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.

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).

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.

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.

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.

Investigating Linkages Between Spatiotemporal Patterns of the COVID-19 Delta Variant and Public Health Interventions in Southeast Asia: Prospective Space-Time Scan Statistical Analysis Method.

BACKGROUND: The COVID-19 Delta variant has presented an unprecedented challenge to countries in Southeast Asia (SEA). Its transmission has shown spatial heterogeneity in SEA after countries have adopted different public health interventions during the process. Hence, it is crucial for public health authorities to discover potential linkages between epidemic progression and corresponding interventions such that collective and coordinated control measurements can be designed to increase their effectiveness at reducing transmission in SEA. OBJECTIVE: The purpose of this study is to explore potential linkages between the spatiotemporal progression of the COVID-19 Delta variant and nonpharmaceutical intervention (NPI) measures in SEA. We detected the space-time clusters of outbreaks of COVID-19 and analyzed how the NPI measures relate to the propagation of COVID-19. METHODS: We collected district-level daily new cases of COVID-19 from June 1 to October 31, 2021, and district-level population data in SEA. We adopted prospective space-time scan statistics to identify the space-time clusters. Using cumulative prospective space-time scan statistics, we further identified variations of relative risk (RR) across each district at a half-month interval and their potential public health intervention linkages. RESULTS: We found 7 high-risk clusters (clusters 1-7) of COVID-19 transmission in Malaysia, the Philippines, Thailand, Vietnam, and Indonesia between June and August, 2021, with an RR of 5.45 (P<.001), 3.50 (P<.001), 2.30 (P<.001), 1.36 (P<.001), 5.62 (P<.001), 2.38 (P<.001), 3.45 (P<.001), respectively. There were 34 provinces in Indonesia that have successfully mitigated the risk of COVID-19, with a decreasing range between -0.05 and -1.46 due to the assistance of continuous restrictions. However, 58.6% of districts in Malaysia, Singapore, Thailand, and the Philippines saw an increase in the infection risk, which is aligned with their loosened restrictions. Continuous strict interventions were effective in mitigating COVID-19, while relaxing restrictions may exacerbate the propagation risk of this epidemic. CONCLUSIONS: The analyses of space-time clusters and RRs of districts benefit public health authorities with continuous surveillance of COVID-19 dynamics using real-time data. International coordination with more synchronized interventions amidst all SEA countries may play a key role in mitigating the progression of COVID-19.

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.

Echinococcus multilocularis drives the polarization of macrophages by regulating the RhoA-MAPK signaling pathway and thus affects liver fibrosis.

Echinococcus multilocularis is a small parasite that causes alveolar echinococcosis. It primarily induces liver disorder, such as liver fibrosis and even liver cancer, which severely endangers human lives. This study aims to explore the efficacy of Echinococcus multilocularis soluble antigen in preventing and alleviating alveolar echinococcosis-induced liver fibrosis and determine the underlying mechanism. We first identified the optimal dose and time of Echinococcus multilocularis soluble antigen. The protein levels of key genes in the RhoA-MAPK signaling pathway were remarkably upregulated in RAW264.7 and Ana-1 cells induced with 80 µg/mL Echinococcus multilocularis soluble antigen for 8 h. Interestingly, the upregulated expression levels were remarkably reversed by the RhoA, JNK, ERK, or p38 inhibitor, confirming the significance of the RhoA-MAPK signaling pathway. In addition, the relative contents of M2 polarization markers IL-10 and Arg-1 in macrophages induced with 80 µg/mL Echinococcus multilocularis soluble antigen for 8 h increased, whereas those of M1 polarization markers IL-12 and NOS-2 decreased. Mouse hepatic stellate cells were the key components of the hepatocellular carcinoma tumor microenvironment. Hepatic stellate cells were activated by Echinococcus multilocularis soluble antigen and transformed into the morphology of myofibroblasts in response to liver disorders. By detecting the marker of myofibroblast formation, RhoA inhibitor remarkably reduced the positive expression of α-SMA in mouse hepatic stellate cells induced with Echinococcus multilocularis soluble antigen. Therefore, Echinococcus multilocularis soluble antigen remarkably activated the RhoA-MAPK pathways in macrophages, further inducing the polarization of macrophages and ultimately causing liver fibrosis. HYPOTHESIS: We hypothesize that infection with Echinococcus multilocularis activates the RhoA-MAPK signaling pathway and subsequently induces macrophage polarization to promote hepatic stellate cells activation leading to liver fibrosis. AIMS: To investigate the mechanism by which soluble antigen of Echinococcus multilocularis affects liver fibrosis through the RhoA-MAPK pathway driving polarization of macrophages. GOALS: To identify new pathways of intervention and drug targets for the regulation of macrophage polarity phenotype switching and the attenuation or inhibition of the development and treatment of liver fibrosis caused by Echinococcus multilocularis infection.

Application of polymerized porcine hemoglobin in the ex vivo normothermic machine perfusion of rat livers.

Background: In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion (NMP) may reduce preservation injury, improve graft viability and potentially allows ex vivo assessment of graft viability before transplantation. The polymerized porcine hemoglobin is a kind of hemoglobin oxygen carrier prepared by crosslinking porcine hemoglobin by glutaraldehyde to form a polymer. The pPolyHb has been proved to have the ability of transporting oxygen which could repair the organ ischemia-reperfusion injury in rats. Objective: In order to evaluate the effectiveness of rat liver perfusion in vitro based on pPolyHb, we established the NMP system, optimized the perfusate basic formula and explored the optimal proportion of pPolyHb and basal perfusate. Methods: The liver was removed and perfused for 6 h at 37°C. We compared the efficacy of liver perfusion with different ratios of pPolyHb. Subsequently, compared the perfusion effect using Krebs Henseleit solution and pPolyHb perfusate of the optimal proportion, and compared with the liver preserved with UW solution. At 0 h, 1 h, 3 h and 6 h after perfusion, appropriate samples were collected for blood gas analysis and liver injury indexes detection. Some tissue samples were collected for H&E staining and TUNEL staining to observe the morphology and detect the apoptosis rate of liver cells. And we used Western Blot test to detect the expression of Bcl-2 and Bax in the tissues. Results: According to the final results, the optimal addition ratio of pPolyHb was 24%. By comparing the values of Bcl-2/Bax, the apoptosis rate of pPolyHb group was significantly reduced. Under this ratio, the results of H&E staining and TUNEL staining showed that the liver morphology was well preserved without additional signs of hepatocyte ischemia, biliary tract injury, or hepatic sinusoid injury, and hepatocyte apoptosis was relatively mild. Conclusion: Through the above-mentioned study we show that within 6 h of perfusion based on pPolyHb, liver physiological and biochemical activities may essentially be maintained in vitro. This study demonstrates that a pPolyHb-based perfusate is feasible for NMP of rat livers. This opens up a prospect for further research on NMP.

Integrative Analysis of the Gut Microbiota and Metabolome for In Vitro Human Gut Fermentation Modeling.

This study aimed to find the best in vitro fermentation method by integrative analysis of the gut microbiota and metabolome. We selected five different media: brain heart infusion broth, Luria-Bertani broth, Mueller-Hinton broth, anaerobe basal broth, and anaerobic medium base (AMB). After in vitro fermentation, the gut microbiota and metabolites were analyzed at different culture times. The results showed that different culture media have different effects on the bacterial community structure and metabolites. The integrative analysis of gut microbiota and metabolism also proved that AMB medium is effective in keeping a stable bacterial community structure and producing less metabolites and short-chain fatty acids by simulating the nutrient-poor microenvironment in the human gut during in vitro fermentation. Thus, culturing with AMB medium for 48 h is the most suitable in vitro model for human gut microbiota fermentation, which provides an alternative approach for diet and health research.

The Anti-Colon Cancer Effects of Essential Oil of Curcuma phaeocaulis Through Tumour Vessel Normalisation.

BACKGROUND: Normalising tumour vessels had become a significant research focus in tumour treatment research in recent years. Curcumae rhizoma (CR) is an essential plant in traditional Chinese medicine as it promotes blood circulation and removes blood stasis. Similarly, CR improves local blood circulation. PURPOSE: We explored the anti-colon cancer effects of essential oil from CR (OCR) by investigating its role in normalising tumour vessels. We also provided a basis for research and development into new anti-cancer drugs. METHODS: We used colon cancer as a research focus to investigate OCR. We established an in vitro co-culture model of colon cancer cells and human umbilical vein endothelial cells (HUVEC). We also established an in vivo subcutaneous implant colon cancer model in nude mice. These studies allowed us to evaluate the comprehensive effects of OCR in in vivo and in vitro colon cancer and its role in normalising tumour blood vessels. RESULTS: In vitro, we found that OCR inhibited Human colon cancer cells (HCT116) and HUVEC cell proliferation and inhibited vascular endothelial growth factor-a (VEGFa) mRNA and protein expression in HUVECs in a co-culture system. Our in vivo studies showed that OCR inhibited colon cancer tumour growth, reduced angiogenesis in tumours and increased vascular endothelial (VE)-cadherin and pericyte coverage in tumour vessels. CONCLUSIONS: OCR inhibited colon cancer growth both in in vivo and in vitro models, reduced angiogenesis in tumours, improved tumour vessel structures and normalised tumour vessels.

Comprehensive Analysis of miRNAs and Target mRNAs between Immature and Mature Testis Tissue in Chinese Red Steppes Cattle.

This study aims to screen potential regulators and regulate fecundity networks between microRNAs (miRNAs) and target genes. The bovine testes of immature and mature Chinese Red Steppes were performed by genome-wide analysis of mRNAs and miRNAs. Compared with testicular tissues of newborns, 6051 upregulated genes and 7104 downregulated genes in adult cattle were identified as differentially expressed genes (DEGs). The DEGs were significantly enriched in 808 GO terms (p < 0.05) including male gonad development, male genitalia development, spermatogenesis, and sperm motility. Moreover, DEGs were also significantly enriched in 105 KEGG pathways (p < 0.05), including cGMP-PKG signaling pathway and calcium signaling pathway. To explore the expression of miRNA-regulated gene expression, 896 differentially expressed target genes negatively regulated with the expression levels of 31 differentially expressed miRNAs (DERs) were predicted and analyzed, and a network-integrated analysis was constructed. Furthermore, real-time PCR was performed to verify the expression levels of DEGs and DERs. Our results identified novel candidate DEGs and DERs correlated with male reproduction and intricate regulating networks between miRNAs and genes, which will be valuable for future genetic and epigenetic studies of sperm development and maturity, as well as providing valuable insights into the molecular mechanisms of male fertility and spermatogenesis in cattle.

First-In-Human Phase I Study of a Next-Generation, Oral, TGFß Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer.

PURPOSE: A novel, selective, next-generation transforming growth factor beta (TGFß) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. PATIENTS AND METHODS: This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). RESULTS: Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. CONCLUSIONS: LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.

Safety and Antitumor Activity of α-PD-L1 Antibody as Monotherapy or in Combination with α-TIM-3 Antibody in Patients with Microsatellite Instability-High/Mismatch Repair-Deficient Tumors.

PURPOSE: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors. However, 50%-60% do not respond to single-agent anti-programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6-12 months. This phase Ib trial evaluated safety and antitumor activity of anti-PD-L1 antibody LY3300054 monotherapy or in combination with anti-TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors. PATIENTS AND METHODS: Eligible patients ≥18 years without prior anti-PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor-resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti-TIM-3 antibody (cycles 1-2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability. RESULTS: Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. CONCLUSIONS: LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI-H/dMMR tumors.

Comparative Genome-Wide Alternative Splicing Analysis of Longissimus Dorsi Muscles Between Japanese Black (Wagyu) and Chinese Red Steppes Cattle.

Alternative splicing is a ubiquitous regulatory mechanism in gene expression that allows a single gene generating multiple messenger RNAs (mRNAs). Significant differences in fat deposition ability and meat quality traits have been reported between Japanese black cattle (Wagyu) and Chinese Red Steppes, which presented a unique model for analyzing the effects of transcriptional level on marbling fat in livestock. In previous studies, the differentially expressed genes (DGEs) in longissimus dorsi muscle (LDM) samples between Wagyu and other breeds of beef cattle have been reported. In this study, we further investigated the differences in alternative splicing in LDM between Wagyu and Chinese Red Steppes cattle. We identified several alternative splicing types including cassette exon, mutually exclusive exons, alternative 5' splice site, alternative 3' splice site, alternative start exon, and intron retention. In total, 115 differentially expressed alternatively spliced genes were obtained, of which 17 genes were enriched in the metabolic pathway. Among the 17 genes, 5 genes, including MCAT, CPT1B, HADHB, SIRT2, and DGAT1, appeared to be the novel spliced candidates that affect the lipid metabolism in cattle. Additionally, another 17 genes were enriched in the Gene Ontology (GO) terms related to muscle development, such as NR4A1, UQCC2, YBX3/CSDA, ITGA7, etc. Overall, altered splicing and expression levels of these novel candidates between Japanese black cattle and Chinese Red Steppes revealed by RNA-seq suggest their potential involvement in the muscle development and fat deposition of beef cattle.

Phase 1b study of galunisertib and ramucirumab in patients with advanced hepatocellular carcinoma.

BACKGROUND: Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-ß signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF-targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC). METHODS: This is a multicenter, open-label, phase 1b study of galunisertib, an inhibitor of TGF-ß receptor 1, and ramucirumab, an anti-VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha-fetoprotein and TGF-ß kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1-14 of a 28-day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks. RESULTS: Eight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose-limiting toxicities were observed. Treatment-related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment-related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose-proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively. CONCLUSION: Combination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFß signaling enhances efficacy of VEGF-targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab.

Safety and activity of the TGFß receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer.

BACKGROUND: We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFß) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens. METHODS: This was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1-14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase. RESULTS: The galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes. CONCLUSION: Galunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFß inhibition might be a more suitable approach. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02734160.

Inhibition of Fibroblast Activation in Uterine Leiomyoma by Components of Rhizoma Curcumae and Rhizoma Sparganii.

Background: The herbs Rhizoma Curcumae and Rhizoma Sparganii (RCRS) are often used in traditional Chinese medicine for the treatment of uterine leiomyoma (UL). The effectiveness of RCRS for the treatment of UL has been confirmed in our previous studies. Purpose: This study aimed to investigate the molecular mechanism by which RCRS inhibits the activation of fibroblast activation protein (FAP) and prevents UL in rats. Study Design and Methods: A Sprague Dawley (SD) rat model of UL was established via estrogen and progesterone load combined with external stimulation. Histological analyses, enzyme-linked immunosorbent assays, and western blotting were performed to evaluate the effect of RCRS on UL and elucidate its mechanism of action. Results: Our data showed that the treatment of SD rats with RCRS significantly reduced the expression of extracellular matrix component collagen, FAP, and transforming growth factor beta (a FAP-activating factor) and the phosphorylation of the cell proliferation pathway-related signaling factors AKT/MEK/ERK. Conclusion: Our results suggest that RCRS is effective in the prevention and treatment of UL in rats, and RCRS may exert its functions by inhibiting the activation of tumor-associated fibroblasts and cell proliferation and by improving the tumor extracellular matrix.

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.

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.