National Jewish Health

About: National Jewish Health is a healthcare organization based out in Denver, Colorado, United States. It is known for research contribution in the topics: Asthma & T cell. The organization has 883 authors who have published 833 publications receiving 79201 citations. The organization is also known as: National Jewish Medical and Research Center.

Changes in cyclic adenosine 3':5'-monophosphate-dependent protein kinases during the progression of urethan-induced mouse lung tumors.

Abstract: The cyclic adenosine 3′:5′-monophosphate (cAMP)-dependent protein kinases in lung adenomas are functionally different from those of normal lung. The relevance of this change to neoplastic conversion was examined by comparing tumor kinases with those obtained from the normal cell of origin and by studying the kinases at different stages of tumor growth. Lung tumors were collected from A strain mice at different times after a single injection of urethan. These tumors are predominantly of alveolar type two cell origin, and cAMP-binding proteins in extracts from isolated type two cells and from lung adenomas at various stages of tumor progression were compared. Both the incorporation of the cAMP photoaffinity analogue, cyclic 8-azidoadenosine 3′:5′-[ 32 P]monophosphate (8-N 3 -[ 32 P]cAMP), into the regulatory subunits of the type I (R I ) and type II (R II ) cAMP-dependent protein kinases and the autophosphorylation of R II were similar in extracts from whole normal lung and from type two cells. Altered protein kinases are thus not characteristic of normal type two cells. Lung tumors showed a decrease in photodetectable R II which correlated in degree with tumor size and extent of anaplasticity. This decreased R II photolabeling during tumor growth was associated with increased R II autophosphorylation. In contrast, decreased R II photolabeling in extracts from neonatal lung is accompanied by a substantial decrease in R II autophosphorylation. The characteristics of R II during normal development thus clearly differ from those during neoplastic development. An increase in the amount of an M r 37,000 proteolytic fragment derived from R-subunits was also noted as a function of tumor progression. DEAE-cellulose chromatography of tumor cytosol showed that the increase in the amount of M r 37,000 protein was accompanied by increased subunit dissociation of the type I isozyme. The dissociated R I subunit has been shown to be more sensitive to cleavage by a Ca 2+ -dependent neutral protease than when R I was in the holoenzyme form. This protease is present in both normal lung and lung adenomas, and its activity increases during the later stages of tumor progression. A comparison of cAMP binding and the light-induced covalent incorporation of 8-N 3 -[ 32 P]cAMP showed that, for both R I and R II , photoincorporation was about 75% as efficient as noncovalent binding. In contrast, although the M r 37,000 fragment can be photolabeled with low concentrations of 8-N 3 -[ 32 P]cAMP, noncovalent cAMP binding to the endogenous M r 37,000 fragment could not be demonstrated with a standard filtration assay. Such altered cAMP binding characteristics following Ca 2+ -dependent proteolysis of R-subunits would allow significant synergism of cAMP and Ca 2+ on protein kinase activation.

TRPM6 kinase activity regulates TRPM7 trafficking and inhibits cellular growth under hypomagnesic conditions.

Abstract: The channel kinases TRPM6 and TRPM7 are both members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels and the only known fusions of an ion channel pore with a kinase domain. TRPM6 and TRPM7 form functional, tetrameric channel complexes at the plasma membrane by heteromerization. TRPM6 was previously shown to cross-phosphorylate TRPM7 on threonine residues, but not vice versa. Genetic studies demonstrated that TRPM6 and TRPM7 fulfill non-redundant functions and that each channel contributes uniquely to the regulation of Mg(2+) homeostasis. Although there are indications that TRPM6 and TRPM7 can influence each other's cellular distribution and activity, little is known about the functional relationship between these two channel-kinases. In the present study, we examined how TRPM6 kinase activity influences TRPM7 serine phosphorylation, intracellular trafficking, and cell surface expression of TRPM7, as well as Mg(2+)-dependent cellular growth. We found TRPM7 serine phosphorylation via the TRPM6 kinase, but no TRPM6 serine phosphorylation via the TRPM7 kinase. Intracellular trafficking of TRPM7 was altered in HEK-293 epithelial kidney cells and DT40 B cells in the presence of TRPM6 with intact kinase activity, independently of the availability of extracellular Mg(2+), but TRPM6/7 surface labeling experiments indicate comparable levels of the TRPM6/7 channels at the plasma membrane. Furthermore, using a complementation approach in TRPM7-deficient DT40 B-cells, we demonstrated that wild-type TRPM6 inhibited cell growth under hypomagnesic cell culture conditions in cells co-expressing TRPM6 and TRPM7; however, co-expression of a TRPM6 kinase dead mutant had no effect-a similar phenotype was also observed in TRPM6/7 co-expressing HEK-293 cells. Our results provide first clues about how heteromer formation between TRPM6 and TRPM7 influences the biological activity of these ion channels. We show that TRPM6 regulates TRPM7 intracellular trafficking and TRPM7-dependent cell growth. All these effects are dependent upon the presence of an active TRPM6 kinase domain. Dysregulated Mg(2+)-homeostasis causes or exacerbates many pathologies. As TRPM6 and TRPM7 are expressed simultaneously in numerous cell types, understanding how their relationship impacts regulation of Mg(2+)-uptake is thus important knowledge.

Rituximab for the treatment of connective tissue disease-associated interstitial lung disease

Abstract: Objective: To describe our experience with rituximab (RTX) as treatment for a diverse spectrum of chronic connective tissue disease-associated interstitial lung disease (CTD-ILD). Methods: Twenty-four subjects with CTD-ILD were included. All had pulmonary function testing before and after their first RTX infusion. Each subject was evaluated in a multidisciplinary autoimmune and ILD outpatient clinic. Data were extracted by retrospective review of complete medical records. Results: Most subjects were middle-aged white women with rheumatoid arthritis (RA) (n=15) and a nonspecific interstitial pneumonia (NSIP) pattern on high-resolution chest computed tomography scans (n=17). Sixteen subjects received a corticosteroid-sparing agent at the time of RTX initiation; mostly mycophenolate mofetil (n=8). RTX administration was not associated with corticosteroid-sparing effects: 13 subjects were on prednisone at the time of the initial RTX cycle, and 9 remained on prednisone at 6 months after (mean daily dosage 10.2±16.2 mg before vs. 5.6±11.0 mg after, p=0.27). RTX had no appreciable effect on pulmonary physiology; however, individual trajectories for percentage predicted forced vital capacity (FVC%) were highly variable. The underlying CTD (RA vs. non-RA) and ILD pattern did not appear to affect response to RTX. Among 14 subjects who received multiple RTX cycles, FVC% trajectories were variable: FVC% increased in eight and declined in six. Respiratory infections were the most common post-RTX adverse event. Conclusion: In this small, retrospective study of chronic CTD-ILD, RTX was not associated with changes in FVC% or corticosteroid-sparing effects. Controlled, prospective studies are needed to more confidently define the effects of RTX in CTD-ILD. (Sarcoidosis Vasc Diffuse Lung Dis 2015; 32: 296-304)

Default network response to a working memory challenge after withdrawal of continuous positive airway pressure treatment for obstructive sleep apnea.

Abstract: Lower working memory performance and altered brain activity have been reported in studies of obstructive sleep apnea (OSA) patients. However, little is known about the effect of treatment of OSA on brain function, particularly effects on default network processing. We previously reported increased brain response to a working memory challenge in active regions and decreased response in relatively deactivated a priori regions of interest (ROIs) following withdrawal of continuous positive airway pressure (CPAP) treatment. This follow-up analysis was conducted to examine the effects of CPAP withdrawal on default network processing using empirically defined ROIs analyses (i.e., in ROIs exhibiting significant deactivation in the sample). Ten OSA patients performed a 2-Back working memory task during functional magnetic resonance imaging in two separate conditions, following regular CPAP use, and after two nights of CPAP withdrawal. Eleven clusters of significant 2-Back-related deactivation consistent with the default network were identified and further examined for CPAP withdrawal effects. Significant further deactivation relative to the treatment adherent baseline was observed in the majority of these ROIs during the withdrawal condition. The magnitude of deactivation during withdrawal was significantly associated with better working memory performance in the posterior cingulate and right postcentral gyrus, and greater sleepiness in the left and right medial frontal gyrus. Results suggest that default network functions are further suspended as a result of a shifting of attention towards a more difficult active task in the context of lowered attentional capacity related to sleepiness.

A comparison of anti-DNA antibodies from serum and kidney eluates of NZB x NZW F1 mice.

Abstract: The qualitative aspects of anti-DNA antibodies from the serum and those eluted from the kidney of (NZB x NZW)F1 (B/W) mice were evaluated in terms of their class and subclass specificity, avidity and isoelectric profile Serum anti-DNA binding was demonstrated in both the IgG and IgM classes In addition, all subclasses of IgG studied (IgG1, IgG2a, and IgG2b) were shown to bind DNA Avidity measurements indicate that the avidity of isolated serum IgG for 125I labeled DNA decreases with age in B/W mice, while the avidity of isolated serum IgM remains relatively unchanged Anti-DNA antibodies eluted from kidneys were found to be predominantly of the IgG1 and IgG2a subclasses Equal amounts of both high and low avidity antibodies to DNA were demonstrated in the kidney eluates at all ages studied Furthermore, the dissociation curves of these antibodies remained relatively unchanged with age The isoelectric spectrum of serum antibodies to DNA obtained from mice at 4 to 11 months of age demonstrated considerable heterogeneity covering the pH range of 6 to 85 In contrast, the anti-DNA antibodies eluted from the kidney are slightly more basic in nature having isoelectric points between 72 to 90 This study suggests that distinct subpopulations of anti-DNA antibodies exist and that these may play an important role in the development of murine lupus nephritis