GlobalTort

GlobalTort

The Intersection Among Torts, Science, Corporate Law, Insurance & Bankruptcy

Epigenetic Events, Stem Cells, and Blood Vessel Cells

Posted in Science

What is the process by which stem cells decide (or are told) to “differentiate” into particular types of cells? It’s a complex story researchers are starting to unravel in small pieces.

A new piece of the puzzle is now moving into sight as researchers  at the University of Illinois at Chicago identified:

a molecular mechanism that directs embryonic stem cells to mature into endothelial cells — the specialized cells that form blood vessels. Understanding the processes initiated by this mechanism could help scientists more efficiently convert stem cells into endothelial cells for use in tissue repair, or for engineering blood vessels to bypass blockages in the heart . The report, published online in the journal Stem Cell Reports, identifies two enzymes that alter the expression of certain genes needed for embryonic cells to differentiate and become endothelial cells. The enzymes work by an “epigenetic” modification — a chemical change to DNA, or certain proteins that interact with DNA, that changes the activity of genes without changing the DNA itself. Changes to the proteins around which DNA is wound, called histones, can up-regulate the expression of genes by exposing them to the cellular machinery that translates their DNA.”

The rest of the short version of the story is told in a June 26, 2015 story at ScienceDaily. (And yes, I plead guilty to shameless promotion of anything that is tied to both  1) biotech and 2) University of Illinois.)

The full story is the article:

  1. Liangtang Wu, Kishore K. Wary, Sergei Revskoy, Xiaopei Gao, Kitman Tsang, Yulia A. Komarova, Jalees Rehman, Asrar B. Malik. Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells. Stem Cell Reports, 2015; DOI: 10.1016/j.stemcr.2015.05.016

New: “Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma.”

Posted in Asbestos, Asbestos Bankruptcy, Asbestos Trusts, Cancer, Science

Researchers continue to generate more and more data and hypotheses regarding mesothelioma in persons with a germline (inherited) BAP1 mutation. The newest paper went online yesterday, from Carbone, Pass and Yang, among others. The abstract states:

Abstract

Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1+/- mouse model, we found that, compared with their wild-type littermates, BAP1+/- mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1+/- mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.Oncogene advance online publication, 29 June 2015; doi:10.1038/onc.2015.243.

1:   Napolitano A, Pellegrini L, Dey A, Larson D, Tanji M, Flores EG, Kendrick B, Lapid D, Powers A, Kanodia S, Pastorino S, Pass HI, Dixit V, Yang H, Carbone M., Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene. 2015 Jun 29. doi: 10.1038/onc.2015.243. [Epub ahead of print] PubMed

Cellular Level Research: “Inflammatory cytokines contribute to asbestos-induced injury of mesothelial cells”

Posted in Asbestos, Asbestos Bankruptcy, Cancer

Another of the growing number of  studies of cell level reactions of cells to chrysotile and amphibole fibers.  Also, note the fiber type parallels.

Abstract

Background

Several diseases have been related to asbestos exposure, including the pleural tumor mesothelioma. The mechanism of pleural injury by asbestos fibers is not yet fully understood. The inflammatory response with release of mediators leading to a dysregulation of apoptosis may play a pivotal role in the pathophysiology of asbestos-induced pleural disease.

Objective

To determine whether pro-inflammatory cytokines produced by asbestos-exposed pleural mesothelial cells modify the injury induced by the asbestos.

Methods

Mouse pleural mesothelial cells (PMC) were exposed to crocidolite or chrysotile asbestos fibers (3.0 μg/cm2) for 4, 24, or 48 h and assessed for viability, necrosis and apoptosis, and the production of cytokines IL-1β, IL-6 and macrophage inflammatory protein-2 (MIP-2). Cells exposed to fibers were also treated with antibodies anti-IL-1β, anti-IL-6, anti- IL-1β+anti-IL-6 or anti-MIP-2 or their irrelevant isotypes, and assessed for apoptosis and necrosis. Non-exposed cells and cells treated with wollastonite, an inert particle, were used as controls.

Results

Mesothelial cells exposed to either crocidolite or chrysotile underwent both apoptosis and necrosis and released cytokines IL-1β, IL-6 and MIP-2. In the crocidolite group, apoptosis and the levels of all cytokines were higher than in the chrysotile group, at comparable concentrations. Neutralization of IL-1β andIL-6, but not MIP-2, inhibited apoptosis and necrosis, especially in the cells exposed to crocidolite fibers.

Conclusions

Both crocidolite and chrysotile asbestos fibers induced apoptosis and produced an acute inflammatory response characterized by elevated levels of IL-1β, IL-6 and MIP-2 in cultured mouse PMC. IL-1β and IL-6, but not MIP-2, were shown to contribute to asbestos-induced injury, especially in the crocidolite group.

Acencio, MM, et al “Inflammatory cytokines contribute to asbestos-induced injury of mesothelial cells”, June 10, 2015, Lung, Epub ahead of print, http://link.springer.com/article/10.1007%2Fs00408-015-9744-4.

Virtues of Open Access to Big Data on Claiming and Payment Systems

Posted in Asbestos, Asbestos Bankruptcy, Fraud by Insurers and Their Lawyers, Health Insurer Discrimination Against Persons with Chronic Diseases, Insurance, Litigation Industry, Mass Tort Issues, Science

Access to “big data” is important to multiple aspects of claiming and payments systems. For example, secrecy in data helps some health insurance companies avoid analysis and compilation of data on how often they deny access to stem cell transplants to persons with cancer. Blocking access to data also helps health insurers make it harder for patients and/or doctors to learn if they’ve been systematically cheated out of payments.  Similarly, some property damage insurers seek to block access to “data” on claims and payments after “big storms,” and rewriting of expert reports to deny payments to persons with damaged property. Secrecy also is thought to help litigants on all sides of many issues as they try to take advantage of actual or perceived asymmetries in access to information. In view of these realities, it is therefore no surprise that litigants on all sides tend to seek and argue for data secrecy that blocks access by groups interested in examining “big data” for whatever it may reveal about claims for and payments of money.

Sadly, the desire for secrecy is especially strong among the asbestos bankruptcy trusts that hold the most “big data” on asbestos claiming. This is especially frustrating because once upon a time, David Austern (of the Manville Trust) and some other trusts actively disseminated the “big data” they held on asbestos claiming. Indeed, back in 2009, I described in detail the Manville Trust’s regrettable retreat into secrecy through actions of its Trustees (not David), and cited to some of the obligatory references on the value of sunlight.

It is easy to doubt that society benefits from secrecy on the longest running and most costly “mass tort” in history, which in general has failed to serve the interests of “future claimants.” In other contexts, the federal government and others seek to increase disclosure of big data to encourage more intelligent and wide-spread scrutiny of claiming and payments for systems intended to serve the interests of current and future claimants.  Indeed, back in 2010, the Obama Administration announced plans to release Medicare data so that private “bounty hunters” could root out fraud, as described in a March 29, 2010 article at FierceHealth IT . More recently, much more Medicare data was released, and the Obama Administration (CMS) June 1, 2015 statement went on at length as to the virtues of  releasing massive amounts of Medicare data for analysis by interested persons. There, CMS explained the following regarding the vast scale and scope of Medicare data disclosures:

“As part of the Administration’s efforts to promote better care, smarter spending, and healthier people, today CMS is posting the third annual release of the Medicare hospital utilization and payment data (both inpatient and outpatient) and the second annual release of the physician and other supplier utilization and payment data. The announcement was made at the annual Health Datapalooza conference in Washington, DC.

“These data releases will give patients, researchers, and providers continued access to information to transform the health care delivery system,” said acting CMS Administrator Andy Slavitt. “It’s important for consumers, their providers, researchers and other stakeholders to understand the delivery of care and spending under the Medicare program.”

The Medicare hospital utilization and payment data consists of information for 2013 about the average amount a hospital bills for services that may be provided in an inpatient stay or outpatient visit. The hospital data includes payment and utilization information for services that may be provided in connection with the 100 most common Medicare inpatient stays and 30 selected outpatient procedures at over 3,000 hospitals in all 50 states and the District of Columbia. The top 100 inpatient stays represented in the hospital inpatient data are associated with approximately $62 billion in Medicare payments and over 7 million hospital discharges.
  
The Medicare Part B physician, practitioner, and other supplier utilization and payment data consists of information on services and procedures provided to Medicare beneficiaries by physicians and other healthcare professionals. The data also shows payment and submitted charges, or bills, for those services and procedures by provider. It allows for comparisons by physician, specialty, location, types of medical services and procedures delivered, Medicare payment, and submitted charges. The new 2013 dataset has information for over 950,000 distinct health care providers who collectively received $90 billion in Medicare payments. Hospitals, physicians, and other health care providers determine what they will charge for services and procedures provided to patients and these “charges” are the amount the hospital or provider generally bills for the service or procedure, but the amount paid is determined by Medicare’s physician fee schedule or other payment methodologies. CMS protects beneficiaries’ personal information in all its data releases.

“Data transparency facilitates a vibrant health data ecosystem, promotes innovation, and leads to better informed and more engaged health care consumers,” said Niall Brennan, CMS chief data officer and director of the Office of Enterprise and Data Analytics. “CMS will continue to release the hospital and physician data on an annual basis so we can enable smarter decision making about care that is delivered in the health care system.”

The Administration has set measurable goals and a timeline to move Medicare toward paying providers based on the quality, rather than the quantity, of care they give patients. These data releases are part of a wide set of initiatives to achieve better care, smarter spending, and healthier people through our health care system. Open sharing of data securely, timely, and more broadly supports insight and innovation in health care delivery.  

Today’s data release adds to the unprecedented information recently released on Medicare Part D prescription drugs prescribed by physicians and other health care providers.”

 

SCOTUS, Overreach, and Be Careful What You Wish For

Posted in Litigation Industry, Policy Issues

The past week’s rulings at SCOTUS are bad news for at least some who (accurately or not) label themselves as “conservatives.”  Some lawyers are now explicitly arguing that overreach is hurting “conservative” causes at SCOTUS because “cause” lawsuits are resulting in litigation of extreme, overreaching views/arguments. That’s the thesis of this June 25 NYT article.

In a perhaps related vein, one might also note Justice Scalia’s dissents and language have resulted in mocking web sites and articles at Slate and elsewhere about “the Scalia insult generator.”

 “Be careful what you wish for” may be at work, yet again.

Nanotubes and Molecular Pathways of Invaders into Cells in Lungs

Posted in Asbestos, Cancer, Science

Research continues on the molecular pathways that are affected as lungs are invaded particles. One can and should look for parallels between invaders. A new abstract provides information on pathways affected by carbon wall nanotubes.

“Biological oxidative responses are involved in the toxicity of multiwall carbon nanotubes (MWCNTs), which may cause asbestos-like pathogenicity. Superoxide dismutase 2 (SOD-2) has been proposed as a biomarker of early responses to mesothelioma-inducing fibers. This study was conducted to investigate the alteration of SOD-2 expression in the human mesothelial cell lines Met-5A after exposure to nontoxic doses of MWCNTs and the potential signaling pathway. The parameters measured included the viability, morphological change, superoxide formation, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and messenger RNA (mRNA)/protein levels of SOD-2. Our results showed that MWCNTs upregulated SOD-2 expression at both mRNA and protein level. Coincidently, both superoxide formation and ERK1/2 phosphorylation were observed in Met-5A cells exposed to MWCNTs and were diminished by pretreatment with the reactive oxidative species (ROS) scavenger, N-acetyl-L-(+)-cysteine (NAC). To further investigate the role of ROS/ERK1/2 in MWCNTs-induced SOD-2 overexpression, prior to MWCNTs exposure, cells were pretreated with the Mitogen-activated protein kinase kinase 1/2 (MEK 1/2) inhibitor (U0126) or with NAC. Both pretreatments decreased the MWCNTs-induced overexpression of SOD-2. These results suggest that upregulation of SOD-2 in Met-5A cells exposed to MWCNTs is mediated by ROS formation and ERK1/2 activation.”

  1. Published online before print June 25, 2015, doi:10.1177/1091581815591223International Journal of Toxicology June 25, 2015 1091581815591223

Garlock’s Tort System Trial Record – 2014 Summary by Bates White

Posted in Asbestos, Asbestos Bankruptcy, Litigation Industry

There’s much spin by many sides as to the Garlock chapter 11 outcome.  Facts are more useful. This link provides two pages from a fall 2014 presentation by Bates White as to Garlock’s trial record in the tort system. One  page identifies the presentation, and the second page provides an easy to read chart summarizing Garlock’s trial record in the tort system. (I cannot claim to have fact checked the numbers; I assume Bates White accurately summarized the record.)

 

Big Tobacco Moving into Positive Science?

Posted in Cancer, Science, Tobacco

Big tobacco asserts it’s now trying to use science in a positive way, instead of simply using them to create “doubt.” The story is told in a June 23, 2015 story from Reuters. The intro is pasted below:

WASHINGTON (Reuters) – Scientists who have devoted years developing medicines to cure disease are now working for tobacco companies to make e-cigarettes.

Philip Morris International Inc has hired more than 400 scientists and technical staff at its research facility in Neuchatel, Switzerland, including toxicologists, chemists, biologists, biostatisticians and regulatory affairs experts.

Altria Group Inc, makers of Marlboro, has recruited dozens of scientific and healthcare experts, as have independent e-cigarette companies such as NJOY. They bring experience developing inhalation devices and navigating the U.S. Food and Drug Administration, valuable knowledge in the new world of electronic cigarettes.

They say they’re trying to improve public health.

“We were looking at drugs that make people very ill and maybe extend their life by 12 to 14 weeks,” said Gizelle Baker, a PMI biostatistician based in Neuchatel who previously worked at the cancer drug developer Poniard Pharmaceuticals. “If you have a product that prevents cancer in the first place you can have a much bigger impact on public health.”

The goal is to improve the current generation of e-cigarettes and, where possible, provide evidence that they reduce the risk of disease. Companies that succeed could have an advantage in a market that Bonnie Herzog, an analyst at Wells Fargo Securities, sees surpassing combustible cigarettes in the U.S. within the next decade.
Read more at http://newsdaily.com/2015/06/in-twist-scientists-join-tobacco-companies-to-fight-cancer/#7giK2s4zyXgekAQ2.99

More Deja Vu All Over Again – Benzene Litigation and Insurance Company Arguments

Posted in Asbestos, Benzene, Insurance, Litigation Industry

Yogi Berra probably never dreamed of the number of times his line would reused. In any event, it applies well to insurance companies dancing around coverage issues for benzene litigation, as they’ve done many times in asbestos litigation. HarrisMartin’s Benzene publication provides an example (paywall) in a June 4, 2015 article.  The summary provided in the article (see below) reads as if the arguments were lifted directly from brief on asbestos coverage issues:

“Continental and National Union issued commercial general liability policies to Valspar between 1971 and 2004. In 2006, Continental began incurring costs associated with the defense of Valspar in four benzene lawsuits alleging exposure to products manufactured by the company. The lawsuits implicated policies issued by both insurers based on the alleged exposures, which occurred between 1966 and 1990.

Continental sued National Union, seeking contribution under a theory that it owed Valspar a duty to defend against the underlying benzene claims and therefore had an equitable obligation to contribute to defense costs incurred by another insurer in connection with the lawsuits.

In March 2013, the court awarded partial summary judgment to Continental, determining that National Union had a duty to defend Valspar and, as a result, a duty to contribute to defense costs incurred by Continental. However, the court’s ruling left open the question of how much National Union was required to reimburse Continental.”