A phase Ib/II study of galunisertib in combination with nivolumab in solid tumors and non-small cell lung cancer.

BACKGROUND: In this phase Ib/II open-label study, tumor immune suppression was targeted in patients with advanced refractory solid tumors and patients with recurrent/refractory non-small cell lung cancer (NSCLC) using galunisertib with nivolumab. METHODS: Eligible patients were ≥ 18 years old, had an Eastern Cooperative Oncology Group performance status ≤ 1, and were treatment-naive for anti-programmed cell death-1, its ligand, or transforming growth factor ß receptor 1 kinase inhibitors. Phase Ib was an open-label, dose-escalation assessment of the safety and tolerability of galunisertib with nivolumab in patients with advanced refractory solid tumors. Phase II evaluated the safety of galunisertib with nivolumab in NSCLC patients who had received prior platinum-based treatment but were immuno-oncology agent-naive. RESULTS: This trial was conducted between October 2015 and August 2020. No dose-limiting toxicities were observed in phase I. In the phase II NSCLC cohort (n = 25), patients received 150 mg twice daily galunisertib (14 days on/14 days off dosing schedule for all phases) plus nivolumab at 3 mg/kg (intravenously every 2 weeks). In this phase, the most frequent treatment-related adverse events (AEs) were pruritus (n = 9, 36%), fatigue (n = 8, 32%), and decreased appetite (n = 7, 28%). No grade 4 or 5 treatment-related AEs were observed. Six (24%) patients had confirmed partial response (PR) and 4 (16%) had stable disease; 1 additional patient had confirmed PR after initial pseudo-progression. The median duration of response was 7.43 months (95% confidence interval [CI]: 3.75, NR). Among the 7 responders, including the delayed responder, 1 had high PD-L1 expression (≥ 50%). The median progression-free survival was 5.26 months (95% CI: 1.77, 9.20) and the median overall survival was 11.99 months (95% CI: 8.15, NR). Interferon gamma response genes were induced post-treatment and cell adhesion genes were repressed, although the association of these observations with tumor response and clinical outcomes was not statistically powered due to limited samples available. CONCLUSIONS: The study met its primary endpoint as galunisertib combined with nivolumab was well tolerated. Preliminary efficacy was observed in a subset of patients in the Phase 2 NSCLC cohort. TRIAL REGISTRATION: Trial registered with ClinicalTrials.gov (NCT02423343; 22.04.2015).

Quantifying Urban Activities Using Nodal Seismometers in a Heterogeneous Urban Space.

Earth's surface is constantly vibrating due to natural processes inside and human activities on the surface of the Earth. These vibrations form the ambient seismic fields that are measured by sensitive seismometers. Compared with natural processes, anthropogenic vibrations dominate the seismic measurements at higher frequency bands, demonstrate clear temporal and cyclic variability, and are more heterogeneous in space. Consequently, urban ambient seismic fields are a rich information source for human activity monitoring. Improving from the conventional energy-based seismic spectral analysis, we utilize advanced signal processing techniques to extract the occurrence of specific urban activities, including motor vehicle counts and runner activities, from the high-frequency ambient seismic noise. We compare the seismic energy in different frequency bands with the extracted activity intensity at different locations within a one-kilometer radius and highlight the high-resolution information in the seismic data. Our results demonstrate the intense heterogeneity in a highly developed urban space. Different sectors of urban society serve different functions and respond differently when urban life is severely disturbed by the impact of the COVID-19 pandemic in 2020. The anonymity of seismic data enabled an unprecedented spatial and temporal resolution, which potentially could be utilized by government regulators and policymakers for dynamic monitoring and urban management.

The Function and Regulation Mechanism of Non-Coding RNAs in Muscle Development.

Animal skeletal muscle growth is regulated by a complex molecular network including some non-coding RNAs (ncRNAs). In this paper, we review the non-coding RNAs related to the growth and development of common animal skeletal muscles, aiming to provide a reference for the in-depth study of the role of ncRNAs in the development of animal skeletal muscles, and to provide new ideas for the improvement of animal production performance.

Petrositis caused by fluconazole-resistant candida: case report and literature review.

BACKGROUND: Petrositis is a rare and fatal complication associated with otitis media. It is most likely caused by bacterial infections, but in some cases it is caused by fungal infections. CASE STUDY: The case in this report is associated with fungal petrositis. The clinical symptoms are: ear pain from chronic otitis media, severe headache, peripheral facial palsy and diplopia. The case was finally confirmed through imaging of middle ear, bacterial culture, pathology, and blood Metagenomic next-generation sequencing (mNGS) test. The patient was treated with sensitive antifungal drugs. CONCLUSION: Drug treatment is conservative but efficient method in this case. mNGS can provide pathogenic reference, when antibiotic is not efficient enough for fungal infections or drug-resistant fungal infections cases. This allows we to adjust drug use for the treatment.

Diverse Flavonoids from the Roots of Indigofera stachyodes.

Three new flavonoids, 4'-O-ß-D-glucopyranosyl-2S,3R-3,7-dihydroxy-3'-methoxyflavan (1), (3R)-7,4'-dihydroxy-5,3'-methoxychalcone (2), (3S)-7,2',3'-trihydroxy-6,4'-dimethoxylisoflavan (3), and one new natural occurring product, (3S)-6,2',3'-trihydroxy-7,4'-dimethoxylisoflavan (4), together with eleven known ones (5-15), were isolated from the roots of Indigofera stachyodes. The structures of these compounds were confirmed by UV, IR, MS, and NMR spectroscopic analysis. The absolute configurations of new compounds were elucidated by ECD spectra and chemical method. All the isolated flavonoids were screened for their antioxidant abilities to scavenge DPPH and ABTS+ . As results, compounds 2-4, 10, and 15 exhibited remarkable scavenging activity against both ABTS+ and DPPH, with the IC50 values less than 20 µM. In addition, compounds 1, 6-9, and 13 exhibited potential antioxidant scavenging activities, IC50 values were in the range of 17.96∼85.91 µM.

IGFBP7 downregulation or overexpression effect on bovine preadipocyte differentiation.

The insulin-like growth factor binding-protein 7 (IGFBP7) has binding affinities to IGFs and is able to either positively or negatively regulate the IGFs signaling pathway. It also plays a crucial role in cell growth, differentiation and development in an IGF-independent manner. Herein, we investigated the specific regulation of the gene encoding for IGFBP7during the differentiation process of the adipocyte cells of the Yan Yellow Cattle by interfering with or by overexpressing the IGFBP7 gene. As a result, we found that the mRNA expression levels of IGFBP7 were significantly increased during the formation of progenitor cells. In addition, the expression levels of the lipoprotein lipase (LPL) and transcription factors (PPARγ, C/EBPα) were also significantly increased. IGFBP7 gene overexpression and RNA interfering promoted and inhibited respectively the lipid accumulation and triglyceride production in mature adipocytes, and the expression of the LPL and transcription factors (PPARγ, C/EBPα). The changes in the protein expression levels of IGFBP7 and adipogenic factors were in accord with the changes observed in the mRNA levels. In conclusion, our results indicate that IGFBP7 plays an important regulatory role in the differentiation of preadipocyte cells.

ALDH1A1 effect on Yan Yellow Cattle preadipocyte differentiation.

Aldehyde dehydrogenase 1A1 (ALDH1A1) is a cytosolic enzyme that mainly catalyzes the oxidation of acetaldehyde into acetic acid and participates in the regulation of differentiation and gene expression in fat cell growth and development. However, the physiological role of ALDH1A1 in the formation of fat cell precursors in the Yan Yellow Cattle is still not clear. Herein, we investigated the specific regulation of the gene encoding for ALDH1A1 during the differentiation process of the adipocyte cells of the Yan Yellow Cattle by interfering or overexpressing the ALDH1A1 gene. As a result, we found that the mRNA expression levels of ALDH1A1 were significantly increased during the formation of progenitor cells. In addition, the expression levels of the Lipoprotein lipase (LPL) and transcription factors (PPARγ, C/EBPα) were also significantly increased. ALDH1A1 gene overexpression and RNA interfering promoted and inhibited respectively the lipid accumulation and triglyceride production in mature adipocytes, and the expression of the LPL and transcription factors (PPARγ, C/EBPα). The changes in the protein expression levels of ALDH1A1 and adipogenic factors were in accord with the changes observed in the mRNA levels. In conclusion, our results indicate that ALDH1A1 plays an important regulatory role in the differentiation of preadipocyte cells.

Detection of InDel variations within seven candidate genes and their associations with phenotypic traits in three cattle breeds.

The Xinjiang brown cattle, Red steppe cattle, and Yunling cattle are indigenous cultivated cattle breeds in Chinese frontier provinces, and they produce high-grade beef and milk products, however, their genetic diversity in many important genes related to excellent meat and milk production is still unknown. Our previous studies have found that several candidate genes (e.g., SREBP1c and PAX7) were associated with bovine economically important phenotypic traits, but none has been reported in the above-mentioned three cattle breeds. Since the InDel (insertion/deletion) marker becomes a useful tool applied in the animal molecular breeding, herein, we firstly found that the InDel variations of seven candidate genes in these cattle. Results showed that the genotypic and allelic distributions of these seven genes were remarkably different among these three cattle (p < 0.05 or p < 0.01). Furthermore, the InDel variations of SREBP1c and PAX7 genes were significantly associated with eight phenotypic traits in Xinjiang brown cattle (p < 0.05 or p < 0.01), respectively, suggesting that they can become the useful DNA markers.

Effects of puerarin on the AKT signaling pathway in bovine preadipocyte differentiation.

OBJECTIVE: Puerarin has the potential of regulating the differentiation of preadipocytes, but its mechanism of action has not yet been elucidated. Adipocytes found in adipose tissue, the main endocrine organ, are the main sites of lipid deposition, and are widely used as a cell model in the study of in vitro fat deposition. This study aimed to investigate the effects of puerarin on adipogenesis in vitro. METHODS: Puerarin was added to the culture medium during the process of adipogenesis. The proliferation and differentiation of bovine preadipocytes was measured through cell viability and staining with Oil Red O. The content of triacylglycerol (TG) was measured using a triglyceride assay kit. The mRNA and protein expression levels of adipogenic genes, peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding protein-α (C/EBPα), were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. RESULTS: The addition of puerarin significantly increased adipogenesis of bovine preadipocytes and enhanced the mRNA and protein level expression of PPARγ (p&lt;0.01). The expression of P-Akt increased after adipogenic hormonal induction, whereas puerarin significantly increased PPARγ expression by promoting the Akt signaling component, P-Akt. The mechanism of adipogenesis was found to be related to the phosphorylation level of Ser473, which may activate the downstream signaling of the Akt pathway. CONCLUSION: Puerarin was able to promote the differentiation of preadipocytes and improve fat deposition in cattle. The mechanism of adipogenesis was found to be related to the phosphorylation level of Ser473.

The effects of CCR7 and related signaling pathways on Leishmania major -infected human dendritic cells.

OBJECTIVES: In our research, we aimed to investigate the roles of CC-chemokine receptor 7 (CCR7) and relevant signaling pathways in Leishmania major-infected human dendritic cells (DCs). METHODS: Differentially expressed genes (DEGs) in L. major-infected human DCs were selected out and visualized using R program. Kyoto Encyclopedia of Genes and Genomes pathway analysis was conducted for investigation of significantly enriched signaling pathways and Gene Ontology enrichment analysis was carried out for the unveiling of enriched Molecular Functions and Biological Processes in L. major-infected human DCs. Besides, Hub gene was screened out using weighted gene coexpression network analysis and Cytoscape. In addition, enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction were used for detection of relative expression of CCR7, interleukin-12 (IL-12), and interferon-γ (IFN-γ) in L. major-infected human DCs and western blot analysis was used for detection of relative expression of CCR7 and other proteins in JAK-STAT signaling pathway in L. major-infected human DCs. RESULTS: CCR7 was upregulated and both chemokine and JAK-STAT signaling pathway were activated in L. major-infected human DCs. During the L. major infection, total number of L. major-infected human DCs were increased, as well as the relative expression levels of CCR7, IL-12, and IFN-γ and proteins in the JAK-STAT signaling pathway. Overexpression of CCR7 not only increased expression levels of IL-12 and IFN-γ but also activated the JAK-STAT signaling pathway to affect the leishmaniasis progression. CONCLUSION: L. major infection-induced activation of CCR7, as well as JAK2 and STAT1, might well upregulate the expression of BAX yet suppress the expression of both Bcl2 and c-Jun to affect leishmaniasis progression.

MicroRNA-205 affects mouse granulosa cell apoptosis and estradiol synthesis by targeting CREB1.

MicroRNA-205 (miR-205) is involved in various physiological and pathological processes, but its biological function in follicular atresia remains unclear. In this study, we investigated miR-205 expression in mouse granulosa cells (mGCs) and analyzed its functions in primary mGCs by performing a series of in vitro experiments. Quantitative real-time polymerase chain reaction showed that miR-205 expression was significantly higher in early atretic follicles and progressively atretic follicles than in healthy follicles. miR-205 overexpression in mGCs significantly promoted apoptosis and caspase-3/9 activities, as well as inhibited estrogen (E2) release and cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1, a key gene in E2 production) expression. Bioinformatics and luciferase reporter assays revealed that the gene encoding cyclic AMP response element (CRE)-binding protein 1 (CREB1) was a direct target of miR-205 in mGCs. CREB1 upregulation partially rescued the effects of miR-205 on apoptosis, caspase-3/9 activities, E2 production, and CYP19A1 expression on mGCs. These results indicate that miR-205 might play an important role in ovarian follicular development and provide new insights into follicular atresia.

In vitro efficacies of solubility-improved mebendazole derivatives against Echinococcus multilocularis.

Recently, we introduced an epoxy group to mebendazole by a reaction with epichlorohydrin and obtained two isoforms, mebendazole C1 (M-C1) and mebendazole C2 (M-C2). The in vitro effects of mebendazole derivatives at different concentrations on Echinococcus multilocularis protoscoleces and metacestodes as well as cytotoxicity in rat hepatoma (RH) cells were examined. The results demonstrated that the solubility of the two derivatives was greatly improved compared to mebendazole. The mortality of protoscoleces in vitro reached to 70-80% after 7 days of exposure to mebendazole or M-C2, and M-C2 showed higher parasiticidal effects than mebendazole (P > 0.05). The parasiticidal effect of M-C1 was low, even at a concentration of 30 µm. The percentage of damaged metacestodes that were treated with mebendazole and M-C2 in vitro at different concentrations were similar, and M-C1 exhibited insignificant effects on metacestodes. Significant morphological changes on protoscoleces and metacestodes were observed after treatment with mebendazole and M-C2. In addition, the introduction of an epoxy group to mebendazole also reduced its cytotoxicity in RH cells. Our results demonstrate that the introduction of an epoxy group not only improved the solubility of mebendazole, but also increased its parasiticidal effects on E. multilocularis and reduced its cytotoxicity in RH cells.

Three-Dimensional Computerized Model Based on the Sonourethrogram: A Novel Technique to Evaluate Anterior Urethral Stricture.

PURPOSE: The sonourethrogram is a useful alternative to the traditional retrograde urethrogram to evaluate anterior urethral strictures. With the development of 3-dimensional reconstructive techniques 3-dimensional urethral imaging can provide more accurate and useful information to enable the surgeon to make the best surgical decisions. We evaluated the accuracy and efficacy of a 3-dimensional reconstructed digital model of the urethra based on the sonourethrogram to assess anterior urethral disease. MATERIALS AND METHODS: A total of 50 patients with an anterior urethral stricture and 10 healthy volunteers were enrolled in this study from April 2014 to January 2017. All patients and volunteers underwent sonourethrogram and retrograde urethrogram. Three-dimensional urethral models were reconstructed based on the sonourethrogram. Stricture length and location on retrograde urethrogram or sonourethrogram based images were compared with those found at operation. RESULTS: The 3-dimensional digital model revealed the entire anterior urethra, including the navicular fossa, and the penile and bulbar parts. The semitransparent model clearly demonstrated the structure of the corpus spongiosum and inside the urethral lumen. Further information on spongiofibrosis could also be seen in the 3-dimensional digital model. There was no significant difference in stricture length or location in the 3-dimensional model compared with retrograde urethrogram imaging and actual surgical findings. However, the latest technique could only reconstruct the short segment of the anterior urethra due to the probe width limitation. CONCLUSIONS: The 3-dimensional computerized model based on the sonourethrogram is a novel and effective technique of evaluating anterior urethral strictures.

Genome-wide assessment of genetic diversity and population structure insights into admixture and introgression in Chinese indigenous cattle.

BACKGROUND: China exhibits a great diversity of ecosystems and abundant cattle resources, with nearly 30 million cattle from 53 indigenous breeds reared in specific geographic regions. To explore the genetic diversity and population structure of Chinese indigenous cattle, a population genetic analysis at both the individual and population levels was conducted and the admixture analysis was performed. We genotyped 572 samples from 20 Chinese indigenous cattle breeds using GeneSeek Genomic Profiler Bovine LD (GGP-LD, 30 K) and downloaded the published data of 77 samples from 4 worldwide commercial breeds genotyped with Illumina BovineSNP50 Beadchip (SNP50, 50 K). RESULTS: In principal component analysis (PCA) and neighbour-joining (NJ) tree analysis, samples of the same breeds were grouped together, leading to clear separation from other breeds. And Chinese indigenous cattle were clustered into two groups of southern and northern breeds, originated from Asian Bos indicus lineage and Eurasian Bos taurus lineage, respectively. In STRUCTURE K = 2, a clear transition occurred from the northern breeds to the southern breeds. Additionally, the northern breeds contained a smaller Eurasian taurine (62.5%) descent proportion than that reported previously (more than 90%). In STRUCTURE K = 3, a distinct descent was detected in the southern Chinese breeds, which could reflect a long-term selection history of Chinese indigenous cattle. The results from TreeMix and f3 statistic provided the evidence of an admixture history between southern breeds and northern breeds. CONCLUSIONS: Consistent with the observed geographical distributions, Chinese indigenous cattle were divided into two genetic clusters, northern indigenous cattle and southern indigenous cattle. Three improved breeds in the northern area also exhibited northern indigenous ancestry. We found that the breeds distributed in the northern China showed more southern lineage introgression than previously reported. Central-located populations appeared to the admixture between southern and northern lineages, and introgression events from European cattle were observed in Luxi Cattle, Qinchuan Cattle and Jinnan Cattle. The study revealed the population structures and levels of admixture pattern among Chinese indigenous cattle, shedding light on the origin and evolutionary history of these breeds.

RNA-Seq Analysis Reveals a Positive Role of HTR2A in Adipogenesis in Yan Yellow Cattle.

In this study, we performed high throughput RNA sequencing at the primary bovine preadipocyte (Day-0), mid-differentiation (Day-4), and differentiated adipocyte (Day-9) stages in order to characterize the transcriptional events regulating differentiation and function. The preadipocytes were isolated from subcutaneous fetal bovine adipose tissues and were differentiated into mature adipocytes. The adipogenic characteristics of the adipocytes were detected during various stages of adipogenesis (Day-0, Day-4, and Day-9). We used RNA sequencing (RNA-seq) to investigate a comprehensive transcriptome information of adipocytic differentiation. Compared to the pre-differentiation stage (Day-0), 2510 genes were identified as differentially expressed genes (DEGs) at the mid-differentiation stage (Day-4). We found 2446 DEGs in the mature adipocytic stage relative to the mid-differentiation stage. Some adipogenesis-related transcription factors, CCAAT-enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) were differentially expressed at Day-0, Day-4, and Day-9. We further investigated the adipogenic function of 5-hydroxytryptamine receptor 2A (HTR2A) in adipogenesis. Overexpression of HTR2A stimulated the differentiation of preadipocytes, and knockdown of HTR2A had opposite effects. Furthermore, functional enrichment analysis of DEGs revealed that the PI3K-Akt signaling pathway was the significantly enriched pathway, and HTR2A regulated adipogenesis by activating or inhibiting phosphorylation of phospho-AKT (Ser473). In summary, the present study provides the first comparative transcription of various periods of adipocytes in cattle, which presents a solid foundation for further study into the molecular mechanism of fat deposition and the improvement of beef quality in cattle.

Heat shock protein 47 effects on hepatic stellate cell-associated receptors in hepatic fibrosis of Schistosoma japonicum-infected mice.

The study aimed to explore the regulation of heat shock protein 47 (HSP47) on expressions of receptors associated with hepatic stellate cell (HSC) in liver fibrosis mouse models induced by Schistosoma japonicum (S. japonicum). Mouse fibroblasts (NIH/3T3) were transfected with HSP47 shRNA plasmid by lipofectamine transfection, and experimental fibrosis in HSCs was studied in S. japonicum mouse models treated with HSP47 shRNA in vivo. HSP47 expression was assessed using Western blot and real-time PCR. Flow cytometry was adopted to determine the expression of cell membrane receptors. HSP47-shRNA could markedly down-regulate the expression of collagen (Col1a1 and Col3a1). The expressions of HSP47, endothelin receptor A (ETAR) and endothelin receptor B (ETBR) significantly increased in the liver tissue of infected mice. However, the expressions of ETAR and HSP47 and ETBR remarkably decreased after the administration of HSP47 shRNA in vitro and in vivo. ETAR and ETBR levels were found to be positively correlated with HSP47 expression. HSP47 might exert influence on liver fibrosis via the regulation of ETAR and ETBR.

Impact of medical and psychiatric multi-morbidity on mortality in diabetes: emerging evidence.

BACKGROUND: Multi-morbidity, or the presence of multiple chronic diseases, is a major problem in clinical care and is associated with worse outcomes. Additionally, the presence of mental health conditions, such as depression, anxiety, etc., has further negative impact on clinical outcomes. However, most health systems are generally configured for management of individual diseases instead of multi-morbidity. The study examined the prevalence and differential impact of medical and psychiatric multi-morbidity on risk of death in adults with diabetes. METHODS: A national cohort of 625,903 veterans with type 2 diabetes was created by linking multiple patient and administrative files from 2002 through 2006. The main outcome was time to death. Primary independent variables were numbers of medical and psychiatric comorbidities over the study period. Covariates included age, gender, race/ethnicity, marital status, area of residence, service connection, and geographic region. Cox regression was used to model the association between time to death and multi-morbidity adjusting for relevant covariates. RESULTS: Hypertension (78%) and depression (13%) were the most prevalent medical and psychiatric comorbidities, respectively; 23% had 3+ medical comorbidities, 3% had 2+ psychiatric comorbidities and 22% died. Among medical comorbidities, mortality risk was highest in those with congestive heart failure (hazard ratio, HR = 1.92; 95% CI 1.89-1.95), Lung disease (HR = 1.42; 95% CI 1.40-1.44) and cerebrovascular disease (HR = 1.39; 95% CI 1.37-1.40). Among psychiatric comorbidities, mortality risk was highest in those with substance abuse (HR = 1.50; 95% CI 1.46-1.54), psychoses (HR = 1.16; 95% CI 1.14-1.19) and depression (HR = 1.05; 95% CI 1.03-1.07). There was an interaction between medical and psychiatric comorbidity (p = 0.003) so stratified analyses were performed. HRs for effect of 3+ medical comorbidity (2.63, 2.66, 2.15) remained high across levels of psychiatric comorbidities (0, 1, 2+), respectively. HRs for effect of 2+ psychiatric comorbidity (1.69, 1.63, 1.42, 1.38) declined across levels of medical comorbidity (0, 1, 2, 3+), respectively. CONCLUSIONS: Medical and psychiatric multi-morbidity are significant predictors of mortality among older adults (veterans) with type 2 diabetes with a graded response as multimorbidity increases.

[Analysis of chemical constituents of volatile components from Jia Ga Song Tang by GC-MS].

OBJECTIVE: To analyze the chemical components of volatile components from Jia Ga Song Tang. METHODS: The volatile oils were extracted by water steam distillation. The chemical components of essential oil were analyzed by GC-MS and quantitatively determined by a normalization method. RESULTS: 103 components were separated and 87 components were identified in the volatile oil of Zingiberis Rhizoma. 58 components were separated and 38 components were identified in the volatile oil of Myristicae Semen. 49 components were separated and 38 components were identified in the volatile oil of Amomi Rotundus Fructus. 89 components were separated and 63 components were identified in the volatile oil of Jia Ga Song Tang. CONCLUSION: Eucalyptol, ß-phellandrene and other terpenes were the main compounds in the volatile oil of Jia Ga Song Tang. Changes in the kinds and content of volatile components can provide evidences for scientific and rational compatibility for Jia Ga Song Tang.

Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study.

PURPOSE: Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. MATERIALS AND METHODS: Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. RESULTS: The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). CONCLUSIONS: RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01170663.

Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008.

BACKGROUND: Despite progress, many hypertensive patients remain uncontrolled. Defining characteristics of uncontrolled hypertensives may facilitate efforts to improve blood pressure control. METHODS AND RESULTS: Subjects included 13,375 hypertensive adults from National Health and Nutrition Examination Surveys (NHANESs) subdivided into 1988 to 1994, 1999 to 2004, and 2005 to 2008. Uncontrolled hypertension was defined as blood pressure ≥140/≥90 mm Hg and apparent treatment-resistant hypertension (aTRH) when subjects reported taking ≥3 antihypertensive medications. Framingham 10-year coronary risk was calculated. Multivariable logistic regression was used to identify clinical characteristics associated with untreated, treated uncontrolled on 1 to 2 blood pressure medications, and aTRH across all 3 survey periods. More than half of uncontrolled hypertensives were untreated across surveys, including 52.2% in 2005 to 2008. Clinical factors linked with untreated hypertension included male sex, infrequent healthcare visits (0 to 1 per year), body mass index <25 kg/m2, absence of chronic kidney disease, and Framingham 10-year coronary risk <10% (P<0.01). Most treated uncontrolled patients reported taking 1 to 2 blood pressure medications, a proxy for therapeutic inertia. This group was older, had higher Framingham 10-year coronary risk than patients controlled on 1 to 2 medications (P<0.01), and comprised 34.4% of all uncontrolled and 72.0% of treated uncontrolled patients in 2005 to 2008. We found that aTRH increased from 15.9% (1998-2004) to 28.0% (2005-2008) of treated patients (P<0.001). Clinical characteristics associated with aTRH included ≥4 visits per year, obesity, chronic kidney disease, and Framingham 10-year coronary risk >20% (P<0.01). CONCLUSION: Untreated, undertreated, and aTRH patients have consistent characteristics that could inform strategies to improve blood pressure control by decreasing untreated hypertension, reducing therapeutic inertia in undertreated patients, and enhancing therapeutic efficiency in aTRH.