How Rights of Nature laws are transforming governance to address environmental crises through more ecologically sustainable approaches to development. With the window of opportunity to take ...meaningful action on climate change and mass extinction closing, a growing number of communities, organizations, and governments around the world are calling for Rights of Nature (RoN) to be legally recognized. RoN advocates are creating new laws that recognize natural ecosystems as subjects with inherent rights, and appealing to courts to protect those rights. Going beyond theory and philosophy, in this book Craig Kauffman and Pamela Martin analyze the politics behind the creation and implementation of these laws, as well as the effects of the laws on the politics of sustainable development. Kauffman and Martin tell how community activists, lawyers, judges, scientists, government leaders, and ordinary citizens have formed a global movement to advance RoN as a solution to the environmental crises facing the planet. They compare successful and failed attempts to implement RoN at various levels of government in six countries—Bolivia, Colombia, Ecuador, India, New Zealand, and the United States—asking why these laws emerged and proliferated in the mid-2000s, why they construct RoN differently, and why some efforts at implementation are more successful than others. As they analyze efforts to use RoN as a tool for constructing more ecocentric sustainable development, capable of achieving the 2030 Agenda for Sustainable Development goal of living “in harmony with Nature,” Kauffman and Martin show how RoN jurisprudence evolves through experimentation and reshapes the debates surrounding sustainable development.
General labels tend to obscure objective realities upon which disability rights are based and can deny individuals with disabilities their educational and civil rights. Undoubtedly, stigma can come ...from labels unnecessarily categorizing people into separate groups. However, stigma does not reside primarily in disability categories/terms but in what people think of words’ referents. The replacement of the old disability categories/terms with new ones is a case of what is called the “euphemism treadmill,” showing how concepts and mentally represented realities, not words, are the key issue. However, in the case of disabilities, scientific names are unavoidable for the purposes of research, education, advocacy, and social welfare. Some people try to avoid naming special education and its derivatives just as they do in the case of disability categories. We argue that scientifically validated disability and special education labels are necessary and legitimate classifications required for progress in disability research and practice. They provide the most direct route to legally protecting and serving individuals with educational disabilities.
We investigated the biologic and pharmacologic activities of a chromosome region maintenance 1 (CRM1) inhibitor against human non-small cell lung cancer (NSCLC) cells both in vitro and in vivo.
The ...in vitro and in vivo effects of a novel CRM1 inhibitor (KPT-330) for a large number of anticancer parameters were evaluated using a large panel of 11 NSCLC cell lines containing different key driver mutations. Mice bearing human NSCLC xenografts were treated with KPT-330, and tumour growth was assessed.
KPT-330 inhibited proliferation and induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines. Moreover, the combination of KPT-330 with cisplatin synergistically enhanced the cell kill of the NSCLC cells in vitro. Human NSCLC tumours growing in immunodeficient mice were markedly inhibited by KPT-330. Also, KPT-330 was effective even against NSCLC cells with a transforming mutation of either exon 20 of EGFR, TP53, phosphatase and tensin homologue, RAS or PIK3CA, suggesting the drug might be effective against a variety of lung cancers irrespective of their driver mutation.
Our results support clinical testing of KPT-330 as a novel therapeutic strategy for NSCLC.
Drugs that target the chief mediator of nuclear export, chromosome region maintenance 1 protein (CRM1) have potential as therapeutics for leukemia, but existing CRM1 inhibitors show variable ...potencies and a broad range of cytotoxic effects. Here, we report the structural analysis and antileukemic activity of a new generation of small-molecule inhibitors of CRM1. Designated selective inhibitors of nuclear export (SINE), these compounds were developed using molecular modeling to screen a small virtual library of compounds against the nuclear export signal (NES) groove of CRM1. The 2.2-Å crystal structure of the CRM1-Ran-RanBP1 complex bound to KPT-251, a representative molecule of this class of inhibitors, shows that the drug occupies part of the groove in CRM1 that is usually occupied by the NES, but penetrates much deeper into the groove and blocks CRM1-directed protein export. SINE inhibitors exhibit potent antileukemic activity, inducing apoptosis at nanomolar concentrations in a panel of 14 human acute myeloid leukemia (AML) cell lines representing different molecular subtypes of the disease. When administered orally to immunodeficient mice engrafted with human AML cells, KPT-251 had potent antileukemic activity with negligible toxicity to normal hematopoietic cells. Thus, KPT-SINE CRM1 antagonists represent a novel class of drugs that warrant further testing in AML patients.
Selinexor is an oral inhibitor of the nuclear export protein Exportin 1 (XPO1) with demonstrated antitumor activity in solid and hematological malignancies. We evaluated the efficacy and safety of ...selinexor in heavily pretreated, recurrent gynecological malignancies.
In this phase 2 trial, patients received selinexor (35 or 50 mg/m2 twice-weekly BIW or 50 mg/m2 once-weekly QW) in 4-week cycles. Primary endpoint was disease control rate (DCR) including complete response (CR), partial response (PR) or stable disease (SD) ≥12 weeks. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety.
114 patients with ovarian (N = 66), endometrial (N = 23) or cervical (N = 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1–11), 2 (1–5), and 3 (1–6) respectively. DCR was 30% (ovarian 30%; endometrial 35%; cervical 24%), which included confirmed PRs in 8%, 9%, and 4% of patients with ovarian, endometrial, and cervical cancer respectively. Median PFS and OS for patients with ovarian, endometrial and cervical cancer were 2.6, 2.8 and 1.4 months, and 7.3, 7.0, and 5.0 months, respectively. Common Grade 3/4 adverse events (AEs) were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Patients with ovarian cancer receiving 50 mg/m2 QW had fewer high-grade AEs with similar efficacy as BIW treatment.
Selinexor demonstrated single-agent activity and disease control in patients with heavily pretreated ovarian and endometrial cancers. Side effects were a function of dose level and treatment frequency, similar to previous reports, reversible and mitigated with supportive care.
•Selinexor, an oral XPO1 inhibitor, demonstrated single-agent activity in ovarian, endometrial, and cervical cancers.•Selinexor was safe and tolerable; side effects were predominantly grade 1/2.•Frequently reported grade 3/4 events were thrombocytopenia, fatigue, anemia, nausea, and hyponatremia.•These data support further development of selinexor in advanced gynecological malignancies.
•Explains how “weak” rights of nature (RoN) laws and norms strengthened in Ecuador.•Key obstacles were politicization of the issue and judges’ lack of knowledge.•Activists facilitated judicial ...momentum by “working below the radar.”•Instrumental use of RoN laws by the state built precedent and educated judges.•Knowledgeable judges are unilaterally invoking/applying RoN in their sentences.
In 2008, Ecuador became the world’s first country to include rights of Nature (RoN) in its constitution. The constitution presents RoN as a tool for building a new form of sustainable development based on the Andean Indigenous concept sumak kawsay (buen vivir in Spanish), which is rooted in the idea of living in harmony with Nature. While much is written on the ethical arguments regarding RoN (and buen vivir), few studies analyze how RoN might be implemented. We fill this gap by explaining why some efforts to apply Ecuador’s RoN laws succeeded while others failed. We compare 13 RoN lawsuits using an original framework for analyzing the pathways and strategies RoN advocates (and their opponents) use to build (and counter) momentum behind judicial processes meant to buttress the enforcement of contested RoN norms. The case descriptions and analysis draw on primary documents and in-depth interviews conducted during 2014–15. Through process tracing, we identified key structural conditions and strategic decisions shaping the outcomes in each case. Our findings as of 2016 reveal unexpected pathways of influence involving a symbiotic process among civil society, state agencies, and the courts. Surprisingly, civil society pressure was the least successful pathway, as activists lost high-profile lawsuits. Nevertheless, they facilitated judicial momentum by working on less-politicized local cases and training lower-level judges. Instrumental use of RoN laws by the state produced unintended consequences, including establishing precedent and educating judges. Knowledgable judges are unilaterally applying RoN in their sentencing, even when neither claimants nor defendants allege RoN violations. Ecuador’s cases demonstrate how “weak” RoN laws can strengthen, providing important insight into the global contestation over sustainable development and the strategies and legal tools being used to advance a post-neoliberal development agenda rooted in harmony with nature.
RNA interference screening identified XPO1 (exportin 1) among the 55 most vulnerable targets in multiple myeloma (MM). XPO1 encodes CRM1, a nuclear export protein. XPO1 expression increases with MM ...disease progression. Patients with MM have a higher expression of XPO1 compared with normal plasma cells (P<0.04) and to patients with monoclonal gammopathy of undetermined significance/smoldering MM (P<0.0001). The highest XPO1 level was found in human MM cell lines (HMCLs). A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1. The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A (CDC25A) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway. Western blotting and reverse transcription-PCR confirm that c-MYC, CDC25A and BRD4 are all downregulated after treatment with KPT-276. KPT-276 reduced monoclonal spikes in the Vk*MYC transgenic MM mouse model, and inhibited tumor growth in a xenograft MM mouse model. A phase I clinical trial of an analog of KPT-276 is ongoing in hematological malignancies including MM.
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A universal tool in the culture-based study of bacterial viruses (bacteriophages, or phages) is the agar overlay, which is used in the isolation of new viruses, and in their ...quantification and purification. Here, simple optimizations that increase efficiency and throughput in agar overlay based isolation and cultivation of virus-host systems are presented. The agar overlay is streamlined to minimize steps and materials. Serial purification of viruses from viral colonies (plaques) is optimized to eliminate steps by combining purification by serial re-streaking with the optimized agar overlay approach. Finally, recommendations are made for efficient archival and storage of virus plaques. In sum, this work presents:
•Tube-free Agar Overlays: rapid plaque assays with fewer steps and materials•Molten Streaking for Singles: rapid tube-free serial purification of viruses•Archiving Plaques: saving virus purification for later
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