A tumor metastasis‐associated molecule TWIST1 is a favorable target for cancer immunotherapy due to its immunogenicity

Although neoantigens are one of the most favorable targets in cancer immunotherapy, it is less versatile and costly to apply neoantigen‐derived cancer vaccines to patients due to individual variation. It is, therefore, important to find highly immunogenic antigens between tumor‐specific or associated antigens that are shared among patients. Considering the cancer immunoediting theory, immunogenic tumor cells cannot survive in the early phase of tumor progression including two processes: elimination and equilibrium. We hypothesized that highly immunogenic molecules are allowed to be expressed in tumor cells after an immune suppressive tumor microenvironment was established, if these molecules contribute to tumor survival. In the current study, we focused on TWIST1 as a candidate for highly immunogenic antigens because it is upregulated in tumor cells under hypoxia and promotes tumor metastasis, which is observed in the late phase of tumor progression. We demonstrated that TWIST1 had an immunogenic peptide sequence TWIST1_140–162, which effectively activated TWIST1‐specific CD4⁺ T‐cells. In a short‐term culture system, we detected more TWIST1‐specific responses in breast cancer patients compared with in healthy donors. Vaccination with the TWIST1 peptide also showed efficient expansion of TWIST1‐reactive HTLs in humanized mice. These findings indicate that TWIST1 is a highly immunogenic shared antigen and a favorable target for cancer immunotherapy.     

Assessment of the value of detecting specific IgA antibodies for the diagnosis of a recently acquired primary Toxoplasma infection

OBJECTIVE: To assess the value of detecting IgA antibodies for the diagnosis of a recently acquired primary Toxoplasma infection. METHODS: IgA antibodies were screened in sera from 87 women with different serological profiles of Toxoplasma gondii IgM and IgG antibodies and Toxoplasma-specific IgG avidity. The IgM and IgG antibodies and the IgG avidity were measured with an automated Vitek Immuno Diagnostic Assay System (VIDAS). Anti-T.gondii IgA was measured with Platelia Toxo IgA TMB kits. RESULTS: All 12 sera obtained from women with clinical and/or serological evidence of a recently acquired Toxoplasma infection were positive for IgA. In 42 serum samples obtained more than 6 months after T. gondii infection from women with no clinical evidence of infection, but who had a positive IgM test and a high IgG avidity index, the IgA-enzyme linked immunosorbent assay (ELISA) test results were positive, negative, and doubtful in 16 (38.1%), 23 (54.8%), and 3 (7.1%) sera, respectively. In eight women, IgA was detected in sera collected more than 9 months after the onset of infection. The IgA test result was also positive in 11 of 12 sera (91.7%) obtained from women with no clinical evidence of toxoplasmosis, but who had a positive IgM test and a borderline IgG avidity index. The IgA-ELISA was negative in 21 sera obtained more than 2 years after the onset of T. gondii infection from women with no clinical evidence of toxoplasmosis, but who had a negative IgM test and a positive IgG test. CONCLUSION: These results show that IgA is not a dependable marker for a recently acquired primary Toxoplasma infection.     

Prevention of surgical adhesions with gelatine sealing sheet in a canine adhesion model

Open in a separate window OBJECTIVESAlthough reoperation has been increasingly performed in cardiovascular surgery in recent years, preventing surgical adhesions remains an unsolved complication. Therefore, this study aimed to investigate whether gelatine sealing sheets are more effective than fibrin sealing sheets in preventing surgical adhesions.METHODSBilateral femoral arteries of 20 beagle dogs under general anaesthesia were pricked with syringe needles, and gelatine and fibrin sealing sheets were applied on the bleeding points to make canine adhesion models. The femoral artery was harvested after 4 and 12 weeks to evaluate adhesion formations. The adhesive grade was quantified by scoring the area and strength of adhesion tissues. Histological staining was performed to examine the structural features of surgical adhesions.RESULTSSignificantly fewer macroscopic adhesions were observed with gelatine sealing sheets than those with fibrin sealing sheets at 4 and 12 weeks postoperatively. Microscopically, CD3+ T lymphocytes at 4 and 12 weeks postoperatively in gelatine sealing sheets were significantly lower than those in fibrin sealing sheets. Microvessel density determined by CD34 at 4 and 12 weeks postoperatively in gelatine sealing sheets was also significantly lower than those in fibrin sealing sheets.CONCLUSIONSThe gelatine sealing sheets are more effective than the fibrin sealing sheets in preventing surgical adhesions. These findings suggest that the gelatine sealing sheet may help prevent adhesions and thus be a therapeutically effective biomaterial in vascular surgery.     

Development of the Japanese version of the Pediatric Quality of Life Inventory™ Brain Tumor Module

Background

The Pediatric Quality of Life Inventory? (PedsQL?) is a widely-used modular instrument for measuring health-related quality of life in children aged 2 to 18 years. The PedsQL? Brain Tumor Module is comprised of six scales: Cognitive Problems, Pain and Hurt, Movement and Balance, Procedural Anxiety, Nausea, and Worry. In the present study, we developed the Japanese version of the PedsQL? Brain Tumor Module and investigated its feasibility, reliability, and validity among Japanese children and their parents.

Methods

Translation equivalence and content validity were verified using the standard back-translation method and cognitive debriefing tests. Participants were recruited from 6 hospitals in Japan and the Children's Cancer Association of Japan, and questionnaires were completed by 137 children with brain tumors and 166 parents. Feasibility of the questionnaire was determined based on the amount of time required to complete the form and the percentage of missing values. Internal consistency was assessed using Cronbach's coefficient alpha. Test-retest reliability was assessed by retesting 22 children and 27 parents. Factorial validity was verified by exploratory factor analyses. Known-groups validity was described with regard to whole brain irradiation, developmental impairment, infratentorial tumors, paresis, and concurrent chemotherapy. Convergent and discriminant validity were determined using Generic Core Scales and State-Trait Anxiety Inventory for children.

Results

Internal consistency was relatively high for all scales (Cronbach's coefficient alpha > 0.70) except the Pain and Hurt scale for the child-report, and sufficient test-retest reliability was demonstrated for all scales (intraclass correlation coefficient = 0.45-0.95). Factorial validity was supported through exploratory factor analysis (factor-item correlation = 0.33-0.96 for children, 0.55-1.00 for parents). Evaluation of known-groups validity confirmed that the Cognitive Problems scale was sensitive for developmental impairment, the Movement and Balance scale for infratentorial tumors or paresis, and the Nausea scale for a patient currently undergoing chemotherapy. Convergent and discriminant validity with the PedsQL? Generic Core Scales and State-Trait Anxiety Inventory for children were acceptable.

Conclusions

The Japanese version of the PedsQL? Brain Tumor Module is suitable for assessing health-related quality of life in children with brain tumors in clinical trials and research studies.     

Single-stage repair for ascending aortic aneurysm,artery stenosis and occlusion of neck vessels caused by Takayasu arteritis

Takayasu arteritis results in a variety of vascular symptoms, and there are some cases in which progressive vascular lesions require surgical intervention. We present a case with ascending aortic aneurysm, right common carotid artery stenosis, left common carotid artery occlusion and left subclavian artery stenosis caused by Takayasu arteritis that was successfully treated with total arch replacement and ascending aorta to right internal carotid artery bypass.     

Expression of parathyroid hormone/parathyroid hormone-related peptide receptor 1 in normal and diseased bladder detrusor muscles: a clinico-pathological study

Background

To investigate the expression of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor 1 (PTH1R) in clinical specimens of normal and diseased bladders. PTHrP is a unique stretch-induced endogenous detrusor relaxant that functions via PTH1R. We hypothesized that suppression of this axis could be involved in the pathogenesis of bladder disease.

Methods

PTH1R expression in clinical samples was examined by immunohistochemistry. Normal kidney tissue from a patient with renal cancer and bladder specimens from patients undergoing ureteral reimplantation for vesicoureteral reflux or partial cystectomy for urachal cyst were examined as normal control organs. These were compared with 13 diseased bladder specimens from patients undergoing bladder augmentation. The augmentation patients ranged from 8 to 31 years old (median 15 years), including 9 males and 4 females. Seven patients had spinal disorders, 3 had posterior urethral valves and 3 non-neurogenic neurogenic bladders (Hinman syndrome).

Results

Renal tubules, detrusor muscle and blood vessels in normal control bladders stained positive for PTH1R. According to preoperative urodynamic studies of augmentation patients, the median percent bladder capacity compared with the age-standard was 43.6% (range 1.5–86.6%), median intravesical pressure at maximal capacity was 30 cmH₂O (range 10–107 cmH₂O), and median compliance was 3.93 ml/cmH₂O (range 0.05–30.3 ml/cmH₂O). Detrusor overactivity was observed in five cases (38.5%). All augmented bladders showed negative stainings in PTH1R expression in the detrusor tissue, but positive staining of blood vessels in majority of the cases.

Conclusions

Downregulation of PTH1R may be involved in the pathogenesis of human end-stage bladder disease requiring augmentation.     

Effect on vein graft intimal hyperplasia of nuclear factor-kB decoy transfection using the second generation of HVJ vector

AIM: Vein graft stenosis due to intimal hyperplasia (IH) is the main cause of graft failure. We examined possibilities of nuclear factor-kB (NF-kB) expression in vein grafts, and inhibitive effects of NF-kB decoy on the gene expression and subsequent vein graft IH. METHODS: Fifteen mongrel dogs underwent femoral artery replacement with autogenous vein grafts. Group I: grafts were retrieved at a predetermined time and subjected to NF-kB binding activity assay; Groups II and III: grafts were transfected with scrambled (II-a, III-a) or NF-kB (II-b, III-b) decoy using hemagglutinating virus of Japan envelope before implantation. Grafts were retrieved 7 days after implantation for evaluation of intercellular adhesion molecule-1 (ICAM-1) mRNA expression (Group II) and 4 weeks after implantation for comparison of IH by morphometric analysis (Group III). RESULTS: NF-kB binding activity was increased in a time-dependent manner, with a peak 2 days after implantation. The ratio between ICAM-1 and glyceraldehyde-3-phosphate dehydrogenase mRNA expression in II-b was significantly lower than that in II-a (0.347 +/- 0.07 versus 0.612+/-0.08; P = 0.047). The ratio of intimal cross-section area to luminal cross-section area of III-b was significantly lower than that of the III-a (0.096+/-0.03 versus 0.461+/-0.11; P = 0.048). CONCLUSION: NF-kB binding activity in vein grafts increases after implantation, and transfection of NF-kB decoy before implantation may reduce IH through the inhibition of ICAM-1 expression.     

Living With Stillborn Babies as Family Members: Japanese Women Who Experienced Intrauterine Fetal Death After 28 Weeks Gestation

My purpose in this qualitative research was to describe the meaning of fetal death in the lives of Japanese women in a local community by interviewing women who experienced intrauterine fetal death (IUFD) after 28 weeks of gestation in chronological order from the time they were told of the fetal death to the present day. The study included 17 women who had experienced fetal death and who raised the dead child through “the development process of becoming a parent” and “the grieving process after the loss of a child,” comprising a year-long grieving process.     

Daily exercise lowers blood pressure and reduces visceral adipose tissue areas in overweight Japanese men

OBJECTIVE: To investigate the link between a reduction in blood pressure (BP) and daily exercise. DESIGN: Cross-sectional and longitudinal clinical intervention study with exercise education. SUBJECTS: 43 overweight Japanese men aged 32-59 years (BMI, 29.0+/-2.3 kg/m2) at baseline. Among the participants, a randomly selected 23 overweight men (BMI, 28.5+/-1.7) were further enrolled into the 10 months exercise program. MEASUREMENTS: BP was measured every week and steps per day were also recorded every day throughout the observation period. Fat distribution was evaluated by visceral fat (V) and subcutaneous fat (S) areas measured with computed tomography (CT) scanning at umbilical level, at before, 5 months and after intervention. Anthropometric parameters were also measured at same point. Aerobic exercise level, muscle strength, flexibility and calorie intake and insulin resistance (HOMA index) were investigated at before and after the study. RESULTS: In a cross sectional analysis, systolic BP (SBP) and diastolic BP (DBP) were significantly correlated with body composition. In a second longitudinal analysis, SBP was significantly reduced at 2 months and DBP was also reduced at 3 months, and almost maintained until the end of the observation period. Increasing daily walking was observed in 3 months and maintained until 10 months. Body composition, aerobic exercise level, muscle strength, flexibility and insulin resistance were significantly improved. There was positive correlation between DeltaDBP and Deltavisceral fat area (1-5, 5-10, 1-10 months). By stepwise multiple regression analysis, only Deltavisceral fat area was independently related to DeltaDBP at a significant level (1-10 months: DeltaDBP=-0.608+0.105Deltavisceral fat area, r2=0.227, P=0.0334). CONCLUSION: The present study indicated daily exercise lowers BP and visceral fat area is the critical factor for BP change.     

Influence of cytochrome P450 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke previously treated with clopidogrel

This randomized double-blind crossover study aimed to investigate the influence of cytochrome P450 (CYP) 2C19 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke treated with clopidogrel. Patients received clopidogrel 75 mg/day for >?4 weeks. Subsequently, patients received prasugrel 3.75 mg/day (group A; n?=?64) or 2.5 mg/day (group B; n?=?65) for 4 weeks followed by a 4 week switched-dose regimen. To assess the influence of CYP2C19 polymorphisms, patients were classified as extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs). The primary endpoint was P2Y₁₂ reaction units (PRU) at the end of each 4 week treatment. A significant reduction in PRU was noted after treatment with prasugrel 3.75 mg/day compared with the pre-dose value (after treatment with clopidogrel) (p?<?0.0001). By CYP2C19 phenotypes, a significant reduction in PRU was noted in IMs and PMs after treatment with prasugrel 3.75 mg/day and in PMs after treatment with prasugrel 2.5 mg/day, as compared with the pre-dose value (p?<?0.0001). The plasma concentration of the active metabolite of clopidogrel was relatively low in PMs compared to EMs and IMs; prasugrel was similar across all CYP2C19 phenotypes. No major or clinically significant hemorrhagic adverse events occurred. By CYP2C19 phenotype, the antiplatelet effects of prasugrel were greater with 3.75 mg/day in IMs and PMs, and with 2.5 mg/day in PMs compared with clopidogrel 75 mg/day, without safety concerns. CYP2C19 polymorphisms did not affect the plasma concentration of the active metabolite of prasugrel or its antiplatelet effects. (JapicCTI-101044).