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Supplementary Data from Deregulated GSK3 Sustains Gastrointestinal Cancer Cells Survival by Modulating Human Telomerase Reverse Transcriptase and Telomerase

Purpose: Glycogen synthase kinase-3 (GSK3) regulates multiple cell signaling pathways and has been implicated in glucose intolerance, neurodegenerative disorders, and inflammation. We investigated the expression, activity, and putative pathologic role of GSK3 in gastrointestinal, pancreatic, and liver cancers.Experimental Design: Colon, stomach, pancreatic, and liver cancer cell lines; nonneoplastic HEK293 cells; and matched pairs of normal and tumor tissues of stomach and colon cancer patients were examined for GSK3 expression and its phosphorylation at serine 9 (inactive form) and tyrosine 216 (active form) by Western immunoblotting and for GSK3 activity by in vitro kinase assay. The effects of small-molecule GSK3 inhibitors and of RNA interference on cell survival, proliferation, and apoptosis were examined in vitro and on human colon cancer cell xenografts in athymic mice. The effects of GSK3 inhibition on human telomerase reverse transcriptase (hTERT) expression and telomerase activity were compared between colon cancer and HEK293 cells.Results: Cancer cell lines and most cancer tissues showed increased GSK3 expression and increased tyrosine 216 phosphorylation and activity but decreased serine 9 phosphorylation compared with HEK293 cells and nonneoplastic tissues. Inhibition of GSK3 resulted in attenuated cell survival and proliferation and increased apoptosis in most cancer cell lines and in HT-29 xenografts in rodents but not in HEK293 cells. GSK3 inhibition in colon cancer cells was associated with decreased hTERT expression and telomerase activity.Conclusion: The results indicate that deregulated GSK3 sustains gastrointestinal cancer cells survival through modulation of hTERT and telomerase. (Clin Cancer Res 2009;15(22):68109)

Kampo Medicine is a traditional Japanese medicine that is well-integrated in modern medicine. Anti-cancer agents are highly developed, and evidence of standard treatment has accumulated. Kampo Medicine is needed to support patients with cancer who lose vital energy and feel cold. Cancer chemotherapy is associated with various adverse reactions, such as anorexia, general malaise/fatigue, and peripheral neuropathy, which are refractory to modern therapy. Recently, evidence of Kampo Medicines for these symptoms has been reported as randomized controlled trials (RCTs). The Japan Society for Oriental Medicine celebrated the first 20 years of the activities of evidence-based medicine (EBM) committee in June 2021. Among the activities of the EBM committee, Evidence Reports of Kampo Treatment contains RCTs and meta-analyses, including RCTs on cancer supportive care. There is accumulating evidence for the following Kampo formula for each symptom: Hangeshashinto for mucositis, rikkunshito for anorexia, goshajinkigan and ninjin'yoeito for peripheral neuropathy, hochuekkito for general malaise/fatigue, and shakuyakukanzoto for myalgia/arthralgia. However, there is insufficient evidence, and further clinical trials are needed. Supportive care with Kampo Medicine will lead to a more complete standard treatment for cancer.

Potential disparities between cancer patients with and without disabilities remained to be validate in Japan. We surveyed retrospective data on hospital cancer registration as well as information on disability certificates obtained through the Hokushin Ganpro database. In total, 93,545 cancer patients in 10 principal hospitals covering the region of northwestern Japan were registered with the Hokushin Ganpro database between 2010 and 2015. The database included the following data: diagnosis date, cancer type, staging, treatment, cancer detection process, and possession of a disability certificate. We found that 2983 patients, which accounted for 3.2% of the total patients, had disabilities. No significant differences in gender, age at diagnosis, cancer stage distribution, and cancer incidence rates were observed between the disabled and non-disabled patients. Even though the proportion of early-stage cancer among disabled patients differed only slightly from that in non-disabled patients, early-stage cancer was more frequently diagnosed in patients with disabilities during their regular hospital visits than in those without disabilities, who had more opportunity for early cancer detection during cancer screening. According to in-house data reflecting treatment period and process from a single hospital, all 16 disabled patients treated with chemotherapy completed the treatment until disease progression or end of predetermined cycles. These results indicate that deep disparities between cancer patients with and without disabilities are not apparent and that the disabled patients in the region of northwestern Japan receive appropriate hospital follow-up.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD), in which abnormal lipid metabolism plays an important role in disease progression, has become a pandemic. Abnormal lipid metabolism, for example an increased fat intake, has been thought to be an initial factor leading to NAFLD. The small intestine is the main site of dietary lipid absorption. A number of clinical trials have shown that acupuncture has positive effects in the regulation of lipid metabolism, which is closely associated with the progression of NAFLD. We therefore hypothesized that, acupuncture can improve the conditions of NAFLD by regulating intestinal absorption of lipid. AIM To study the role of acupuncture treatment in the improvement of metabolic syndrome secondary to NAFLD by mouse model. METHODS 8-wk-old male C57BL/6J mice were fed a methionine- and choline-deficient diet for 3 wk. Then, all mice were separated randomly into acupoints group (AG) or non-acupoints group (NG) with high fat diet feeding. Needling treatment was performed at Zu san li, Guan yuan and Yong quan acupoints as acupuncture treatment to AG mice while non-acupoints place to NG mice. Finally, mice were anesthetized with an injection of ketamine-medetomidine and euthanized by exsanguination. RESULTS An apparent improvement of obesity was found in AG mice after acupuncture treatment. In AG mice, the body weight was much lower (22.6 ± 1.2 g vs 28.1 ± 1.0 g, P < 0.005) in comparison to NG mice. The length of small intestine in AG mice was significantly shorter (26.7 ± 2.3 cm vs 32.7 ± 2.7 cm, P < 0.005). A large amount of chyme was observed in the lumen of the AG small intestine. The expression of microsomal triglyceride transfer protein, apolipoprotein B and apolipoprotein C2 was downregulated. Triacylglycerols (TGs), total cholesterol and nonesterified fatty acid (NEFA) levels of the small intestinal tissue were significantly higher in AG mice, but the serum TGs and NEFA levels were reduced in AG mice. CONCLUSION These results indicate that acupuncture at Zu san li, Guan yuan and Yong quan suppressed lipid absorption by downregulating the expression of apolipoproteins in the small intestine.

Peripheral neuropathy (PN) is an intractable side effect of oxaliplatin, with no effective prophylaxis so far. Ninjin’yoeito (NYT), a Kampo medicine, is protective against oxaliplatin-induced neuronal cell injury in vitro and ameliorates oxaliplatin-induced PN in vivo. Thus, this randomized controlled trial was aimed at clarifying NYT’s prophylactic effect for oxaliplatin-induced cumulative PN. 52 patients with colorectal cancers of pathological stage 3 received postoperative adjuvant chemotherapy with the CapeOX regimen: eight cycles of capecitabine (2400 mg/m2) plus oxaliplatin (130 mg/m2) at 3-week intervals. They were randomly assigned to NYT administration and non-administration groups. NYT (9.0 g/day) was administered from day 1 of cycle 1 in the NYT group. The NYT was administered orally daily throughout each cycle. The primary endpoint was the grade of cumulative PN at the end of eight cycles. The secondary endpoints included relative dose intensity (RDI) of oxaliplatin, recurrence-free survival (RFS), and overall survival (OS). 40 patients (n = 20 in both groups) completed 8 chemotherapy cycles. The incidence of grade 2 or greater cumulative PN at the 8th chemotherapy cycle was significantly lower in the NYT group (2/20, 10.0%) than in the control group (11/20, 55.0%, P

Scirrhous gastric cancer frequently develops into peritoneal carcinomatosis with malignant ascites, leading to an extremely poor prognosis. We had demonstrated that paracrine hepatocyte growth factor (HGF)-induced MET activation promotes peritoneal carcinomatosis with ascites formation. The vascular endothelial growth factor (VEGF) receptor (VEGFR)/VEGF axis facilitates tumor progression and formation of malignant ascites. This study investigated the role of MET and VEGFR2 in the development of peritoneal carcinomatosis with malignant ascites. Cabozantinib is a dual inhibitor of MET and VEGFR2. We examined the effects of cabozantinib on MET- and VEGFR2-mediated progression of peritoneal carcinomatosis in human scirrhous gastric cancer in vitro and in vivo. Cabozantinib inhibited HGF-stimulated proliferation of scirrhous cancer cell lines NUGC4 and GCIY, with a high potential to generate peritoneal carcinomatosis with ascites fluid, as well as the constitutive proliferation of MKN45 cells with MET amplification. Cabozantinib also inhibited the phosphorylation of both MET and VEGFR2 in scirrhous cancer cells and HGF- or VEGF-stimulated HUVECs. It effectively reduced ascitic fluid and prolonged the survival of NUGC4-inoculated nude mice. In clinical specimens, malignant ascites fluid from patients with peritoneal carcinomatosis contained high levels of HGF and VEGF. Our results strongly suggest that MET- and VEGFR2-mediated signaling pathways play pivotal roles in the pathogenesis of peritoneal carcinomatosis in scirrhous gastric cancer. Thus, the dual blockade of MET and VEGFR2 signaling may be a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer.

Objective To provide an evidence-based recommendation for the management of olfactory dysfunction in accordance with the consensus reached by the Subcommittee of the Japanese Clinical Practice Guideline for olfactory dysfunction in the Japanese Rhinologic Society. Methods Seven clinical questions (CQs) regarding the management of olfactory dysfunction were formulated by the subcommittee of the Japanese Clinical Practice Guideline for olfactory dysfunction. We searched the literature published between April 1990 and September 2014 using PubMed, the Cochrane Library, and Ichushi Web databases. The main search terms were “smell disorder,” “olfactory dysfunction,” “olfactory loss,” “olfactory disturbance,” “olfactory impairments,” “olfaction disorder,” “smell disorder,” “anosmia,” “cacosmia,” and “dysosmia.” Based on the results of the literature review and the expert opinion of the Subcommittee, 4 levels of recommendation, from A—strongly recommended to D—not recommended, were adopted for the management of olfactory dysfunction. Results Both oral and locally administered corticosteroids have been strongly recommended for patients with olfactory dysfunction due to chronic rhinosinusitis. Nasal steroid spray and antihistamine drugs have been moderately recommended for patients with allergic rhinitis. Although no drugs have been deemed to be truly effective for post-viral olfactory dysfunction by randomized-controlled trials (RCTs) or placebo-controlled trials, olfactory training using odorants has been reported to be effective for improving olfactory function. There is considerable evidence that olfactory testing is useful for differential diagnosis, prediction of disease progression, and early detection of cognitive decline in neurodegenerative diseases. Conclusion The Clinical Practice Guideline has developed recommendations for the management of various aspects of olfactory dysfunction.

Background. Ninjin’yoeito (NYT), a traditional Japanese (Kampo) medicine that originates from China, has been used to treat qi and blood deficiency based on its original concept. Kampo medicine has been widely used to treat many conditions and disorders combined with western medicine or Kampo medicine alone in modern situation. Aims. We reviewed randomized controlled trials (RCTs) of NYT and discussed various standpoints regarding its use in modern situation. Methods. We searched PubMed, Cochrane Library, and Evidence Reports of Kampo Treatment (EKAT) for articles written in English, and Ichushi, J-Stage, and EKAT for those written in Japanese. Articles published before January 1, 2019, were retrieved using the keywords “ninjinyoeito” and “ninjin’yoeito,” and RCTs were selected from these extracted articles. Result. Of 734 articles, 13 were RCTs, 46 were non-RCTs or studies of other designs, 15 were case reports, and 36 were experimental studies using NYT. NYT was evaluated for its use as a treatment for cancer and related conditions, refractory blood diseases and conditions, and otorhinolaryngologic symptom in 13 RCTs. Based on the use of Kampo medicine in modern situation called as Yasui’s classification, 10 of 13 RCTs were categorized as “the side effects of Western medicinal treatment are mitigated when combined with Kampo treatment” and the remaining 3 were categorized as “treatment effect of Kampo medicine is increased in combination with standard Western medicinal treatment.” Conclusion. Several studies demonstrated the efficacy of NYT in refractory diseases and other conditions, and the accompanied side effects of treatment with western medicine.

Background In Taiwan, numerous studies have been conducted to investigate the use of complementary and alternative medicine (CAM). However, most of them focused on specific diseases or the use of particular methods. Therefore, the results of those studies were quite different and difficult to compare with those of studies from other countries. The International CAM Questionnaire (I-CAM-Q), meanwhile, is a unified tool that can provide comparable results for studies conducted worldwide. Thus, the aim of this study was to discover the proportions of people in Taiwan receiving CAM treatments from different types of health care providers by using an adapted version of I-CAM-Q (I-CAM-QT). Methods I-CAM-QT was developed by translating the Korean version of I-CAM-Q (I-CAM-QK) into traditional Chinese language because of the similarity of CAM usage and doctor licensing system. This study had two stages: the first was a pretest survey used to adjust the questionnaire, while the second was an internet-based survey used to collect data from the community. Results Of the 1200 survey respondents, 37% and 37.7% were prescribed or advised to use Chinese herbal medicine (CHM) by Western medicine (WM) physicians and traditional Chinese medicine (TCM) doctors, respectively. Other than CHM, dietary supplements and massage were the forms of CAM most commonly prescribed or recommended by WM physicians or TCM doctors. Overall, walking and relaxation techniques were the most commonly used self-help practices (used by 61.9% and 40.4% of the respondents, respectively). Additionally, 70.3% of the respondents had used at least one kind of dietary supplement in the past 12 months. Conclusion Regarding the utilization of CAM in Taiwan, this internet-based survey revealed that CHM, dietary supplements, and massage were the types of CAM most commonly prescribed or recommended by WM physicians or TCM doctors.

Introduction Although there have been several national survey studies on complementary and alternative medicine (CAM) use in Japan, previous studies have not been compared with investigations conducted in other countries. An international CAM questionnaire known as I-CAM-Q was developed through a two-day international workshop in 2006. The purpose of this study was to investigate the use of CAM by the general Japanese population using a modified version of the I-CAM-Q for the Japanese (I-CAM-QJ). Methods We developed the I-CAM-QJ to conduct an internet survey of 3,208 participants from the general population of Japan in February 2016. The respondents included 1,592 males (49.6%), 1,348 university graduates (38.8%), 1,105 individuals in good health (34.4%), and 1,028 individuals with long-term illness or disability (32.0%). Results Of the 3,208 respondents, 411 participants reported CAM use during the past 12 months (12.8%). The following therapies and products were used: Kampo medicines (over-the-counter Kampo medicines: 15.7%; prescribed Kampo medicines: 15.4%), dietary supplements 11.8%, massage services 3.9%, and physical therapy 3.5%. Regarding the use of self-care methods during the last 12 months, the following methods and products were used: bath salts 25.8% and walking 25.3%. Conclusions An internet survey on CAM use by the general Japanese population with a modified I-CAM-Q (I-CAM-QJ) revealed that Kampo medicines and dietary supplements were the most commonly used CAMs in Japan.

Objective Although the use of complementary and alternative medicine (CAM) by the general population has been surveyed previously, the provision of CAM by Japanese physicians in private clinics has not been studied. Universal health insurance system was established in Japan in 1961, and most CAMs are not on the drug tariff. We aimed to clarify the current status of CAM provided by physicians at private clinics in Japan. Methods We conducted an internet survey on 400 directors/physicians of private clinics nationwide on the provision of CAM from February 6 to February 10, 2017. Survey items included attributes of subjects, presence/absence of sections or facilities for provision of CAM, proportions of health insurance coverage for medical practices, and source of information. Private clinic was defined as a clinic run by one physician, with less than 20 beds. Results Commonly provided CAMs were Kampo (traditional Japanese herbal) medicines (34.8%) and supplements/health foods (19.3%). CAMs on the drug tariff were provided in 46.5% of cases at the clinics, but only 16.5% of cases were provided CAMs which were not on the drug tariff, at different neighboring facilities. Among different specialties, Kampo medicines were prescribed at obstetrics/gynecology (54.0%), orthopedics (44.4%), and dermatology (43.0%). Clinics not providing any CAM accounted for 53.5%. With regard to health insurance coverage, 96.8% of the clinics provided only or mainly health services on the universal national health insurance tariff (29.8% and 67.0%, respectively). Conclusion Kampo medicines represent the most commonly used CAM in private clinics in Japan, and universal national health insurance coverage is considered to be the reason for the high rate of their use.

Background: The information site for evidence-based Japanese Integrative Medicine (eJIM) was launched by the Japanese Ministry of Health, Labour and Welfare to enable patients, medical staff, and others to obtain appropriate information, but it has not been objectively evaluated by users. The present study aimed to assess the usability of the eJIM website from the viewpoint of the general population. Methods: We held a focus group discussion with 12 persons in November 2016, conducted an Internet survey of 1107 people (general population) in February 2017, and assessed their understanding of basic concepts of complementary and alternative medicine and usefulness of the contents after browsing the eJIM website. Levels of functional, communicative, and critical health literacy were also assessed. Results: Most patients had never visited the eJIM website, because basic terms such as “integrative medicine” and “evidence” were not fully understood. Most overseas information in English was difficult to understand for the general Japanese population, although approximately 50% of the information was translated into Japanese. The degree of appropriate responses depended on health literacy level. Conclusion: The usability of eJIM website was low, because the currently available information did not meet the needs of the general population. Moreover, simpler expressions and visual tools would help the general population to understand the website contents more easily. A further survey that considers cultural and quantitative perspectives is warranted. Keywords: Complementary and alternative medicine, Health literacy, Japan, The information site for evidence-based Japanese Integrative Medicine (eJIM), Usability

Early detection of extravasation is important, but conventional methods of detection lack objectivity and reliability. This study evaluated the predictive validity of thermography for identifying extravasation during intravenous antineoplastic therapy. Of 257 patients who received chemotherapy through peripheral veins, extravasation was identified in 26. Thermography was performed every 15 to 30 minutes during the infusions. Sensitivity, specificity, positive predictive value, and negative predictive value using thermography were 84.6%, 94.8%, 64.7%, and 98.2%, respectively. This study showed that thermography offers an accurate prediction of extravasation.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases with no approved treatment. Zonarol, an extract from brown algae, has been proven to have anti-inflammatory and antioxidant effects. In this study, we investigated the role of zonarol in the progression of methionine- and choline-deficiency (MCD) diet-induced NAFLD in mice. After oral treatment with zonarol, a lighter body weight was observed in zonarol group (ZG) mice in comparison to control group (CG) mice. The NAFLD scores of ZG mice were lower than those of CG mice. Hepatic and serum lipid levels were also lower in ZG mice with the reduced expression of lipid metabolism-related factors. Furthermore, ZG mice showed less lipid deposition, less inflammatory cell infiltration and lower inflammatory cytokine levels in comparison to CG mice. Moreover, the numbers of 8-hydroxy-20-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic and serum thiobarbituric acid reactive substances (TBARS) were significantly lower in comparison to CG mice. The expression levels of nuclear factor erythroid 2 related factor 2 (Nrf2), as well as its upstream and downstream molecules, changed in ZG mice. Zonarol could prevent the progression of NAFLD by decreasing inflammatory responses, oxidative stress and improving lipid metabolism. Meanwhile the Nrf2 pathway may play an important role in these effects.

The application of systematic review (SR) has been increased rapidly in the field of cancer treatment. Complementary and alternative medicine (CAM) for cancer is no exception. The aim of this review is to evaluate and summarize systematic reviews on the CAM use in breast cancer patients. Search sources were Centre for Reviews and Dissemination (CRD), Cochrane Database of Systematic Reviews (CDSR), and PubMed. In addition, we assessed the quality of SR with the Assessing the Methodological Quality of Systematic Reviews (AMSTAR). This review did not consider control groups and outcomes. Thirty-four SRs met a set of criteria. According to interventions, there were twenty SRs which included yoga, acupuncture, and herbal medicines. Meta-analysis of 19 out of 34 reviews showed the followings: (1) acupuncture had a beneficial effect on the frequency of hot flushes, (2) yoga had a beneficial effect on depression and health-related QOL, (3) mindfulness-based stress reduction (MBSR) had a beneficial effect on anxiety and depression, (4) combination of herbal medicine and chemotherapy synergistically improved clinical outcomes, (5) acupuncture did not show significant effect on the severity of hot flushes and cancer-related pain, (6) yoga was unable to be confirmed as having an effect on cancer-related pain and physical well-being. Given the results of AMSTAR, 9 out of 34 reviews were of high quality and 3 reviews were deemed to be of low quality. In conclusion, since most SRs were at moderate or high quality levels, CAM could be helpful for treating specific symptoms related to breast cancer.