Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis

Introduction  

Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis.     

Effect of selenomethionine on N-methylnitronitrosoguanidine-induced colonic aberrant crypt foci in rats.

An association between low selenium intake and the incidence or prevalence of cancers is well known. Selenium in the form of selenomethionine supplemented in drinking water has been found to be highly effective in reducing tumour incidence and preneoplastic foci during the development of hepatocarcinogenesis in rats in our previous studies. Here, an attempt has been made to investigate whether the dose and form of selenium found to be effective during hepatocarcinogenesis is equally effective in N-methylnitronitrosoguanidine-induced colorectal carcinogenesis in terms of antioxidant defence enzyme systems, DNA chain breaks and incidences of aberrant crypt foci. Treatment with selenomethionine either on initiation or on selection/promotion, or during the entire experiment showed that selenomethionine was most effective in regulating the cellular antioxidant defence systems, DNA chain break control and reducing aberrant crypt foci in the colorectal tissues of rats. Our results also confirm that selenium is particularly effective in limiting the action of the carcinogen during the initiation phase of this colorectal carcinogenesis, just as we found with hepatocarcinogenesis in our previous studies.     

Herpes simplex virus type 1 amplicon vector-mediated gene transfer to muscle.

Herpes simplex virus type 1 (HSV-1) amplicon vectors were evaluated for feasibility in gene therapy of Duchenne's muscular dystrophy (DMD). An amplicon vector expressing enhanced green fluorescent protein (eGFP) was examined for transduction efficiency and cytotoxicity in cultured muscle cells, and for transduction efficiency, duration of transgene expression, and immunogenicity in tibialis anterior (TA) muscles of neonatal mice. Transduction efficiencies in murine and human myoblasts were 60-90 and 50-60%, respectively, when myoblasts were transduced at multiplicities of infection (MOIs) of 1-5. Similar transduction efficiencies were observed in myotubes of both species. No cytotoxic effects were noticed at an MOI of 10, the highest MOI tested. An amplicon vector, HyMD, containing the full-length mouse dystrophin cDNA and its muscle creatine kinase (MCK) promoter-enhancer, with a total size of 26 kb, was constructed and used to transduce mdx mouse myotubes. The expression of dystrophin in these cells was demonstrated by immunocytochemistry. After injecting 4-6 x 10(5) transduction units (TU) of HSVGN amplicon vectors, 10-50% of myofibers in the injected TA muscles expressed GFP. Although transgene expression was attenuated over time, significant improvement in long-term transgene expression and persistence of vector DNA was achieved, when compared with the first generation of recombinant HSV-1 vectors. Immunohistochemistry showed a modest CD4(+) lymphocyte infiltration in the vicinity of the injection. A gradually developed CD8(+) lymphocyte infiltration was also seen, most likely related to the antigenicity of the transgene product, GFP. We conclude that the HSV-1 amplicon vector is a promising vehicle for gene delivery in DMD. However, new strategies need to be evaluated to increase the stability of transgene expression.     

Targeted disruption of the estrogen receptor-alpha gene in female mice: characterization of ovarian responses and phenotype in the adult.

Targeted disruption of the mouse estrogen receptor-alpha gene (estrogen receptor-alpha knockout; ERKO) results in a highly novel ovarian phenotype in the adult. The ERKO mouse model was used to characterize ER alpha-dependent processes in the ovary. Visualization of the ovaries of 10-, 20-, and 50-day-old wild-type (WT) and ERKO mice showed that the ERKO phenotype developed between 20 and 50 days of age. Developmental progression through the primordial, primary, and antral follicle stages appeared normal, but functional maturation of preovulatory follicles was arrested resulting in atresia or in anovulatory follicles, which in many cases formed large, hemorrhagic cysts. Corpora lutea were absent, which also indicates that the normal biochemical and mechanical processes that accomplish ovulation were compromised. Northern and ribonuclease protection analyses indicated that ERKO ovary FSH receptor (FSHR) messenger RNA (mRNA) expression was approximately 4-fold greater than in WT controls. Ovarian LH receptor (LHR) mRNA expression was also higher in the ERKO animals. Cellular localization studies by in situ hybridization analysis of ERKO ovaries showed a high level of LHR mRNA expression in the granulosa and thecal layers of virtually all the antral follicles. Ribonuclease protection analyses showed that ovarian progesterone receptor and androgen receptor mRNA expression were similar in the two groups. These results indicated that ER alpha action was not a prerequisite for LHR mRNA expression by thecal or granulosa cells or for ovarian expression of progesterone receptor mRNA. Ovarian estrogen receptor beta (ER beta) was detected immunohistochemically, was sharply compartmentalized to the granulosa cells, and was expressed approximately equally in the ERKO animals and the WT controls. In contrast, ER alpha staining was present in the thecal cells but not the granulosa cells of the WT animals. The summary findings indicate that in the adult the major cause of the ERKO phenotype is high circulating LH interacting with functional LHR of the theca and granulosa cells. These features result in a failure of the normal maturational events leading to successful ovulation and luteinization and presumably involve both hypothalamic-pituitary and intraovarian mechanisms dependent upon ER alpha action. The presence of ER beta in the granulosa cells did not rescue the phenotype of the ovary.     

TNF receptor gene therapy results in suppression of IgG2a anticollagen antibody in collagen induced arthritis

BACKGROUND: Therapeutic strategies to block tumour necrosis factor alpha (TNFalpha) activity in experimental autoimmune arthritis models and rheumatoid arthritis (RA) have proved highly successful, and provide sustained beneficial effects. OBJECTIVE: To examine whether TNFalpha inhibition has immunological activity beyond the reduction of inflammation in collagen induced arthritis (CIA), an established experimental model of RA. METHODS: Arthritic DBA/1 mice received single periarticular injections of retroviral constructs encoding human TNF receptor (TNF-R) into the affected arthritic paw, at the onset of arthritis. Severity of arthritis, antibodies to collagen type II (CII), and extent of pathological joint damage of arthritic paws were compared between TNF-R and media treated (control) animals 3, 7, 14, 21, and 49 days after disease onset. RESULTS: Severity of CIA was significantly decreased in TNF-R treated animals compared with controls, 14-34 days after disease onset. Joint destruction was reduced in TNF-R injected joints and in the uninjected contralateral and ipsilateral paws of TNF-R treated animals. Seven days after disease onset, TNF-R treated mice had lower levels of inflammatory Th1 driven IgG2a antibodies to CII (p<0.05) than controls. This altered the anticollagen IgG2a:IgG1 ratio towards Th2 driven IgG1. CONCLUSIONS: Local TNF-R gene therapy in CIA appears to have systemic effects on the anti-CII antibodies. The overall influence of TNF-R gene therapy is that it inhibits the progression of CIA mainly by suppressing the inflammatory Th1 response rather than by stimulating a Th2 response. Therefore, periarticular TNF-R gene therapy may have excellent therapeutic potential in RA.     

Alcoholic organic brain disease: nosology and pathophysiologic mechanisms

Study of alcoholic chronic organic brain syndrome may have applicability to the large population of alcoholics with less severe cerebral dysfunction. Brain impairment in alcoholics may be conceptualized as two clinically and neuropathologically distinguishable organic brain syndromes: alcohol amnestic disorder or Korsakoff's psychosis (KP) and alcoholic dementia. Alcoholic organic brain disease may result from two interacting pathophysiological processes: nutritional (thiamine) deficiency and ethanol neurotoxicity. Subcortical periventricular lesions associated with KP result primarily from thiamine deficiency, whereas ethanol neurotoxicity and various secondary effects of alcoholism may contribute to the cortical neuropathological changes associated with alcoholic dementia. These two patterns of brain damage may be differentiable in individual alcoholics using cognitive tests and other measures of CNS function and, therefore, allow selection of a treatment strategy based on pathophysiological considerations. Studies in animals and humans suggest that a genetic predisposition to thiamine deficiency may contribute to alcoholism-associated dysfunction of brain and other organ systems and possibly have a causative role in the development of alcoholism.     

Culture media variation as related to in vitro aging of human fibroblasts: I. Effects on population doubling, nuclear volume and nuclear morphology

The relative effect of five commonly used culture media (MEM, BME, McCoy's 5A, M199 and HMEM) on the population doubling level (PDL), nuclear volume and nuclear morphology was examined during in vitro senescence of WI-38 human fetal fibroblasts. Statistical analyses showed that cells grown in M199 had a significantly lower PDL than that of cells cultured in any other medium. The PDL in McCoy's 5A was significantly lower compared to that in BME, MEM and HMEM. Cells grown in BME, MEM and HMEM showed similar PDL. It was found that the nuclei of aged cells grown in M199 were significantly larger in volume than cells aged in any other medium. The average increases in nuclear volume of cells during aging in BME, MEM and McCoy's 5A were statistically equivalent. The increase in nuclear volume in HMEM was significantly smaller than that of cells aging in M199 and was longer than that of cells aging in BME or MEM. Linear regression analysis showed that there was a linear increase in nuclear volume as a function of PDL for cells aged in all five media. However, the rate of increase in nuclear volume with increasing PDL varied from medium to medium. There was no significant difference between media on induction of abnormal nuclear morphology as related to PDL. The relative effects of all five media were not uniform on the three cellular parameters investigated during in vitro aging of WI-38 cells. It is, therefore, suggested that one should keep this medium differential in mind to allow meaningful comparison of possible changes in various morphological parameters during in vitro senescence of diploid human fibroblasts such as WI-38.     

Phenotypic characterisation of breast cancer: the role of CDC42

Purpose

We aimed to evaluate the adoption of hypofractionated whole-breast irradiation (HF-WBI) over time and factors related to its adoption for patients undergoing lumpectomy. We also examined whether HF-WBI can increase the overall use of radiotherapy.

Methods

Using data from the National Cancer Database between 2004 and 2013, we identified 528,051 invasive and 190,431 ductal carcinoma in situ (DCIS) patients who underwent lumpectomy. HF-WBI was defined as 2.5–3.33 Gy/fraction to the breast, whereas conventional therapy (CF-WBI) was defined as 1.8–2.0 Gy/fraction.

Results

The usage of HF-WBI among invasive cancer patients increased from 0.7% in 2004 to 15.6% in 2013, and among DCIS patients, HF-WBI increased from 0.4% in 2004 to 13.4% in 2013. However, these changes only lead to a slight increase in the overall use of radiotherapy. Interestingly, for DCIS patients who lived ≥50 miles from hospitals, the uptake of HF-WBI translated to a moderate increase in the overall use of radiotherapy (58% in 2004 to 63% in 2013). Multivariable logistic regression showed that older age, node-negative or smaller tumor, living in mountain states, rural area, or ≥50 miles from hospitals, and treated in large or academic cancer centers were associated with elevated HF-WBI use. The median duration of finishing radiotherapy for HF-WBI was 26 days, compared to 47 days for CF-WBI.

Conclusions

Although HF-WBI can save 3 weeks of patient time, its adoption remained low in the US. There was only a slight increase in the overall use of radiotherapy among patients undergoing lumpectomy.

     

Odontogenic Tumours of Jaw: A Prospective Study on Clinico-Pathological Profile and Their Management

Odontogenic tumours are a group of heterogeneous diseases that range from hamartomatous or non-neoplastic tissue proliferations to benign neoplasms to malignant tumours with metastatic potential. They are rare, comprising about <2–3% of all oral and maxillofacial biopsy specimens. The aim of the present study was to determine the clinico-pathological presentation of this heterogeneous group of lesions and review of literature. The present study was conducted in the ENT department of a Government Medical College and Hospital, West Bengal, India, over the period of 5 years from January 2011 to December 2015. It included a total of 15 patients who were clinico-radiologically diagnosed as odontogenic tumours, and were given appropriate treatment. Their diagnostic and management approaches are discussed. Among 15 odontogenic tumours, 13 were benign and two were malignant. Male to female ratio was 2:3. Mandible to maxilla ratio was 1.8:1. The patients were in between 4 and 56 years of age with highest incidence in 3rd decade of life. All patients are doing well till date with a minimum follow-up of 1 year. Incisional biopsy is considered as gold standard for preoperative diagnosis but FNAC can offer clinicians a less invasive alternative. CT is the choice of investigation for study of lesion, analysis of its extension and surgical planning. The challenge to proper management lies in balancing between conservative and radical approach to reduce morbidity and recurrence both. Final diagnosis is made by post-operative histopathological examination.