Von Hipple Lindau and Ubiquitin

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Figures 1: Ultrasound and CT images. There are cysts in the pancreas and kidneys. There are complex solid masses in both kidneys. There is tumor invasion of the right renal vein and IVC.

Figure 2: Chromosomal location for VHL gene

Von Hippel - Lindau syndrome is a multisystem disease characterized by hemangioblastomas of the cerrebellum, spinal cord, and retina, renal, pancreatic and hepatic cysts, clear cell renal cell carcinoma,endolymphatic sac tumors and pheochromocytoma. Retinal hemangioblastomas may be the first sign of VHL causing visual problems. Cerebellar hemangioblastomas may present with headache, vomiting, and ataxia. Multiple renal cysts are common in VHL syndrome. Renal cell carcinoma is the leading cause of mortality. Usually this is the clear cell type developing either within a cyst or in the surrounding parenchyma. Pheochromocytomas can be asymptomatic, but may cause hypertension. Endolymphatic sac tumors can cause hearing loss.

Changes in patterns of gene expression can result from relatively small changes in the concentrations of sequence - specific transcription factors. Hypoxia-inducible factor-1 (HIF 1) is a transcription factor found in mammalian cells cultured under reduced oxygen tension that plays an essential role in cellular and systemic homeostatic responses to hypoxia. (HIF 1 location 14q21-24). VHL encodes a ligase that promotes Ubiquitin degradation of the alpha subunits of the hypoxia-inducible transcription factors HIF 1, HIF 2, and HIF 3, leading to their degradation by the proteasome. Consequently, renal carcinomas with mutations in VHL have high steady-state levels of HIF expression. Functional studies show that HIF is sufficient for transformation caused by loss of VHL, thereby establishing HIF as the primary oncogenic driver in kidney cancers.

Loss of VHL sensitizes cancer cells to the rapomycin (mTOR) inhibitor CCI - 779 in vitro and in mouse models. Growth arrest caused by CCI - 779 correlated with a block in translation of mRNA encoding HIF 1A. VHL - deficient tumors showed increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR - dependent manner. The findings provided preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggested that FDG - PET scans may have use as a pharmacodynamic marker in this setting.

The highly vascular tumors associated with von Hippel - Lindau syndrome overproduce angiogenic peptides such as vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). VEGF mRNA is upregulated in von Hippel - Lindau syndrome-associated tumors.

VHL and transcription factor Sp1 directly interact with an inhibitory effect on Sp 1, suggesting that loss of transcription factor Sp1 inhibition may be important in the pathogenesis of von Hippel - Lindau syndrome and renal cell carcinoma. 12q13.1 is the most probable location of the SP 1 gene.

Reference: OMIM 608537

Addendum: Very interesting article by Prassad et al related to this case in Radiology for Nov-Dec 2006 with interesting commentary by Dr Peter L. Choyke

Follicular Lymphoma of the Duodenum; Volume Rendered PET-CT , BCL 2 and Apoptosis

Figure 1: PET CT with VR fusion images. Intense abnormal 18-FDG uptake is seen in the second portion og the duodenum.

Figure 2: Diagram outlining the action of Bcl-2 on the apoptosis sequence. Bcl-2 blocks Bak and Bax (also Bcl2 gene family members) from activating the release of cytochrome c and the capsase Source: Modified figure from Oakes Laboratory UCSF

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Follicular lymphoma is the most common of the non-Hodgkin's lymphomas. The tumor is composed of follicle center cells, usually a mixture of cleaved follicle center cellsor small cells and large noncleaved follicle center cells, or large cells". Large cells also known as centrocytes are the majority, but small cells or centroblasts are always present. Rarely follicular lymphomas consist almost entirely of centroblasts.

A translocation between chromosome 14 and 18 has been associated with the development of Follicular lymphoma, and results in the overexpression of the bcl2 (B-cell lymphoma 2) gene. This overexpression causes a blockage of apoptosis. Bcl-2 family genes govern mitochondrial membrane permeabilisation (MMP) and can be either pro-apoptopic (i.e. Bax, Bak and Bok) or anti-apoptopic (i.e. Bcl-2, Bcl-xL, and Bcl-w). There are a total of 25 known genes in the Bcl-2 family. There are several theories concerning how the actions Bcl-2 gene family on apoptosis. Modulation of cell death may be achieved by activation or inactivation of an inner mitochondrial permeability transition (PT) pore, which is involved in the regulation of matrix Ca2+, pH, and voltage. Some Bcl-2 family proteins can induce or inhibit the release of cytochrome c in to the cytosol which, once there, activates caspase-9 and caspase-3, leading to apoptosis. Zamzami et al. (1998) related the release of cytochrome c to the actions of the PT pore on the inner mitochondrial membrane. The site of action for the Bcl-2 family is mostly on the outer mitochondrial membrane.Within the mitochondria are the caspases, the apoptogenic factors like cytochrome that if released execute apoptosis. Bcl-2 proteins either promote the escape of these factors, or keep them locked in the mitochondria. The protein Bcl-2 is an anti-apoptotic protein that resides in the outer mitochondrial membrane and the membrane of the endoplasmic reticulum. Over expression of Bcl-2 is known to block cytochrome c release, possibly through the inhibition of Bax and Bak. Bcl-2 genes have been implicated in cancer, including melanoma, breast, prostate and lung carcinomas. It is also thought to be involved in resistance to conventional cancer treatment (Bast et al., 2000). In follicular B-cell lymphoma, t(14;18) translocation which places the Bcl-2 gene next to the immunoglobulin heavy chain gene locus occurs.The Bcl-2 gene is deregulated, leading to the transcription of excessively high levels of anti-apoptopic bcl-2 protein (Vaux et al 1988). Targeted therapies are being developed. Genasense, an antisense oligonucleotide drug (G3139) has been developed to target Bcl-2. An antisense DNA or RNA strand is non-coding sequence of nucleotides, complementary to the coding strand of the target protein. An antisense drug is a short sequence of RNA which hybridises with and inactivates mRNA, preventing the protein from being formed.It was shown that the proliferation of human lymphoma s (with t(14;18) translocation) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. Genasense is complementary to the first 6 codons of Bcl-2 mRNA (Dias and Stein 2002). These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial is currently underway (Mavoromatis and Cheson 2004). There is no consensus regarding the best treatment for follicular lymphoma, conservative observation, alkylators, anthracycline regimens like. CHOP, rituximab, stem cell transplanation have all been used. The disease is generally regarded as incurablewith the exception of localised disease, which can be cured by radiation. The typical pattern is one of good responses, followed by relapse years later. Median survival is around 10 years, ranging from less than one year, to more than 20 years. Some patients may never need treatment.

References

Dias N, Stein CA. Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. Eur J Pharm Biopharm 2002;54:263-9. PMID 12445555.

Oltersdorf T, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 435:677-681. PMID: 15902208

Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988;335:440-2. PMID: 3262202.

Mavromatis BH, Cheson BD. Novel therapies for chronic lymphocytic leukemia. Blood Rev 2004;18:137-48. PMID 15010151.

Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G. Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene 1998;16:2265-82. PMID 9619836

Myocardial Ischemia, Reperfusion Injury, Heat Shock Proteins and Chaperones

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Fig1: Tc99m Sestamibi Cardiac SPECT scan: reversible perfusion defect consistant with left anterior descending artery territory ischemia (arrows) Fig2: 3D conformational model of HSP 70 (source: imike.blogs.sapo.pt/ arquivo/hsp702.jpg)

Myocardial infarct and ischemia remain the number one cause of death in developed nations. Improved diagnosis and treatment have allowed the rapid reperfusion of myocardial tissue by surgical, interventional or pharmacological means, decreasing mortality and morbidity. Prolonged ischemia results in severe infarction and necrosis, reperfusion produces few beneficial effects and may contribute further to tissue reperfusion injury, including arrhythmia and myocardial stunning. Ischemic damage takes place in the absence of oxygen, whereas reperfusion damage is thought to be induced predominantly by oxygen-free radicals. The presence of oxygen-free radicals may contribute to calcium overload, protein malfolding, and partial protein denaturation leading to a decreased calcium binding and dysfunction of myofilament proteins. Myocardial protection against ischemia/reperfusion injury has been the subject of experimental and clinical research. In many animal species including humans, HSP (Heat Shock Proteins) 70/72 are upregulated during ischemia. During cardiac surgery the HSP induction is widely referred to as "ischemic preconditioning". The protective effect of HSP 70 against reperfusion injury and myocardial dysfunction can be explained with the known "chaperone" function of members of the HSP 70 family. Chaperones are proteins that bind to other proteins, facilitating proper protein folding, assembly, transport and translocation. They are highly conserved and could play a role in buffering mutations that could otherwise cause protein malfolding. In that role they could be important for evolution and biodiversity.

Source: Protection Against Myocardial Dysfunction After a Brief Ischemic Period in Transgenic Mice Expressing Inducible Heat Shock Protein 70 Susanne U. Trost, Jeffrey H. Omens, William J. Karlon, Markus Meyer, Ruben Mestril, James W. Covell, and Wolfgang H. Dillmann Division of Endocrinology & Metabolism, and Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0618. J. Clin. Invest. Vol 101. No 4. Feb 1998 855-862