Expert Opinion Pleading: Any Merit to Special Certificates of Merit?

Civil litigation reform to reduce frivolous civil lawsuits was a hot topic in the most recent Presidential debates. It has stirred much recent interest and action in state and federal legislatures. Some new developments involve special pleading norms. Lawmakers will likely debate and implement new special pleading requirements in coming years, often involving certificates of merit. Such certificates are now required for most or some professional malpractice claims in several states. Illinois adopted a certificate of merit standard for product liability actions, while certificates of merit for certain childhood sexual abuse claims are necessary in both California and Louisiana. As debate continues over the need for and benefits of such special pleading requirements, lawmakers should ensure that empirical evidence supports any new legislation. In implementing new certificates of merit, careful attention must be directed to constitutional issues, as well as to policy questions involving the breadth of coverage, the nature of any needed expert opinion, the opportunity for pre-filing discovery, and the possible sanctions upon noncompliance. Upon reviewing various approaches to the use of special certificates of merit to reduce frivolous lawsuits, certain provisions for any future legislation are recommended to address the problems raised by current statutes. To address ambiguities in the breadth of coverage, certificate of merit requirements should be limited to claims where expert testimony is necessary to establish a prima facie case. Expert opinions should be required only after the initial pleadings have been completed, after there has been some opportunity for discovery, and only when the court deems them necessary. Expert opinions filed only for the purpose of certifying the merits of the civil action should not normally be admissible unless the experts are expected to testify at trial. Most would agree with President Clinton who said in the 1996 Presidential debates that frivolous civil lawsuits should be reduced as long as deserving claimants are also not denied recovery. Easier said than done

The Substantive Elements in the New Special Pleading Laws

Recently there have emerged new special pleading standards applicable to discrete substantive law claims or to certain remedial requests. These norms often raise troubling procedure/substance questions in separation of powers and choice of law settings. The questions are especially difficult where the standards are hard to locate; to distinguish from nonpleading laws; and to differentiate by rationale(s). In the separation of powers setting, these questions must be approached only after undertaking a distinct and detailed analysis of each relevant government's allocation of lawmaking duties. American governments differ significantly in these allocations. In the choice of law setting, these questions can arise in circumstances involving Erie, reverse-Erie and choice of state law. The procedure/substance issues here must be approached only after undertaking a close look at functions, not labels; at the possibility of false conflicts; and without a parochial view as to the possible location or designation of the special pleading norms of other interested governments

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding-sites that drive hTERT expression, but this model cannot fully account for differences in wild-type (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here, we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing. We show that promoter mutations exert a detrimental effect on the folding of one of these G-quadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression produces cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and induction of senescence by decreasing telomerase activity and telomere length. We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress, hTERT.National Science Foundation [CH-1609514, CHE-1415883]; National Institutes of Health [5R01CA153821, 1R01GM085585]; Stand Up To Cancer Melanoma Research Alliance/Melanoma Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0612]Publication Date (Web): September 19, 2016. 12 month embargo.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells