A Case-By-Case Approach to Pleading Scienter Under the Private Securities Litigation Reform Act of 1995

Securities fraud litigation under Rule lOb-5 threatens all publicly traded companies: according to the Stanford Securities Class Action Clearinghouse, in 1998 a securities fraud lawsuit was filed for nearly every day that the stock markets were open. Some of these lawsuits appear to be frivolous, triggered by inevitable fluctuations in stock prices (so-called fraud by hindsight complaints), while others represent legitimate efforts at private enforcement of the securities laws. Disposition on the pleadings is a critical defense strategy for all securities lawsuits. Securities fraud lawsuits that withstand a 12(b)(6) motion almost always settle, regardless of the actual merits of the case or the probability of success at trial, because of the massive discovery and defense costs associated with such suits. Because Rule lOb-5 requires a showing of scienter, a mental state embracing intent to deceive, manipulate, or defraud, defendants can often successfully dispose of a securities fraud case before being forced to settle by challenging the plaintiff\u27s scienter pleading. For these reasons, the standard for pleading scienter is an appropriate context in which to balance the competing interests of eliminating abusive claims and permitting meritorious ones

The effects of subliminal weapons effect on aggressive behavior in college level students

This study evaluated the difference in displayed aggression in subjects randomly assigned to either a subliminal weapons effect condition or to a controlled condition. 30 students from a small public University in New Jersey signed up for the study to receive credit for their introductory psychology course. The subjects were then randomly assigned to one of the two conditions; the subliminal weapons effect conditioned consisted of a poster of Scarface holding a gun pointed toward the subject on the blackboard (the poster had a sign asking that it not be removed by a professor). The controlled condition had no stimuli on the blackboard. The subjects then completed a survey dealing with their attitude of the dining hall. The results showed that the subjects in the weapons effect condition showed a significantly higher level of aggression than the control group did

Zen and the Art of Jursiprudence

Lawyer bashing is by no means a remarkable phenomenon. It was not remarkable when Shakespeare wrote, [t]he first thing we do, let\u27s kill all the lawyers, and it\u27s not remarkable today. Paul Campos, however, has written a particularly readable example, blending venerable Western lawyer-bashing and pop psychology with unsystematic invocations of Eastern religion. Jurismania is named after Campos\u27s theory that the American legal system has a lot in common with a person suffering from an obsessive-compulsive disorder, an addiction to law that does neither the patient nor those around him much good. In Jurismania, Campos criticizes our insistence on regulating and legalizing every aspect of our lives, and our insistence on exclusive rationality. Campos argues, with regular Taoist allusions, that rationality is not and cannot be the exclusive solution to the questions law raises, and that irrational methods are and should be employed. Campos\u27s intended audience is the general reader whose experience of American law has made him or her wonder if there might not be something wrong with it (pp. vii-viii). Should that audience take Campos\u27s critique seriously, it will strike close to the heart of law and the legal profession. Thus, although they are not the target audience, lawyers ought to think about Jurismania because it reflects and amplifies a perspective that may be common to many nonlawyers who encounter the legal system

Net uptake of L-glutamate and GABA by high affinity synaptosomal transport systems.

Abstract-Reuptake of neuroactive amino acids by high affinity transport systems in the CNS is thought to terminate the neurotransmitter activity of these substances. This notion has been challenged since the homoexchange of synaptosomal and exogenous glutam am ate and the corresponding homoexchange of synaptosomal and exogenous GABA has been demonstrated. We reported that depolarizing media (56 mM-KCI, 1 m~-CaCl,) lowers the GABA content of synaptosomes. In such synaptosomes, net and apparent (radioactive) GABA uptake are similar. When rat cortical synaptosomes (1 mg protein/ml) are incubated with 10 p~-['~C]~-glutamate, net and apparent (radioactive) uptake are similar. When the synaptosome levels are decreased to 0.5 mg protein/ml or less, then net uptake becomes a fraction of radioactive uptake (exchange ensues). Net glutam am ate uptake is Na+-dependent and temperaturedependent. Furthermore, a 1 mM concentration of KCI or RbCl supports net L-glutamate and GABA uptake. LiCl, NH,Cl, CsCl and choline chloride are ineffective. In addition. diaminobutyric acid (but not fi-alanine) inhibits net and apparent GABA uptake. The demonstration of net uptake of L-glutamate and GABA by their respective high affinity systems is consonant with the idea that these systems may play a role in neurotransmitter inactivation in the synaptic region

Synchronous development of KIT positive acute myeloid leukemia in a patient with gastrointestinal stromal tumor

We report a case of synchronous occurrence of KIT-positive acute myeloid leukemia (AML) and gastrointestinal stromal tumor (GIST). A 63-year-old woman was hospitalized for dizziness, and abdominal computed tomography revealed an exophytic gastric mass and hepatic metastasis. The patient was diagnosed with GIST and was administered imatinib (400 mg/day) for the metastatic unresectable tumor. After 2 weeks of imatinib treatment, the patient developed pancytopenia, which persisted even after the drug was discontinued, thereby necessitating bone marrow biopsy. Biopsy examination indicated AML, and karyotyping revealed a complex karyotype. We did not observe point mutations at residues D816 and N822 of KIT. Therefore, the patient received standard induction chemotherapy, but on the 18th day after completion of chemotherapy, she died of septic shock and multi-organ failure. Since KIT plays an important role in both GIST and AML, we consider that both these malignancies may have been associated with each other

How does conformational flexibility influence key structural features involved in activation of anaplastic lymphoma kinase?

Anaplastic Lymphoma Kinase (ALK) plays a major role in developing tumor processes and therefore has emerged as a validated therapeutic target. Applying atomistic molecular dynamics simulations on the wild type enzyme and the nine most frequently occurring and clinically important activation mutants we revealed important conformational effects on key interactions responsible for the activation of the enzyme

Selective glucocorticoid receptor properties of GSK866 analogs with cysteine reactive warheads

Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective GC ligand-binding strategies, classified as selective glucocorticoid receptor (GR) agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). In the current study, GSK866 analogs with electrophilic covalent-binding warheads were developed with potential SEGRA properties to improve their clinical safety profile for long-lasting topical skin disease applications. Since the off-rate of a covalently binding drug is negligible compared to that of a non-covalent drug, its therapeutic effects can be prolonged and typically, smaller doses of the drug are necessary to reach the same level of therapeutic efficacy, thereby potentially reducing systemic side effects. Different analogs of SEGRA GSK866 coupled to cysteine reactive warheads were characterized for GR potency and selectivity in various biochemical and cellular assays. GR-and NF kappa B dependent reporter gene studies show favorable anti-inflammatory properties with reduced GR transactivation of two non-steroidal GSK866 analogs UAMC-1217 and UAMC-1218, whereas UAMC-1158 and UAMC-1159 compounds failed to modulate cellular GR activity. These results were further supported by GR immuno-localization and S211 phospho-GR western analysis, illustrating significant GR phosphoactivation and nuclear translocation upon treatment of GSK866, UAMC-1217, or UAMC-1218, but not in case of UAMC-1158 or UAMC-1159. Furthermore, mass spectrometry analysis of tryptic peptides of recombinant GR ligand-binding domain (LBD) bound to UAMC-1217 or UAMC-1218 confirmed covalent cysteine-dependent GR binding. Finally, molecular dynamics simulations, as well as glucocorticoid receptor ligand-binding domain (GR-LBD) coregulator interaction profiling of the GR-LBD bound to GSK866 or its covalently binding analogs UAMC-1217 or UAMC-1218 revealed subtle conformational differences that might underlie their SEGRA properties. Altogether, GSK866 analogs UAMC-1217 and UAMC-1218 hold promise as a novel class of covalent-binding SEGRA ligands for the treatment of topical inflammatory skin disorders