Repairing Family Law

Scholars in the burgeoning field of law and emotion have paid surprisingly little attention to family law. This gap is unfortunate because law and emotion has the potential to bring great insights to family law. This Article begins to fill this void, and inaugurate a larger debate about the central role of emotion in family law, by exploring the intriguing and significant consequences for the regulation of families that flow from a theory of intimacy first articulated by psychoanalytic theorist Melanie Klein. According to Klein, individuals love others, inevitably transgress against those they love out of hate and aggression, feel guilt about the transgression, and then seek to repair the damage. This Article argues that the legal process embodied in the substance, procedure, and practice of traditional family law is at odds with the human process of love, hate, guilt, and reparation. In contexts as far ranging as divorce, child welfare, and adoption, family law is predicated on a binary model of love and hate, with no accounting for guilt and the drive to reparation. This Love-Hate Model actively thwarts the cycle of intimacy, greatly diminishing the opportunity for repair in familial relationships. In short, reparation as a normative goal receives far too little attention in family law. Although several important reforms have begun to move family law away from the Love-Hate Model, these reforms are undertheorized and incomplete and sometimes actively challenged. An overarching theory is needed both to undergird current reforms and to encourage others, thus moving family law more fully in a reparative direction. To replace the prevailing Love-Hate Model, this Article proposes a Reparative Model of family law that would recognize the full cycle of emotions and facilitate the reparative drive. A Reparative Model would modify the substance of family law to recognize the ongoing relationships that often persist even after legal relationships are altered. It would reform the process of family law by de-emphasizing adversarial decisionmaking. And it would change the practice of family law by reconceiving the role of the family law attorney. Ultimately, the Reparative Model yields new perspectives on a range of theoretical and practical problems in contemporary family law, providing a framework for the law to account for the full, and complex, emotional reality of familial relationships

The SCLtTAxBCR-ABL transgenic mouse model closely reflects the differential effects of dasatinib on normal and malignant hematopoiesis in chronic phase-CML patients

The second generation tyrosine kinase inhibitor (TKI) dasatinib is a clinically approved drug for chronic myeloid leukemia (CML) as well as Ph+ acute lymphoblastic leukemia. In addition to its antileukemic effects, dasatinib was shown to impact on normal hematopoiesis and cells of the immune system. Due to the fact that the murine in vivo studies so far have not been performed in a chronic-phase CML model under steady-state conditions, our aim was to study the hematopoietic effects of dasatinib (20 mg/kg p.o.) in BCR-ABL expressing SCLtTAxBCR-ABL double transgenic (dtg) mice. Dasatinib robustly antagonized the CML phenotype in vivo in our transgenic mouse model, and this effect included both mature and immature cell populations. However, similar to patients with CML, the fraction of Lin(neg)Sca-1(+)KIT(+)CD48(neg)CD150(+) hematopoietic stem cells was not reduced by dasatinib treatment, suggesting that these cells are not oncogene-addicted. Moreover, we observed differential effects of dasatinib in these animals as compared to wild-type (wt) animals: while granulocytes were significantly reduced in dtg animals, they were increased in wt mice. And Ter119(+) erythrocytic and B220(+) B cells were increased in dtg mice but decreased in wt mice. Finally, while dasatinib induced a shift from CD49b/NK1.1 positive NK cells from the bone marrow to the spleen in wt animals, there was no change in dtg mice. In conclusion, the present mouse model provides a useful tool to study mechanisms of TKI resistance and dasatinib-associated beneficial effects and adverse events.Peer reviewe

Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival

Recent evidence suggests CML stem cells are insensitive to kinase inhibitors and responsible for minimal residual disease in treated patients. We investigated whether CML stem cells, in a transgenic mouse model of CML-like disease or derived from patients, are dependent on Bcr-Abl. In the transgenic model, following re-transplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off, were able to persist in vivo and re-initiate leukemia in secondary recipients upon Bcr-Abl re-expression. Bcr-Abl knockdown in human CD34+ CML cells cultured for 12 days in physiological growth factors achieved partial inhibition of Bcr-Abl and downstream targets p-CrkL and p-STAT5, inhibition of proliferation and colony forming cells, but no reduction of input cells. The addition of dasatinib further inhibited p-CrkL and p-STAT5, yet only reduced input cells by 50%. Complete growth factor withdrawal plus dasatinib further reduced input cells to 10%, however the surviving fraction was enriched for primitive leukemic cells capable of growth in long-term culture initiating cell assay and expansion upon removal of dasatinib and addition of growth factors. Together these data suggest that CML stem cell survival is Bcr-Abl kinase independent and suggest curative approaches in CML must focus on kinase-independent mechanisms of resistance

Therapeutic inhibition of FcgammaRIIb signaling targets leukemic stem cells in chronic myeloid leukemia

Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcgammaRIIb, CD32b) for being critical in LSC resistance and show that targeting FcgammaRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcgammaRIIb upregulation in primary CML stem cells. FcgammaRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcgammaRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcgammaRIIb-BTK axis in primary CML CD34(+) cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition

Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells

Clinical development of imatinib in CML established continuous target inhibition as a paradigm for successful tyrosine kinase inhibitor (TKI) therapy. However, recent reports suggested that transient potent target inhibition of BCR-ABL by highdose TKI (HD-TKI) pulse-exposure is sufficient to irreversibly commit cells to apoptosis. Here, we report a novel mechanism of prolonged intracellular TKI activity upon HD-TKI pulse-exposure (imatinib, dasatinib) in BCR-ABL-positive cells. Comprehensive mechanistic exploration revealed dramatic intracellular accumulation of TKIs which closely correlated with induction of apoptosis. Cells were rescued from apoptosis upon HD-TKI pulse either by repetitive drug wash-out or by overexpression of ABC-family drug transporters. Inhibition of ABCB1 restored sensitivity to HD-TKI pulse-exposure. Thus, our data provide evidence that intracellular drug retention crucially determines biological activity of imatinib and dasatinib. These studies may refine our current thinking on critical requirements of TKI dose and duration of target inhibition for biological activity of TKIs.Daniel B. Lipka, Marie-Christine Wagner, Marek Dziadosz, Tina Schnöder, Florian Heidel, Mirle Schemionek, Junia V. Melo, Thomas Kindler, Carsten Müller-Tidow, Steffen Koschmieder and Thomas Fische

Expression of the psl operon in pseudomonas aeruginosa PAO1 biofilms: PslA performs an essential function in biofilm formation

The psl gene cluster, comprising 15 cotranscribed genes from Pseudomonas aeruginosa, was recently identified as being involved in exopolysaccharide biosynthesis and biofilm formation. In this study, we investigated the regulation of the psl gene cluster and the function of the first gene in this cluster, the pslA gene. PslA shows strong similarities to UDP-glucose lipid carriers. An isogenic marker-free pslA deletion mutant of P. aeruginosa PAO1 deficient in attachment and biofilm formation was used for complementation studies. The expression of only the pslA gene, comprising a coding region of 1,437 bp, restored the biofilm-forming phenotype of the wild type, indicating that PslA is required for biofilm formation by nonmucoid P. aeruginosa. The promoter region of the psl gene cluster, which encodes PslA-PslO, was identified by rapid amplification of cDNA 5′ ends. Promoter assays using transcriptional fusions to lacZ and gfp indicated a constitutive expression of the psl cluster in planktonic cells and a highly regulated and localized expression in biofilms, respectively. Expression of the psl cluster in biofilms was almost exclusively found in the centers of microcolonies, as revealed by confocal laser scanning microscopy. These data suggest that constitutive expression of the psl operon enables efficient attachment to surfaces and that regulated localized psl operon expression is required for biofilm differentiation