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1.  Radical nephrectomy and regional lymph node dissection for locally advanced type 2 papillary renal cell carcinoma in an at-risk individual from a family with hereditary leiomyomatosis and renal cell cancer: a case report 
BMC Cancer  2016;16:232.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant tumor susceptibility syndrome, and the disease-related gene has been identified as fumarate hydratase (fumarase, FH). HLRCC-associated kidney cancer is an aggressive tumor characterized by early metastasis to regional lymph nodes and distant organs. Since early diagnosis and provision of definitive therapy is thought to be the best way to reduce the tumor burden, it is widely accepted that germline testing and active surveillance for an at-risk individual from a family with HLRCC is very important. However, it still remains controversial how we should treat HLRCC-associated kidney cancer. We successfully treated the patient with locally advanced HLRCC-associated kidney cancer, who has received active surveillance because of at-risk individual, by radical nephrectomy and extended retroperitoneal lymph node dissection, and examined surgically resected samples from a molecular point of view.
Case presentation
We recommended that 13 at-risk individuals from a family with HLRCC should receive active surveillance for early detection of renal cancer. A 48-year-old woman with a left renal tumor and involvement of multiple regional lymph nodes with high accumulation of fluorine-18-deoxyglucose on positron emission tomography was treated with axitinib as a neoadjuvant therapy. Preoperative axitinib induced the shrinkage of the tumor with decreased fluorine-18-deoxyglucose accumulation. Resected samples showed two thirds tumor tissue necrosis as well as high expression of serine/threonine kinase Akt and low expression of nuclear factor E2-related factor 2 (Nrf2) which activates anti-oxidant response and protects against oxidative stress in viable cancer cells. Targeted next-generation sequencing revealed that FH mutation and loss of the second allele were completely identical between blood and tumor samples, suggesting that FH mutation plays a direct role in FH-deficient RCC. She has remained well after radical operation for over 33 months.
FH mutation plays a role in tumorigenic feature, a metabolic shift to aerobic glycolysis, and increased an anti-oxidant response phenotype in HLRCC-associated kidney cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2272-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4794818  PMID: 26983443
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC); Type 2 papillary renal cell carcinoma; Axitinib; Fumarate hydratase (FH); Targeted next-generation sequencing
2.  Predictive value of skin invasion in recurrent head and neck cancer patients treated by hypofractionated stereotactic re-irradiation using a cyberknife 
This study aimed to elucidate the influence of skin invasion in patients with recurrent head and neck cancer treated with re-irradiation using stereotactic radiotherapy.
We reviewed 104 patients treated using CyberKnife in four institutions.
Nine cases of skin invasion were recognized (8.6 %). Larger tumors tended to exhibit skin invasion. The skin invasion (+) group showed a lower response rate (0/9, 0 %) than the skin invasion (−) group (56/95, 59 %) (p = 0.002). The skin invasion (+) group showed lower local control (LC) and progression free survival (PFS) rates, both 0 % at 6 months, than the skin invasion (−) group, which had a LC of 69 % (p = 0.0001) and a PFS of 48 % at 1 year (p = 0.0157). Median survival time and one-year survival rates for the skin invasion (+) and (−) groups were 6.6 vs. 15.3 months and 14 % vs. 59 % (p = 0.0005), respectively. No patient with skin invasion survived more than 14.4 months. The percentage of patients who developed grade 3 or higher toxicity was 44 % in the skin invasion (+) group and 18 % in the skin invasion (−) group (p = 0.14).
Skin invasion is an important predictor of poor prognosis in recurrent head and neck cancer after re-irradiation with stereotactic radiation therapy.
PMCID: PMC4608108  PMID: 26471020
Head Neck cancer; Reirradiation; Stereotactic radiotherapy; CyberKnife; Skin invasion
3.  A second-generation Bacillus cell factory for rare inositol production 
Bioengineered  2014;5(5):331-334.
Some rare inositol stereoisomers are known to exert specific health-promoting effects, including scyllo-inositol (SI), which is a promising therapeutic agent for Alzheimer disease. We recently reported a Bacillus subtilis cell factory that performed the efficient production of SI from the cheapest and most abundant isomer myo-inositol (MI). In the cell factory all “useless” genes involved in MI and SI metabolism were deleted and overexpression of the key enzymes, IolG and IolW, was appended. It converted 10 g/L MI into the same amount of SI in 48 h of cultivation. In this addendum, we discuss further improvement in the cell factory and its possible applications.
PMCID: PMC4156495  PMID: 25482235
Bacillus subtilis; scyllo-inositol; myo-inositol; bioconversion; Alzheimer disease
4.  Pulmonary Macrophages Attenuate Hypoxic Pulmonary Vasoconstriction via β3AR/iNOS Pathway in Rats Exposed to Chronic Intermittent Hypoxia 
PLoS ONE  2015;10(7):e0131923.
Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central β1-adrenergic receptors (AR) (brain) and peripheral β2AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate β3AR. However, the relationship between IH and β3AR in the modification of HPV is unknown. It has been observed that chronic stimulation of β3AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates β3AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4–21% O2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of pro-inflammatory pulmonary macrophages. In these macrophages, both β3AR and iNOS were upregulated and stimulation of the β3AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of β3AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β3AR/iNOS signaling in chronic IH.
PMCID: PMC4489089  PMID: 26132492
5.  Role of vaginal pallor reaction in predicting late vaginal stenosis after high-dose-rate brachytherapy in treatment-naive patients with cervical cancer 
Journal of Gynecologic Oncology  2015;26(3):179-184.
To assess actual rates of late vaginal stenosis and identify predisposing factors for complications among patients with previously untreated cervical cancer following high-dose-rate brachytherapy.
We performed longitudinal analyses of 57 patients using the modified Dische score at 6, 12, 18, 24, 36, and 60 months after treatment, which consisted of 15 interstitial brachytherapys and 42 conventional intracavitary brachytherapys, with a median follow-up time of 36 months (range, 6 to 144 months).
More than half of the patients developed grade 1 (mild) vaginal stenosis within the first year of follow-up, and grade 2 (97.5%, moderate) to grade 3 (severe) stenosis gradually increased with time. Actual stenosis rates for grade 1, 2, and 3 were 97.5% (95% confidence interval [CI], 92.7 to 97.5), 60.7% (95% CI, 42.2 to 79.3), and 7.4% (95% CI, 0 to 18.4) at 3 years after treatment. Pallor reaction grade 2-3 at 6 months was only a statistically significant predisposing factor for grade 2-3 late vaginal stenosis 3 years or later with a hazard ratio of 3.48 (95% CI, 1.32 to 9.19; p=0.018) by a multivariate Cox proportional hazard model. Patients with grade 0-1 pallor reaction at 6 months showed a grade ≥2 vaginal stenosis rate of 53%, whereas the grade 2-3 pallor reaction group achieved a grade ≥2 vaginal stenosis rate at 3 years at 100% (p=0.001).
High-dose-rate brachytherapy was associated with high incidence of late vaginal stenosis. Pallor reaction grade 2-3 at 6 months was predictive of late grade 2-3 vaginal stenosis at 3 years after treatment. These findings should prove helpful for patient counseling and preventive intervention.
PMCID: PMC4510333  PMID: 25925294
Brachytherapy; Constriction, Pathologic; Pallor; Prospective Studies; Uterine Cervical Neoplasms
6.  A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using interstitial brachytherapy: treatment planning and quality assurance 
In Japan, breast-conserving surgery with closed cavity has generally been performed for breast cancer patients, and accelerated partial breast irradiation (APBI) is considered difficult because Asian females generally have smaller breast sizes than Western females. Therefore, common identification of target and treatment plan method in APBI is required. A prospective multicenter study was conducted in Japan to determine institutional compliance with APBI using high-dose-rate interstitial brachytherapy (ISBT) designed for Japanese female patients.
For this study, 46 patients were recruited at eight institutions from January 2009 to December 2011. The reproducibility of the ISBT–APBI plan was evaluated using three criteria: (1) minimum clinical target volume dose with a clip dose ≥ 6 Gy/fraction, (2) irradiated volume constraint of 40-150 cm3, and (3) uniformity of dose distribution, expressed as the dose non-uniformity ratio (DNR, V150/V100) < 0.35. The ISBT–APBI plan for each patient was considered reproducible when all three criteria were met. When the number of non-reproducible patients was ≤ 4 at study completion, APBI at this institution was considered statistically reproducible.
Half of the patients (52 %) had a small bra size (A/B cup). The mean values of the dose-constrained parameters were as follows: Vref, 117 cm3 (range, 40-282), DNR, 0.30 (range, 0.22-0.51), and clip dose, 784 cGy (range, 469-3146). A total of 43/46 treatment plans were judged to be compliant and ISBT–APBI was concluded to be reproducible.
This study showed that multi-institutional ISBT–APBI treatment plan was reproducible for small breast patient with closed cavity.
PMCID: PMC4461989  PMID: 26040632
APBI; HDR; Brachytherapy
7.  Signet ring cell carcinoma of the ampulla of vater: Report of a case and a review of the literature 
•Signet ring cell carcinoma in the ampulla of vater is extremely uncommon.•Investigation to confirm the histological origin of signet ring cell carcinoma by immunohistochemical staining might inform the treatment strategy and identify patients with ampullary signet ring cell carcinoma who may have a good prognosis.
Signet ring cell carcinoma (SRCC) of the ampulla of vater is a very rare tumor that is reported infrequently in the literature.
Presentation of case
A 59-year-old woman visited our hospital for evaluation of elevated transaminase levels. On laboratory examination of tumor marker levels, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19–9 levels were normal, and DUPAN-2 was elevated. Computed tomography (CT) confirmed a 2 cm, enhanced mass in the periampullary region, with marked common bile duct dilatation. Endoscopic retrograde cholangiopancreatography (ERCP) showed a swollen papilla of vater, with a reddish, erosive mucosa. Histological examination of biopsy samples from the ampulla of vater showed signet ring cell carcinoma (SRCC). The patient underwent radical pancreatoduodenectomy. Pathological examination showed that the SRCC had infiltrated into the duodenal muscularis propria and pancreatic parenchyma, and lymph node metastases were identified around the abdominal aorta and common hepatic artery. Based on the immunohistochemical staining patterns of the positive results for CDX2 and MUC2, the tumor cells in the present case appeared to have an intestinal type origin. The ampullary cancer was diagnosed as T3bN1M1, Stage IV according to the International Union Against Cancer TNM classification (UICC). After undergoing adjuvant chemotherapy with cisplatin–gemcitabine chemotherapy for 6 months, the patient has remained disease-free in the 7 months since surgery.
SRCC of intestinal-type origin is associated with a favorable outcome.
Investigation to confirm the histological origin of SRCC by immunohistochemical staining might inform the treatment strategy and identify patients with ampullary SRCC who may have a good prognosis.
PMCID: PMC4486405  PMID: 26057354
SRCC, signet ring cell carcinoma; PD, pancreatoduodenectomy; PPPD, pylorus-preserving pancreatoduodenectomy; Ampulla of vater; Signet ring cell carcinoma; Pancreatoduodenectomy
8.  Clinically significant association between the maximum standardized uptake value on 18F-FDG PET and expression of phosphorylated Akt and S6 kinase for prediction of the biological characteristics of renal cell cancer 
BMC Cancer  2015;15:114.
The relationship between the clinicopathological features and molecular changes associated with standardized uptake value (SUV) determined by Positron emission tomography (PET) with [18F] fluorodeoxyglucose (18F-FDG PET) in human renal cell carcinoma (RCC) has not been elucidated. On the other hand, overactivation of the phosphatidylinositol 3’kinase (PI3K), serine/threonine kinase Akt, and mammalian target of rapamycin (mTOR) pathway has been detected in a variety of human cancers, including RCC. So far, little is known about the relationship between the SUV and these proteins in human RCC. Thus, it is important to study the relevance of SUV with clinicopathological features in human RCCs from a molecular point of view.
Seventy-seven consecutive patients with RCC who underwent nephrectomy and pretreatment determination of the maximum SUV (SUVmax) by 18F-FDG PET were analyzed. We investigated the relationship between the SUVmax, phosphorylated-Akt (Ser-473) (pAkt(Ser-473)), phosphorylated-Akt (Thr-308) (pAkt(Thr-308), and phosphorylated-S6 ribosomal protein (Ser-235/236) (pS6) protein levels in the primary tumor and various clinicopathological features.
The average SUVmax of the primary tumor was 6.9 (1.5 to 40.3). A higher SUVmax was correlated with higher expression of pAkt(Ser-473), pAkt (Thr-308), and pS6 protein in the primary tumor. A higher SUVmax and increased expression of pAkt (Ser-473), pAkt (Thr-308), and pS6 of the primary tumor was associated with less tumor differentiation, a higher pT stage, regional lymph node involvement, microscopic vascular invasion, and distant metastasis, as well as with early relapse following radical nephrectomy in patients who had localized or locally advanced RCC without distant metastasis (cTanyNanyM0) and with shorter overall survival in all patients.
A higher SUVmax on 18F-FDG PET is associated with elevated tumor levels of pAkt and pS6 protein and with aggressive behavior and metastatic potential of RCC, as well as with early relapse following radical nephrectomy and shorter overall survival. These findings suggest that SUVmax may be useful for predicting the biological characteristics of RCC.
PMCID: PMC4357069  PMID: 25784113
Renal cell carcinoma (RCC); Positron emission tomography (PET); [18F]fluorodeoxyglucose (18F-FDG); Maximum standardized uptake value (SUVmax); Akt; S6 ribosomal protein
9.  Hyperphosphorylation of DegU cancels CcpA-dependent catabolite repression of rocG in Bacillus subtilis 
BMC Microbiology  2015;15:43.
The two-component regulatory system, involving the histidine sensor kinase DegS and response regulator DegU, plays an important role to control various cell processes in the transition phase of Bacillus subtilis. The degU32 allele in strain 1A95 is characterized by the accumulation of phosphorylated form of DegU (DegU-P).
Growing 1A95 cells elevated the pH of soytone-based medium more than the parental strain 168 after the onset of the transition phase. The rocG gene encodes a catabolic glutamate dehydrogenase that catalyzes one of the main ammonia-releasing reactions. Inactivation of rocG abolished 1A95-mediated increases in the pH of growth media. Thus, transcription of the rocG locus was examined, and a novel 3.7-kb transcript covering sivA, rocG, and rocA was found in 1A95 but not 168 cells. Increased intracellular fructose 1,6-bisphosphate (FBP) levels are known to activate the HPr kinase HPrK, and to induce formation of the P-Ser-HPr/CcpA complex, which binds to catabolite responsive elements (cre) and exerts CcpA-dependent catabolite repression. A putative cre found within the intergenic region between sivA and rocG, and inactivation of ccpA led to creation of the 3.7-kb transcript in 168 cells. Analyses of intermediates in central carbon metabolism revealed that intracellular FBP levels were lowered earlier in 1A95 than in 168 cells. A genome wide transcriptome analysis comparing 1A95 and 168 cells suggested similar events occurring in other catabolite repressive loci involving induction of lctE encoding lactate dehydrogenase.
Under physiological conditions the 3.7-kb rocG transcript may be tightly controlled by a roadblock mechanism involving P-Ser-HPr/CcpA in 168 cells, while in 1A95 cells abolished repression of the 3.7-kb transcript. Accumulation of DegU-P in 1A95 affects central carbon metabolism involving lctE enhanced by unknown mechanisms, downregulates FBP levels earlier, and inactivates HPrK to allow the 3.7-kb transcription, and thus similar events may occur in other catabolite repressive loci.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-015-0373-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4348106  PMID: 25880922
Bacillus subtilis; Two-component regulatory system; Catabolite repression; Transcription; Metabolites
10.  Definitive radiotherapy for primary vaginal cancer: correlation between treatment patterns and recurrence rate 
Journal of Radiation Research  2015;56(2):346-353.
The purpose of this study was to determine the outcomes and optimal practice patterns of definitive radiotherapy for primary vaginal cancer. Between 1993 and 2012, 49 patients were treated with definitive radiotherapy for primary vaginal cancer in three hospitals. Of these, 15 patients (31%) had clinically positive regional lymph node metastasis. A total of 34 patients (70%) received external beam radiotherapy with high-dose-rate brachytherapy (interstitial or intracavitary), and 8 (16%) (with small superficial Stage I tumors) were treated with local radiotherapy. The median follow-up was 33 months (range: 1–169 months). The 3-year overall survival (OS), disease-free survival (DFS), and loco-regional control (LRC) rates were 83%, 59% and 71%, respectively. In multivariate analysis, the histological type (P = 0.044) was significant risk factors for LRC. In Federation of Gynecology and Obstetrics (FIGO) Stage I cases, 3 of 8 patients (38%) who did not undergo prophylactic lymph node irradiation had lymph node recurrence, compared with 2 of 12 patients (17%) who underwent prophylactic pelvic irradiation. For Stage III–IV tumors, the local recurrence rate was 50% and the lymph node recurrence rate was 40%. Patients with FIGO Stage I/II or clinical Stage N1 had a higher recurrence rate with treatment using a single modality compared with the recurrence rate using combined modalities. In conclusion, our treatment outcomes for vaginal cancer were acceptable, but external beam radiotherapy with brachytherapy (interstitial or intracavitary) was needed regardless of FIGO stage. Improvement of treatment outcomes in cases of FIGO Stage III or IV remains a significant challenge.
PMCID: PMC4380060  PMID: 25614068
high-dose-rate brachytherapy; prophylactic pelvic irradiation; radiotherapy; vaginal cancer
11.  Multiple hepatic sclerosing hemangioma mimicking metastatic liver tumor successfully treated by laparoscopic surgery: Report of a case 
•Sclerosing hemangioma should be included among the differential diagnoses of multiple liver tumors in patients with colorectal cancer.•Laparoscopic hepatectomy is useful for diagnostic therapy for undiagnosed multiple liver tumors.•This report is the first to describe multiple hepatic sclerosing hemangiomas treated by laparoscopic surgery.
Hepatic sclerosing hemangioma is a very rare benign tumor, characterized by fibrosis and hyalinization occurring in association with degeneration of a hepatic cavernous hemangioma. We report here a rare case of multiple hepatic sclerosing hemangioma mimicking metastatic liver tumor that was successfully treated using laparoscopic surgery.
Presentation of case
A 67-year-old woman with multiple liver tumors underwent single-incision laparoscopic sigmoidectomy under a diagnosis of advanced sigmoid cancer with multiple liver metastases. Examination of surgical specimens of sigmoid colon revealed moderately differentiated adenocarcinoma invading the serosa, and no lymph node metastases. Serum levels of carcinoembryonic antigen and carbohydrate antigen 19-9 remained within normal limits throughout the course. Two months after sigmoidectomy, the patient underwent laparoscopic partial hepatectomy of S1 and S6 of the liver and cholecystectomy. Histopathological examination showed that the tumors mainly comprised hyalinized tissue and collagen fibers with sporadic vascular spaces on hematoxylin and eosin-stained sections, yielding a diagnosis of multiple hepatic sclerosing hemangioma. No evidence of recurrence has been seen as of 21 months postoperatively.
Differentiating multiple sclerosing hemangiomas from metastatic liver tumors was quite difficult because the radiological findings were closely compatible with liver metastases. Laroscopic hepatectomy provided less blood loss, a shorter duration of hospitalization, and good cosmetic results.
Sclerosing hemangioma should be included among the differential diagnoses of multiple liver tumors in patients with colorectal cancer. Laparoscopic hepatectomy is useful for diagnostic therapy for undiagnosed multiple liver tumors.
PMCID: PMC4353964  PMID: 25679307
Hepatic sclerosing hemangioma; Laparoscopic liver resection; Metastatic liver tumor
12.  β2-Adrenergic Receptor-Dependent Attenuation of Hypoxic Pulmonary Vasoconstriction Prevents Progression of Pulmonary Arterial Hypertension in Intermittent Hypoxic Rats 
PLoS ONE  2014;9(10):e110693.
In sleep apnea syndrome (SAS), intermittent hypoxia (IH) induces repeated episodes of hypoxic pulmonary vasoconstriction (HPV) during sleep, which presumably contribute to pulmonary arterial hypertension (PAH). However, the prevalence of PAH was low and severity is mostly mild in SAS patients, and mild or no right ventricular hypertrophy (RVH) was reported in IH-exposed animals. The question then arises as to why PAH is not a universal finding in SAS if repeated hypoxia of sufficient duration causes cycling HPV. In the present study, rats underwent IH at a rate of 3 min cycles of 4–21% O2 for 8 h/d for 6w. Assessment of diameter changes in small pulmonary arteries in response to acute hypoxia and drugs were performed using synchrotron radiation microangiography on anesthetized rats. In IH-rats, neither PAH nor RVH was observed and HPV was strongly reversed. Nadolol (a hydrophilic β1, 2-blocker) augmented the attenuated HPV to almost the same level as that in N-rats, but atenolol (a hydrophilic β1-blocker) had no effect on the HPV in IH. These β-blockers had almost no effect on the HPV in N-rats. Chronic administration of nadolol during 6 weeks of IH exposure induced PAH and RVH in IH-rats, but did not in N-rats. Meanwhile, atenolol had no effect on morphometric and hemodynamic changes in N and IH-rats. Protein expression of the β1-adrenergic receptor (AR) was down-regulated while that of β2AR was preserved in pulmonary arteries of IH-rats. Phosphorylation of p85 (chief component of phosphoinositide 3-kinase (PI3K)), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) were abrogated by chronic administration of nadolol in the lung tissue of IH-rats. We conclude that IH-derived activation of β2AR in the pulmonary arteries attenuates the HPV, thereby preventing progression of IH-induced PAH. This protective effect may depend on the β2AR-Gi mediated PI3K/Akt/eNOS signaling pathway.
PMCID: PMC4211686  PMID: 25350545
13.  Genome Sequences of Two Nondomesticated Bacillus subtilis Strains Able To Form Thick Biofilms on Submerged Surfaces 
Genome Announcements  2014;2(5):e00946-14.
Genomes of two nondomesticated strains of Bacillus subtilis subspecies subtilis, NDmed and NDfood, have been sequenced. Both strains form very thick and spatially complex biofilms on submerged surfaces. Moreover, biofilms of the NDmed isolate were shown to be highly resistant to antimicrobials action.
PMCID: PMC4175202  PMID: 25291767
14.  Transitioning from conventional radiotherapy to intensity-modulated radiotherapy for localized prostate cancer: changing focus from rectal bleeding to detailed quality of life analysis 
Journal of Radiation Research  2014;55(6):1033-1047.
With the advent of modern radiation techniques, we have been able to deliver a higher prescribed radiotherapy dose for localized prostate cancer without severe adverse reactions. We reviewed and analyzed the change of toxicity profiles of external beam radiation therapy (EBRT) from the literature. Late rectal bleeding is the main adverse effect, and an incidence of >20% of Grade ≥2 adverse events was reported for 2D conventional radiotherapy of up to 70 Gy. 3D conformal radiation therapy (3D-CRT) was found to reduce the incidence to ∼10%. Furthermore, intensity-modulated radiation therapy (IMRT) reduced it further to a few percentage points. However, simultaneously, urological toxicities were enhanced by dose escalation using highly precise external radiotherapy. We should pay more attention to detailed quality of life (QOL) analysis, not only with respect to rectal bleeding but also other specific symptoms (such as urinary incontinence and impotence), for two reasons: (i) because of the increasing number of patients aged >80 years, and (ii) because of improved survival with elevated doses of radiotherapy and/or hormonal therapy; age is an important prognostic factor not only for prostate-specific antigen (PSA) control but also for adverse reactions. Those factors shift the main focus of treatment purpose from survival and avoidance of PSA failure to maintaining good QOL, particularly in older patients. In conclusion, the focus of toxicity analysis after radiotherapy for prostate cancer patients is changing from rectal bleeding to total elaborate quality of life assessment.
PMCID: PMC4229926  PMID: 25204643
prostate cancer; radiotherapy; rectal bleeding; incontinence; genitourinary symptom; erectile dysfunction
15.  Molecular Characterization of a Novel N-Acetyltransferase from Chryseobacterium sp. 
N-Acetyltransferase from Chryseobacterium sp. strain 5-3B is an acetyl coenzyme A (acetyl-CoA)-dependent enzyme that catalyzes the enantioselective transfer of an acetyl group from acetyl-CoA to the amino group of l-2-phenylglycine to produce (2S)-2-acetylamino-2-phenylacetic acid. We purified the enzyme from strain 5-3B and deduced the N-terminal amino acid sequence. The gene, designated natA, was cloned with two other hypothetical protein genes; the three genes probably form a 2.5-kb operon. The deduced amino acid sequence of NatA showed high levels of identity to sequences of putative N-acetyltransferases of Chryseobacterium spp. but not to other known arylamine and arylalkylamine N-acetyltransferases. Phylogenetic analysis indicated that NatA forms a distinct lineage from known N-acetyltransferases. We heterologously expressed recombinant NatA (rNatA) in Escherichia coli and purified it. rNatA showed high activity for l-2-phenylglycine and its chloro- and hydroxyl-derivatives. The Km and Vmax values for l-2-phenylglycine were 0.145 ± 0.026 mM and 43.6 ± 2.39 μmol · min−1 · mg protein−1, respectively. The enzyme showed low activity for 5-aminosalicylic acid and 5-hydroxytryptamine, which are reported as good substrates of a known arylamine N-acetyltransferase and an arylalkylamine N-acetyltransferase. rNatA had a comparatively broad acyl donor specificity, transferring acyl groups to l-2-phenylglycine and producing the corresponding 2-acetylamino-2-phenylacetic acids (relative activity with acetyl donors acetyl-CoA, propanoyl-CoA, butanoyl-CoA, pentanoyl-CoA, and hexanoyl-CoA, 100:108:122:10:<1).
PMCID: PMC3957623  PMID: 24375143
16.  Clinical Significance of Serum Soluble T Cell Regulatory Molecules in Clear Cell Renal Cell Carcinoma 
BioMed Research International  2014;2014:396064.
To clarify the role of serum soluble T cell regulatory molecules in clear cell renal cell carcinoma (CCRCC), we measured the serum levels of soluble interleukin-2 receptor (sIL-2R), soluble B7-H3 (sB7-H3), and soluble cytotoxic T lymphocyte associated antigen-4 (sCTLA-4) in 70 CCRCC patients and 35 healthy controls. We investigated correlations between the serum levels of these soluble T cell regulatory molecules and the pathological grade, clinical stage, and prognosis of CCRCC. We also assessed the relations among each of these soluble molecules. As a result, the serum level of sIL-2R was significantly higher in CCRCC patients than in healthy controls (P < 0.05). In addition, elevation of serum sIL-2R was significantly correlated with the clinical stage (P < 0.001), and the survival of patients with high sIL-2R levels was shorter than that of patients with low sIL-2R levels (P < 0.05). Furthermore, the serum level of sB7-H3 was also significantly correlated with the clinical stage (P < 0.05), while the sIL-2R and sB7-H3 levels showed a positive correlation with each other (R = 0.550, P < 0.0001). These results indicate that the serum level of sIL-2R reflects tumor progression in CCRCC patients. In addition, the possibility was suggested that the IL-2/IL-2R and B7-H3 pathways may be involved in the progression of CCRCC.
PMCID: PMC4095742  PMID: 25089268
17.  The Rho-kinase inhibitor HA-1077 suppresses proliferation/migration and induces apoptosis of urothelial cancer cells 
BMC Cancer  2014;14:412.
Activation of Rho, one of the small GTPases, and its major downstream target Rho-kinase (ROCK) promotes the development and metastasis of cancer. We previously showed that elevation of Rho and ROCK expression was associated with tumor invasion, metastasis, and an unfavorable prognosis in patients with urothelial cancer of the bladder or upper urinary tract.
We investigated the effects of a ROCK inhibitor on the growth, migration, and apoptosis of bladder cancer cells. We also examined phosphorylation of RhoA (RhoA activity) by measuring its GTP-bound active form and assessed the expression of ROCK to explore the underlying molecular mechanisms.
Lysophosphatidic acid (LPA) and geranylgeraniol (GGOH) induced an increase of cell proliferation and migration in association with promotion of RhoA activity and upregulation of ROCK expression. The ROCK inhibitor fasudil (HA-1077) suppressed cell proliferation and migration, and also induced apoptosis in a dose-dependent manner. HA-1077 dramatically suppressed the expression of ROCK-I and ROCK-II, but did not affect RhoA activity.
These findings suggest that ROCK could be a potential molecular target for the treatment of urothelial cancer.
PMCID: PMC4081468  PMID: 24908363
18.  Potential risk of alpha-glucosidase inhibitor administration in prostate cancer external radiotherapy by exceptional rectal gas production: a case report 
Radiotherapy is a standard treatment for prostate cancer, and image-guided radiotherapy is increasingly being used to aid precision of dose delivery to targeted tissues. However, precision during radiotherapy cannot be maintained when unexpected intrafraction organ motion occurs.
Case presentation
We report our experience of internal organ motion caused by persistent gas production in a patient taking an alpha-glucosidase inhibitor. A 68-year-old Japanese man with prostate cancer visited our institution for treatment with helical tomotherapy. He suffered from diabetes mellitus and took an alpha-glucosidase inhibitor. Routine treatment planning computed tomography showed a large volume of rectal gas; an enema was given to void the rectum. Subsequent treatment planning computed tomography again showed a large volume of gas. After exercise (walking) to remove the intestinal gas, a third scan was performed as a test scan without tight fixation, which showed a sufficiently empty rectum for planning. However, after only a few minutes, treatment planning computed tomography again showed extreme accumulation of gas. Therefore, we postponed treatment planning computed tomography and consulted his doctor to suspend the alpha-glucosidase inhibitor, which was the expected cause of his persistent gas. Four days after the alpha-glucosidase inhibitor regimen was suspended, we took a fourth treatment planning computed tomography and made a treatment plan without gas accumulation. Thereafter, the absence of rectal gas accumulation was confirmed using daily megavolt computed tomography before treatment, and the patient received 37 fractions of intensity-modified radiotherapy at 74Gy without rectal gas complications. In this case study, the alpha-glucosidase inhibitor induced the accumulation of intestinal gas, which may have caused unexpected organ motion, untoward reactions, and insufficient doses to clinical targets.
We suggest that patients who are taking an alpha-glucosidase inhibitor for diabetes should discontinue use of that particular medicine prior to beginning radiotherapy.
PMCID: PMC4046525  PMID: 24886457
Tomotherapy; Alpha-glucosidase inhibitor; Prostate cancer; Internal organ motion
19.  Comparison of three tannases cloned from closely related lactobacillus species: L. Plantarum, L. Paraplantarum, and L. Pentosus 
BMC Microbiology  2014;14:87.
Tannase (tannin acyl hydrolase, EC specifically catalyzes the hydrolysis of the galloyl ester bonds in hydrolyzable tannins to release gallic acid. The enzyme was found not only in fungal species but also many bacterial species including Lactobacillus plantarum, L. paraplantarum, and L. pentosus. Recently, we identified and expressed a tannase gene of L. plantarum, tanLpl, to show remarkable differences to characterized fungal tannases. However, little is known about genes responsible for tannase activities of L. paraplantarum and L. pentosus. We here identify the tannase genes (i.e. tanLpa and tanLpe) of the above lactobacilli species, and describe their molecular diversity among the strains as well as enzymological difference between species inclusive of L. plantarum.
The genes encoding tannase, designated tanLpa and tanLpe, were cloned from Lactobacillus paraplantarum NSO120 and Lactobacillus pentosus 21A-3, which shared 88% and 72% amino acid identity with TanLpl, cloned from Lactobacillus plantarum ATCC 14917T, respectively. These three enzymes could comprise a novel tannase subfamily of independent lineage, because no other tannases in the databases share significant sequence similarity with them. Each of tanLpl, tanLpa, and tanLpe was expressed in Bacillus subtilis RIK 1285 and recombinant enzymes were secreted and purified. The Km values of the enzymes on each galloyl ester were comparable; however, the kcat/Km values of TanLpa for EGCg, ECg, Cg, and GCg were markedly higher than those for TanLpl and TanLpe. Their enzymological properties were compared to reveal differences at least in substrate specificity.
Two tannase genes responsible for tannase activities of L. paraplantarum and L. pentosus were identified and characterized. TanLpl, TanLpa and TanLpe forming a phylogenetic cluster in the known bacterial tannase genes and had a limited diversity in each other. Their enzymological properties were compared to reveal differences at least in substrate specificity. This is the first comparative study of closely related bacterial tannases.
PMCID: PMC4233993  PMID: 24708557
20.  Polysaccharide-Degrading Thermophiles Generated by Heterologous Gene Expression in Geobacillus kaustophilus HTA426 
Applied and Environmental Microbiology  2013;79(17):5151-5158.
Thermophiles have important advantages over mesophiles as host organisms for high-temperature bioprocesses, functional production of thermostable enzymes, and efficient expression of enzymatic activities in vivo. To capitalize on these advantages of thermophiles, we describe here a new inducible gene expression system in the thermophile Geobacillus kaustophilus HTA426. Six promoter regions in the HTA426 genome were identified and analyzed for expression profiles using β-galactosidase reporter assay. This analysis identified a promoter region upstream of a putative amylose-metabolizing gene cluster that directed high-level expression of the reporter gene. The expression was >280-fold that without a promoter and was further enhanced 12-fold by maltose addition. In association with a multicopy plasmid, this promoter region was used to express heterologous genes. Several genes, including a gene whose product was insoluble when expressed in Escherichia coli, were successfully expressed as soluble proteins, with yields of 0.16 to 59 mg/liter, and conferred new functions to G. kaustophilus strains. Remarkably, cellulase and α-amylase genes conferred the ability to degrade cellulose paper and insoluble starch at high temperatures, respectively, generating thermophiles with the potential to degrade plant biomass. Our results demonstrate that this novel expression system expands the potential applications of G. kaustophilus.
PMCID: PMC3753961  PMID: 23793634
21.  High-dose-rate interstitial brachytherapy for mobile tongue cancer: preliminary results of a dose reduction trial 
To compare the outcome of our facility with another about the shortened schedule (60 Gy in 10 fractions to 54 Gy in 9 fractions) of high-dose-rate interstitial brachytherapy (HDR ISBT) for mobile tongue cancer.
Material and methods
Eighteen patients were treated with HDR ISBT as a monotherapy in dose reduction schedule with some unique technique to determine the border of tumor accuracy (lugol's staining and metal marker), and to minimize adverse effect (lead-lined silicon block) at our facility.
The 2-year local and regional control rates and cause-specific survival rate were 82%, 80%, and 83% and moderate to severe late complications occurred in five patients (28%), which were almost the same treatment results achieved by another facility.
We recommend 54 Gy in 9 fractions over 7 days as a feasible treatment to reduce patient discomfort in mobile tongue cancer patients.
PMCID: PMC4003422  PMID: 24790616
dose reduction; high-dose-rate brachytherapy; tongue cancer
22.  High-dose-rate brachytherapy as monotherapy for prostate cancer: technique, rationale and perspective 
High-dose-rate (HDR) brachytherapy as monotherapy is a comparatively new brachytherapy procedure for prostate cancer. Although clinical results are not yet mature enough, it is a highly promising approach in terms of potential benefits for both radiation physics and radiobiology. In this article, we describe our technique for monotherapeutic HDR prostate brachytherapy, as well as the rationale and theoretical background, with educational intent.
PMCID: PMC4003433  PMID: 24790627
prostate cancer; radiotherapy; high-dose-rate (HDR) brachytherapy; monotherapy; hypofractionation
23.  Axitinib for preoperative downstaging of renal cell carcinoma with sarcomatoid differentiation and direct invasion of the duodenum and inferior vena cava: a case report 
OncoTargets and therapy  2014;7:289-295.
Renal cell carcinoma (RCC) with sarcomatoid differentiation is invasive, refractory to treatment, and has a higher mortality. Therefore, systemic therapy is still challenging, and the curative resection of localized or locally advanced RCC with sarcomatoid differentiation is very important. Axitinib is a potent and selective second-generation vascular endothelial growth factor receptor tyrosine kinase inhibitor with improved safety and tolerability. Axitinib is generally recommended as second-line therapy for advanced RCC because the phase III axitinib versus sorafenib in advanced RCC (AXIS) trial demonstrated that it achieved longer progression-free survival than sorafenib in patients with metastatic RCC after failure of an approved first-line regimen.
We present a 73-year-old man who had a large (13 cm in diameter) right RCC with sarcomatoid differentiation that directly invaded the duodenum and inferior vena cava. The patient presented with gastrointestinal bleeding, was unable to eat solid food, and had become emaciated. Thus, his classification was poor risk with anemia, hypercalcemia, and poor performance status, according to the Memorial Sloan-Kettering Cancer Center criteria. He seemed unlikely to survive if radical nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed. To reduce the tumor burden and potential operative complications, we administered axitinib as first-line neoadjuvant therapy.
Six weeks of treatment reduced the tumor burden without causing severe toxicities. Subsequently, radical right nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed successfully. The pathological treatment effect of axitinib was grade 2 (two-thirds necrosis). The resected tumor showed a heterogeneous reaction for phosphorylated Akt (Ser-473) by Western blotting and immunohistochemistry, indicating that parts of the tumor were sensitive to axitinib and other parts were not.
Axitinib might be promising as preoperative or neoadjuvant therapy for locally advanced RCC (>cT3b or >cTanyN1).
PMCID: PMC3931632  PMID: 24627641
renal cell carcinoma; sarcomatoid differentiation; axitinib; tyrosine kinase inhibitors; phosphorylated Akt
24.  Death from axillary haemorrhage during haemodialysis in a patient with a history of microscopic polyangiitis 
BMJ Case Reports  2012;2012:bcr1120115194.
An older female with a history of microscopic polyangiitis underwent haemodialysis through an end-to-side anastomosis between the left basilica vein and brachial artery. During the last haemodialysis session, repeated punctures induced haemorrhage that required brachial compression. Twenty min posthaemodialysis, haemorrhage had expanded from the axilla to the left lateral thorax. Autopsy disclosed axillary haematoma. The haemorrhage was not derived from punctured vessels or the left axillary artery. Although neither an alveolar nor a glomerular microscopic polyangiitis lesion was detected, fragility of the axillary small vessels due to microscopic polyangiitis, ageing, atherosclerosis and steroid therapy were underlying factors in the haematoma. Aspirin and heparin may have promoted haemorrhage, while shunt vessel stenosis with disturbed flow may have increased the axillary vessel pressure when the shunt vessels were compressed for haemostasis. This is the first report of a death due to haemorrhage from ruptured axillary vessels related to haemodialysis or microscopic polyangiitis.
PMCID: PMC3263122  PMID: 22665880
25.  An improved Bacillus subtilis cell factory for producing scyllo-inositol, a promising therapeutic agent for Alzheimer’s disease 
Bacillus subtilis 168 possesses an efficient pathway to metabolize some of the stereoisomers of inositol, including myo-inositol (MI) and scyllo-inositol (SI). Previously we reported a prototype of a B. subtilis cell factory with modified inositol metabolism that converts MI into SI in the culture medium. However, it wasted half of initial 1.0% (w/v) MI, and the conversion was limited to produce only 0.4% (w/v) SI. To achieve a more efficient SI production, we attempted additional modifications.
All “useless” genes involved in MI and SI metabolism were deleted. Although no elevation in SI production was observed in the deletion strain, it did result in no wastage of MI anymore. Thus additionally, overexpression of the key enzymes, IolG and IolW, was appended to demonstrate that simultaneous overexpression of them enabled complete conversion of all MI into SI.
The B. subtilis cell factory was improved to yield an SI production rate of 10 g/L/48 h at least. The improved conversion was achieved only in the presence of enriched nutrition in the form of 2% (w/v) Bacto soytone in the medium, which may be due to the increasing demand for regeneration of cofactors.
PMCID: PMC3878828  PMID: 24325193
Bacillus subtilis; scyllo-inositol; myo-inositol; Bioconversion; Alzheimer’s disease

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