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Concept: Copyright

265

The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis and loss of intervertebral disc proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan. This article is protected by copyright. All rights reserved.

Concepts: DNA, Protein, Gene, Gene expression, Atherosclerosis, Organism, Copyright, KILL

151

Methoxyflurane was developed as an anaesthetic agent and introduced into clinical practice in 1960. It soon became evident that it possessed analgesic properties that other drugs did not. Due to toxicity concerns, it lost favour in general anaesthesia and had been largely abandoned by the late 1970’s. The manufacturer withdrew it in 1999, and the Food and Drug Administration in the United States did not renew its license in 2005. It has also been withdrawn by the European Union. However, it continues to be used in Australasia, primarily as an inhaled self-administered analgesic by emergency services immediately following trauma. It has become attractive for use in dental practice, likely due to its effectiveness as an analgesic and its additional sedative qualities. Its acceptance is controversial as its use in dentistry is largely elective. Despite its good safety record in analgesic doses, adverse reactions have been recorded. Practitioners should be well aware of risks associated with its use before considering administration, and carefully assess whether or not there are equally good alternative options that do not the carry the same risks. Methoxyflurane is reviewed below with an emphasis on its use in dental practice. This article is protected by copyright. All rights reserved.

Concepts: Clinical trial, European Union, United States, Anesthesia, Dentistry, All rights reserved, Copyright, Legal terms

148

Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long-acting PTH analog, [Ala(1,3,12,18,22) , Gln(10) ,Arg(11) ,Trp(14) ,Lys(26) ]-PTH(1-14)/PTHrP(15-36) (LA-PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intra-venous administration of LA-PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near-normal levels for longer than 48 hours, while PTH(1-34) and PTH(1-84), each injected at a dose 80-fold higher than that used for LA-PTH, increased sCa and decreased sPi only modestly and transiently (< 6 hours). LA-PTH also exhibited enhanced and prolonged efficacy versus PTH(1-34) and PTH(1-84) for elevating sCa when administered subcutaneously (SC) into monkeys. Daily SC administration of LA-PTH (1.8 nmol/kg) into TPTX rats for 28-days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long-acting PTH analogs as potential therapies for patients with hypoparathyroidism. This article is protected by copyright. All rights reserved.

Concepts: Bone, Parathyroid hormone, Bone resorption, Calcium metabolism, Parathyroid gland, Hypoparathyroidism, Hyperparathyroidism, Copyright

147

Psoriasis is a chronic inflammatory immune-mediated autoimmune skin disorder. The histamine H4 receptor (H4R) agonist 4-methylhistamine (4-MH) plays an important role in immunomodulation of inflammatory responses associated with allergic inflammatory diseases. In this study, we investigated the effects of H4R agonist 4-MH on the development of imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice and explored the immunoregulatory mechanism involved. The total clinical severity scores were significantly ameliorated by treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg). Histological analysis of the skin revealed that 4-MH (20 mg/kg) and 4-MH (40 mg/kg) significantly attenuated the psoriatic phenotypes, including epidermal hyperplasis, hyperkeratosis, and lymphocytes infiltration. Treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg) led to reductions in the levels of Th1 cytokines (TNF-α, IFN-α, and IL-27) in the serum and dorsal skin, whereas Th17 cytokines levels (IL-17A and IL-23) did not change in response to treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg). Furthermore, the number of CD4(+) CD25(+) FoxP3(+) regulatory T (Treg) cells was significantly increased by treatment with 4-MH (40 mg/kg). Taken together, these results imply that H4R agonist 4-MH might be an effective immunomodulatory approach for treatment of patients with psoriasis and the effects may be related to inhibited epidermal alteration, selectively reduced Th1 pro-inflammatory cytokines, and recruited CD4(+) CD25(+) FoxP3(+) Treg cells. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Inflammation, Asthma, Receptor antagonist, Inverse agonist, Copyright, Histamine H4 receptor, 4-Methylhistamine

146

When using our arms to interact with the world, unintended body motion can introduce movement error. A mechanism which could detect and compensate for such motion would be beneficial. Observations of arm movements evoked by vestibular stimulation provide some support for this mechanism. However, the physiological function underlying these artificially-evoked movements is unclear from previous research. For such a mechanism to be functional, it should only operate when the arm is being controlled in an earth-fixed rather than body-fixed reference frame. In the latter case, compensation would be unnecessary and even deleterious. To test this hypothesis, subjects were gently rotated in a chair while asked to maintain their outstretched arm pointing either towards earth-fixed (EF) or body-fixed (BF) memorised targets. Galvanic vestibular stimulation (GVS) was applied concurrently during rotation to isolate the influence of vestibular input, uncontaminated by inertial factors. During the EF task, GVS produced large polarity-dependent corrections in arm position. These corrections mimicked those evoked when chair velocity was altered without any GVS, indicating a compensatory arm response to a sensation of altered body motion. In stark contrast, corrections were completely absent during the BF task, despite the same chair movement profile and arm posture. These effects persisted when we controlled for differences in limb kinematics between the two tasks. Our results demonstrate that vestibular control of the upper-limb maintains reaching accuracy during unpredictable body motion. The observation that such responses only occurred when reaching within an EF reference frame confirms the functional nature of vestibular-evoked arm movement. This article is protected by copyright. All rights reserved.

Concepts: Scientific method, Observation, Vestibular system, Classical mechanics, Special relativity, Copyright, Frame of reference, Galvanic Vestibular Stimulation

144

Multiwalled carbon nanotubes (MWCNT) have a fibrous structure and physical properties similar to asbestos and have been shown to induce malignant mesothelioma of the peritoneum after injection into the scrotum or peritoneal cavity in rats and mice. For human cancer risk assessment, however, data after administration of MWCNT via the airway, the exposure route that is most relevant to humans, is required. The present study was undertaken to investigate the carcinogenicity of MWCNT-N (NIKKISO Co., Ltd) after administration to the rat lung. MWCNT-N was fractionated by passing it through a sieve with a pore size of 35 μm. The average lengths of the MWCNT were 4.2 μm before filtration and 2.6 μm in the flow-through fraction; the length of the retained MWCNT could not be determined. 10-week-old F344/Crj male rats were divided into 5 groups: no treatment, vehicle control, MWCNT-N before filtration, MWCNT-N flow-through, and MWCNT-N retained groups. Administration was by the trans-tracheal intrapulmonary spraying (TIPS) method. Rats were administered a total of 1 mg/rat during the initial 2-weeks of the experiment and then observed up to 109 weeks. The incidences of malignant mesothelioma and lung tumors (bronchiolo-alveolar adenomas and carcinomas) were 6/38 and 14/38, respectively, in the three groups administered MWCNT and 0/28 and 0/28, respectively, in the control groups. All malignant mesotheliomas were localized in the pericardial pleural cavity. The sieve fractions did not have a significant effect on tumor incidence. In conclusion, administration of MWCNT to the lung in the rat induces malignant mesothelioma and lung tumors. This article is protected by copyright. All rights reserved.

Concepts: Cancer, Oncology, Lung cancer, Rat, Carbon nanotube, Mesothelioma, Asbestos, Copyright

128

Due to the remarkable global surge in activity in rare diseases research over the last six years, including contributions by the International Rare Diseases Research Consortium (IRDiRC), the Consortium’s 2020 goals have been largely achieved by 2017. Though these developments are gratifying, enormous challenges remain. With this paradox in mind, IRDiRC set new global rare disease goals for the coming decade with the ultimate aim of improved health for people living with rare diseases worldwide. This article is protected by copyright. All rights reserved.

Concepts: Medicine, Epidemiology, Prevalence, All rights reserved, Copyright

121

In 2011, the International Rare Diseases Research Consortium (IRDiRC) was formed to unite public and private sector funders of research, patient advocacy groups, and scientific researchers to advance rare diseases research worldwide. Six years after its official launch, IRDiRC is now reflecting on its progress and achievements toward its ambitious goals for the rare diseases research collective - to develop 200 new therapies and the means to diagnose most rare genetic diseases by the year 2020. This article is protected by copyright. All rights reserved.

Concepts: Scientific method, Genetic disorder, Science, Research, All rights reserved, Rare disease, Copyright, Advocacy

58

Sharing research data by depositing it in connection with a published article or otherwise making data publicly available sometimes raises intellectual property questions in the minds of depositing researchers, their employers, their funders, and other researchers who seek to reuse research data. In this context or in the drafting of data management plans, common questions are (1) what are the legal rights in data; (2) who has these rights; and (3) how does one with these rights use them to share data in a way that permits or encourages productive downstream uses? Leaving to the side privacy and national security laws that regulate sharing certain types of data, this Perspective explains how to work through the general intellectual property and contractual issues for all research data.

Concepts: Law, Human rights, Property, Copyright, Intellectual property, Property law, Civil and political rights

53

GM crops are the most studied crops in history. Approximately 5% of the safety studies on them show adverse effects that are a cause for concern, and tend to be featured in media reports. Although these reports are based on just a handful of GM events, they are used to cast doubt on all GM crops. Furthermore, they tend to come from just a few laboratories and are published in less important journals. Importantly, a close examination of these reports invariably shows methodological flaws that invalidate any conclusions of adverse effects. Twenty years after commercial cultivation of GM crops began, a bona fide report of an adverse health effect due to a commercialized modification in a crop has yet to be reported. This article is protected by copyright. All rights reserved.

Concepts: Scientific method, Agriculture, Epistemology, Report, Alternative medicine, Adverse effect, All rights reserved, Copyright