ATF6ß Deficiency Elicits Anxiety-like Behavior and Hyperactivity Under Stress Conditions.

Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER) stress-regulated transcription factor that induces expression of major molecular chaperones in the ER. We recently reported that ATF6ß, a subtype of ATF6, promoted survival of hippocampal neurons exposed to ER stress and excitotoxicity, at least in part by inducing expression of calreticulin, an ER molecular chaperone with high Ca2+-binding capacity. In the present study, we demonstrate that ATF6ß deficiency in mice also decreases calreticulin expression and increases expression of glucose-regulated protein 78, another ER molecular chaperone, in emotional brain regions such as the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala. Comprehensive behavioral analyses revealed that Atf6b-/- mice exhibit anxiety-like behavior in the light/dark transition test and hyperactivity in the forced swim test. Consistent with these results, PFC and hypothalamic corticotropin-releasing hormone (CRH) expression was increased in Atf6b-/- mice, as was circulating corticosterone. Moreover, CRH receptor 1 antagonism alleviated anxiety-like behavior in Atf6b-/- mice. These findings suggest that ATF6ß deficiency produces anxiety-like behavior and hyperactivity via a CRH receptor 1-dependent mechanism. ATF6ß could play a role in psychiatric conditions in the emotional centers of the brain.

Management of elderly patients with unresectable pancreatic cancer.

Systemic chemotherapy plays important role in pancreatic cancer not only for palliative treatment of unresectable disease, but also for neoadjuvant and adjuvant treatment of resectable disease. Most clinical trials of systemic chemotherapy have been conducted in non-elderly patients, and the results cannot always be extrapolated to elderly patients because of the uniqueness of this population. The number of elderly patients with pancreatic cancer has increased in an aging society; therefore, there is an urgent need to develop specific treatments for elderly patients with pancreatic cancer. Gemcitabine or S-1 monotherapy is generally considered appropriate even for vulnerable elderly patients. FOLFIRINOX is considered inapplicable based on its safety profile. Gemcitabine plus nab-paclitaxel and nanoliposomal irinotecan with fluorouracil plus folinic acid can be administered to elderly patients, because the phase III trials have shown the efficacy and safety for patients including those who were 75 years or older. However, the feasibility of these therapies for elderly patients is still under debate since the number of elderly populations was relatively small in these studies. To determine the indication for these regimens in the elderly, the background of each patient should be considered. Geriatric assessment such as the Geriatric 8 and the Geriatric Nutritional Risk Index can identify vulnerabilities and are therefore recommended in daily clinical practice as well as in clinical studies of elderly patients. It is expected that geriatric assessment will elucidate the eligibility criteria for those regimens in elderly individuals. Randomized clinical trials are ongoing to establish a standard treatment in the vulnerable elderly with advanced pancreatic cancer, who cannot tolerate the same regimen as in the non-elderly patients.

A retrospective study on the efficacy of Ninjin'yoeito on fatigue in patients with interstitial pneumonia.

INTRODUCTION: Fatigue, caused by dyspnea associated with progression of interstitial pneumonia (IP), can negatively affect patients' quality of life (QOL). Ninjin'yoeito (NYT), a Chinese herbal medicine, is prescribed for general symptoms of fatigue and for fatigue associated with various respiratory diseases. However, there is a lack of integrated research on the effects of NYT in patients with IP. Therefore, we retrospectively investigated the efficacy of NYT in patients with IP and fatigue. MATERIALS AND METHODS: From the IP patients who had taken NYT, 19 who met the following inclusion criteria were included: (1) age of ≥20 years, (2) fatigue, and (3) history of NYT administration. The primary endpoint was fatigue, which was assessed using the Chalder Fatigue Scale (CFS). The secondary endpoints were loss of appetite and dyspnea, which were evaluated using the Simplified Nutritional Appetite Questionnaire (SNAQ) and modified Medical Research Council (mMRC) scores, respectively. All items were measured before and after 12 weeks of NYT administration. RESULTS: In the enrolled 19 patients (male, 12; female, 7; mean age, 65.8 ± 12.7 years), the underlying diseases were idiopathic pulmonary fibrosis (n = 8), idiopathic pleuroparenchymal fibroelastosis (n = 5), connective tissue disease-related interstitial pneumonia (n = 2), chronic hypersensitivity pneumonitis (n = 3), and nonspecific interstitial pneumonia (n = 1). The CFS score decreased from 17.1 ± 6.8 before administration to 13.4 ± 5.7 after administration of NYT (p = 0.0389). The SNAQ score did not change markedly. The median mMRC score decreased from 3 to 2, however, the difference was not significant. CONCLUSION: Many subtypes of IP are progressive, and a cure cannot be expected in cases of irreversible lung fibrosis. Therefore, a multifaceted approach to improve and maintain the QOL is needed in addition to the standard of care. This study showed that NYT can improve fatigue and help maintain the QOL in IP patients.

Case Report: Efficacy of Ninjin'yoeito Treatment for Idiopathic Pulmonary Fibrosis.

Ninjin'yoeito, a Kampo prescription, was administered to two patients with idiopathic pulmonary fibrosis (IPF) over a period of 12 weeks to improve loss of appetite and lassitude. In Case 1, improvements were observed in appetite, lassitude, and breathlessness, as well as increases or increasing tendencies in body weight, blood albumin level, and hemoglobin (Hb) level. Case 2 showed no changes in appetite but improvements in lassitude and no deterioration of breathlessness. His body weight and his blood albumin and Hb levels increased or showed increasing trends. In both cases, a trend for improvement of respiratory function was observed. In summary, ninjin'yoeito trended to improve the subjective symptoms and nutritional status of a patient with pulmonary fibrosis.

Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide-induced microglial and astrocytic neuroinflammation by increasing NAD.

Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD+ ) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD+ , suppressed cuprizone-induced demyelination, neuroinflammation, and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD+ level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD+ on lipopolysaccharide (LPS)-induced neuroinflammation in mice. Intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS-induced inflammatory responses and glial activation. Pre-administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD+ precursor, increased NAD+ level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS-induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD+ , NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF-κB signaling pathway in microglia. These results suggest that CD38-mediated neuroinflammation is linked to NAD+ consumption and that boosting NAD+ by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain.

A multicenter Phase II study of sorafenib in Japanese patients with advanced hepatocellular carcinoma and Child Pugh A and B class.

OBJECTIVE: To evaluate prospectively the efficacy and safety of sorafenib, which has been the first-line treatment for advanced hepatocellular carcinoma (HCC), in Japanese HCC patients (pts) with not only Child-Pugh (C-P) A class but also C-P B class. METHODS: Sorafenib was administered orally at the dose of 400 mg twice daily for pts with HCC and liver function of C-P score of 5-8. Administration was continued until the detection of disease progression or appearance of unacceptable toxicity. The primary endpoint was time to progression (TTP), and toxicity and the secondary endpoints included objective response, overall survival (OS). RESULTS: Forty C-P A pts and 12 C-P B pts were enrolled. The median TTP in the C-P A pts and C-P B pts was 3.3 months and 3.2 months, respectively. Among the pts with C-P A, complete response, partial response, and stable disease were achieved for 2.5%, 7.5% and 47.5%. Among the pts with C-P B, there were no treatment responses, 66.7% of pts had stable disease. The median OS in the C-P A pts and C-P B pts was 13.4 months and 7.4 months, respectively. With regard to toxicities, fewer C-P A pts experienced Grade 3/4 toxicities than C-P B pts (77.5% vs. 91.6%). There were no treatment-related deaths in either group of patients. CONCLUSIONS: This study shows sorafenib has similar effectiveness in the recent post-approval studies and is well-tolerated in Japanese pts with HCC and Child Pugh A class. Sorafenib should be used with great care for Child Pugh class B pts.

Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial.

BACKGROUND: REACH evaluated ramucirumab in the second-line treatment of patients with advanced hepatocellular carcinoma. In the intent-to-treat population (n = 565), a significant improvement in overall survival (OS) was not observed. In patients with an elevated baseline α-fetoprotein (AFP) level (400 ng/mL or greater), an improvement in OS was demonstrated. An analysis of the Japanese patients in REACH was performed. METHODS: An analysis was performed with the subset of the intent-to-treat population enrolled in Japan (n = 93). RESULTS: The median OS was 12.9 months for the ramucirumab arm (n = 45) and 8.0 months for the placebo arm (n = 48) [hazard ratio (HR) 0.621 (95 % confidence interval (CI) 0.391-0.986); P = 0.0416]. The median progression-free survival was 4.1 months for the ramucirumab arm and 1.7 months for the placebo arm [HR 0.449 (95 % CI 0.285-0.706); P = 0.0004]. The objective response rates were 11 % for the ramucirumab arm and 2 % for the placebo arm (P = 0.0817). The grade 3 or higher treatment-emergent adverse events occurring in more than 5 % of patients with a higher incidence for the ramucirumab arm (n = 44) than for the placebo arm (n = 47) were ascites (7% vs 2 %), hypertension (7 % vs 2 %), and cholangitis (7 % vs 0 %). In patients with a baseline AFP level of 400 ng/mL or greater, the median OS was 12.9 months for the ramucirumab arm (n = 20) and 4.3 months for the placebo arm (n = 22) [HR 0.464 (95 % CI 0.232-0.926); P = 0.0263]. CONCLUSIONS: In the Japanese patients in REACH, ramucirumab treatment improved OS, including in patients with a baseline AFP level of 400 ng/mL or greater; improvements in progression-free survival and objective response rate were also demonstrated. The safety profile of ramucirumab was acceptable and well tolerated in Japanese patients. ClinicalTrials.gov identifier NCT01140347.

Sai-rei-to-induced lung injury: a case report and brief review of the literature.

An 81-year-old man was admitted to our hospital due to persistent fever and dyspnea with pulmonary infiltrates. He was treated successfully by discontinuing his current medications, including Sai-rei-to, and administering glucocorticoids. Drug lymphocyte stimulation tests showed a positive result for Sai-rei-to alone, and the resumption of other regular drugs did not re-induce the lung injury. Therefore, we diagnosed the patient with Sai-rei-to-induced lung injury. Sai-rei-to is a combination drug that consists of Sho-saiko-to and Gorei-san. This paper briefly reviews drug-induced lung injury caused by Sai-rei-to or its components with a case report.

A transcatheter arterial chemotherapy using a novel lipophilic platinum derivative (miriplatin) for patients with small and multiple hepatocellular carcinomas.

BACKGROUND/PURPOSE: Miriplatin is a platinum complex developed to treat hepatocellular carcinoma (HCC) through administration into the hepatic artery as a sustained-release formulation suspended in lipiodol. A single-institute pilot study was conducted to investigate the antitumor efficacy of miriplatin infusion therapy for small and multiple HCCs. MATERIALS AND METHODS: Small HCCs sized 2 cm or less, judged to be inadequate for curative treatment, were indicated for transcatheter arterial miriplatin infusion therapy. We prospectively investigated the course of patients treated with miriplatin between March 2010 and September 2010. Efficacy was evaluated by computed tomography at 4-8 weeks and the overall evaluation was carried out more than 3 months after treatment. RESULTS: The study included 14 patients, of whom 13 were evaluable for efficacy. Of the 13 patients, one (8%) showed a complete response and three (23%) showed a partial response, with an overall response rate of 31%. Grade 3/4 hematological toxicity including thrombocytopenia was not seen. Increases to grade 3/4 in aspartate aminotransferase and alanine aminotransferase were observed for nonhematological toxicity. Irreversible deleterious changes in hepatic function were not seen. CONCLUSION: Miriplatin infusion therapy showed safe and moderate effects on small HCCs. However, transarterial chemoembolization as a standard therapy cannot be replaced. We await the results of an ongoing study of transarterial chemoembolization with miriplatin.

Inflorescence architecture affects pollinator behaviour and mating success in Spiranthes sinensis (Orchidaceae).

• Despite the wide inflorescence diversity among angiosperms, the effects of inflorescence architecture (three-dimensional flower arrangement) on pollinator behaviour and mating success have not been sufficiently studied in natural plant populations. • Here, we investigated how inflorescence architecture affected inter- and intra-plant pollinator movements and consequent mating success in a field population of Spiranthes sinensis var. amoena (S. sinensis). In this species, the flowers are helically arranged around the stem, and the degree of twisting varies greatly among individuals. The large variation in inflorescence architecture in S. sinensis results from variation in a single structural parameter, the helical angle (the angular distance between neighbour-flower directions). • The numbers of visits per inflorescence and successive probes per visit by leaf-cutting bees decreased with helical angle, indicating that individual flowers of tightly twisted inflorescences received less visitations. As expected from pollinator behaviour, pollinia removal and fruit set of individual flowers decreased with helical angle. Meanwhile, geitonogamy decreased in tightly twisted inflorescences. • Our novel findings demonstrate that natural variation in inflorescence architecture significantly affects pollinator behaviour and reproductive success, suggesting that inflorescence architecture can evolve under pollinator-mediated natural selection in plant populations. We also discuss how diverse inflorescence architectures may have been maintained in S. sinensis populations.

Amelioration of D-galactosamine-induced acute liver injury in rats by dietary supplementation with betaine derived from sugar beet molasses.

The effects of betaine supplementation on D-galactosamine-induced liver injury were examined in terms of hepatic and serum enzyme activities and of the levels of glutathione and betaine-derived intermediates. The rats induced with liver injury showed marked increases in serum enzyme activity, but those receiving dietary supplementation of 1% betaine showed enzyme activity levels similar to a control group without liver injury. Administration of betaine also increased both hepatic and serum glutathione levels, even following D-galactosamine injection. The activity of glutathione-related enzymes was markedly decreased following injection of D-galactosamine, but remained comparable to that of the control group in rats receiving 1% betaine. The concentrations of hepatic S-adenosyl methionine and cysteine showed similar trends to that observed for hepatic glutathione levels. These results indicate that 1% betaine has a hepatoprotective effect by increasing hepatic and serum glutathione levels along with glutathione-related enzyme activities in rats.

Utilization of adzuki bean extract as a natural antioxidant in cured and uncured cooked pork sausages.

A commercial adzuki bean extract (AE) was evaluated for antioxidant effectiveness in cured and uncured cooked pork sausages. TBARS values, instrumental color evaluation and sensory panel scores were assessed. For uncured sausages, AE at 0.2% was equally effective as 0.1% butylated hydroxytoluene (BHT) in reducing TBARS values. Similarly, AE at 0.2% significantly (P<0.01) reduced the TBARS in cured sausages. Incorporation of 0.2% AE into sausages produced higher (P<0.05) CIE lab color a* value and lower (P<0.05) L* and b* values. Sensory panels did not detect any difference in color, odor, taste, flavor, and overall acceptance in uncured pork sausages with addition of 0.2% AE. However, there were adverse changes in the color and odor of cured sausages, even though the taste, flavor, and overall acceptance were similar. Therefore, the results suggest that AE is a potential antioxidant.

Pretreatment effects of moxibustion on the skin permeation and skin and muscle concentrations of salicylate in rats.

The effect of moxibustion on the in vitro and in vivo skin permeation of salicylate was evaluated in rats. First, the effect of moxibustion pretreatment on the elimination pharmacokinetics of salicylate after i.v. injection in rats was determined: no clear difference was observed in the plasma profiles of salicylate (SA) with or without moxibustion pretreatment. However, much higher skin and muscle concentrations of salicylate were observed after its i.v. injection. Next, an in vitro skin permeation study of SA was performed after moxibustion pretreatment. Moxibustion pretreatment increased the skin permeation of SA, and the extent of the increase in SA skin permeation was related to the strength of moxibustion ignition. More intense treatments produced higher skin permeation. A similar enhancement effect on the skin permeation of SA was observed in in vivo studies. Interestingly, the skin/plasma and muscle/plasma ratios of SA were markedly increased by moxibustion pretreatment. These results were due to the induction of enhanced skin permeation and lower clearance into the cutaneous vessels by moxibustion ignition. Combination treatment involving moxibustion and the topical application of drugs such as NSAID may be useful for increasing local pharmaceutical effects by enhancing the drug concentration in the skin and muscle underneath the topical application site.

Adjuvant treatments for resectable hepatocellular carcinoma.

Hepatocellular carcinoma often recurs even after curative resection. Although some encouraging data showing improvements in recurrence-free times have been reported with the use of intraarterial 131I-lipiodol infusion, retinoids, interferon, or immunotherapy after hepatectomy, there is no consensus regarding standard adjuvant therapy for resectable hepatocellular carcinoma. A novel target agent, sorafenib, which has recently become a standard of care for advanced disease, may also be promising in an adjuvant setting to prevent early recurrence after curative surgery. In future trials, it will be important to identify appropriate target populations for each type of adjuvant approach; that is, an agent with definitive antitumor activity for high-risk patients, and one that shows chemoprevention for low-risk patients.

A test of the effect of floral color change on pollination effectiveness using artificial inflorescences visited by bumblebees.

Floral color change has been recognized as a pollination strategy, but its relative effectiveness has been evaluated insufficiently with respect to other floral traits. In this study, effects of floral color change on the visitation pattern of bumblebees were empirically assessed using artificial flowers. Four inflorescence types were postulated as strategies of flowering behavior: type 1 has no retention of old flowers, resulting in a small display size; type 2 retains old flowers without nectar production; type 3 retains old flowers with nectar; and type 4 retains color-changed old flowers without nectar. Effects of these treatments varied depending on both the total display size (single versus multiple inflorescences) and the pattern of flower-opening. In the single inflorescence experiment, a large floral display due to the retention of old flowers (types 2-4) enhanced pollinator attraction, and the number of flower visits per stay decreased with color change (type 4), suggesting a decrease in geitonogamous pollination. Type-4 plants also reduced the foraging time of bees in comparison with type-2 plants. In the multiple inflorescence experiment, the retention of old flowers did not contribute to pollinator attraction. When flowering occurred sequentially within inflorescences, type-4 plants successfully decreased the number of visits and the foraging time in comparison with type-2 plants. In contrast, floral color change did not influence the number of visits, and it extended the foraging time when flowering occurred simultaneously within inflorescences but the opening of inflorescences progressed sequentially within a plant. Therefore, the effectiveness of floral color change is highly susceptible to the display size and flowering pattern within plants, and this may limit the versatility of the color change strategy in nature.

[A case of unresectable colon cancer responding to oral leucovorin+oral tegafur/uracil].

The patient was a 63-year-old man,who first visited our hospital with the chief complaints of left lower quadrant pain and abdominal distension that had developed around November 13, 2004. On close examination, he was diagnosed with sigmoid colon cancer, multiple liver metastasis, and subileus due to a lung metastasis. His operation took place on December 12 of the same year. Intraoperatively, the sigmoid colon was firmly fixed to the retroperitonium, there was a hard node in the pouch of Douglas, and that part of the jejunum was involved. The lesion was judged to be unresectable,and thus loop colostomy, partial jejunectomy and gastrojejunostomy were performed. After the surgery,the patient was treated with 4 courses of therapy with oral Leucovorin (LV, 75 mg) +oral tegafur/uracil (UFT, 400 mg). As a result, the tumor marker levels decreased markedly, the lung metastasis was no longer observed and the liver metastases became smaller. Therefore, a second-look operation was performed on May 30, 2005. This time it was relatively easy to free the sigmoid colon. The node in the pouch of Douglas was no longer observed, and there were only 2 metastatic lesions in the liver (1 each in S 2 and S 6). Sigmoidectomy and partial hepatectomy were performed, and the stoma was closed. The patient made good progress after the operation and was discharged on the 11 th POD. At present he is receiving chemotherapy with UFT+oral LV as an outpatient. As this therapy is relatively easy to perform and imposes only a small burden on patients,we think that it may be effective not only as adjuvant chemotherapy but also as neoadjuvant chemotherapy in some patients.

The prophylactic effectiveness of various antifungal agents against the progression of trichosporonosis fungemia to disseminated disease in a neutropenic mouse model.

Neutropenic mice with latent trichosporonemia were given various antifungal agents (amphotericin B, fluconazole, itraconazole) or saline to determine which antifungal agent could be useful for prophylaxis. The 3-week-survival rate was 80% in the fluconazole group, 50% in the amphotericin B group, 45% in the itraconazole group, and 30% in the saline group. Compared with the other antifungal agents, fluconazole offered superior prophylaxis against the progression of trichosporonosis fungemia to disseminated disease (P<0.05). These results suggest that clinical studies are warranted to investigate fluconazole prophylaxis of trichosporonosis progression in neutropenic patients, such as people receiving chemotherapy and patients who have received solid organ transplants.

A phase I study of hepatic arterial infusion chemotherapy with zinostatin stimalamer alone for hepatocellular carcinoma.

BACKGROUND: Hepatic arterial infusion of zinostatin stimalamer and lipiodol emulsion shows a moderate activity against hepatocellular carcinoma. However, the anti-tumor activity of zinostatin stimalamer alone is uncertain. METHODS: The primary endpoint was to evaluate the frequency of dose-limiting toxicity and determine the maximum-tolerated dose of zinostatin stimalamer when used by intra-arterial infusion. The candidates for this study were patients with hepatocellular carcinoma no longer amenable to established forms of treatment. Hepatic arterial infusion chemotherapy was performed by selectively introducing a catheter into the hepatic artery with zinostatin stimalamer alone. Treatment was repeated at 4-8-week intervals until disease progression or the appearance of unacceptable toxicity. The starting dose of zinostatin stimalamer was 3 mg/m(2), and doses were increased in 1 mg/m(2) increments in successive cohorts. At least three patients were treated at each dose level and three additional patients were treated in the presence of dose-limiting toxicity. RESULTS: Twelve patients were entered into this trial. Dose-limiting toxicity was observed in one of six patients at 3 mg/m(2), and in two of six patients at 4 mg/m(2). The maximum-tolerated dose was judged to be 3 mg/m(2) with liver dysfunction and serum creatinine increase as the dose-limiting toxicity. There was one early death suggested to be related to the protocol treatment. None of the 12 patients achieved an objective tumor response. CONCLUSION: Hepatic arterial infusion with a zinostatin stimalamer of 3 mg/m(2) may be tolerated, but not active, in patients with far advanced hepatocellular carcinoma.