Metastasis of hepatocellular carcinoma to the supramaxillary gingiva and right ventricle

We describe a rare double metastasis of hepatocellular carcinoma to the supramaxillary gingiva and papillary muscle of the right ventricle. The patient was a 72-year-old woman who underwent three sessions of transcatheter arterial embolization for the primary lesions. Control of bleeding from the supramaxillary gingival metastasis was difficult by conservative treatment such as compression with gauze soaked in epinephrine. Therefore, radiotherapy was performed, but it failed to control the bleeding. The patient subsequently died due to hepatic failure. Autopsy revealed metastases of hepatocellular carcinoma to the papillary muscle of the right ventricle and paraaortic lymph node in the abdomen in addition to the supramaxillary gingival metastasis. Histopathological examination showed moderately differentiated hepatocellular carcinoma of both the primary site and metastatic sites to the gingiva and the heart and poorly differentiated in the paraaortic lymph node.     

Adoptive immunotherapy using autologous lymphocytes sensitized with HLA class I-matched allogeneic tumor cells

A 29-year-old female breast cancer patient with multiple bone metastases (HLA-A2) was treated with adoptive transfer using autologous peripheral blood mononuclear cells (PBMCs) activated with the HLA-A2-matched allogeneic GC022588 gastric cancer cell line and interleukin-2 plus an immobilized anti-CD3 antibody culture system. The relief of bone pain in parallel with a decrease of serum carcinoembryonic antigen levels was obtained just after the administration of GC022588-activated effector lymphocytes, and a good quality of life was accomplished for 4 months. The GC022588-activated effector lymphocytes included 44% CD4+, 77% CD8+, and 26% CD4+CD8+ phenotypes, and expressed 25% killing activity against GC022588 stimulator cells at an E/T ratio of 50:1. T cell receptor (TCR) usage analysis for the effector cells showed oligoclonal expression of TCRVbeta1, 3, 9, and 11, especially TCRVbeta5.2, 12, 13.1 and 17, and their killing activity was significantly inhibited in the presence of anti-TCRalphabeta antibody and anti-TCRVbeta12 antibody. SSCP analysis revealed clonotypic bands of TCRVbeta12. These results suggest that shared antigens exist between breast and gastric adenocarcinomas. Allogeneic tumor cells can stimulate PBMCs to generate effector cells with selected TCRCDR3 usages that recognize tumor antigens. These effector lymphocytes may be good candidates for the adoptive immunotherapy of cancer.     

Development and validation of the Stimulant Relapse Risk Scale for drug abusers in Japan

OBJECTIVE: To develop and validate a multidimensional measure of relapse risk for stimulants in Japanese drug abusers. METHODS: A Stimulant Relapse Risk Scale (SRRS) was developed based on the Marijuana Craving Questionnaire and a discussion among three psychiatrists. We created 48 items after confirming the items including a variety of relapse risk, such as craving (expectancy, compulsivity, etc.) and emotionality problems. One hundred inpatients and outpatients with a history of stimulant abuse (71 males and 29 females) were recruited with informed consent, and were administered the SRRS. The Visual Analogue Scale for drug craving (VAS), Addiction Severity Index for Japanese (ASI-J), and data on relapse within 3 and 6 months after the rating were used for the validation. RESULTS: Exploratory factor analysis highlighted five factors: anxiety and intention to use drug (AI), emotionality problems (EP), compulsivity for drug use (CD), positive expectancies and lack of control over drug (PL), and lack of negative expectancy for drug use (NE). These accounted for 48.3% of the total variance. Thirty of the 43 items were classified into the five subscales. Cronbach's alpha coefficient for each subscale ranged from .55 to .82, and was .86 for the total SRRS, indicating their adequate internal consistency. AI, CD, PL, and total SRRS were significantly correlated with the drug-use composite score of the ASI-J, supporting their concurrent validity. AI, PL, NE, and total SRRS were significantly correlated with relapse, implying their predictive validity. CONCLUSIONS: The SRRS has multidimensional psychometric properties useful for assessing the various aspects of stimulant relapse risk.     

Characterization of antibody aggregation: Role of buried,unpaired cysteines in particle formation

Proteins are susceptible to degradation upon exposure to a variety of stresses during product manufacturing, transportation and storage. In this study, we investigated the aggregation properties of a monoclonal antibody during agitation stress. Agitation exclusively led to insoluble aggregates, or particle formation. Removal or modification of the air–liquid interface with a surfactant (e.g., polysorbate) abrogated particle formation. The supernatant postagitation was analyzed using SE-HPLC, FTIR, and AUC analyses and revealed no changes in conformation and aggregation profile when compared to the nonagitated antibody sample. The antibody particles were comprised of a combination of nonnative intermolecular disulfide-linked covalent as well as noncovalent interactions. Analysis of the antibody's unpaired cysteines revealed that the nonnative intermolecular disulfide bonds were formed through buried cysteines, which suggested at least partial unfolding of the antibody domains. FTIR analysis indicated that the particulated antibody maintained significant native-like secondary structure suggesting that particle formation led to minimal structure changes, but capable of exposing free cysteines to solvent to form the nonnative intermolecular disulfide bonds. The results presented in this study indicate the importance of the interactions between the antibody and the air–liquid interface during agitation in the formation of particles and suggests that reduced disulfide bonds may play a significant role in the particulation reaction. This phenomenon can be applicable to other proteins with similar free cysteine and structural characteristics. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:764–781, 2010     

Age-related change in the strength of correlation of lumbar spine bone mineral density with other regions

OBJECTIVES: To investigate whether the strength of correlation of lumbar spine bone mineral density (BMD) with other regions differs with age. METHODS: Subjects were 336 premenopausal women aged 20-49 years and 218 postmenopausal women aged 50-69 years with right-side dominance. Age, height, weight, and years since menopause (YSM) were recorded. Subjects were classified into five subgroups at 10-year increments. BMD of the arms, lumbar spine (L2-4), pelvis, legs, and total body were measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: Regional and total body BMD did not differ among women aged in their 20s, 30s, and 40s. However, in women aged over 50, regional and total body BMD gradually decreased with age. The strength of correlation of lumbar spine BMD with the left arm, right arm, left leg, right leg, and total body BMD gradually increased with advancing age (r=0.422-0.715, 0.376-0.714, 0.476-0.721, 0.491-0.734, and 0.642-0.800, respectively). However, the strength of correlation of lumbar spine BMD with pelvis BMD remained unchanged (r=0.512-0.622). CONCLUSIONS: Correlation of lumbar spine BMD with extremities BMD gradually strengthens with advancing age, while higher correlation of lumbar spine BMD with pelvis BMD remains unchanged. When lumbar spine BMD is predicted using values at sites such as forearm BMD, we should consider the patient's age.     

Smart polymers for responsive drug-delivery systems

The rapid advancement of biomedical research has led to many creative applications for biocompatible polymers. As modern medicine discerns more mechanisms, both of physiology and of pathophysiology, the approach to healing is to mimic, or if possible, to recreate the physiology of healthy functioning. Thus, the area of smart polymers for responsive drug delivery has evolved. The developments fall under two categories: externally regulated or pulsatile systems (also known as 'open-loop' systems) and self-regulated systems (also known as 'closed-loop'). The externally controlled devices apply external triggers for pulsatile delivery such as: ultrasonic, magnetic, electric, light and chemical or biochemical agents. The self-regulated systems, on the other hand, are defined as systems where the controlled variable is detected, and as a result, the system output is adjusted accordingly. The release rate is controlled by feedback information, without any external intervention. The self-regulated systems utilize several approaches for the rate control mechanisms such as thermal, pH-sensitive polymers, enzyme-substrate reactions, pH-sensitive drug solubility, competitive binding, antibody interactions and metal-concentration-dependent hydrolysis.     

High expression of GCLC is associated with malignant melanoma of low oxidative phenotype and predicts a better prognosis

Reactive oxygen species (ROS) are strongly implicated in melanoma development, and treatment with antioxidants has shown efficacy in suppressing malignant transition and progression. Here, we investigated the significance of the glutamate-L: -cysteine ligase catalytic subunit (GCLC) expression, a key regulator of glutathione synthesis, for malignant melanoma. A large set of melanoma cell lines (n?=?36) was analyzed, and higher GCLC levels were associated with lower presence of intracellular ROS and interestingly also lower rates of cell proliferation. Moreover, treatment with the antioxidant N-acetylcysteine efficiently reduced the growth speed of several investigated malignant cells. In addition GCLC expression was significantly linked to a prominent set of cellular antioxidants, accounting for the observed lower basal levels of oxidative stress and higher antioxidative capacity. Key attributes defining the malignant phenotype of melanoma cells including survival, invasiveness, and switch from E-cadherin to N-cadherin expression were more prominent in cells with lower GCLC expression. Our findings were further corroborated by observations in Rag2(-/-)γc(-/-)mice, in which melanoma cells with lower GCLC expression depicted a dramatically stronger tumor growth. Furthermore, prognostic significance of GCLC expression was investigated in patients (n?=?28) with advanced malignant melanoma. High tumor immunoreactivity for GCLC was a significant determinant for better 5-year overall survival. Conclusively, we show for the first time that GCLC may serve a dual role, as a surrogate marker for cellular redox state as well as malignant potential of melanoma cells. These promising results regarding its prognostic significance as well as its potential as a pharmacological target require further in-depth investigations.     

Effects of periodic and continued resistance training on muscle CSA and strength in previously untrained men

To determine muscle adaptations to retraining after short-term detraining, we examined the effects of continuous and interrupted resistance training on muscle size and strength in previously untrained men. Fifteen young men were divided into continuous training (CTr) or retraining (RTr) groups and performed high-intensity bench press training. The CTr group trained continuously for 15 weeks, while the RTr group trained for 6 weeks, stopped for a 3-week detraining period and resumed training at week 10. After the initial training phase, increases (P<0·01) in one repetition maximum (1-RM) and magnetic resonance imaging-measured triceps brachii and pectorals major muscle cross-sectional areas (CSAs) were similar in both groups. Muscle CSA and 1-RM increased (P<0·05) continuously for the CTr group, but the muscle adaptations were lower (P<0·05) after the last 6-week training period than after the initial phase. In the RTr group, there were no significant decreases in muscle CSA and 1-RM after the 3-week detraining period, and increases in muscle CSA after retraining were similar to those observed after initial training. Ultimately, improvements in 1-RM and muscle CSA in both groups were similar after the 15-week training period. Our results suggest that compared with continuous 15-week training, 3-week detraining does not inhibit muscle adaptations.     

AN AUTOPSY CASE OF MENKES KINKY HAIR DISEASE

An autopsy cases of Menkes kinky hair disease in a 1 year and 8 months old male infant is presented and compared with the morphological findings of the previous literatures. The main pathological changes are atrophy of the whole cerebellar cortex and bilateral temporal lobe, atrophy with demyelination of the white matter, tortuous running of the cerebral arteries, multiple diverticulosis of the urinary bladder and hyaline-like deposition in the gastric submucosa. Microscopically, the peculiar degenerative change of Purkinje cell (somal sprout) is the only characteristic lesion in our case and the others. It is suggested that Menkes kinky hair disease may be a syndrome due to metabolic disturbance appearing not only in ectoderm such as the central nervous system, but also in mesoderm such as connective tissue and bone.