a median of 12.9-year follow-up. Overall life satisfaction was inversely associated with all-cause mortality (adjusted HR 0.94 [95% CI: 0.93-0.95] per 1 score increment). Health satisfaction showed the strongest association with all-cause mortality, with a fully adjusted HR of 0.52 (95% CI: 0.49-0.55) for high/extreme satisfaction and 0.63 (95% CI: 0.59-0.66) for moderate satisfaction, compared with unsatisfaction (P-trend<0.001), independent of other satisfaction components, regardless of physical health and sociodemographics. The association for family, friendship, work and financial satisfaction was attenuated when adjusted for other life satisfaction components. Similar findings were observed for cause-specific mortality. LIMITATIONS Observational study with single baseline measurement of life satisfaction precludes the ability to establish causal relationship. CONCLUSIONS Higher overall life satisfaction was associated with lower mortality. As the major contributor to lower mortality regardless of physical health and sociodemographics, health satisfaction could be an important target of positive psychological interventions for longevity.
-
4.
Efficacy and safety of atezolizumab/bevacizumab in patients with HCC after prior systemic therapy: A global, observational study.
Joerg, V, Scheiner, B, D Alessio, A, Fulgenzi, CAM, Schönlein, M, Kocheise, L, Lohse, AW, Huber, S, Wege, H, Kaseb, A, et al
Hepatology communications. 2023;(11)
-
-
Free full text
-
Abstract
BACKGROUND Since the introduction of the combination treatment of anti-programmed death-ligand 1 antibody atezolizumab and anti-VEGF antibody bevacizumab (AB), median overall survival in HCC has drastically improved. However, evidence on the efficacy and safety of the novel treatment standard in patients with prior exposure to systemic treatment is scarce. The aim of this global, multicenter, observational study was to evaluate the efficacy and safety of AB in patients after previous systemic therapy. METHODS We screened our global, multicenter, prospectively maintained registry database for patients who received any systemic therapy before AB. The primary end point was overall survival; secondary end points were time-to-progression, progression-free survival, objective response rate, and safety (rate and severity of adverse events). RESULTS Among 493 patients who received AB for unresectable HCC, 61 patients received prior systemic therapy and were included in this analysis. The median age of the study population was 66 years, with 91.8% males. Predominant risk factors for HCC were viral hepatitis (59%) and alcohol (23%). Overall survival for AB was 16.2 (95% CI, 14.5-17.9) months, time-to-progression and progression-free survival were 4.1 (95% CI, 1.5-6.6) and 3.1 (95% CI, 1.1-5.1) months, respectively. The objective response rate was 38.2% (7.3% with complete and 30.9% with partial response). Overall survival was not influenced by treatment line (2nd vs. >2nd) or previous systemic treatment modality (tyrosine kinase inhibitors vs. immune checkpoint inhibitors). Treatment-related adverse events of all grades according to Common Terminology Criteria for Adverse Events were documented in 42.6% of patients, with only 13.1% of grade ≥3, including one death. CONCLUSION In this observational study, AB emerges as a safe and efficacious treatment option in patients with HCC previously treated with other systemic therapy.
-
5.
Progression patterns and therapeutic sequencing following immune checkpoint inhibition for hepatocellular carcinoma: An international observational study.
Talbot, T, D'Alessio, A, Pinter, M, Balcar, L, Scheiner, B, Marron, TU, Jun, T, Dharmapuri, S, Ang, C, Saeed, A, et al
Liver international : official journal of the International Association for the Study of the Liver. 2023;(3):695-707
-
-
Free full text
-
Abstract
BACKGROUND AND AIMS Different approaches are available after the progression of disease (PD) to immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC), including the continuation of ICI, treatment switching to tyrosine kinase inhibitors (TKIs) and cessation of anticancer therapy. We sought to characterise the relationship between radiological patterns of progression and survival post-ICI, also appraising treatment strategies. METHODS We screened 604 HCC patients treated with ICIs, including only those who experienced PD by data cut-off. We evaluated post-progression survival (PPS) according to the treatment strategy at PD and verified its relationship with radiological patterns of progression: intrahepatic growth (IHG), new intrahepatic lesion (NIH), extrahepatic growth (EHG), new extrahepatic lesion (NEH) and new vascular invasion (nVI). RESULTS Of 604 patients, 364 (60.3%) experienced PD during observation. Median PPS was 5.3 months (95% CI: 4.4-6.9; 271 events). At the data cut-off, 165 patients (45%) received no post-progression anticancer therapy; 64 patients (17.6%) continued ICI beyond PD. IHG (HR 1.64 [95% CI: 1.21-2.22]; p = .0013) and nVI (HR 2.15 [95% CI: 1.38-3.35]; p = .0007) were associated with shorter PPS. Multivariate models adjusted for progression patterns, treatment line and albumin-bilirubin grade and Eastern Cooperative Oncology Group performance status at PD confirmed receipt of ICI beyond PD with (HR 0.17, 95% CI: 0.09-0.32; p < .0001) or without subsequent TKI (HR 0.39, 95% CI: 0.26-0.58; p < .0001) as predictors of prolonged PPS versus no anticancer therapy. CONCLUSIONS ICI-TKI sequencing is a consolidated option in advanced HCC. nVI and IHG predict a poorer prognosis. Despite lack of recommendation, the continuation of ICI beyond progression in HCC is adopted clinically: future efforts should appraise which patients benefit from this approach.
-
6.
Efficacy and safety of Zicuiyin decoction on diabetic kidney disease: A multicenter, randomized controlled trial.
Liu, J, Gao, LD, Fu, B, Yang, HT, Zhang, L, Che, SQ, Xu, Y, Du, X, Liu, ZC, Xue, Y, et al
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2022;:154079
Abstract
BACKGROUD Zicuiyin (ZCY) decoction created by Xichun Zhang in the Qing dynasty has been used on diabetes mellitus and complications for more than two centuries in China. Huangkui capsule (HKC) is a listed Chinese patent medicine to treat diabetic kidney disease (DKD). To determine whether ZCY is non-inferior to HKC in the treatment of DKD, a multicenter, parallel-control, open-label, randomized clinical trial was conducted. METHODS In this clinical trial, 88 DKD patients were recruited at three centers in Tianjin from January 2018 to December 2019. They were randomized to receive HKC (2.5 g, TID) or ZCY (crude drug amount 75 g, 150 ml, BID) for eight weeks based on routine treatment. The primary outcome was the change of estimated glomerular filtration rate (eGFR). The secondary outcomes included change of serum creatinine (SCr), urinary albumin excretion rate, 24 h urinary protein, urinary albumin-creatinine ratio, glycosylated hemoglobin A1c, symptom scores, and microbiota compositions profiles. RESULTS The change of eGFR in HKC and ZCY groups were -7.08 ± 24.65 and 2.57 ± 18.49 ml/min/1.73 m2, respectively (p < 0.05). The 95% lower confidence limit for the difference between the estimated means was 1.93 ml/min/1.73 m2, establishing the superiority of ZCY. Compared to HKC, ZCY could significantly decrease SCr and symptom scores (p < 0.05). There were no significant differences in other outcomes between the two groups (p > 0.05). ZCY ameliorated gut microbiota dysbiosis, including increased Prevotellaceae and Lactobacillaceae and decreased Enterobacteriales, Clostridiaceae and Micrococcaceae. No severe adverse events were reported in any group. CONCLUSIONS ZCY had better efficacy in improving and protecting kidney function. It would be an alternative option to treat DKD, especially those who decline eGFR and gut microbiota dysbiosis. TRIAL REGISTRATION Chinese Clinical Trial Registry: ChiCTR-OON-17012076. Registered July 21, 2017.
-
7.
Reproducible safety and efficacy of atezolizumab plus bevacizumab for HCC in clinical practice: Results of the AB-real study.
Fulgenzi, CAM, Cheon, J, D'Alessio, A, Nishida, N, Ang, C, Marron, TU, Wu, L, Saeed, A, Wietharn, B, Cammarota, A, et al
European journal of cancer (Oxford, England : 1990). 2022;:204-213
Abstract
BACKGROUND IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC). METHODS We generated a prospectively maintained database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia and USA. Clinico-pathologic characteristics were assessed for their prognostic influence on overall survival (OS) and progression-free survival (PFS) in univariable and multivariate analyses. Overall response rate by RECIST v1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0 were reported. RESULTS Out of 433 patients, 296 Child-Pugh A and ECOG performance status01 patients received atezolizumab plus bevacizumab in first line and were included. Patients were mostly male (82.7%), cirrhotic (75%) with history of viral hepatitis (65.9%). Overall, 68.9% had Barcelona Clinic Liver Cancer C-stage HCC with portal vein tumour thrombosis (PVTT, 35%) and extrahepatic spread (EHS, 51.7%). After a median follow-up of 10.0 months (95% confidence interval (CI): 9.4-10.4), median OS and PFS were 15.7 (95% CI: 14.5-NE) and 6.9 months (95% CI: 6.1-8.3), respectively. In the response-evaluable patients (n = 273), overall response rate was 30.8%. Overall, 221 patients (74.6%) developed TRAEs, with 70 (23.6%) reporting grade 3 or higher TRAEs; 25 (8.4%) patients had bleeding events. OS was independently associated with baseline Albumin-bilirubin (ALBI) grade and PVTT. Shorter PFS was associated with AFP≥ 400 ng/ml, worse ALBI and presence of EHS. CONCLUSION This global observational study confirms the reproducible safety and efficacy of atezolizumab plus bevacizumab in routine clinical practice. Within Child-Pugh-A criteria, the presence of PVTT and higher ALBI grade identify patients with poorer survival.
-
8.
Cardiac MRI segmentation of the atria based on UU-NET.
Wang, Y, Li, ST, Huang, J, Lai, QQ, Guo, YF, Huang, YH, Li, YZ
Frontiers in cardiovascular medicine. 2022;:1011916
Abstract
BACKGROUND AND OBJECTIVE In today's society, people's work pressure, coupled with irregular diet, lack of exercise and other bad lifestyle, resulting in frequent cardiovascular diseases. Medical imaging has made great progress in modern society, among which the role of MRI in cardiovascular field is self-evident. Based on this research background, how to process cardiac MRI quickly and accurately by computer has been extensively discussed. By comparing and analyzing several traditional image segmentation and deep learning image segmentation, this paper proposes the left and right atria segmentation algorithm of cardiac MRI based on UU-NET network. METHODS In this paper, an atrial segmentation algorithm for cardiac MRI images in UU-NET network is proposed. Firstly, U-shaped upper and lower sampling modules are constructed by using residual theory, which are used as encoders and decoders of the model. Then, the modules are interconnected to form multiple paths from input to output to increase the information transmission capacity of the model. RESULTS The segmentation method based on UU-NET network has achieved good results proposed in this paper, compared with the current mainstream image segmentation algorithm results have been improved to a certain extent. Through the analysis of the experimental results, the image segmentation algorithm based on UU-NET network on the data set, its performance in the verification set and online set is higher than other grid models. The DSC in the verification set is 96.7%, and the DSC in the online set is 96.7%, which is nearly one percentage point higher than the deconvolution neural network model. The hausdorff distance (HD) is 1.2 mm. Compared with other deep learning models, it is significantly improved (about 3 mm error is reduced), and the time is 0.4 min. CONCLUSION The segmentation algorithm based on UU-NET improves the segmentation accuracy obviously compared with other segmentation models. Our technique will be able to help diagnose and treat cardiac complications.
-
9.
The Effects of Exercise Habit on Albuminuria and Metabolic Indices in Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study.
Kuo, HY, Huang, YH, Wu, SW, Chang, FH, Tsuei, YW, Fan, HC, Chiang, WF, Hsiao, PJ
Medicina (Kaunas, Lithuania). 2022;(5)
Abstract
Background and Objectives: Diabetes mellitus (DM) can cause macrovascular and microvascular complications, potentially resulting in further life-threatening complications. In general, the global prevalence of type 2 DM is increasing. To date, the care of DM comprises three aspects: diet, medication and exercise; among them, exercise is the most economical. Albuminuria is associated with renal injury and the progress of chronic kidney disease (CKD). The effects of habitual exercise in patients with new onset of diabetic kidney disease (DKD) have not been generally recognized. Our aim was to conduct an observational study regarding the effects of regular exercise on proteinuria and associated metabolic indices in patients with newly diagnosed type 2 DM. To investigate the effects of an exercise habit on albuminuria and the metabolic indices including renal function, blood glucose, and plasma lipids among patients with newly diagnosed type 2 DM. Materials and Methods: A cross-sectional study was conducted on newly diagnosed DM patients in two teaching hospitals in Taiwan from 1 June to 31 December 2020. The DM patients participated in the Diabetes Shared Care Network. According to the DM care mode, the patients’ blood biochemical results were analysed. Based on exercise duration, the patients were divided into two groups, i.e., the exercise group (≥150 min per week) and the non-exercise group (<150 min per week). Clinical demographic features and laboratory examination including blood and urine biochemistries were determined. Results: A total of 229 patients including 99 males (43.2%) and 130 females (56.8%) participated in the study. The proportion of DM patients with normoalbuminuria was higher (p < 0.05) in the exercise group (69.8%) than in the non-exercise group (53.7%), and the proportion of DM patients with micro or macroalbuminuria was lower in the exercise group (30.2%) than in the non-exercise group (46.3%). Levels of glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), triglycerides (TG) and high-density lipoprotein (HDL) were significantly different in both groups. Compared with the non-exercise group, lower HbA1c (6.89 ± 0.69 vs. 7.16 ± 1.05%) (p < 0.05), lower FPG (121.9 ± 25.7 vs. 140.5 ± 42.4 mg/dL) (p < 0.05), lower TG (115.6 ± 53.6 vs. 150.2 ± 15.4 mg/dL) (p < 0.05), and higher HDL (50.3 ± 11.4 vs. 44.1 ± 9.26 mg/dL) (p < 0.05) levels were noted in the exercise group. Conclusions: Regular exercise remains imperative and may bear an impact on albuminuria, blood glucose, and plasma lipids among type 2 DM patients. Therefore, medical staff and healthcare providers should encourage patients to maintain an exercise duration ≥150 min per week for preventing and controlling DM progression.
-
10.
Characterization of the Chimeric PriB-SSBc Protein.
Lin, ES, Huang, YH, Huang, CY
International journal of molecular sciences. 2021;(19)
Abstract
PriB is a primosomal protein required for the replication fork restart in bacteria. Although PriB shares structural similarity with SSB, they bind ssDNA differently. SSB consists of an N-terminal ssDNA-binding/oligomerization domain (SSBn) and a flexible C-terminal protein-protein interaction domain (SSBc). Apparently, the largest difference in structure between PriB and SSB is the lack of SSBc in PriB. In this study, we produced the chimeric PriB-SSBc protein in which Klebsiella pneumoniae PriB (KpPriB) was fused with SSBc of K. pneumoniae SSB (KpSSB) to characterize the possible SSBc effects on PriB function. The crystal structure of KpSSB was solved at a resolution of 2.3 Å (PDB entry 7F2N) and revealed a novel 114-GGRQ-117 motif in SSBc that pre-occupies and interacts with the ssDNA-binding sites (Asn14, Lys74, and Gln77) in SSBn. As compared with the ssDNA-binding properties of KpPriB, KpSSB, and PriB-SSBc, we observed that SSBc could significantly enhance the ssDNA-binding affinity of PriB, change the binding behavior, and further stimulate the PriA activity (an initiator protein in the pre-primosomal step of DNA replication), but not the oligomerization state, of PriB. Based on these experimental results, we discuss reasons why the properties of PriB can be retrofitted when fusing with SSBc.