Factors Contributing to the Prognosis after Second-line Therapy with Ramucirumab in Advanced Hepatocellular Carcinoma.

Objective Multiple therapeutic agents exist for advanced hepatocellular carcinoma (HCC), but prognostic factors in second-line and subsequent therapies are unclear. Ramucirumab is a molecular-targeted agent effective against hepatocytes with alpha-fetoprotein (AFP) >400 ng/mL after sorafenib failure. We examined the prognostic factors and efficacy of ramucirumab with prior therapy other than sorafenib. Methods In our retrospective multicenter study, 33 patients were treated with ramucirumab for HCC with prior therapy other than sorafenib, including 1 patient who received 2 lines of ramucirumab. We analyzed background factors, liver reserve, the prognosis, and treatment duration and efficacy. Results The median albumin-bilirubin (ALBI) value showed little change during ramucirumab treatment. The ALBI value improved in 32% of patients, and their prognoses were better than in those who did not improve. Response and efficacy rates were not as high as those in the REACH-2 study but were similar when limited to patients with 2,500 ng/mL AFP. Thirteen patients received further treatment after ramucirumab failure and they had a significantly better prognosis from ramucirumab administration and also had a significantly better prognosis from the start of the first tyrosine kinase inhibitor than who did not received further treatment. In univariate and multivariate analyses of prognostic factors, the continuation of treatment with another drug after ramucirumab failure and a good ALBI value at initiation were significant. The presence of a ramucirumab response and treatment duration were not associated with the prognosis. A good ALBI value at initiation and ALBI value improvement during treatment were also identified as independent factors associated with eligibility for further treatment after ramucirumab failure. The treatment line did not correlate with the availability of treatment with another drug after treatment failure. Conclusions ALBI value improvement with ramucirumab treatment allows for subsequent treatment after failure and an improved overall prognosis.

Atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma progressing after molecular targeted therapy: A multicenter prospective observational study.

To evaluate the efficacy of atezolizumab plus bevacizumab treatment in patients with hepatocellular carcinoma (HCC) previously treated with molecular targeted agents (MTAs). Thirty-one patients treated with atezolizumab plus bevacizumab for unresectable HCC and previously treated with MTAs were enrolled in this study. The treatment lines ranged from second to sixth lines. The treatment effect on HCC differed from that during first-line treatment. The treatment effect was determined using the Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST. The treatment response was different for each MTA immediately prior to atezolizumab + bevacizumab treatment. Tumors treated with lenvatinib followed by atezolizumab + bevacizumab showed rapid growth for a short period of time followed by shrinkage. However, patients who received ramucirumab, sorafenib, and regorafenib did not show such changes. This was likely because of differences in the mechanism of action of the MTA administered immediately beforehand. The side-effect profile differed from that observed in the IMbrave150 phase 3 study of atezolizumab plus bevacizumab, which showed more adverse events related to hepatic reserve. Patients treated with the combination of atezolizumab and bevacizumab after lenvatinib therapy may experience rapid tumor growth and subsequent shrinkage.

Phosphorus toxicity disrupts Rubisco activation and reactive oxygen species defence systems by phytic acid accumulation in leaves.

Phosphorus (P) is an essential mineral nutrient for plants. Nevertheless, excessive P accumulation in leaf mesophyll cells causes necrotic symptoms in land plants; this phenomenon is termed P toxicity. However, the detailed mechanisms underlying P toxicity in plants have not yet been elucidated. This study aimed to investigate the molecular mechanism of P toxicity in rice. We found that under excessive inorganic P (Pi) application, Rubisco activation decreased and photosynthesis was inhibited, leading to lipid peroxidation. Although the defence systems against reactive oxygen species accumulation were activated under excessive Pi application conditions, the Cu/Zn-type superoxide dismutase activities were inhibited. A metabolic analysis revealed that excessive Pi application led to an increase in the cytosolic sugar phosphate concentration and the activation of phytic acid synthesis. These conditions induced mRNA expression of genes that are activated under metal-deficient conditions, although metals did accumulate. These results suggest that P toxicity is triggered by the attenuation of both photosynthesis and metal availability within cells mediated by phytic acid accumulation. Here, we discuss the whole phenomenon of P toxicity, beginning from the accumulation of Pi within cells to death in land plants.

Characterization of Na+ exclusion mechanism in rice under saline-alkaline stress conditions.

This study was designed to elucidate the physiological responses of two rice genotypes to different pH levels under high saline stress. A salt-tolerant cultivar, FL478, and a salt-sensitive cultivar, IR29, were exposed to saline-alkaline solutions supplemented with 50 mM Na at pH 9 (severe), pH 8 (moderate), and pH 7 (mild) for three weeks. The results indicated that FL478 is relatively saline-alkaline tolerant compared to IR29, and this was evident from its higher dry mass production, lower Na+ concentration in the leaf blades, and maintenance of water balance under both mild and moderate saline-alkaline stress conditions. In both cultivars, Na+ concentrations in the leaf blades were considerably higher at pH 8 than at pH 7, indicating that high alkaline stress promoted Na+ accumulation under highly saline conditions. FL478 plants had lower Na+/K+ ratios in leaf blades and leaf sheaths than IR29 plants under saline-alkaline stress at both pH 7 and pH 8. To understand the mechanisms behind the difference in saline-alkaline tolerance between the two rice genotypes, transcript levels of the genes encoding Na+ transport proteins were analyzed. In response to mild and moderate saline-alkaline stress conditions, salt-tolerant FL478 had highly induced expression of the OsHKT1;5 gene in the roots, corresponding to lower Na+ accumulation in the leaf blades. Induction of high expression of the OsSOS1 gene in the roots of FL478 implied that Na may be effectively exported from cytosols to apoplasts in the roots resulting in sequestration of Na+ to outside of the roots and loading Na+ in xylem transpiration stream. On the other hand, the salt-sensitive IR29 had lower expression of the genes related to Na+ transporters, such as the OsHKT1;5 gene and the OsSOS1 gene, in the roots, leading to higher Na+ accumulation in the shoots. Expression of the determinant genes for alkaline tolerance, such as K+ and Fe acquisition and acidification of the rhizosphere was highly induced in FL478, but not in IR29. Thus, molecular analysis suggested that genes encoding Na+ transport proteins are involved in regulating Na+ transport under saline-alkaline stress in both salt-tolerant and salt-sensitive rice cultivars, and this is useful information for improving saline-alkaline tolerance traits of rice in the future.

Effects of drought stress on growth, solute accumulation and membrane stability of leafy vegetable, huckleberry (Solanum scabrum Mill.).

The present study sought to investigate the factors implicated in growth impairment of huckleberry (a leafy vegetable) under water stress conditions. To achieve this, seedlings of plant were subjected to control, mild stress and severe stress conditions for 30 days. Plant growth, plant water relation, gas exchange, oxidative stress damage, electrolyte leakage rate, mineral content and osmolyte accumulation were measured. Water deficit markedly decreased leaf, stem and root growth. Leaf photosynthetic rate was tremendously reduced by decrease in stomatal conductance under stress conditions. Malondialdehyde (MDA) content markedly increased under mild (82%) and severe (131%) stress conditions, while electrolyte leakage rate (ELR) increased by 59% under mild stress and 3-fold under severe stress. Mineral content in leafwas high in stressed plants, while proline content markedly increased under mild stress (12-fold) and severe stress (15-fold), with corresponding decrease in osmotic potential at full turgor and an increase in osmotic adjustment. These results suggest that maintenance of high mineral content and osmotic adjustment constitute important adaptations in huckleberry under water deficit conditions and that growth depression under drought stress would be mainly caused by increased electrolyte leakage resulting from membrane damage induced by oxidative stress.

Salinity-induced expression of HKT may be crucial for Na(+) exclusion in the leaf blade of huckleberry (Solanum scabrum Mill.), but not of eggplant (Solanum melongena L.).

Reduced Na(+) accumulation in the leaf blade is an important aspect of salinity tolerance and high affinity K(+) transporters (HKTs) are known to play a significant role in the process. Huckleberry and eggplant have previously been shown to display 'excluder' and 'includer' characteristics, respectively, under salt stress, but the underlying mechanisms have not been investigated. Here, we isolated the cDNA of the HKT homologs, Solanum scabrum HKT (SsHKT) from huckleberry and Solanum melongena HKT (SmHKT) from eggplant, and analyzed their expressions in different tissues under salt stress. SsHKT expression was markedly induced in the root (28-fold) and stem (7-fold), with a corresponding increase in Na(+) accumulation of 52% and 29%, respectively. Conversely, eggplant accumulated 60% total Na(+) in the leaf blade, with a lower SmHKT expression level in the root (3-fold). Huckleberry also maintained a higher K(+)/Na(+) ratio in the leaf blade compared to eggplant, due to the reduction of its Na(+) concentration and unaltered K(+) concentration. Functional analysis demonstrated that SsHKT-mediated Na(+) influx inhibited yeast growth under Na(+) stress, and that SsHKT did not complement the growth of the K(+) uptake-deficient CY162 strain under K(+)-limiting conditions. These results suggest that the Na(+) accumulation characteristics of both plants are caused by the differential expression of HKT genes, with SsHKT exerting a greater control over the ability of Na(+) to reach the leaf blade in huckleberry, than SmHKT does in eggplant.

The therapeutic effects of the herbal medicine, Juzen-taiho-to, on amyloid-beta burden in a mouse model of Alzheimer's disease.

Innate immunity, especially that involving macrophage function, reportedly diminishes with advancing age and in patients with Alzheimer's disease (AD). In this study, we tried to elicit the non-specific activation of peripheral macrophages by oral administration of the herbal medicine Juzen-taiho-to (JTT), to assess its effect as a possible treatment for AD patients. Amyloid-beta protein precursor transgenic mice were used as a model of AD to clarify the effect of JTT. Activated macrophages derived from bone marrow cross the blood-brain barrier, and then develop into microglia, which phagocytose aggregated amyloid-beta (Abeta) in senile plaques. Here we show that orally administered JTT increased the number of CD11b-positive ramified microglia in the mouse brain. The immunohistochemical examination of brain sections stained with polyclonal anti-Abeta antibody showed reduced Abeta burden, and Abeta levels were also decreased in the insoluble fractions of brain homogenates, as determined by ELISA. Thus, the activation of peripheral macrophages by JTT might be a potential new therapeutic strategy for AD.