Characteristics of patients with longer treatment period of lenvatinib for unresectable hepatocellular carcinoma: A post-hoc analysis of post-marketing surveillance study in Japan.

Patient profiles suitable for long-term lenvatinib treatment for unresectable hepatocellular carcinoma (uHCC) are yet to be fully understood. This post-hoc analysis aimed to identify such patient characteristics and explore the impact of treatment duration and relative dose intensity (RDI) on treatment outcomes. The data were obtained from 703 patients in a multicenter, prospective cohort study in Japan. Lenvatinib-naïve patients with uHCC were enrolled between July 2018 and January 2019 and were followed up for 12 months. Moreover, patients were dichotomized using the median treatment duration into the longer- (≥177 days; n = 352) or shorter-treatment (<177 days; n = 351) groups. The longer-treatment group often had better performance status, lower Child-Pugh score and better modified albumin-bilirubin grade than the shorter treatment group (p<0.05 for all). The objective response rate (47.6% vs. 28.2%; p<0.001) and disease control rate (92.4% vs. 60.2%; p<0.001) were both significantly higher in the longer-treatment groups than in the shorter-treatment groups. The proportion of patients with any adverse drug reactions was generally similar between the two treatment groups. Within the longer-treatment group, the disease control rate was high regardless of dose modification (i.e., RDI <100% vs. ≥100% during the initial 177 days) (91.2% vs. 98.0%). In conclusion, patients with longer treatment tended to have better overall conditions. Lenvatinib dose modifications at the physician's discretion, considering the balance between effectiveness and safety, may contribute to the long-term treatment.

Study on the therapeutic effect and mechanism of Tangningtongluo Tablet on diabetic mice.

AIMS: To investigate the therapeutic effects of Tangningtongluo Tablet on diabetic mice and its mechanism. This study was established the scientific basis for the clinical application of Tangningtongluo Tablet in the treatment of diabetes mellitus and provided data supporting the transformation of Tangningtongluo Tablet from an in-hospital preparation to a new Chinese medicine. METHODS: In this study, a diabetic mouse model was established by high-glucose and high-fat diet feeding in combination with STZ injection for 4 weeks. Glucose metabolism, lipid metabolism, liver histomorphological changes and liver function related indexes were detected, pancreatic histomorphological changes and insulin resistance related indexes were observed, and the expression of pathway related proteins and inflammatory factors were examined. RESULTS: Glycemia and glycated hemoglobin were reduced in diabetic mice after the treatment of Tangningtongluo Tablet, and glucose tolerance and lipid results were modified. The insulin resistance status of the mice was diminished and tissue damage to the pancreas and liver was repaired. Expression of ERS/NF-κB related pathway proteins was reduced in liver tissues, and inflammatory factors such as TNF-α, IL-6 and IL-1ß were reduced in serum. CONCLUSIONS: Tangningtongluo Tablet could reduce blood glucose in diabetic mice, regulate the disorder of lipid metabolism, enhance insulin sensitivity, improve insulin resistance, repair pancreatic tissue damage and protect mouse liver in diabetic mice. The mechanism of action might be related to the regulation of ERS/NF-κB signaling pathway and the reduction of TNF-α, IL-6 and IL-1ß production.

The Prevalence, Coinfection, and Evolutionary and Molecular Characteristics of Prevalent Goose Circovirus in Guangdong, China.

To understand the prevalence, coinfection with other viruses, underlying genetic evolution, recombination, and molecular biological characteristics of goose circovirus (GoCV) in Guangdong, China, from December 2019 to August 2020, 310 tissue samples of geese showing stunted growth and feather disorder syndrome were collected from this region and analyzed. GoCV, Tembusu virus, waterfowl paramyxovirus, avian influenza virus, fowl adenovirus type 4, and duck plague virus were detected with PCR or real-time PCR. Thirty-one complete GoCV viral genomes were obtained from 164 PCR-verified GoCV nucleotide-positive samples and subjected to phylogenetic analysis, gene recombination analysis, and genome secondary structure prediction. The results showed that more than half of the samples were GoCV positive, and 31.1% of the GoCV-positive samples were from coinfections with at least one of the other viruses. The phylogenetic analysis showed that the GoCVs could be divided into three genome types. The genes of most main epidemic strains now circulating in Guangdong belonged to the Ia subtype, and some strains gradually formed a new Ib subtype. The secondary structure of the viral genome was similar to that of other known circoviruses. Furthermore, B cell linear epitope prediction and protein structure homology modeling of the viral capsid protein were performed based on the viral amino acid sequences. The results showed that the spatial structure of the capsid protein of the 31 sequenced strains was similar to that of duck circovirus and consisted of two ß-sandwich conformations. A total of five B cell linear epitopes were predicted, and four of them were mapped on the predicted model of the capsid protein of GoCVs. This report provides a reference for the epidemiology of GoCV in Guangdong, understanding the elemental composition of the virus genes and proteins, selecting representative vaccine strains, constructing targeted immune preparations for GoCV, and strengthening prevention and control of the disease.

Prevalencia, coinfección y características evolutivas y moleculares del circovirus del ganso prevalente en Guangdong, China. Para comprender la prevalencia, la coinfección con otros virus, su evolución genética subyacente, la recombinación y las características biológicas moleculares del circovirus del ganso (GoCV) en Guangdong, China, de diciembre de 2019 a agosto de 2020, 310 se recolectaron muestras de tejido de gansos que presentaban retraso en el crecimiento y síndrome del trastorno de las plumas en esta región y fueron analizadas. Se detectaron mediante PCR o por PCR en tiempo real el circovirus del ganso, el virus Tembusu (TMUV), el paramixovirus de aves acuáticas (WFPV), el virus de la influenza aviar (AIV), el adenovirus del pollo tipo 4 (Fadv-4) y el virus de la enteritis viral del pato (DPV). Se obtuvieron 31 genomas virales completos del circovirus del ganso de 164 muestras positivas de nucleótidos de circovirus del ganso verificadas por PCR y se sometieron a análisis filogenético, a análisis de recombinación de genes y predicción de la estructura secundaria del genoma. Los resultados mostraron que más de la mitad de las muestras eran positivas para circovirus del ganso y el 31.1% de las muestras positivas para circovirus del ganso eran de coinfecciones con al menos uno de los otros virus. El análisis filogenético mostró que los circovirus del ganso podrían dividirse en tres tipos de genomas. Los genes de la mayoría de las principales cepas epidémicas que ahora circulan en Guangdong pertenecían al subtipo Ia, y algunas cepas formaron gradualmente un nuevo subtipo Ib. La estructura secundaria del genoma viral era similar a la de otros circovirus conocidos. Además, la predicción del epítope lineal de células B y el modelo de la homología de la estructura de la proteína de la cápside viral se realizaron basándose en las secuencias de aminoácidos virales. Los resultados mostraron que la estructura espacial de la proteína de la cápside de las 31 cepas secuenciadas era similar a la del circovirus de pato y consistía de dos conformaciones de tipo sándwich ß. Se predijo un total de cinco epítopes lineales de células B y cuatro de ellos se mapearon en el modelo predicho de la proteína de la cápside del circovirus del ganso. Este informe proporciona una referencia para la epidemiología de circovirus del ganso en Guangdong, entendiendo la composición elemental de los genes y proteínas del virus, seleccionando cepas de vacunas representativas, construyendo preparaciones de blancos inmunitarios para circovirus del ganso y fortaleciendo la prevención y el control de la enfermedad.

Translational Research of Peritoneal Dialysis Solution with Dissolved Molecular Hydrogen.

BACKGROUND: Improved biocompatibility of peritoneal dialysis solution (PDS) is crucial for peritoneal membrane preservation, thereby ensuring long-term peritoneal dialysis (PD) and preventing encapsulating peritoneal sclerosis. We previously reported the protective effect of molecular hydrogen (H2) on mesothelial cells from PDS in nonuremic rats. SUMMARY: In the present study, we examined the effect of H2-containing PDS (commercially available neutral pH type) regarding the protection of peritoneal tissue in experimental chronic kidney disease rats. Furthermore, we conducted a 2-week clinical trial in which H2-containing PDS was used in place of standard PDS and its feasibility was examined. In the experimental study, test solutions were injected through the subcutaneous port into the abdomen for 3 weeks. Histological study revealed a significant increase in the number of mesothelial cells and a significant decrease in peritoneal thickness in the H2-PD group as compared to the control and PD groups. Also, results of immunostaining analysis revealed increased vimentin and apoptotic cells in the membrane of the PD group, indicating that H2 may play a role in ameliorating PDS-induced peritoneal injury and preserving peritoneal integrity. In the clinical trial with 6 prevalent PD patients, all subjects completed the study with no adverse effects. Moreover, there were substantial changes in surrogate markers, such as increased CA125 and mesothelin, in the effluent in selected cases, suggesting enhanced mesothelial regeneration by H2. Key Message: H2-enriched PDS is a candidate novel PDS with improved biocompatibility. Further, our results support the significance of H2-PD clinical trials in the future.

Next-generation molecular diagnosis: single-cell sequencing from bench to bedside.

Single-cell sequencing (SCS) is a fast-growing, exciting field in genomic medicine. It enables the high-resolution study of cellular heterogeneity, and reveals the molecular basis of complicated systems, which facilitates the identification of new biomarkers for diagnosis and for targeting therapies. It also directly promotes the next generation of genomic medicine because of its ultra-high resolution and sensitivity that allows for the non-invasive and early detection of abnormalities, such as aneuploidy, chromosomal translocation, and single-gene disorders. This review provides an overview of the current progress and prospects for the diagnostic applications of SCS, specifically in pre-implantation genetic diagnosis/screening, non-invasive prenatal diagnosis, and analysis of circulating tumor cells. These analyses will accelerate the early and precise control of germline- or somatic-mutation-based diseases, particularly single-gene disorders, chromosome abnormalities, and cancers.

Effect of a hydrogen (H2)-enriched solution on the albumin redox of hemodialysis patients.

Elevated oxidative stress (OS) is associated with severe cardiovascular disease and premature death among patients treated with hemodialysis (HD). Oxidative stress is enhanced by contact between blood and dialysis membranes during HD sessions. This study aimed to clarify whether hydrogen (H2), which is a known antioxidant, is capable of suppressing increased OS induced during HD sessions. Eight patients on regular HD treatment were studied. Two HD sessions were performed in a cross-over design trial using standard and hydrogen-enriched solutions (mean of 50 p.p.b. H2; H2-HD). Blood samples were obtained from the inlet and outlet of the dialyzer during HD to determine changes in plasma levels of glutathione, hydrogen peroxide, and albumin redox state as a marker of OS. Comparison of inlet and outlet blood revealed significant decreases in total glutathione and reduced glutathione, as well as significant increases in hydrogen peroxide in both HD treatments. However, the mean proportion of reversibly oxidized albumin in outlet serum was significantly lower than that in inlet serum following the H2-HD session, whereas no significant changes were found in the standard solution session, suggesting that "intra-dialyzer" OS is reduced by H2 -HD. In conclusion, the application of H2-enriched solutions could ameliorate OS during HD.

Molecular epidemiology of PRRSV in South China from 2007 to 2011 based on the genetic analysis of ORF5.

Porcine reproductive and respiratory syndrome virus (PRRSV) has proven to be highly genetically variable; however, comprehensive information regarding the virus's genetic diversity in South China is limited. In this study, a total of 3199 clinical samples were collected from 267 pig farms suspected of PRRSV infection between 2007 and 2011. The ORF5 genes of 51 PRRSV-positive samples were sequenced and analyzed. The 51 study strains were divided into three primary subgenotypes. Fourty-five of the strains belonged to subgenotype I and were closely related to the highly pathogenic PRRSV (HP-PRRSV) strains. The subgenotype I strains were generally clustered into genetically similar groups by year. Only one of the strains belonged to subgenotype II, clustering with the classical North American type, VR2332. Five of the strains were grouped into subgenotype III, which occupied a separate branch and was closely related to the recently isolated novel field strains, QYYZ and GM2. The 5 subgenotype III strains shared an amino acid identity with the remaining 46 study strains ranging from 79.6%-83.6%. Amino acid analysis showed extensive mutations in subgenotype III; the diverse genetic mutations of these novel strains are of great concern.

Potentiation of the P2X3 ATP receptor by PAR-2 in rat dorsal root ganglia neurons, through protein kinase-dependent mechanisms, contributes to inflammatory pain.

Proinflammatory agents trypsin and mast cell tryptase cleave and activate protease-activated receptor-2 (PAR-2), which is expressed on sensory nerves and causes neurogenic inflammation. P2X3 is a subtype of the ionotropic receptors for adenosine 5'-triphosphate (ATP), and is mainly localized on nociceptors. Here, we show that a functional interaction of the PAR-2 and P2X3 in primary sensory neurons could contribute to inflammatory pain. PAR-2 activation increased the P2X3 currents evoked by α, ß, methylene ATP in dorsal root ganglia (DRG) neurons. Application of inhibitors of either protein kinase C (PKC) or protein kinase A (PKA) suppressed this potentiation. Consistent with this, a PKC or PKA activator mimicked the PAR-2-mediated potentiation of P2X3 currents. In the in vitro phosphorylation experiments, application of a PAR-2 agonist failed to establish phosphorylation of the P2X3 either on the serine or the threonine site. In contrast, application of a PAR-2 agonist induced trafficking of the P2X3 from the cytoplasm to the plasma membrane. These findings indicate that PAR-2 agonists may potentiate the P2X3, and the mechanism of this potentiation is likely to be a result of translocation, but not phosphorylation. The functional interaction between P2X3 and PAR-2 was also confirmed by detection of the α, ß, methylene-ATP-evoked extracellular signal-regulated kinases (ERK) activation, a marker of neuronal signal transduction in DRG neurons, and pain behavior. These results demonstrate a functional interaction of the protease signal with the ATP signal, and a novel mechanism through which protease released in response to tissue inflammation might trigger the sensation to pain through P2X3 activation.

Characteristic effects of methylglyoxal and its degraded product formate on viability of human histiocytes: a possible detoxification pathway of methylglyoxal.

Methylglyoxal (MGO) is a toxic and highly reactive alpha-oxoaldehyde, elevated in the states of various diseases underlying enhanced oxidative stress. Furthermore, MGO has been reported to generate another aldehyde, formic acid (FA). In this sense, investigating the biological property of FA is crucially important. The present study examined the effects of MGO and FA on cell viability using the U937 human histiocytic cell line. FA showed a dose-dependent increase in cell viability at the concentrations of MGO in which cell viability decreased. The mechanism of the increase by FA involved the presence of endogenous hydrogen peroxide (H2O2) and tetrahydrofolate in the folate pathway, whereas that of the decrease in cell viability by MGO involved interaction with H2O2 and oxidative damage. These findings suggest that FA production by MGO degradation may play a role in attenuation of oxidative cellular injury caused by MGO. We hypothesize that FA generation pathway constitutes a detoxification system for MGO.

Agonist of proteinase-activated receptor 2 increases painful behavior produced by alpha, beta-methylene adenosine 5'-triphosphate.

Proteinase-activated receptor (PAR) 2 is expressed in a subset of primary afferent neurons and is involved in inflammatory nociception. The P2X3 ion channel is localized on nociceptors of sensory neurons. Using immunohistochemistry, we showed that many P2X3s are co-expressed with the PAR2 in rat dorsal root ganglia neurons. Nocifensive behavior induced by alphabeta-methylene adenosine 5'-triphosphate (ATP) injection to the hind paw was significantly augmented after the application of PAR2 agonists. Fos expression induced by the alphabeta-methylene ATP injection in dorsal horn neurons was also increased after the pre-application of PAR2 agonists. These findings indicate that PAR2 agonists may potentiate the sensitivity of P2X3 ion channel to noxious stimuli, and the interaction between PAR2 and P2X3 may be an important mechanism underlying inflammatory pain.