This book considers who should undertake humanitarian intervention in response to an ongoing or impending humanitarian crisis, such as found in Rwanda in early 1994, Kosovo in 1999, and Darfur more ...recently. The doctrine of the responsibility to protect asserts that when a state is failing to uphold its citizens' human rights, the international community has a responsibility to protect these citizens, including by undertaking humanitarian intervention. It is unclear, however, which particular agent should be tasked with this responsibility. Should we prefer intervention by the UN, NATO, a regional or subregional organization (such as the African Union), a state, a group of states, or someone else? This book answers this question by, first, determining which qualities of interveners are morally significant and, second, assessing the relative importance of these qualities. For instance, is it important that an intervener have a humanitarian motive? Should an intervener be welcomed by those it is trying to save? How important is it that an intervener will be effective and what does this mean in practice? The book then considers the more empirical question of whether (and to what extent) the current interveners actually possess these qualities, and therefore should intervene. For instance, how effective can we expect UN action to be in the future? Is NATO likely to use humanitarian means? Overall, it develops a particular normative conception of legitimacy for humanitarian intervention. It uses this conception of legitimacy to assess not only current interveners, but also the desirability of potential reforms to the mechanisms and agents of humanitarian intervention.
We have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics to cancer cells. Preclinical studies showed that epidermal growth factor receptor (EGFR)-targeted, ...paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in xenograft models. To examine the safety of the minicell delivery system, we initiated a first-time-in-human, open-label, phase I clinical study of EGFRminicellsPac in patients with advanced solid tumors.
Patients received 5 weekly infusions followed by a treatment free week. Seven dose levels (1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 dose-escalation design. Primary objectives were safety, tolerability and determination of the maximum tolerated dose. Secondary objectives were assessment of immune/inflammatory responses and antitumor activity.
Twenty eight patients were enrolled, 22 patients completed at least one cycle of EGFRminicellsPac; 6 patients did not complete a cycle due to rapidly progressive disease. A total of 236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single patient. Most common treatment-related adverse events were rigors and pyrexia. No deaths resulted from treatment-related adverse events and the maximum tolerated dose was defined as 1x1010 EGFRminicellsPac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNFα and anti-inflammatory IL-10 was observed. Anti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat dosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease as their best response.
This is the first study in humans of a novel biological system that can provide targeted delivery of a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted minicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients with advanced solid tumors with modest clinical efficacy observed. Further study in Phase II trials is planned.
Australian New Zealand Clinical Trials Registry ACTRN12609000672257.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Doctors are being encouraged to have end-of-life conversations with people with chronic illness, ethics committees are hastily convened and in some parts of the world, health care providers have to ...face the prospects of no more critical care beds available. Rapid Guidance for Critical Care (National Institute of Clinical Health and Excellence (NICE), 2020) published in response to the pandemic, places the focus on how and when to use frailty on admission to help patients, clinicians and families make rapid and timely admission decisions. By necessity, many family conversations are also taking place via telephone, with little opportunity for reading important non-verbal cues (Hall et al., 1995), thereby diminishing the quality of that end-of-life communication.End-of-life care So, how do health professionals prepare for providing large scale end-of-life care in critical care in a pandemic? (2010, p 293) outlines four key aspects; Stuff (stockpiling equipment and palliative medication such as opioids, anti-psychotics for delirium/nausea, antimuscarinic agents for secretions and syringe drivers, sub-cutaneous butterflies for medication administration); Staff (identifying staff with expertise, education, preparing protocols and guidelines for practice, ensuring grief/bereavement counsellors), Space (maximising existing palliative care beds/hospice facilities and identifying non-clinical areas appropriate for large numbers of people to die) and Systems (ensure advance care plans and care plans in place, triage for specialist palliative care, liaison across provider networks to access knowledge and facilitate direct access for clinicians needing consultation support).
α,α‐Difluoroketones are valuable compounds and can be used as synthetic intermediates for the synthesis of fluorinated molecules, but they also have a direct application in medicinal chemistry, ...particularly as inhibitors for hydrolytic enzymes. This Microreview will summarize the major methods currently available for the synthesis of α,α‐difluoroketones, highlighting methods involving direct C–F bond formation, as well as those using pre‐difluorinated building blocks.
This review describes the key methods for the synthesis of α,α‐difluoroketones. These compounds are key synthetic building blocks, as well as being used as enzyme inhibitors. Effective methods for their synthesis include direct fluorination approaches and the use of pre‐difluorinated building blocks, including cross‐coupling and radical reactions.
Methods for the fluorination of organoboron compounds are described. This review will cover the fluorination of aromatic and aliphatic systems using both electrophilic and nucleophilc sources of ...fluorine. Emerging methods for radiofluorination using
18
F for the synthesis of PET-imaging agents are also described.
This review presents the methods available for the fluorination and radiofluorination of aromatic and aliphatic organoboron compounds.
Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of ...this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers.
EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs).
Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
LEDs for photons, physiology and food Pattison, P M; Tsao, J Y; Brainard, G C ...
Nature (London),
11/2018, Letnik:
563, Številka:
7732
Journal Article
Recenzirano
Lighting based on light-emitting diodes (LEDs) not only is more energy efficient than traditional lighting, but also enables improved performance and control. The colour, intensity and distribution ...of light can now be controlled with unprecedented precision, enabling light to be used both as a signal for specific physiological responses in humans and plants, and as an efficient fuel for fresh food production. Here we show how a broad and improved understanding of the physiological responses to light will facilitate greater energy savings and provide health and productivity benefits that have not previously been associated with lighting.
In advanced atherosclerosis, macrophage apoptosis coupled with defective phagocytic clearance of the apoptotic cells (efferocytosis) promotes plaque necrosis, which precipitates acute ...atherothrombotic cardiovascular events. Oxidative and endoplasmic reticulum (ER) stress in macrophages are important causes of advanced lesional macrophage apoptosis. We now show that proapoptotic oxidative/ER stress inducers trigger another stress reaction in macrophages, autophagy. Inhibition of autophagy by silencing ATG5 or other autophagy mediators enhances apoptosis and NADPH oxidase-mediated oxidative stress while at the same time rendering the apoptotic cells less well recognized by efferocytes. Most importantly, macrophage ATG5 deficiency in fat-fed Ldlr−/− mice increases apoptosis and oxidative stress in advanced lesional macrophages, promotes plaque necrosis, and worsens lesional efferocytosis. These findings reveal a protective process in oxidatively stressed macrophages relevant to plaque necrosis, suggesting a mechanism-based strategy to therapeutically suppress atherosclerosis progression and its clinical sequelae.
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► Proapoptotic oxidative stress induces autophagy in macrophages (Mϕs) ► Inhibition of autophagy enhances oxidative stress and apoptosis in Mϕs ► Atheromata of Mϕ-Atg5−/−Ldlr−/− mice have increased apoptosis and plaque necrosis ► Apoptotic Atg5−/− Mϕs are poorly recognized by phagocytes in vitro and in atheromata
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