RECENT DEVELOPMENTS IN PROPERTY INSURANCE LAW Schreiner, William A.; Rooney, Carol M.; Lewis, William R. ...
Tort trial & insurance practice law journal,
01/2010, Volume:
45, Issue:
2
Journal Article
4 Relying heavily on Johnson, a Texas federal court granted an insured's motion to compel appraisal with respect to alleged property damage and business interruption losses, notwithstanding the ...insurer's arguments that the only issues for resolution were the duration of the period of restoration and other issues regarding the scope of covered damage.5 However, in Pearl River County School District v. RSUI Indemnity Co.,6 a federal court in Mississippi declined to follow Johnson and denied an insured's motion to compel appraisal where the court determined that coverage issues existed, and held that the court itself was required to determine coverage issues prior to submitting the matter for appraisal of the subject losses. By holding that the proper measure for bad faith damages arising out of Hurricane Katrina claims under Louisiana Statutes 22:658 is 25 percent of the covered damages, and not the 50 percent award provided by an amendment to that law in August 2006, Neal Auction may be significant for any ongoing Katrina-related bad faith claims.180 Also during the survey period, the Supreme Court of Alabama affirmed a bad faith verdict in State Farm Fire if Casualty Co. v. Wonderful Counselor Apostolic Faith Church.181 In a significant Indiana case, the Indiana Court of Appeals affirmed an award of consequential damages for breach of the insurance contract to a policyholder in excess of the insurance policy's limits in Rockford Mutual Insurance Co. v. Pirtle.182 In so holding, the court clarified earlier Indiana bad faith case law that suggested otherwise.183
B. Timeliness of Demand or Refusal to Appraise While most pobcies provide for mandatory appraisal if the parties dispute the amount of loss, the right to appraisal may be waived if it is not invoked ...in a timely fashion. ... in Ragas v. State Farm Fire & Casualty Co.,5 the U.S. District Court for the Eastern District of Louisiana held that an insured's demand for appraisal was untimely when it was made eight months after btigation commenced. ... in Rogers v. State Farm Fire & Casualty Co.,8 because the policyholder was not prejudiced in any way, the court held that State Farm did not waive its right to appraisal where it initially demanded appraisal before suit was filed, the policyholder refused to enter into appraisal, and State Farm did not renew the demand until over fourteen months after suit was filed and State Farm had "substantially invoked the litigation process."
Abstract
The NCI recently performed microarray expression analysis on its 60-panel of human tumor cell lines. This revealed important information, with some cell lines shown to be from a different ...tissue of origin than originally believed. Traditionally, potential anti-cancer agents have been evaluated in these in vitro models, and then moved into the corresponding in vivo xenograft model(s) based on the in vitro results. It has been shown that drugs which are effective in vitro are not necessarily effective in vivo and vice versa. Systematic microarray analysis of traditional xenograft models in conjunction with their in vitro counterparts has not been performed. The development of a human tumor xenograft in a mouse might be expected to lead to changes in gene expression, and this could account, in some instances, for the disconnect in results observed between in vitro and in vivo models. Our aim was to perform a genetic analysis against the entire human genome using 24 cell lines from 11 differing tissues of origin that were implanted into immune-deficient mice to establish a xenograft model for each. Once the tumors reached approximately 1 cm3 in size, the tumors were removed, cut into approx. 2-3 mm3 fragments, and an in vivo tumor passage was established. Microarray expression in fragments of those xenografted tumors was compared to microarray expression in the cell line from which they were developed. The total mRNA for each sample was split into 3 replicates, and analyzed against the entire human genome using standard Affx WT procedures. The results showed that over 60% (15 of 24) of the xenograft samples clustered with the cell line from which it was developed, whereas approximately 40% (9 of 24) did not, revealing that major changes in gene expression had occurred in 40% of these xenograft samples. Furthermore, when analyzed alone, these particular 24 cell line samples clustered according to their tissue of origin, whereas the tumor fragment samples did not appear to cluster. On the basis of these data we are currently performing the same analysis on an additional 25 tumor fragments and their corresponding matched cell lines to allow for a more accurate, in-depth cluster analysis. These data strongly suggest that although precedent exists to select in vitro models on the basis of their tissue of origin, no such precedent exists for in vivo models. In vivo models should be more carefully selected to ensure that the model chosen is still representative of the tissue to be tested. It follows that a drug candidate effective in a particular in vitro model might be expected to show activity in other in vitro lines from the same tissue of origin. However, a drug candidate effective in a particular in vivo model representative of a tissue of origin should not be expected to show efficacy in other in vivo models representing the same tissue type.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4418. doi:10.1158/1538-7445.AM2011-4418
Abstract
The total mRNA for each sample of 51 human tumor cell lines representative of 16 different tissues of origin was split into 3 replicates, and analyzed against the entire human genome using ...standard Affx WT procedures. Approximately 50% of the samples (25 out of the 51 cell lines tested) exhibited low-level clustering related to their tissue of origin. The remaining 50% (26 out of the 51 cell lines tested) did not cluster with other samples of the same tissue of origin. These data reveal the importance of testing potential anticancer agents in multiple models representative of several different tumors of origin, as there is a 50% chance that the model chosen is not actually representative of the intended tissue of origin. This analysis also showed that the pancreatic cancer cell line CFPAC-1 did not cluster with any other cell line tested, revealing the unique genetic profile of this cell line. Interestingly, the reported lung cancer cell lines NCI-H69 and NCI-H82 clustered more closely with leukemic lines than with lung or any other solid tumor. This is particularly interesting as these lines are known to grow/behave more like a suspension culture than a monolayer. The NCI recently published its genetic analysis of their 60-panel, and they revealed that the MDA-MB-435 cell line, traditionally thought to be a breast cancer cell line, more closely resembled a melanoma line; hence, it was re-classified as a melanoma (likely a metastasized melanoma that was taken from the breast site). Our analysis reveals that another traditional breast cancer cell line, UISO-BCA-1, also clusters more closely with the melanomas (including the MDA-MB-435 cell line), suggesting that this cell line also may have been misclassified. Based on these data, we suggest that any potential anticancer agent showing activity in a particular cell line should be tested in other cell lines that cluster with the active line, and not merely in other lines supposedly representative of the same tissue of origin. Furthermore, in early stage testing, it would be more prudent to test several cell lines from different clusters, rather than several cell lines from different tissues of origin. It follows that by testing orphan drugs against several cell lines from each cluster, it would be possible to significantly narrow (and possibly identify), the likely drug target.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3943. doi:10.1158/1538-7445.AM2011-3943
In cells, biosynthetic machinery coordinates protein synthesis and folding to optimize efficiency and minimize off-pathway outcomes. However, it has been difficult to delineate experimentally the ...mechanisms responsible. Using fluorescence resonance energy transfer, we studied cotranslational folding of the first nucleotide-binding domain from the cystic fibrosis transmembrane conductance regulator. During synthesis, folding occurred discretely via sequential compaction of N-terminal, α-helical, and α/β-core subdomains. Moreover, the timing of these events was critical; premature α-subdomain folding prevented subsequent core formation. This process was facilitated by modulating intrinsic folding propensity in three distinct ways: delaying α-subdomain compaction, facilitating β-strand intercalation, and optimizing translation kinetics via codon usage. Thus, de novo folding is translationally tuned by an integrated cellular response that shapes the cotranslational folding landscape at critical stages of synthesis.
Identification of human leukocyte antigen (HLA)-bound peptides by liquid chromatography-tandem mass spectrometry (LC-MS/MS) is poised to provide a deep understanding of rules underlying antigen ...presentation. However, a key obstacle is the ambiguity that arises from the co-expression of multiple HLA alleles. Here, we have implemented a scalable mono-allelic strategy for profiling the HLA peptidome. By using cell lines expressing a single HLA allele, optimizing immunopurifications, and developing an application-specific spectral search algorithm, we identified thousands of peptides bound to 16 different HLA class I alleles. These data enabled the discovery of subdominant binding motifs and an integrative analysis quantifying the contribution of factors critical to epitope presentation, such as protein cleavage and gene expression. We trained neural-network prediction algorithms with our large dataset (>24,000 peptides) and outperformed algorithms trained on datasets of peptides with measured affinities. We thus demonstrate a strategy for systematically learning the rules of endogenous antigen presentation.
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•24,000 HLA class I peptides were identified through a scalable MS-based pipeline.•Mono-allelic data revealed binding motifs that were validated biochemically.•Comprehensive analyses provide an updated portrait of antigen processing rules.•Neural networks were trained for 16 alleles and outperform standard by 2-fold.
HLA class I binding prediction has traditionally been based on biochemical binding experiments. Abelin and colleagues present an LC-MS/MS-based workflow and analytical framework that greatly accelerates gains in prediction performance. Key advances include the discovery of sequence motifs and improved quantification of the roles of gene expression and proteasomal processing.
The effects of plant color, pericarp thickness, pigmented testa, and spreader genes on phenols and antioxidant activity levels of 13 sorghum genotypes were evaluated. Total phenols, condensed ...tannins, flavan-4-ols, and anthocyanins were measured. Antioxidant activity levels using the 2,2‘-azinobis(3-ethyl-benzothiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl assays were evaluated. Sorghums with a pigmented testa and spreader genes (B1 B2 S) had the highest levels of phenols and antioxidant activity. In addition, sorghums with purple/red plants (PQ) and thick pericarp (z) genes had increased levels of phenols and antioxidant activity. Sorghums with a black pericarp had higher levels of flavan-4-ols and anthocyanins than the other varieties. This suggests that genes for plant color, pericarp thickness, presence of a pigmented testa, and spreader genes increase phenols and antioxidant activity levels. This information can be useful in the production of sorghums with increased phenols and antioxidant activity levels. Keywords: Sorghum bicolor (L.) Moench; total phenols; flavan-4-ols; anthocyanins; antioxidant activity; ABTS; DPPH
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that results in functional deficits. However, these functional declines are often not able to be quantified in clinical trials for ...DMD until after age 7. In this study, we hypothesized that (1)H2O T2 derived using (1)H-MRS and MRI-T2 will be sensitive to muscle involvement at a young age (5-7 years) consistent with increased inflammation and muscle damage in a large cohort of DMD subjects compared to controls.
MR data were acquired from 123 boys with DMD (ages 5-14 years; mean 8.6 SD 2.2 years) and 31 healthy controls (age 9.7 SD 2.3 years) using 3-Tesla MRI instruments at three institutions (University of Florida, Oregon Health & Science University, and Children's Hospital of Philadelphia). T2-weighted multi-slice spin echo (SE) axial images and single voxel 1H-MRS were acquired from the lower leg and thigh to measure lipid fraction and (1)H2O T2.
MRI-T2, (1)H2O T2, and lipid fraction were greater (p<0.05) in DMD compared to controls. In the youngest age group, DMD values were different (p<0.05) than controls for the soleus MRI-T2, (1)H2O T2 and lipid fraction and vastus lateralis MRI-T2 and (1)H2O T2. In the boys with DMD, MRI-T2 and lipid fraction were greater (p<0.05) in the oldest age group (11-14 years) than the youngest age group (5-6.9 years), while 1H2O T2 was lower in the oldest age group compared to the young age group.
Overall, MR measures of T2 and lipid fraction revealed differences between DMD and Controls. Furthermore, MRI-T2 was greater in the older age group compared to the young age group, which was associated with higher lipid fractions. Overall, MR measures of T2 and lipid fraction show excellent sensitivity to DMD disease pathologies and potential therapeutic interventions in DMD, even in the younger boys.
Optimal flowering time is critical to the success of modern agriculture. Sorghum is a short-day tropical species that exhibits substantial photoperiod sensitivity and delayed flowering in long days. ...Genotypes with reduced photoperiod sensitivity enabled sorghum's utilization as a grain crop in temperate zones worldwide. In the present study, Ma1, the major repressor of sorghum flowering in long days, was identified as the pseudoresponse regulator protein 37 (PRR37) through positional cloning and analysis of SbPRR37 alleles that modulate flowering time in grain and energy sorghum. Several allelic variants of SbPRR37 were identified in early flowering grain sorghum germplasm that contain unique loss-of-function mutations. We show that in long days SbPRR37 activates expression of the floral inhibitor CONSTANS and represses expression of the floral activators Early Heading Date 1, FLOWERING LOCUS T, Zea mays CENTRORADIALIS 8, and floral induction. Expression of SbPRR37 is light dependent and regulated by the circadian clock, with peaks of RNA abundance in the morning and evening in long days. In short days, the evening-phase expression of SbPRR37 does not occur due to darkness, allowing sorghum to flower in this photoperiod. This study provides insight into an external coincidence mechanism of photoperiodic regulation of flowering time mediated by PRR37 in the short-day grass sorghum and identifies important alleles of SbPRR37 that are critical for the utilization of this tropical grass in temperate zone grain and bioenergy production.
Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. ...The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS.
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