230 research outputs found
Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy
A major challenge of targeted cancer therapy is the selection for drugâresistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is a central regulator of protein homeostasis and a promising antiâcancer target because of its vital role in cell growth and survival. One ATPâcompetitive p97 inhibitor, CBâ5083, has entered clinical trials. Selective pressure on HCT116 cells treated with CBâ5083 identified 5 different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CBâ5083 resistant p97 mutants, N660K and T688A, were also resistant to several other ATPâcompetitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMSâ873 and UPCDCâ30245 were unaffected by these mutations. We also established a CBâ5083 resistant cell line that harbors a new p97 double mutation (D649A/T688A). While CBâ5083, NMSâ873, and UPCDCâ30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMSâ873 and UPCDCâ30245 were 30âfold more potent than CBâ5083 in inhibiting the CBâ5083 resistant D649A/T688A double mutant. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATPâcompetitive p97 inhibitors arises during antiâcancer treatment
Course of FEV1 after Onset of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients
Rationale: Bronchiolitis obliterans syndrome (BOS), defined by loss
of lung function, develops in the majority of lung transplant recipients.
However, there is a paucity of information on the subsequent
course of lung function in these patients.
Objectives: To characterize the course of FEV1 over time after development
of BOS and to determine the predictors that influence the
rate of functional decline of FEV1.
Methods: FEV1% predicted (FEV1%pred) trajectories were studied
in 111 lung transplant recipients with BOS by multivariate, linear,
mixed-effects statistical models.
Measurements and Main Results: FEV1%pred varied over time after
BOS onset, with the steepest decline typically seen in the first 6
months (12% decline; p < 0.0001). Bilateral lung transplant recipients
had significantly higher FEV1%pred at BOS diagnosis (71 vs.
47%; p < 0.0001) and at 24 months after BOS onset (58 vs. 41%;
p = 0.0001). Female gender and pretransplant diagnosis of idiopathic
pulmonary fibrosis were associated with a steeper decline
in FEV1%pred in the first 6 months after BOS diagnosis (p = 0.02
and 0.04, respectively). A fall in FEV1 greater than 20% in the
6 months preceding BOS (termed ârapid onsetâ) was associated
with shorter time to BOS onset (p = 0.01), lower FEV1%pred at
BOS onset (p < 0.0001), steeper decline in the first 6 months (p =
0.03), and lower FEV1%pred at 2 years after onset (p = 0.0002).
Conclusions: Rapid onset of BOS, female gender, pretransplant diagnosis
of idiopathic pulmonary fibrosis, and single-lung transplantation
are associated with worse pulmonary function after BOS onset.Supported in part by National Institutes of Health grants K23 HL077719 (V.N.L.)
and K24 HL04212 (F.J.M.), and by a grant from the American Society of Transplantation/
Chest Foundation (V.N.L.).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91969/1/2007 AJRCCM Course of FEV1 after Onset of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients.pd
Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy
A major challenge of targeted cancer therapy is the selection for drugâresistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is a central regulator of protein homeostasis and a promising antiâcancer target because of its vital role in cell growth and survival. One ATPâcompetitive p97 inhibitor, CBâ5083, has entered clinical trials. Selective pressure on HCT116 cells treated with CBâ5083 identified 5 different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CBâ5083 resistant p97 mutants, N660K and T688A, were also resistant to several other ATPâcompetitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMSâ873 and UPCDCâ30245 were unaffected by these mutations. We also established a CBâ5083 resistant cell line that harbors a new p97 double mutation (D649A/T688A). While CBâ5083, NMSâ873, and UPCDCâ30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMSâ873 and UPCDCâ30245 were 30âfold more potent than CBâ5083 in inhibiting the CBâ5083 resistant D649A/T688A double mutant. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATPâcompetitive p97 inhibitors arises during antiâcancer treatment
Mesenchymal stromal cells in bronchoalveolar lavage as predictors of bronchiolitis obliterans syndrome
Rationale: Bronchoalveolar lavage fluid (BAL) from human lung
allografts demonstrates the presence of a multipotentmesenchymal
stromal cell population. However, the clinical relevance of this novel
cellular component of BAL and its association with bronchiolitis
obliterans syndrome (BOS), a disease marked by progressive airflow
limitation secondary to fibrotic obliteration of the small airways,
remains to be determined.
Objectives: In this study we investigate the association of number of
mesenchymal stromal cells in BAL with development of BOS in
human lung transplant recipients.
Methods:Mesenchymal colony-forming units (CFUs)were quantitated
in a cohort of 405 BAL samples obtained from 162 lung transplant
recipients. Poisson generalized estimating equations were used to
determine the predictors of BAL mesenchymal CFU count.
Measurements and Main Results: Higher CFU counts were noted early
post-transplantation; time from transplant to BAL of greater than
3 months predicted 0.4-fold lower CFU counts (P = 0.0001). BOS
diagnosis less than or equal to 365 days before BAL was associated
with a 2.11-fold higher CFU count (P = 0.02). There were 2.62- and
2.70-fold higher CFU counts noted in the presence of histologic
diagnosis of bronchiolitis obliterans (P = 0.05) and organizing
pneumonia (0.0003), respectively. In BAL samples obtained from
BOS-free patients greater than 6 months post-transplantation (n =
173), higher mesenchymal CFU counts (>=10) significantly predicted
BOS onset in both univariate (hazard ratio, 5.61; 95%CI, 3.03â10.38;
P < 0.0001) andmultivariate (hazard ratio, 5.02; 95%CI, 2.40â10.51;
P < 0.0001) Cox regression analysis.
Conclusions: Measurement of mesenchymal CFUs in the BAL provides
predictive information regarding future BOS onset.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91951/1/2011 AJRCCM Mesenchymal stromal cells in bronchoalveolar lavage as predictors of bronchiolitis obliterans syndrome.pd
Dietary fibers inhibit obesity in mice, but host responses in the cecum and liver appear unrelated to fiber-specific changes in cecal bacterial taxonomic composition
Peer reviewedPublisher PD
Avian influenza at both ends of a migratory flyway: characterizing viral genomic diversity to optimize surveillance plans for North America
Although continental populations of avian influenza viruses are genetically distinct, transcontinental reassortment in low pathogenic avian influenza (LPAI) viruses has been detected in migratory birds. Thus, genomic analyses of LPAI viruses could serve as an approach to prioritize species and regions targeted by North American surveillance activities for foreign origin highly pathogenic avian influenza (HPAI). To assess the applicability of this approach, we conducted a phylogenetic and population genetic analysis of 68 viral genomes isolated from the northern pintail (Anas acuta) at opposite ends of the Pacific migratory flyway in North America. We found limited evidence for Asian LPAI lineages on wintering areas used by northern pintails in California in contrast to a higher frequency on breeding locales of Alaska. Our results indicate that the number of Asian LPAI lineages observed in Alaskan northern pintails, and the nucleotide composition of LPAI lineages, is not maintained through fall migration. Accordingly, our data indicate that surveillance of Pacific Flyway northern pintails to detect foreign avian influenza viruses would be most effective in Alaska. North American surveillance plans could be optimized through an analysis of LPAI genomics from species that demonstrate evolutionary linkages with European or Asian lineages and in regions that have overlapping migratory flyways with areas of HPAI outbreaks
Structural insights into the function of the catalytically active human Taspase1
19 pags., 7 figs., 2 tabs.Taspase1 is an Ntn-hydrolase overexpressed in primary human cancers, coordinating cancer cell proliferation, invasion, and metastasis. Loss of Taspase1 activity disrupts proliferation of human cancer cells in vitro and in mouse models of glioblastoma. Taspase1 is synthesized as an inactive proenzyme, becoming active upon intramolecular cleavage. The activation process changes the conformation of a long fragment at the C-terminus of the α subunit, for which no full-length structural information exists and whose function is poorly understood. We present a cloning strategy to generate a circularly permuted form of Taspase1 to determine the crystallographic structure of active Taspase1. We discovered that this region forms a long helix and is indispensable for the catalytic activity of Taspase1. Our study highlights the importance of this element for the enzymatic activity of Ntn-hydrolases, suggesting that it could be a potential target for the design of inhibitors with potential to be developed into anticancer therapeutics.This project has been funded in whole with Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Chemical Biology Consortium contract no. HHSN261200800001E
Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia
Idiopathic interstitial pneumonias are a diverse group of lung diseases
with varied prognoses. We hypothesized that changes in
physiologic and radiographic parameters would predict survival.
We retrospectively examined 80 patients with usual interstitial
pneumonia and 29 patients with nonspecific interstitial pneumonia.
Baseline characteristics were examined together with 6-month
change in forced vital capacity, diffusing capacity for carbon monoxide,
and ground glass infiltrate and fibrosis on high resolution computed
tomography. Patients with usual interstitial pneumonia were
more likely to have a statistically significant or marginally significant
decline in lung volume, diffusing capacity for carbon monoxide,
and an increase in ground glass infiltrates (p <= 0.08) compared
with patients with nonspecific interstitial pneumonia. For patients
with usual interstitial pneumonia, change in forced vital capacity
was the best physiologic predictor of mortality (p = 0.05). In a
multivariate Cox proportional hazards model controlling for histopathologic
diagnosis, gender, smoking history, baseline forced vital
capacity, and 6-month change in forced vital capacity, a decrease
in forced vital capacity remained an independent risk factor for
mortality (decrease > 10%; hazard ratio 2.47; 95% confidence interval
1.29, 4.73; p = 0.006). We conclude that a 6-month change
in forced vital capacity gives additional prognostic information to
baseline features for patients with idiopathic interstitial pneumonia.Supported by National Institutes of Health NHLBI grants P50HL46487, NIH/NCRR
3 MO1 RR00042-33S3, NIH/NIA P60 AG08808-06, NHLBI, 1 K24 HL04212, and
1 K23 HL68713.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91973/1/2003 AJRCCM - Prognostic Implications of Physiologic and Radiographic Changes in Idiopathic Interstitial Pneumonia.pd
Middle pleistocene glaciation in Patagonia dated by cosmogenic-nuclide measurements on outwash gravels
The well-preserved glacial record in Argentine Patagonia offers a ~ 1 Ma archive of terrestrial climate extremes in southern South America. These glacial deposits remain largely undated beyond the range of radiocarbon dating at ca. 40 ka. Dating old glacial deposits (> several 105 a) by cosmogenic surface exposure methods is problematic because of the uncertainty in moraine degradation and boulder erosion rates. Here, we show that cobbles on outwash terraces can reliably date âoldâ glacial deposits in the Lago PueyrredĂłn valley, 47.5° S, Argentina. Favorable environmental conditions (e.g., aridity and strong winds) have enabled continuous surface exposure of cobbles and preservation of outwash terraces. The data demonstrate that nuclide inheritance is negligible and we therefore use the oldest surface cobbles to date the deposit. 10Be concentrations in outwash cobbles reveal a major glacial advance at ca. 260 ka, concurrent with Marine Isotope Stage 8 (MIS 8) and dust peaks in Antarctic ice cores. A 10Be concentration depth-profile in the outwash terrace supports the age and suggests a low terrace erosion rate of ca. 0.5 mm kaâ 1. We compare these data to exposure ages obtained from associated moraines and find that surface boulders underestimate the age of the glaciation by ~ 100 ka; thus the oldest boulders in this area do not date closely moraine deposition. The 10Be concentration in moraine cobbles help to constrain moraine degradation rates. These data together with constraints from measured 26Al/10Be ratios suggest that all moraine boulders were likely exhumed after original deposition. We determine the local Last Glacial Maximum (LGM) occurred at ~ 27â25 ka, consistent with the maximum LGM in other parts of Patagonia
Idiopathic interstitial pneumonia: Do community and academic physicians agree on diagnosis?
Rationale: Treatment and prognoses of diffuse parenchymal lung
diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis
among observers is difficult.
Objectives: Evaluate diagnostic agreement between academic and
community-based physicians for patients with DPLDs, and determine
if an interactive approach between clinicians, radiologists,
and pathologists improved diagnostic agreement in community
and academic centers.
Methods: Retrospective review of 39 patients with DPLD. A total of
19 participants reviewed cases at 2 community locations and 1
academic location. Information from the history, physical examination,
pulmonary function testing, high-resolution computed tomography,
and surgical lung biopsy was collected. Data were presented
in the same sequential fashion to three groups of physicians on
separate days.
Measurements and Main Results: Each observerâs diagnosis was coded
into one of eight categories. A statistic allowing formultiple raters
was used to assess agreement in diagnosis. Interactions between
clinicians, radiologists, and pathologists improved interobserver
agreement at both community and academic sites; however, final
agreement was better within academic centers (Kappa= 0.55â0.71) than
within community centers (Kappa=0.32â0.44). Clinically significant
disagreement was present between academic and communitybased
physicians (Kappa=0.11â0.56). Community physicians were more
likely to assign a final diagnosis of idiopathic pulmonary fibrosis
compared with academic physicians.
Conclusions: Significant disagreement exists in the diagnosis of
DPLD between physicians based in communities compared with
those in academic centers. Wherever possible, patients should be
referred to centers with expertise in diffuse parenchymal lung disorders
to help clarify the diagnosis and provide suggestions regarding
treatment options.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91941/1/2007 AJRCCM Idiopathic interstitial pneumonia - Do community and academic physicians agree on diagnosis.pd
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