Early Prediction of Response Focused on Tumor Markers in Atezolizumab plus Bevacizumab Therapy for Hepatocellular Carcinoma.

Despite the promising efficacy of atezolizumab plus bevacizumab (atezo/bev), some patients with unresectable hepatocellular carcinoma (HCC) experience disease progression. This retrospective study, which included 154 patients, aimed to evaluate predictors of treatment efficacy of atezo/bev for unresectable HCC. Factors associated with treatment response were examined, focusing on tumor markers. In the high-alpha-fetoprotein (AFP) group (baseline AFP ≥ 20 ng/mL), a decrease in AFP level > 30% was an independent predictor of objective response (odds ratio, 5.517; p = 0.0032). In the low-AFP group (baseline AFP < 20 ng/mL), baseline des-gamma-carboxy prothrombin (DCP) level < 40 mAU/mL was an independent predictor of objective response (odds ratio, 3.978; p = 0.0206). The independent predictors of early progressive disease were an increase in AFP level ≥ 30% at 3 weeks (odds ratio, 4.077; p = 0.0264) and the presence of extrahepatic spread (odds ratio, 3.682; p = 0.0337) in the high-AFP group and up-to-seven criteria, OUT (odds ratio, 15.756; p = 0.0257) in the low-AFP group. In atezo/bev therapy, focusing on early AFP changes, baseline DCP, and tumor burden of up-to-seven criteria are useful in predicting response to treatment.

Community-based responses for tackling environmental and socio-economic change and impacts in mountain social-ecological systems.

Mountain social-ecological systems (SES) are often rich in biological and cultural diversity with sustained human-nature interactions. Many mountain SES are experiencing rapid environmental and socio-economic change, demanding viable action for conservation to sustain ecosystem services for the benefit of their communities. This paper is a synthesis of 71 case studies of mountain-specific SES, submitted to the International Partnership for the Satoyama Initiative (IPSI) that identifies major drivers of change, associated impacts, and response strategies. We find that overexploitation, land use change, demographic change, and the regional economy are the most prevalent drivers of change in the IPSI mountain SES, leading to negative consequences for biodiversity, livelihoods, indigenous knowledge, and culture. To counter these challenges in the study SES, stakeholders from the public, private, and civil society sectors have been implementing diverse legal, behavioral, cognitive, technological, and economic response strategies, often with strong community participation. We outline the lessons learned from the IPSI case studies to show how community-based approaches can contribute meaningfully to the sustainable management of mountain landscapes.

Outcome-Based Assessment of the Payment for Mountain Agriculture: A Community-Based Approach to Countering Land Abandonment in Japan.

Agricultural land accounts for 37% of the world's terrestrial area, and the multiple functions of agroecosystems-providing food, soil and water retention, and various cultural services-are of great importance for sustainable land management. To ensure that multifunctionality, payment for ecosystem services (PES) schemes have been developed for heterogeneous agroecosystems. However, the effects of the schemes have not been fully measured because, in most cases, they have been implemented as action-oriented programs rather than outcome-based payments. This study examines the effect of a community-based PES (CB-PES) program on the prevention of farmland abandonment to assess the agricultural outcomes of PES implementation in hilly and mountainous areas in Japan. We interviewed farmers in enrolled communities, mapped enrolled plots, and analyzed agricultural census data on the socioeconomic characteristics and farmland management conditions of 12,261 farmers in 960 agricultural communities in a typical hilly and mountainous area of Noto Peninsula in northern Japan. The results confirm that direct payments are effective in enhancing community management and in preventing additional farmland abandonment. In addition, we found that several socioeconomic and environmental factors at both the community and farmer levels-including geographical conditions, collective management activities, absence of successors, farm scale, and off-farm income dependency-simultaneously affected the farmland abandonment process. Specifically, collective practices within and between communities is a significant factor in preventing farmland abandonment more than collaboration with outsiders. Considering the depopulation and aging of rural communities throughout Japan, intercommunity enrollment could improve the effectiveness of CB-PES by upscaling the current payment scheme to maintain community functions.

Mesenchymal Stem Cells Induce a Fibrolytic Phenotype By Regulating mmu-miR-6769b-5p Expression in Macrophages.

Liver transplantation is the only radical treatment for decompensated cirrhosis, but its use is limited owing to a shortage of donors; hence, there is an urgent need for new treatments. Previously, we developed a liver-regeneration therapy using autologous bone marrow-derived mesenchymal stem cells (BMSCs), which is under clinical investigation. Cell-cell interactions between BMSCs and macrophages (Mφs) participate in the improvement of liver function and alleviation of liver fibrosis, although the associated mechanisms have not been elucidated. Therefore, in this study, we investigated phenotypic changes in Mφs caused by interactions with BMSCs, as well as the underlying mechanisms. Co-culturing lipopolysaccharide (LPS)-stimulated murine bone marrow-derived Mφs (BMDMs) with BMSCs substantially upregulated matrix metalloproteinase 9 (Mmp9), Mmp12, and Mmp13 expression, and downregulated tumor necrosis factor alpha (Tnfα) expression. To identify humoral factors involved in phenotypic changes occurring in Mφs, microarray analysis was performed with microRNAs (miRNAs) derived from extracellular vesicles in the supernatant of co-cultured BMSCs and LPS-stimulated BMDMs. We found that miR-6769b-5p was highly expressed and that transfecting miR-6769b-5p mimic upregulated MMP9 in LPS-stimulated BMDMs and downregulated Tnfα and interleukin-1 beta (Il-1ß). MiR-6769b-5p expression in BMDMs was decreased by LPS stimulation but was increased by co-culture with BMSCs. Microarray and pathway analyses of gene expression in LPS-stimulated, miR-6769b-5p-transfected BMDMs revealed changes in the eukaryotic initiation factor 2-signaling pathway and decreased the expression of activating transcription factor 4 (Atf4). LPS-stimulated BMDMs exhibited increased MMP9 expression and decreased the expression of Tnfα and Il-1ß by ATF4 knockdown. These findings indicate that upregulating miR-6769b-5p in BMDMs induced a fibrolytic phenotype, where MMP9 was highly expressed and inflammatory cytokine expression was decreased by the suppression of ATF4 expression. These findings imply that regulating miR-6769b-5p or ATF4 expression in BMDMs may be helpful for treating chronic liver disease.

Hemobilia immediately after transcatheter arterial chemoembolization using drug-eluting beads for hepatocellular carcinoma with intrahepatic bile duct invasion.

Transcatheter arterial chemoembolization (TACE) is used as a palliative treatment for unresectable hepatocellular carcinoma (HCC) worldwide. Recently, a novel drug delivery-embolic agent, the drug-eluting bead (DEB), was introduced for TACE. There are a few reports of tumor hemorrhage after TACE using DEB (DEB-TACE) for HCC. However, there have not been any reports of hemobilia immediately after DEB-TACE for HCC with intrahepatic bile duct invasion. Here, the first such case is reported. A 71-year-old woman was admitted to our hospital to undergo DEB-TACE for multiple HCCs with worsening left intrahepatic bile duct dilatation. She was diagnosed with HCC that extensively invaded the left hepatic duct. After DEB-TACE through the left hepatic artery, a hepatic arteriogram showed extra flow of the contrast agent to the left hepatic and common bile ducts. Therefore, transcatheter arterial embolization (TAE) of the responsible vessel was carried out using coils, and no extra flow of the contrast agent was identified. The patient was discharged 14 days after TAE without deterioration of liver function. Although hemobilia immediately after DEB-TACE is rare, there may be increased potential for hemobilia when DEB-TACE is carried out for HCC with extensive bile duct invasion. We suggest that DEB-TACE may be contraindicated for such cases.

Brain regions expressing Fos during thermoregulatory behavior in rats.

We surveyed the neural substrata for behavioral thermoregulation with immunohistochemical analysis of the expression of Fos protein in the rat brain. We used an operant system in which a rat exposed to heat (40 degrees C) could get cold air (0 degrees C) for 30 s when it moved into the reward area. Rats moved in and out of the reward area of the system periodically and thus maintained their body temperature at a normal level. In the rats performing heat escape behavior (active group), strong Fos immunoreactivity (Fos-IR) was found in the median preoptic nucleus (MnPO), parastrial nucleus (PS), and dorsomedial hypothalamus (DMH) compared with the controls. Another group of rats (passive group) were given the same temperature changes, regardless of the rat's movement, as those obtained by rats of the active group. Fos-IR in the MnPO was also seen in this group. The present results suggest that the PS and DMH play an important role in the genesis of thermoregulatory behavior, whereas the MnPO may be important for detecting changes in ambient and/or body temperatures.

The caudal periaqueductal gray participates in the activation of brown adipose tissue in rats.

To investigate the involvement of the periaqueductal gray (PAG) in the control of non-shivering thermogenesis, we tested the effects of electrical or chemical stimulation of the PAG on thermogenesis of brown adipose tissue (BAT) in urethane anesthetized rats. Electrical stimulation (0.1 mA, 33 Hz, 0.5 ms) or application of D,L-homocysteic acid (0.5 mM, 0.3 micro l) into the lateral region of the caudal PAG (cPAG) elicited BAT thermogenesis, measured as a rise in the local temperature of interscapular BAT. These results suggest that neurons in the cPAG send excitatory efferent signals for BAT thermogenesis.