Classic features of primary systemic amyloidosis (AL amyloidosis) leading to diagnosis of plasma cell myeloma.

The diagnosis of primary systemic amyloidosis, also known as AL (amyloid light-chain) amyloidosis, is often delayed owing to its nonspecific manifestations as well as its rarity. A 64-year-old woman presented with an eight-month history of significant weight loss, anemia, fatigue, and progressive painful cutaneous lesions on her hands, lips, back, perianal, and vulvar area that were originally treated unsuccessfully with antimalarials and systemic corticosteroids. Histopathological examination revealed an amorphous dermis with pale pink material that demonstrated positive birefringence with Congo red staining. Subsequently, the patient underwent a bone marrow biopsy, which uncovered a plasma cell myeloma, the source of her amyloidogenic protein production.

National Trends in Hospitalization for Fever and Neutropenia in Children with Cancer, 2007-2014.

OBJECTIVE: To assess the trends of inpatient resource use and mortality in pediatric hospitalizations for fever with neutropenia in the US from 2007 to 2014. STUDY DESIGN: Using National (Nationwide) Inpatient Sample (NIS) and International Classification of Diseases, Ninth Revision, Clinical Modification codes, we studied pediatric cancer hospitalizations with fever with neutropenia between 2007 and 2014. Using appropriate weights for each NIS discharge, we created national estimates of median cost, length of stay, and in-hospital mortality rates. RESULTS: Between 2007 and 2014, there were 104 315 hospitalizations for pediatric fever with neutropenia. The number of weighted fever with neutropenia hospitalizations increased from 12.9 (2007) to 18.1 (2014) per 100 000 US population. A significant increase in fever with neutropenia hospitalizations trend was seen in the 5- to 14-year age group, male sex, all races, and in Midwest and Western US hospital regions. Overall mortality rate remained low at 0.75%, and the 15- to 19-year age group was at significantly greater risk of mortality (OR 2.23, 95% CI 1.36-3.68, P = .002). Sepsis, pneumonia, meningitis, and mycosis were the comorbidities with greater risk of mortality during fever with neutropenia hospitalizations. Median length of stay (2007: 4 days, 2014: 5 days, P < .001) and cost of hospitalization (2007: $8771, 2014: $11 202, P < .001) also significantly increased during the study period. CONCLUSIONS: Our study provides information regarding inpatient use associated with fever with neutropenia in pediatric hospitalizations. Continued research is needed to develop standardized risk stratification and cost-effective treatment strategies for fever with neutropenia hospitalizations considering increasing costs reported in our study. Future studies also are needed to address the greater observed mortality in adolescents with cancer.

ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Mutations in Cu/Zn superoxide dismutase (SOD1) are responsible for approximately 20 % of the familial ALS cases. ALS-causing SOD1 mutants display a gain-of-toxicity phenotype, but the nature of this toxicity is still not fully understood. The Ras GTPase-activating protein-binding protein G3BP1 plays a critical role in stress granule dynamics. Alterations in the dynamics of stress granules have been reported in several other forms of ALS unrelated to SOD1. To our surprise, the mutant G93A SOD1 transgenic mice exhibited pathological cytoplasmic inclusions that co-localized with G3BP1-positive granules in spinal cord motor neurons. The co-localization was also observed in fibroblast cells derived from familial ALS patient carrying SOD1 mutation L144F. Mutant SOD1, unlike wild-type SOD1, interacted with G3BP1 in an RNA-independent manner. Moreover, the interaction is specific for G3BP1 since mutant SOD1 showed little interaction with four other RNA-binding proteins implicated in ALS. The RNA-binding RRM domain of G3BP1 and two particular phenylalanine residues (F380 and F382) are critical for this interaction. Mutant SOD1 delayed the formation of G3BP1- and TIA1-positive stress granules in response to hyperosmolar shock and arsenite treatment in N2A cells. In summary, the aberrant mutant SOD1-G3BP1 interaction affects stress granule dynamics, suggesting a potential link between pathogenic SOD1 mutations and RNA metabolism alterations in ALS.

Structure and substrate specificity of the pyrococcal coenzyme A disulfide reductases/polysulfide reductases (CoADR/Psr): implications for S(0)-based respiration and a sulfur-dependent antioxidant system in Pyrococcus.

FAD and NAD(P)H-dependent coenzyme A disulfide reductases/polysulfide reductases (CoADR/Psr) have been proposed to be important for the reduction of sulfur and disulfides in the sulfur-reducing anaerobic hyperthermophiles Pyrococcus horikoshii and Pyrococcus furiosus; however, the form(s) of sulfur that the enzyme actually reduces are not clear. Here we determined the structure for the FAD- and coenzyme A-containing holoenzyme from P. horikoshii to 2.7 Å resolution and characterized its substrate specificity. The enzyme is relatively promiscuous and reduces a range of disulfide, persulfide, and polysulfide compounds. These results indicate that the likely in vivo substrates are NAD(P)H and di-, poly-, and persulfide derivatives of coenzyme A, although polysulfide itself is also efficiently reduced. The role of the enzyme in the reduction of elemental sulfur (S(8)) in situ is not, however, ruled out by these results, and the possible roles of this substrate are discussed. During aerobic persulfide reduction, rapid recycling of the persulfide substrate was observed, which is proposed to occur via sulfide oxidation by O(2) and/or H(2)O(2). As expected, this reaction disappears under anaerobic conditions and may explain observations by others that CoADR is not essential for S(0) respiration in Pyrococcus or Thermococcus but appears to participate in oxidative defense in the presence of S(0). When compared to the homologous Npsr enzyme from Shewanella loihica PV-4 and homologous enzymes known to reduce CoA disulfide, the phCoADR structure shows a relatively restricted substrate channel leading into the sulfur-reducing side of the FAD isoalloxazine ring, suggesting how this enzyme class may select for specific disulfide substrates.

False-Positive Uptake in Splenic Hemangioma on 68 Ga-DOTATATE PET/CT.

ABSTRACT: Somatostatin receptor imaging using 68 Ga-DOTATATE PET is widely popular for evaluation of neuroendocrine tumors. 68 Ga-DOTATATE PET/CT shows highest physiologic uptake in spleen followed by other organs such as kidneys, adrenal glands, and liver. Hemangiomas, although rare, are the most common primary benign neoplasm of the spleen, composed of endothelial-lined vascular channels. We present a case of 77-year-old man who underwent 68 Ga-DOTATATE PET/CT scan for evaluation of pancreatic neuroendocrine tumor and incidentally demonstrated intense radiotracer uptake in splenic hemangiomata.

Prohibitin regulates TGF-beta induced apoptosis as a downstream effector of Smad-dependent and -independent signaling.

BACKGROUND: Prohibitin (PHB), a protein located on the inner mitochondrial membrane and nuclei, is an intracellular effector of transforming growth factor-beta (TGF-beta) signaling in prostate cancer cells. This study investigated the involvement of PHB in the apoptosis and survival outcomes of human prostate cancer cell to TGF-beta. shRNA PHB loss of function in prostate cancer cells led to enhanced apoptotic response to TGF-beta via Smad-dependent mechanism. METHOD: TGF-beta activation of Raf-Erk intracellular signaling, led to PHB phosphorylation, decreased inner mitochondrial permeability, and increased cell survival. Calcein-based immunofluorescence studies revealed the functional involvement of PHB in maintaining inner mitochondrial membrane permeability as an integral component of TGF-beta induced apoptosis in prostate cancer cells. RESULTS: These finding indicates that induction of TGF-beta apoptosis is mediated by Smad-dependent and Smad-independent signaling (MAPK) converging at PHB as a downstream effector regulating inner mitochondrial permeability. Putative PHB associated proteins were identified by subjecting TGF-beta treated cells to immunoprecipitation with anti-PHB, and mass spectrometry. A screen for the kinase specific phosphorylation sites of PHB revealed three protein kinase (PKC) binding sites. CONCLUSION: Our results demonstrate that TGF-beta led to upregulation of the PKC inhibitor 14-3-3 protein and promoted its association with PHB, while PHB association with PKC-delta, was inhibited by the MEK1 inhibitor, documenting a critical interdependence between the MEK-ERK signaling and prohibitin phosphorylation. These findings suggest a dual role for PHB as a downstream determinant of the cellular response to TGF-beta via Smad-dependent pathway (apoptosis) and MAPK intracellular signaling (survival).

Transforming growth factor beta and prostate cancer.

The TGF-beta superfamily is the most versatile considering the ability of its members to regulate proliferation, growth arrest, differentiation, and apoptosis of prostatic stromal and epithelial cells as well as the formation of osteoblastic metastases. TGF-beta mediated action in prostate cells follows a complex signaling pathway from binding and phosphorylation of receptor type II to the TbetaRI kinase to Smad activation, resulting in ligand-induced transcription. TGF-beta as an indirect tumor suppressor, its role of regulating tumor induction, as well as tumor suppression depending on the tissue microenvironment merits further exploration. The rationale for targeting growth factors and their receptors for therapeutic intervention is based upon the fact that these proteins represent the most proximate component of the signal transduction cascade. The alternate targeting of intracellular effectors in the signal transduction may be thwarted by cross talk between signaling pathways (such as the Smads in a dynamic interplay with the androgen receptor). TGF-beta within the context of its well-documented apoptosis regulatory actions in the prostate and the significance its key receptor TbetaRII as a potential tumor suppressor, provides a highly attractive candidate for such targeting with high clinical significance for the treatment and diagnosis of prostate cancer.