The efficacy and safety of maternal tenofovir disoproxil fumarate (TDF) in reducing mother‐to‐infant hepatitis B virus (HBV) transmissions is not clearly understood. We conducted a prospective, ...multicenter trial and enrolled 118 hepatitis B surface antigen (HBsAg)– and hepatitis B e antigen–positive pregnant women with HBV DNA ≥7.5 log10 IU/mL. The mothers received no medication (control group, n = 56, HBV DNA 8.22 ± 0.39 log10 IU/mL) or TDF 300 mg daily (TDF group, n = 62, HBV DNA 8.18 ± 0.47 log10 IU/mL) from 30‐32 weeks of gestation until 1 month postpartum. Primary outcome was infant HBsAg at 6 months old. At delivery, the TDF group had lower maternal HBV DNA levels (4.29 ± 0.93 versus 8.10 ± 0.56 log10 IU/mL, P < 0.0001). Of the 121/123 newborns, the TDF group had lower rates of HBV DNA positivity at birth (6.15% versus 31.48%, P = 0.0003) and HBsAg positivity at 6 months old (1.54% versus 10.71%, P = 0.0481). Multivariate analysis revealed that the TDF group had lower risk (odds ratio = 0.10, P = 0.0434) and amniocentesis was associated with higher risk (odds ratio 6.82, P = 0.0220) of infant HBsAg positivity. The TDF group had less incidence of maternal alanine aminotransferase (ALT) levels above two times the upper limit of normal for ≥3 months (3.23% versus 14.29%, P = 0.0455), a lesser extent of postpartum elevations of ALT (P = 0.007), and a lower rate of ALT over five times the upper limit of normal (1.64% versus 14.29%, P = 0.0135) at 2 months postpartum. Maternal creatinine and creatinine kinase levels, rates of congenital anomaly, premature birth, and growth parameters in infants were comparable in both groups. At 12 months, one TDF‐group child newly developed HBsAg positivity, presumably due to postnatal infection and inefficient humoral responses to vaccines. Conclusions: Treatment with TDF for highly viremic mothers decreased infant HBV DNA at birth and infant HBsAg positivity at 6 months and ameliorated maternal ALT elevations. (Hepatology 2015;62:375–386
Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia ...metabolism, immune system regulation, and hormone biosynthesis-all of which are critical for tumor growth. These discoveries, coupled with the understanding of cancer cell metabolic reprogramming, have led to renewed interest in arginine deprivation as a new anticancer therapy. Several arginine deprivation strategies have been developed and entered clinical trials. The main principle behind these therapies is that arginine auxotrophic tumors rely on external arginine sources for growth because they carry reduced key arginine-synthesizing enzymes such as argininosuccinate synthase 1 (ASS1) in the intracellular arginine cycle. To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal.
Aberrant metabolisms have been hypothesized to precede the occurrence of hepatocellular carcinoma (HCC), therefore, we investigated biomarkers associated with subsequent HCC in peripheral bloods ...using metabolomic technologies. A cohort of 475 HCC-naïve liver cirrhotic patients were recruited and prospectively followed. A total of 39 patients developed HCC in the follow-up period. Baseline plasma metabolites were explored using untargeted nuclear magnetic resonance. Candidates were then quantified by ultra-performance liquid chromatography. A series of univairiate and multivariate analysis showed that Phenylalanine (Phe) and Glutamine (Gln) levels are associated with time to HCC, independent of viological etiologies and age. A HCC risk score R was then constructed using the polynomial combination of age, Phe and Gln in the units of micromolar (μM):Formula: see text R correlates with the time to HCC significantly (Hazard ratio HR = 2.368, 95% confidence interval CI 1.760-3.187, P < 0.001). An additional cross-sectional analysis showed that Phe and Gln concentrations both correlates with HCC occurrence in the next 3 years (area under the receiver operating characteristic curve AUC = 0.607 and 0.629, P = 0.033 and 0.010 respectively). In conclusion, phenylalanine and glutamine concentrations in the peripheral blood correlate with subsequent HCC.
Hematite (α-Fe
2
O
3
) nanowhiskers (NWs) synthesized via oxidation of iron-based substrates are a promising photoanode material for photoelectrochemical water splitting. Such synthesized α-Fe
2
O
3
...NWs have been found to contain ordered axial structures. Herein, we reveal that the known (1
1
¯
2)-related ordered structure actually exists in bicrystalline α-Fe
2
O
3
NWs instead of single-crystalline α-Fe
2
O
3
NWs and that it is associated with another known (3
3
¯
0)-related ordered structure. Through a spherical aberration (C
S
)-corrected high-resolution transmission electron microscopy (HR-TEM) investigation, the microstructural characteristic of the (1
1
¯
2)-related ordered structure is verified to be periodic atomic column displacements serving as tensile strain accommodation. The HR-TEM observation are also supported by a monochromated O K-edge EELS analysis, which indicates that α-Fe
2
O
3
NWs hosting the (1
1
¯
2)-related ordered structure are indeed associated with lattice expansion. In sum, our microstructural study elucidates the root cause of the long-asserted relationship between the (1
1
¯
2)-related ordered structure and oxygen vacancy ordering.
Plant cell walls are pivotal battlegrounds between microbial pathogens and their hosts. To penetrate the cell wall and thereby to facilitate infection, microbial pathogens are equipped with a wide ...array of cell wall-degrading enzymes to depolymerize the polysaccharides in the cell wall. However, many of these enzymes and their role in the pathogenesis of microbial pathogens are not characterized, especially those from Oomycetes. In this study, we analyzed the function of four putative endo-beta-1,4-xylanase-encoding genes (ppxyn1–ppxyn4) from
Phytophthora parasitica
, an oomycete plant pathogen known to cause severe disease in a wide variety of plant species. All four genes belong to the glycoside hydrolase family 10 (GH10). Recombinant proteins of ppxyn1, ppxyn2, and ppxyn4 obtained from the yeast
Pichia pastoris
showed degrading activities toward birch wood xylan, but they behaved differently in terms of the conditions for optimal activity, thermostability, and durability. Quantitative RT-PCR revealed upregulated expression of all four genes, especially ppxyn1 and ppxyn2, during plant infection. In contrast, ppxyn3 was highly expressed in cysts and its close homolog, ppxyn4, in germinating cysts. To uncover the role of ppxyn1 and ppxyn2 in the pathogenesis of
P. parasitica
, we generated silencing transformants for these two genes by double-stranded RNA-mediated gene silencing. Silencing ppxyn1 and ppxyn2 reduced the virulence of
P. parasitica
toward tobacco (
Nicotiana benthamiana
) and tomato plants. These results demonstrate the crucial role of xylanase-encoding ppxyn1 and ppxyn2 in the infection process of
P. parasitica
.
The single nucleotide polymorphism (SNP) rs9679162 located on GALNT14 gene predicts therapeutic outcomes in patients with intermediate and advanced hepatocellular carcinoma (HCC), but the molecular ...mechanism remains unclear. Here, the associations between SNP genotypes, GALNT14 expression, and downstream molecular events were determined. A higher GALNT14 cancerous/noncancerous ratio was associated with the rs9679162-GG genotype, leading to an unfavorable postoperative prognosis. A novel exon-6-skipped GALNT14 mRNA variant was identified in patients carrying the rs9679162-TT genotype, which was associated with lower GALNT14 expression and favorable prognosis. Cell-based experiments showed that elevated levels of GALNT14 promoted HCC growth, migration, and resistance to anticancer drugs. Using a comparative lectin-capture glycoproteomic approach, PHB2 was identified as a substrate for GALNT14-mediated O-glycosylation. Site-directed mutagenesis experiments revealed that serine-161 (Ser161) was the O-glycosylation site. Further analysis showed that O-glycosylation of PHB2-Ser161 was required for the GALNT14-mediated growth-promoting phenotype. O-glycosylation of PHB2 was positively correlated with GALNT14 expression in HCC, resulting in increased interaction between PHB2 and IGFBP6, which in turn led to the activation of IGF1R-mediated signaling. In conclusion, the GALNT14-rs9679162 genotype was associated with differential expression levels of GALNT14 and the generation of a novel exon-6-skipped GALNT14 mRNA variant, which was associated with a favorable prognosis in HCC. The GALNT14/PHB2/IGF1R cascade modulated the growth, migration, and anticancer drug resistance of HCC cells, thereby opening the possibility of identifying new therapeutic targets against HCC.
Hematite (α-Fe2O3) nanowhiskers (NWs) with (001) basal faces synthesized via thermal oxidation of iron-based substrates are known to contain an ordered structure. The ordered structure has been ...identified to be related to oxygen vacancy ordering. However, the cause of its formation remains a mystery. In this study, with a high-resolution transmission electron microscopy (HR-TEM) investigation based on negative-Cs imaging (NCSI) and atomic-column position analysis, we observed tensile strain in the above-mentioned α-Fe2O3 NWs and revealed that the ordered structure was actually periodic interplanar gap expansions induced by oxygen vacancy accumulations. These findings were further confirmed in a monochromated electron energy loss spectroscopy (EELS) analysis of the α-Fe2O3 NWs. The EELS data indicated that, in comparison to pristine α-Fe2O3, the α-Fe2O3 NWs possessed expanded average FeO and OO interatomic distances and were oxygen-deficient. Clarifying oxygen deficiency in the α-Fe2O3 NWs was not attributed to an insufficient oxygen supply during the NW growth, we concluded the ordered structure formed to accommodate tensile strain in the α-Fe2O3 NWs. This work demonstrates the applicability of integrating NCSI and monochromated EELS for the examination of strain-induced microstructural and microchemical variations in lightly strained metal oxides.
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•α-Fe2O3 nanowhiskers (NWs) with (001) basal faces synthesized via thermal oxidation of iron-based substrates are strained.•The ordered structure in the α-Fe2O3 (NWs) is periodic interplanar gap expansions induced by oxygen vacancy accumulations.•The ordered structure forms to accommodate tensile strain.•Integrating negative-spherical-aberration imaging and monochromated EELS is effective in analyzing strained metal oxides.
Helicobacter pylori infection can cause gastritis, gastric or duodenal ulcers, mucosa-associated lymphoid tissue lymphoma, gastric cancer, and extra-gastrointestinal manifestations. Ideal treatment ...should be guided by antibiotic susceptibility testing. However, this is not feasible in many regions, so the treatment generally relies on clinical experience and regional culture sensitivity profiles. We aimed to integrate the treatment of pediatric H. pylori infection through a systematic literature review. Databases including PubMed, Cochrane Library, EMBASE, and Scholar were searched using terms containing (Helicobacter OR Helicobacter pylori OR H. pylori) AND (child OR pediatric) for all relevant manuscripts and guidelines, published from January 2011 to December 2021. The eradication rate for pediatric H. pylori infection was not satisfactory using triple therapy, sequential therapy, concomitant therapy, bismuth-based quadruple therapy, or adjuvant therapy with probiotics as the first-line therapy. Most therapies could not achieve the recommended eradication rate of >90%, which may be attributed to varying regional antibiotic resistance and possible poor children’s compliance. More studies are required to establish a best practice for pediatric H. pylori infection treatment.
Inevitable long-term therapy with nucleos(t)ide analogs in patients with chronic hepatitis B virus (HBV) infection has selected reverse-transcriptase (rt) mutants in a substantial proportion of ...patients. Some of these mutants introduce premature stop codons in the overlapping surface (s) gene, including rtA181T/sW172*, which has been shown to enhance oncogenicity. The oncogenicity of another drug-resistant mutant, rtM204I/sW196*, has not been studied. We constructed plasmids harboring rtM204I/sW196* and assessed the in vitro cell transformation, endoplasmic reticulum (ER) stress response, and xenograft tumorigenesis of the transformants. Cellular gene expression was analyzed by cDNA microarray and was validated. The rtM204I/sW196* transformants, compared with the control or wild type, showed enhanced transactivation activities for
, increased cell proliferation, decreased apoptosis, more anchorage-independent growth, and enhanced tumor growth in mouse xenografts. X box-binding protein-1 (
) splicing analysis showed no ER stress response. Altered gene expressions, including up-regulated
and
, and downregulated transforming growth factor beta-induced (
), were unveiled by cDNA microarray and validated by RT-qPCR. The
alteration occurred in transformants with wild type or mutated HBV. The altered
and
were found only with mutated HBV. The rtM204I/sW196* preS/S truncation may endorse the cell transformation and tumorigenesis ability via altered host gene expressions, including
and
. Downregulated
may be a common mechanism for oncogenicity in HBV surface truncation mutants.
Background
The use of antiviral agents, specifically tenofovir disoproxil fumarate (TDF), in pregnant women to prevent mother‐to‐child HBV transmission is a key step towards hepatitis elimination. ...However, data on using tenofovir alafenamide (TAF) is insufficient. The frequent occurrence of postpartum ALT flares may impact the clinical implementation.
Methods
The maternal and infant outcomes were compared in multi‐centre trials of high viral load HBsAg/HBeAg+ pregnant women receiving TAF or TDF from the third trimester until 2 weeks postpartum with intensive follow‐ups. To explore the dynamic pre‐ and postpartum changes in ALT levels, we used a group‐based trajectory model for analysing data of 332 women from three prospective studies.
Results
After treatment, the maternal HBV DNA levels significantly decreased from baseline to delivery: 7.87 ± 0.59 to 3.99 ± 1.07 Log10 IU/mL TAF (n = 78) and 8.30 ± 0.36 to 4.47 ± 0.86 Log10 IU/mL (TDF, n = 53), with viral load reductions of 3.87 versus 3.83 Log10 IU/mL. The HBsAg‐positive rates among 12‐month‐old infants were 1.28% (1/78) versus 1.82% (1/55) respectively (p = 1.00). Of the TAF or TDF‐treated mothers, 25.64% versus 16.98% experienced ALT > 2X ULN, and 11.54% versus 1.89% received extended antiviral treatment. Our model revealed four distinct ALT patterns: stable ALT (87.2%), moderate (8.0%) or marked (2.4%) postpartum flares, or prepartum elevations (2.4%).
Conclusions
TAF effectively reduces mother‐to‐child HBV transmission, but prophylaxis failure still occurred in few cases. Postpartum ALT flares are common in women receiving TAF or TDF during pregnancy. Approximately 12.8% of mothers may require extended postpartum antiviral treatment.
Clinical trial number: NCT03695029 (ClinicalTrials.gov).
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