Harm to the global commons on trial: The role of the prevention principle in international climate adjudication

Although the climate crisis is the result of a failure to prevent environmental harm, the principle of prevention has thus far remained discrete in domestic climate litigation. Similarly, in the context of international climate adjudication, reliance on the prevention principle could seem limited by two main obstacles: its anchor in bilateralism and its normative indeterminacy. This article argues that, on the contrary, the prevention principle could serve important functions in international climate adjudication. First, it shows that climate change falls within the reach of the prevention principle, which aims to protect the environment per se as a community interest. Then it explores two argumentative scenarios that are based on different constructions of the prevention principle, conceived either as a customary duty or as a general principle of international law. In both cases, recourse to the prevention principle can offer numerous advantages, which vary depending on the objectives strategically pursued

Buschke-Ollendorff Syndrome Associated with Elevated Elastin Production by Affected Skin Fibroblasts in Culture

Buschke-Ollendorff syndrome (BOS; McKusick 16670) is an autosomal dominant connective-tissue disorder characterized by uneven osseous formation in bone (osteopoikilosis) and fibrous skin papules (dermatofibrosis lenticularis disseminata). We describe two patients in whom BOS occurred in an autosomal dominant inheritance pattern. The connective tissue of the skin lesions showed both collagen and elastin abnormalities by electron microscopy. Cultured fibroblasts from both patients produced 2–8 times more tropoelastin than normal skin fibroblasts in the presence of 10% calf serum. Involved skin flbroblasts of one patient produced up to eight times normal levels, whereas apparently uninvolved skin was also elevated more than threefold. In a second patient, whose involvement was nearly complete, elastin production was high in involved areas and less so in completely involved skin. Transforming growth factor-β1 (TGFβ1), a powerful stimulus for elastin production, brought about similar relative increases in normal and BOS strains. Basic fibroblast growth factor, an antagonist of TGFβ1-stimulated elastin production, was able to reduce elastin production in basal and TGFβ1 stimulated BOS strains. Elastin mRNA levels were elevated in all patient strains, suggesting that Buschke-Ollendorff syndrome may result, at least in part, from abnormal regulation of extracellular matrix metabolism that leads to increased steady-state levels of elastin mRNA and elastin accumulation in the dermis

Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas.

Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19-89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αβ T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αβ/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases

Clinical and laboratory experience of vorinostat (suberoylanilide hydroxamic acid) in the treatment of cutaneous T-cell lymphoma

The most common cutaneous T-cell lymphomas (CTCLs) – mycosis fungoides (MF) and Sézary Syndrome – are characterised by the presence of clonally expanded, skin-homing helper-memory T cells exhibiting abnormal apoptotic control mechanisms. Epigenetic modulation of genes that induce apoptosis and differentiation of malignant T cells may therefore represent an attractive new strategy for targeted therapy for T-cell lymphomas. In vitro studies show that vorinostat (suberoylanilide hydroxamic acid or SAHA), an oral inhibitor of class I and II histone deacetylases, induces selective apoptosis of malignant CTCL cell lines and peripheral blood lymphocytes from CTCL patients at clinically achievable doses. In a Phase IIa clinical trial, vorinostat therapy achieved a meaningful partial response (>50% reduction in disease burden) in eight out of 33 (24%) patients with heavily pretreated, advanced refractory CTCL. The most common major toxicities of oral vorinostat therapy were fatigue and gastrointestinal symptoms (diarrhoea, altered taste, nausea, and dehydration from not eating). Thrombocytopenia was dose limiting in patients receiving oral vorinostat at the higher dose induction levels of 300 mg twice daily for 14 days. These studies suggest that vorinostat represents a promising new agent in the treatment of CTCL patients. Additional studies are underway to define the exact mechanism (s) of by which vorinostat induces selective apoptosis in CTCL cells and to further evaluate the antitumour efficacy of vorinostat in a Phase IIb study in CTCL patients

Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair

Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, we show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (γH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-h culture of cells with vorinostat, and reculture without the HDACi, γH2AX was undetectable by 2 h in normal cells, while persisting in transformed cells for the duration of culture. Further, we found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is associated with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concentrations that cause little or no normal cell death

Molecular signatures define alopecia areata subtypes and transcriptional biomarkers

AbstractAlopecia areata (AA) is an autoimmune disease typified by nonscarring hair loss with a variable clinical course. In this study, we conducted whole genome gene expression analysis of 96 human scalp skin biopsy specimens from AA or normal control subjects. Based on gene expression profiling, samples formed distinct clusters based on the presence or absence of disease as well as disease phenotype (patchy disease compared with alopecia totalis or universalis). Differential gene expression analysis allowed us to robustly demonstrate graded immune activity in samples of increasing phenotypic severity and generate a quantitative gene expression scoring system that classified samples based on interferon and cytotoxic T lymphocyte immune signatures critical for disease pathogenesis

TIG3 Tumor Suppressor-Dependent Organelle Redistribution and Apoptosis in Skin Cancer Cells

TIG3 is a tumor suppressor protein that limits keratinocyte survival during normal differentiation. It is also important in cancer, as TIG3 level is reduced in tumors and in skin cancer cell lines, suggesting that loss of expression may be required for cancer cell survival. An important goal is identifying how TIG3 limits cell survival. In the present study we show that TIG3 expression in epidermal squamous cell carcinoma SCC-13 cells reduces cell proliferation and promotes morphological and biochemical apoptosis. To identify the mechanism that drives these changes, we demonstrate that TIG3 localizes near the centrosome and that pericentrosomal accumulation of TIG3 alters microtubule and microfilament organization and organelle distribution. Organelle accumulation at the centrosome is a hallmark of apoptosis and we demonstrate that TIG3 promotes pericentrosomal organelle accumulation. These changes are associated with reduced cyclin D1, cyclin E and cyclin A, and increased p21 level. In addition, Bax level is increased and Bcl-XL level is reduced, and cleavage of procaspase 3, procaspase 9 and PARP is enhanced. We propose that pericentrosomal localization of TIG3 is a key event that results in microtubule and microfilament redistribution and pericentrosomal organelle clustering and that leads to cancer cell apoptosis

The gene for a novel epidermal antigen maps near the neurofibromatosis 1 gene

Recently the M17S1 gene, encoding an epidermal antigen thought to play a role in cell adhesion, was mapped to chromosome bands 17q11-q12, placing it in the vicinity of the gene for the genetic disorder neurofi-bromatosis 1 (NF1). The pleomorphic cutaneous lesions of NF1 and the precedent for other genes being embedded within the NF1 gene prompted us to investigate whether the M17S1 gene mapped near, or within, the NF1 gene. Genetic linkage analyses revealed that M17S1 was tightly linked to NF1 and mapped within the interval bounded by D17S58 and D17S54. Physical mapping of an M17S1 cDNA on somatic cell hybrids, yeast artificial chromosomes, and an NF1 patient with a deletion involving an entire NF1 allele demonstrated that M17S1 is located at least 180 kb centromeric to the NF1 gene. The distance between the genes suggests that M17S1 is unlikely to contribute to the NF1 phenotype since a gross chromosomal rearrangement would be required to disrupt expression of both genes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29816/1/0000162.pd

Linking in vitro lipolysis and microsomal metabolism for the quantitative prediction of oral bioavailability of BCS II drugs administered in lipidic formulations

Lipidic formulations (LFs) are increasingly utilized for the delivery of drugs that belong to class II of the Biopharmaceutics Classification System (BCS). The current work proposes, for the first time, the combination of in vitro lipolysis and microsomal metabolism studies for the quantitative prediction of human oral bioavailability of BCS II drugs administered in LFs. Marinol® and Neoral® were selected as model LFs and their observed oral bioavailabilities (Fobserved) obtained from published clinical studies in humans. Two separate lipolysis buffers, differing in the level of surfactant concentrations, were used for digestion of the LFs. The predicted fraction absorbed (Fabs) was calculated by measuring the drug concentration in the micellar phase after completion of the lipolysis process. To determine first-pass metabolism (Fg∙Fh), drug depletion studies with human microsomes were performed. Clearance values were determined by applying the “in vitro half-life approach”. The estimated Fabs and Fg∙Fh values were combined for the calculation of the predicted oral bioavailability (Fpredicted). Results showed that there was a strong correlation between Fobserved and Fpredicted values only when Fabs was calculated using a buffer with surfactant concentrations closer to physiological conditions. The general accuracy of the predicted values suggests that the novel in vitro lipolysis/metabolism approach could quantitatively predict the oral bioavailability of lipophilic drugs administered in LFs