Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside.

Liver diseases impose a huge burden worldwide. Although hepatocyte transplantation has long been considered as a potential strategy for treating liver diseases, its clinical implementation has created some obvious limitations. As an alternative strategy, cell therapy, particularly mesenchymal stem cell (MSC) transplantation, is widely used in treating different liver diseases, including acute liver disease, acute-on-chronic liver failure, hepatitis B/C virus, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Here, we summarize the status of MSC transplantation in treating liver diseases, focusing on the therapeutic mechanisms, including differentiation into hepatocyte-like cells, immunomodulating function with a variety of immune cells, paracrine effects via the secretion of various cytokines and extracellular vesicles, and facilitation of homing and engraftment. Some improved perspectives and current challenges are also addressed. In summary, MSCs have great potential in the treatment of liver diseases based on their multi-faceted characteristics, and more accurate mechanisms and novel therapeutic strategies stemming from MSCs will facilitate clinical practice.

The Validity of Estimated Dietary Amino Acid and Protein Values via the Amino Acid Composition Table 2015.

The amino acid composition table (AACT) plays a pivotal role in examining the association between dietary amino acid intake and physical conditions. The updated version, AACT 2015, has been markedly expanded; however, most additions are not based on analytical values. The Food and Agriculture Organization (FAO) of the United Nations and the World Health Organization (WHO) recommend that protein contents be calculated as the sum of amino acid residues (PROTCAA). However, due to the lack of a validated AACT, protein content calculated as reference nitrogen multiplied by a nitrogen to protein conversion factor (PROTRN) is still commonly used. In this study, validity of the estimated dietary amino acid values via the AACT 2015 was examined by comparing differences between the estimated and analytical values, for 14 consecutive days' meals provided in an elder care facility. There were no major differences between the analytical and estimated values over the 14 d; however, noticeable daily differences sometimes emerged. These results indicate that the AACT 2015 may contain accidental errors, but allows the estimation of habitual amino acid intake. In the near future, PROTCAA will become the international standard. It will be necessary to convert PROTRN values to PROTCAA to refer to past reports and data; we have determined a correction factor (0.896) for this conversion.

The Influence of the Type of Continuous Exercise Stress Applied during Growth Periods on Bone Metabolism and Osteogenesis.

BACKGROUND: In this study, we examined the influence of exercise loading characteristics on bone metabolic responses and bone morphology in the growth phase and adulthood. METHODS: Running exercise (RUN) and jumping exercise (JUM) were used for the exercise loading in 28-day-old male Wistar rats. Bone metabolism was measured by blood osteocalcin (OC) and tartrate-resistant acid phosphatase (TRACP) levels. For bone morphology, the maximum bone length, bone weight, and bone strength of the femur and tibia were measured. RESULTS: A pre- and post-exercise loading comparison in the growth phase showed significantly increased OC levels in the RUN and JUM groups and significantly decreased TRACP levels in the JUM group. On the other hand, a pre- and post-exercise loading comparison in adulthood showed significantly decreased TRACP levels in the RUN and JUM groups. Femur lengths were significantly shorter in the RUN and JUM groups than in the control (CON) group, while bone weight was significantly greater in the JUM group than in the CON group. CONCLUSIONS: Exercise loading activates OC levels in the growth phase and suppresses TRACP levels in adulthood. On the other hand, these results suggest that excessive exercise loading may suppress bone length.

The feasibility and clinical effects of dendritic cell-based immunotherapy targeting synthesized peptides for recurrent ovarian cancer.

BACKGROUND: Despite the increased rate of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Dendritic cell (DC)-based immunotherapy has been developed as a novel strategy for generating antitumor immunity as part of cancer treatments. The present study aimed to assess the feasibility and clinical effects of DC therapy for recurrent ovarian cancer (ROC). METHODS: This retrospective study included 56 ROC patients who initially received standard chemotherapy followed by DC-based immunotherapy targeting synthesized peptides at 2 institutions between March 2007 and August 2013. The adverse events (AEs) and clinical responses were examined. RESULTS: No serious treatment-related AEs were observed. Seventy one percent of the enrolled patients developed an immunologic response. The median survival time (MST) from ROC diagnosis was 30.4 months, and that from the first vaccination was 14.5 months. Albumin levels of ≥4.0 g/dL and lactate dehydrogenase levels of <200 IU/L before vaccination were identified as significant independent factors by multivariate Cox proportional hazard analysis. The MST from the first vaccination in patients with albumin levels of ≥4.0 and <4.0 g/dL were 19.9 and 11.6 months, respectively. The corresponding disease control rates were 36% and 15%, respectively. CONCLUSIONS: Our results demonstrated the feasibility and potential clinical effectiveness of DC-based immunotherapy for ROC patients. Additionally, a good nutritional status might be an important factor for further clinical effects.

Comparison of hypofractionated and conventionally fractionated whole-breast irradiation for early breast cancer patients: a single-institute study of 1,098 patients.

PURPOSE: To evaluate the efficacy and safety of hypofractionated whole-breast irradiation (HF-WBI) compared with conventionally fractionated (CF) WBI. MATERIALS AND METHODS: Patients with early breast cancer (stages 0-II and <3 positive lymph nodes) who had undergone breast-conserving surgery were eligible for the HF-WBI study. HF-WBI was administered at 43.2 Gy in 16 fractions over 3.2 weeks to the whole breast with an additional tumor-bed boost of 8.1 Gy in 3 fractions over 3 days for positive surgical margins or those <5 mm. CF-WBI was administered at 50 Gy in 25 fractions over 5 weeks to the whole breast with an additional tumor-bed boost of 16 Gy in 8 fractions over 1.4 weeks to 6 Gy in 3 fractions over 3 days, depending on margin status. RESULTS: From April 1, 2006, to December 31, 2010, 717 patients were registered and 734 breasts were treated by HF-WBI. In the same period, 381 patients and 393 breasts who matched the study criteria chose CF-WBI, so the total number of patients in this comparison was 1,098. Grade 2 acute skin reactions were observed for 24 patients (3 %) in the HF-WBI group and 53 patients (14 %) in the CF-WBI (p < 0.001) group. The median follow-up period was 27 months. Two cases of intrabreast tumor recurrence were observed in each treatment group. Regional lymph node recurrence was observed in 1 HF-WBI patient and 2 CF-WBI patients. CONCLUSION: HF-WBI is superior to CF-WBI in terms of acute skin reaction and has the same short-term efficacy.

Radiotherapy with fraction size of 2.25 Gy in T1-2 laryngeal and hypopharyngeal cancer.

This study was carried out to evaluate the influence of fraction size 2.25 Gy on local control of T1 and T2 laryngeal and hypopharyngeal cancers. Between August 2002 and December 2010, 80 patients with T1 and T2 laryngeal or hypopharyngeal cancers were treated with definitive radiotherapy with a fraction size of 2.25 Gy. Primary sites were the larynx in 69 and the hypopharynx in 11. Fifty-three patients were T1 and 27 were T2. All patients' pathology was squamous cell carcinoma except one carcinosarcoma. Radiotherapy was delivered 5 days/week with a 4-MV photon beam up to a total dose of 63.0 Gy. Median treatment time was 41 days. Statistical analysis of survival was calculated using the Kaplan-Meier method. No acute toxicity greater than grade 2 (CTCAE ver. 3.0.) including mucositis and dermatitis was observed. All but one patient had a complete response. The partial response patient received salvage surgery. The median follow-up period was 47 months (ranging from 4 to 108 months). No late toxicity greater than 1 was observed. Nine patients developed recurrence, seven local and two neck lymph nodes. Three patients died, one from laryngeal cancer and two from intercurrent diseases. The 5-year local control rates (LCRs) in the entire group, larynx T1, larynx T2 and hypopharynx T1 were 85.8%, 97.6%, 70.1% and 85.7%, respectively. The LCRs of T1 improved compared with our historical control, but not those of T2. The 2.25-Gy fraction size is safe and may have the potential to achieve good LCR in T1 lesions.

The role of chemoradiotherapy in patients with unresectable T4 breast tumors.

PURPOSE: Unresectable T4 tumors of the breast are usually treated with systemic therapies, while the role of local therapies remains debatable. This study aims to evaluate the effectiveness of chemoradiotherapy as a part of T4 breast cancer treatment, and to assess the role of local radiotherapies in patients with unresectable T4 breast tumors. MATERIALS/METHODS: Between February 1998 and June 2010, 39 unresectable T4 breast tumors were treated with chemoradiotherapy at our institutes. Clinical stages included stage IIIB (n = 15), stage IIIC (n = 3), and stage IV (n = 21). Twenty-one cases had undergone previous systemic therapies, whereas the remaining 18 cases reported no history of previous treatment. Radiation doses of 59-66 Gy (median 60 Gy) were administered to the breast in addition to concurrent chemotherapies. Acute adverse effects were assessed on a weekly basis during treatment to 2 weeks after completion of treatment, and were scored by the Common Terminology Criteria for Adverse Events v3.0. Treatment response was assessed at 1 month after completion of chemoradiotherapy. Statistical analysis of survival was calculated using the Kaplan-Meier method. RESULTS: Chemoradiotherapy was completed in all cases. Greater than grade 3 hematological toxicities were observed with regard to lymphocytes (33%), platelets (8%), neutrophils (3%), and hemoglobin (3%). Greater than grade 3 nonhematologic toxicities included chemoradiation dermatitis (23%) and pneumonitis (5%). Sixteen T4 tumors (41%) achieved complete response, whereas 23 (59%) achieved partial response. All patients were treated with chemotherapy and/or endocrine therapy following chemoradiotherapy. The median follow-up period was 20 months (range 3-96 months). Nineteen patients died because of progressive breast cancer. Infield recurrence or relapse was observed in 11 cases during the course of treatment, but only 3 cases were symptomatic. The 2-year overall local control rate was 73.6%, and the survival rate was 65.9%. CONCLUSION: Chemoradiotherapy represents a viable option for local treatment of unresectable T4 breast tumors.

Hyperfractionated radiotherapy with concurrent docetaxel for advanced head and neck cancer: a phase II study.

AIM: To evaluate the value of hyperfractionated radiotherapy with concurrent use of low-dose docetaxel in locally-advanced head and neck squamous cell cancer (HNSCC). PATIENTS AND METHODS: Patients eligible for this study had confirmed diagnosis of HNSCC stages II (>10 cm(3)) to IVB. Radiotherapy was delivered twice daily at 1.2 Gy/fraction to a total dose of 72.0 Gy. Docetaxel (10 mg/m(2)) was administered weekly during radiotherapy. RESULTS: From March 2003 to October 2008, 70 patients were treated. Primary sites included the oropharynx (n=25), hypopharynx (n=24), larynx (n=18), and other sites (n=3). Major grade 3 acute toxicities included mucositis (n=43) and treatment-related pain (n=20). The median follow-up period for surviving patients was 43 months. The 5-year local control rate and overall survival rate were 62.6% and 61.6%, respectively. CONCLUSION: This modality is a valuable treatment option for the management of locally-advanced HNSCC.

Estimation of anxiety and depression in patients with early stage breast cancer before and after radiation therapy.

BACKGROUND: Most previous studies about anxiety and depression in patients undergoing radiotherapy have only measured the quantity of general depression and anxiety and have not studied specific periods of involvement. The aim of this study was to assess anxiety and depression among early breast cancer patients, and the anxiety experienced immediately before and after radiotherapy. METHODS: Women who started radiotherapy for stage I or II breast cancer (n = 172) were asked to answer two questionnaires: the Hospital Anxiety and Depression Scale (HADS) and Radiotherapy Categorical Anxiety Scale immediately before and after radiation therapy. RESULTS: The results showed that the mean scores of anxiety and depression (HADS and Radiotherapy Categorical Anxiety Scale) decreased after radiotherapy. The mean score of depression (HAD-D) in the group receiving conventional radiotherapy was higher than in those receiving hypofractionated radiotherapy before and after radiotherapy. The mean scores of anxiety and depression (HADS) in the endocrine therapy group were lower than in the group without endocrine therapy before treatment. However, the scores after treatment of both groups were not significant. CONCLUSION: Some intervention may be needed to decrease the temporary anxiety and depression raised during radiotherapy for early stage breast cancer patients. This is especially so for patients who do not receive concurrent endocrine therapy and choose the conventional radiotherapy course.

Full-dose capecitabine with local radiotherapy: one of the treatment options for inoperable T4 breast cancer.

A 48-year-old woman presented with a 15-cm diameter tumor in her left breast with fixation to the chest wall and palpable axillary lymph nodes. Pathology study showed pure-type mucinous carcinoma. Pretreatment staging investigations showed multiple lung metastases, which resulted in the diagnosis of T4N2M1 breast cancer. Four cycles of cyclophosphamide 700 mg/m(2)/epirubicin 70 mg/m(2) (CE) were performed initially, but the tumors decreased only within the treatment response criteria of stable disease (SD). The second regimen of docetaxel could not continue due to drug allergy. Two more cycles of CE did not improve the situation. Then, treatment was continued with full-dose capecitabine with local radiotherapy. She received radiotherapy to the left breast and axillary region with 60 Gy/30 fractions/6 weeks and concomitant capecitabine 2400 mg/body twice daily for 21 days; the cycles were repeated every 28 days. After radiotherapy, tumors decreased in size, and the skin ulceration disappeared. She continued to receive capecitabine on the same schedule. She now has no palpable tumor in her left breast and no tumor in the axilla or lung on CT. She is alive and well 6 years after radiotherapy.

An investigation of anxiety about radiotherapy deploying the Radiotherapy Categorical Anxiety Scale.

BACKGROUND: Radiotherapy is one of the major methods for treating cancer, but many patients undergoing radiotherapy have deep concerns about receiving radiation treatment. This problem is not generally appreciated and has not been adequately studied. METHODS: The objective of this investigation was to empirically investigate the anxieties that cancer patients feel towards radiotherapy by using questionnaires to classify and quantitatively measure their concerns. A preliminary interview to develop a questionnaire was carried out with 48 patients receiving radiotherapy to discover their anxieties about on-going treatments. Subsequently, a main study was performed using a questionnaire with 185 patients to classify their types of anxiety and to ascertain the reliability and validity of the responses. Confirmatory factor analysis was then carried out with a 17-item Radiotherapy Categorical Anxiety Scale. RESULTS: Three anxiety factors were abstracted by factor analysis: (1) adverse effects of radiotherapy, (2) environment of radiotherapy, and (3) treatment effects of radiotherapy. Reliability, content validity, and concurrent validity were obtained. The adequacy of the three-factor model of anxiety concerning radiotherapy was confirmed. CONCLUSION: A 17-item Radiotherapy Categorical Anxiety Scale was formulated to quantitatively measure the specific types of anxiety among cancer patients receiving radiotherapy.

Alleviative effects of quercetin and onion on male reproductive toxicity induced by diesel exhaust particles.

Diesel exhaust particles (DEPs) are particulate matter from diesel exhaust that contain many toxic compounds, such as polyaromatic hydrocarbons (PAHs). Some toxicities of PAH are thought to be expressed via aryl hydrocarbon receptors (AhRs). The male reproductive toxicity of DEPs might depend on AhR activation induced by PAHs. We hypothesized that AhR antagonists protect against the male reproductive toxicity of DEPs. Quercetin is a flavonoid and a well-known AhR antagonist, while onion contains many flavonoids, including quercetin. Hence, we examined whether quercetin and onion have alleviative effects against the male reproductive toxicity induced by DEPs. BALB/c male mice were fed quercetin- or onion-containing diets and received 10 injections of DEP suspension or vehicle into the dorsal subcutaneous layer over 5 weeks. The mice were euthanized at 2 weeks, after the last treatment, and their organs were collected. Daily sperm production and total incidence of sperm abnormalities were significantly affected in the DEP groups as compared with the vehicle group, but the total incidence of sperm abnormalities in the quercetin + DEP-treated mice was significantly reduced as compared with the DEP-treated mice. The numbers of Sertoli cells were significantly decreased in DEP-treated mice as compared with the vehicle-treated mice, but, the numbers of Sertoli cells were significantly increased in the quercetin and the onion + DEP-treated mice as compared with the DEP-treated mice. These results clearly indicate alleviative effects of quercetin and onion against the male reproductive toxicity induced by DEP.

Effects of diesel exhaust particles on the male reproductive system in strains of mice with different aryl hydrocarbon receptor responsiveness.

Diesel exhaust particles (DEPs) contain polycyclic aromatic hydrocarbons (PAH) that bind to aryl hydrocarbon receptors (AhRs) and decrease sperm production. Since it is not clear if AhR mediates DEP toxicity, we investigated the effect of DEPs in four strains of mice that have different AhR responsiveness. We treated BALB/c, C57BL/6, ICR and DBA/2 mice with DEP suspensions and compared their toxicity in each strain. In both the vehicle- and DEP-treated groups, ethoxyresorufin-O-deethylase (EROD) activity, as an indirect index of AhR activity, was increased in the order of BALB/c > C57BL/6 > ICR > DBA/2. Only BALB/c and C57BL/6 mice had significantly lower daily sperm production (DSP) than vehicle-treated mice. All strains exhibited increased sperm abnormalities. In particular, the C57BL/6, ICR and DBA/2 mice exhibited significantly increased abnormalities. A significant correlation was found between EROD activity and DSP or incidence of morphologically abnormal sperm. These data suggest that DEP toxicity may affect the male reproductive system in an AhR-dependent manner.

Inhibitory effects of foods and polyphenols on activation of aryl hydrocarbon receptor induced by diesel exhaust particles.

The toxicity of endocrine disrupters is involved in the activation of the aryl hydrocarbon receptor (AhR). We examined the toxicity of diesel exhaust particles (DEPs) using the Ah immunoassay (Ah-I) to study the inhibitory effects of various foods and polyphenols on DEP-induced AhR activation. The toxicity equivalent of DEP was 6,479 +/-58 ng dioxin toxicity equivalent/g (DEQ/g). The relationship between DEP dose and AhR activation was linear up to 27.8 microg/ml. Ginkgo biloba extract (GBE) had the strongest inhibitory effect on DEP-induced AhR activation. Quercetin, a major polyphenol in onions, and GBE showed a strong inhibitory effect. These results show that the DEP-induced AhR activation can be assessed using Ah-I and that the assay is suitable for determining the dioxin toxicity equivalent of DEP. In addition, Ah-I is also effective for screening food and its components that inhibit DEP-induced AhR activation.

Diesel exhaust particle toxicity on spermatogenesis in the mouse is aryl hydrocarbon receptor dependent.

Diesel exhaust particles (DEPs) are particulate matter from diesel exhaust containing many toxic compounds, such as polyaromatic hydrocarbons (PAHs). Some toxicities of PAH are considered to express via aryl hydrocarbon receptor (AhR). We hypothesized that the male reproductive toxicity of DEPs may depend on PAHs. BALB/c male mice received 24.7, 74.0 or 220 microg/mouse DEP suspension or vehicle injected into the dorsal subcutaneous layer 10 times during 5 weeks. The mice were euthanized, and blood and organs were collected 2 weeks after the last treatment. The epididymis weights, relative epididymis weights per body weight and daily sperm productions and viabilities of the 74.0 and 220 microg/mouse DEP-treated groups decreased significantly compared with those of the vehicle group. The total incidence of sperm abnormalities in the 74.0 and 220 microg/mouse DEP-treated groups increased significantly compared with the vehicle group. The seminiferous epithelium area ratios of the 74.0 and 220 microg/mouse DEP-treated groups were significantly higher compared with the vehicle and 24.6 microg/mouse DEP-treated groups. The ratios of seminiferous tubules with elongated-type spermatids in the 74.0 and 220 microg/mouse DEP-treated groups were significantly decreased compared with the vehicle group. The testosterone level and hepatic ethoxyresorufin-O-deethylase (EROD) activity as an indirect index of AhR activity in the 74.0 microg/mouse DEP-treated group were significantly increased compared with those of the vehicle group. These results clearly demonstrated that DEPs suppress testicular function, especially spermatogenesis and sperm motility. These effects may be AhR dependent.

[The role of radiotherapy in breast cancer].

Radiotherapy has been widely used in breast cancer in many situations. These are breast irradiation of breast conserving therapy,post mastectomy regional irradiation,irradiation for regional lymph nodes recurrence,breast irradiation of inoperable locally advanced cases,palliative irradiation of brain metastasis,bone metastasis and so on. The relationship among radiotherapy,surgery and systemic therapy has to be considered in those situations. In breast conserving therapy, the usefulness of breast irradiation is well established. Otherwise, a local controllability depend on a grade of residual tumor cell has not been understand. The authors conducted the survey of 941 cases of positive surgical margins and found that doses more than 60 Gy has a tendency for better local control in post menopausal cases. To reduce patient's burden,3 weeks short course irradiation (Canadian protocol) or accelerated partial breast irradiation have been introduced in breast irradiation. A subgroup which has no need to irradiate to conserving breast had not been identified. The timing between postoperative chemotherapy and irradiation is another point that has to be considered. To reduce distant metastasis,chemotherapy first has been considered better. As for post mastectomy regional irradiation, improvement of local and systemic control has been widely known these days. A timing of systemic therapy and irradiation is a point has to consider. In inoperable or far advanced T 4 tumors, breast irradiation with concurrent chemotherapy must be considered in stead of surgery. We have to know a big shortage in Japanese cancer treatment situation that we have few radiation oncologists or medical physicists in Japan. We have to educate those specialists to catch up with increasing cancer patients.