Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers

Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients

Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease

Pathologic fracture of the femur neck as first manifestation of a minute columnar cell carcinoma of the thyroid gland.

This case report concerns a 64 year-old woman who presented a pathologic fracture of the femur neck. Histologic examination of the performed bone biopsy disclosed the presence of a carcinomatous metastasis with unusual microscopic features. The site of the primary tumor could be unequivocally determined as being the thyroid gland, as immunostaining of the tumor cells showed positivity with anti-thyroglobulin. The thyroidectomy specimen weighed 149 g, was nodular and partially calcified. Exhaustive microscopic examination finally revealed the presence of a minute columnar cell carcinoma, 0.6 cm in diameter, with obvious vascular invasion. This case illustrates well 1) the usefulness of immunostaining with anti-thyroglobulin in cases of bone metastasis with unusual microscopic features and unknown primary, as well as 2) the aggressiveness of this rare type of carcinoma of the thyroid

Myocarditis of mixed connective tissue disease: favourable outcome after intravenous pulsed cyclophosphamide.

A 30-year-old woman with mixed connective tissue disease was admitted with Wernicke's aphasia and progressive dyspnoea with chest pain. Multiple brain infarcts on a computed tomographic scan were compatible with a thromboembolic aetiology. Echocardiography showed marked hypokinesia of the posterior wall, biventricular dilatation and a decreased left-ventricle ejection fraction (40%). A diagnosis of myocarditis was made on myocardial biopsies disclosing interstitial lymphocytic infiltrates and myocardial fibre necrosis. A treatment with steroids and monthly pulsed cyclophosphamide was introduced. The heart function rapidly improved as assessed by a left-ventricle ejection fraction of 55% and remained stable 17 months thereafter