Survival and Failure Outcomes Predicted by Brain Metastasis Volumetric Kinetics in Melanoma Patients Following Upfront Treatment with Stereotactic Radiosurgery Alone.

Introduction The roles of early whole brain radiotherapy (WBRT) and upfront stereotactic radiosurgery (SRS) alone in the treatment of melanoma patients with brain metastasis remain uncertain. We investigated the volumetric kinetics of brain metastasis development and associations with clinical outcomes for melanoma patients who received upfront SRS alone. Methods Volumetric brain metastasis velocity (vBMV) was defined as the volume of new intracranial disease at the time of distant brain failure (DBF) for the first DBF (DBF1) and second DBF (DBF2) averaged over the time since initial or most recent SRS.

Staged Stereotactic Radiosurgery for Large Brain Metastases: Local Control and Clinical Outcomes of a One-Two Punch Technique.

Background: Treatment options are limited for large, unresectable brain metastases.

Objective: To report a single institution series of staged stereotactic radiosurgery (SRS) that allows for tumor response between treatments in order to optimize the therapeutic ratio.

Methods: Patients were treated with staged SRS separated by 1 mo with a median dose at first SRS of 15 Gy (range 10-21 Gy) and a median dose at second SRS of 14 Gy (range 10-18 Gy).

Exploiting pre-rRNA processing in Diamond Blackfan anemia gene discovery and diagnosis.

Diamond Blackfan anemia (DBA), a syndrome primarily characterized by anemia and physical abnormalities, is one among a group of related inherited bone marrow failure syndromes (IBMFS) which share overlapping clinical features. Heterozygous mutations or single-copy deletions have been identified in 12 ribosomal protein genes in approximately 60% of DBA cases, with the genetic etiology unexplained in most remaining patients. Unlike many IBMFS, for which functional screening assays complement clinical and genetic findings, suspected DBA in the absence of typical alterations of the known genes must frequently be diagnosed after exclusion of other IBMFS.

p53-Independent cell cycle and erythroid differentiation defects in murine embryonic stem cells haploinsufficient for Diamond Blackfan anemia-proteins: RPS19 versus RPL5.

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome caused by ribosomal protein haploinsufficiency. DBA exhibits marked phenotypic variability, commonly presenting with erythroid hypoplasia, less consistently with non-erythroid features. The p53 pathway, activated by abortive ribosome assembly, is hypothesized to contribute to the erythroid failure of DBA.

Mitochondrial function is impaired in yeast and human cellular models of Shwachman Diamond syndrome.

Shwachman Diamond syndrome (SDS) is an inherited bone marrow failure syndrome typically characterized by neutropenia, exocrine pancreas dysfunction, metaphyseal chondrodysplasia, and predisposition to myelodysplastic syndrome and leukemia. SBDS, the gene affected in most cases of SDS, encodes a protein known to influence many cellular processes including ribosome biogenesis, mitotic spindle assembly, chemotaxis, and the regulation of reactive oxygen species production. The best characterized role for the SBDS protein is in the production of functional 60S ribosomal subunits.

Impaired growth, hematopoietic colony formation, and ribosome maturation in human cells depleted of Shwachman-Diamond syndrome protein SBDS.

Background: Shwachman-Diamond syndrome (SDS), associated with SBDS mutations, is characterized by pancreatic exocrine dysfunction and marrow failure. Sdo1, the yeast ortholog of SBDS, is implicated in maturation of the 60S ribosomal subunit, with delayed export of 60S-like particles from the nucleoplasm when depleted. Sdo1 is needed for release of the anti-subunit association factor Tif6 from 60S subunits, and Tif6 may not be recycled to the nucleus when Sdo1 is absent.

Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging because the phenotype is highly dependent on the level of RPS19 down-regulation.

Salvador protein is a tumor suppressor effector of RASSF1A with hippo pathway-independent functions.

The RASSF1A tumor suppressor binds and activates proapoptotic MST kinases. The Salvador adaptor protein couples MST kinases to the LATS kinases to form the hippo pathway. Upon activation by RASSF1A, LATS1 phosphorylates the transcriptional regulator YAP, which binds to p73 and activates its proapoptotic effects.

Finding a diamond in the (mouse is) rough.

In this issue of Blood, Devlin and colleagues use a new strategy to create a mouse model for the inherited bone marrow failure syndrome, DBA.The result, while recapitulating certain aspects of the disease and representing a positive step forward, also demonstrates that significant hurdles remain in faithfully creating a mammalian model for DBA.

Direct binding of Fas-associated death domain (FADD) to the tumor necrosis factor-related apoptosis-inducing ligand receptor DR5 is regulated by the death effector domain of FADD.

Members of the tumor necrosis factor superfamily of receptors induce apoptosis by recruiting adaptor molecules through death domain interactions. The central adaptor molecule for these receptors is the death domain-containing protein Fas-associated death domain (FADD). FADD binds a death domain on a receptor or additional adaptor and recruits caspases to the activated receptor.