Lessons from development: A role for asymmetric stem cell division in cancer

Asymmetric stem cell division has emerged as a major regulatory mechanism for physiologic control of stem cell numbers. Reinvigoration of the cancer stem cell theory suggests that tumorigenesis may be regulated by maintaining the balance between asymmetric and symmetric cell division. Therefore, mutations affecting this balance could result in aberrant expansion of stem cells. Although a number of molecules have been implicated in regulation of asymmetric stem cell division, here, we highlight known tumor suppressors with established roles in this process. While a subset of these tumor suppressors were originally defined in developmental contexts, recent investigations reveal they are also lost or mutated in human cancers. Mutations in tumor suppressors involved in asymmetric stem cell division provide mechanisms by which cancer stem cells can hyperproliferate and offer an intriguing new focus for understanding cancer biology. Our discussion of this emerging research area derives insight from a frontier area of basic science and links these discoveries to human tumorigenesis. This highlights an important new focus for understanding the mechanism underlying expansion of cancer stem cells in driving tumorigenesis.     

Fibulin-1 Is Increased in Asthma – A Novel Mediator of Airway Remodeling?

Background

The extracellular matrix is a dynamic and complex network of macromolecules responsible for maintaining and influencing cellular functions of the airway. The role of fibronectin, an extracellular matrix protein, is well documented in asthma. However, the expression and function of fibulin-1, a secreted glycoprotein which interacts with fibronectin, has not been reported. Fibulin-1 is widely expressed in basement membranes in many organs including the lung. There are four isoforms in humans (A–D) of which fibulin-1C and 1D predominate. The objective of this study was to study the expression of fibulin-1 in volunteers with and without asthma, and to examine its function in vitro.

Methodology/Principal Findings

We used immunohistochemistry and dot-blots to examine fibulin-1 levels in bronchial biopsies, bronchoalveolar lavage fluid and serum. Real-time PCR for fibulin-1C and 1D, and ELISA and western blotting for fibulin-1 were used to study the levels in airway smooth muscle cells. The function of fibulin-1C was determined by assessing its role, using an antisense oligonucleotide, in cell proliferation, migration and wound healing. A murine model of airway hyperresponsiveness (AHR) was used to explore the biological significance of fibulin-1. Levels of fibulin-1 were significantly increased in the serum and bronchoalveolar lavage fluid of 21 asthmatics compared with 11 healthy volunteers. In addition fibulin-1 was increased in asthma derived airway smooth muscle cells and fibulin-1C contributed to the enhanced proliferation and wound repair in these cells. These features were reversed when fibulin-1C was suppressed using an antisense oligomer. In a mouse model of AHR, treatment with an AO inhibited the development of AHR to methacholine.

Conclusions

Our data collectively suggest fibulin-1C may be worthy of further investigation as a target for airway remodeling in asthma.     

Gauging U.S. Emergency Medical Services Workers' Willingness to Respond to Pandemic Influenza Using a Threat- and Efficacy-Based Assessment Framework

Background

Emergency Medical Services workers'' willingness to report to duty in an influenza pandemic is essential to healthcare system surge amidst a global threat. Application of Witte''s Extended Parallel Process Model (EPPM) has shown utility for revealing influences of perceived threat and efficacy on non-EMS public health providers'' willingness to respond in an influenza pandemic. We thus propose using an EPPM-informed assessment of EMS workers'' perspectives toward fulfilling their influenza pandemic response roles.

Methodology/Principal Findings

We administered an EPPM-informed snapshot survey about attitudes and beliefs toward pandemic influenza response, to a nationally representative, stratified random sample of 1,537 U.S. EMS workers from May–June 2009 (overall response rate: 49%). Of the 586 respondents who met inclusion criteria (currently active EMS providers in primarily EMS response roles), 12% indicated they would not voluntarily report to duty in a pandemic influenza emergency if asked, 7% if required. A majority (52%) indicated their unwillingness to report to work if risk of disease transmission to family existed. Confidence in personal safety at work (OR = 3.3) and a high threat/high efficacy (“concerned and confident”) EPPM profile (OR = 4.7) distinguished those who were more likely to voluntarily report to duty. Although 96% of EMS workers indicated that they would probably or definitely report to work if they were guaranteed a pandemic influenza vaccine, only 59% had received an influenza immunization in the preceding 12 months.

Conclusions/Significance

EMS workers'' response willingness gaps pose a substantial challenge to prehospital surge capacity in an influenza pandemic. “Concerned and confident” EMS workers are more than four times as likely to fulfill pandemic influenza response expectations. Confidence in workplace safety is a positively influential modifier of their response willingness. These findings can inform insights into interventions for enhancing EMS workers'' willingness to respond in the face of a global infectious disease threat.     

Mild Sensory Stimulation Completely Protects the Adult Rodent Cortex from Ischemic Stroke

Despite progress in reducing ischemic stroke damage, complete protection remains elusive. Here we demonstrate that, after permanent occlusion of a major cortical artery (middle cerebral artery; MCA), single whisker stimulation can induce complete protection of the adult rat cortex, but only if administered within a critical time window. Animals that receive early treatment are histologically and behaviorally equivalent to healthy controls and have normal neuronal function. Protection of the cortex clearly requires reperfusion to the ischemic area despite permanent occlusion. Using blood flow imaging and other techniques we found evidence of reversed blood flow into MCA branches from an alternate arterial source via collateral vessels (inter-arterial connections), a potential mechanism for reperfusion. These findings suggest that the cortex is capable of extensive blood flow reorganization and more importantly that mild sensory stimulation can provide complete protection from impending stroke given early intervention. Such non-invasive, non-pharmacological intervention has clear translational potential.     

Cost-Effectiveness of HIV Testing Referral Strategies among Tuberculosis Patients in India

Background

Indian guidelines recommend routine referral for HIV testing of all tuberculosis (TB) patients in the nine states with the highest HIV prevalence, and selective referral for testing elsewhere. We assessed the clinical impact and cost-effectiveness of alternative HIV testing referral strategies among TB patients in India.

Methods and Findings

We utilized a computer model of HIV and TB disease to project outcomes for patients with active TB in India. We compared life expectancy, cost, and cost-effectiveness for three HIV testing referral strategies: 1) selective referral for HIV testing of those with increased HIV risk, 2) routine referral of patients in the nine highest HIV prevalence states with selective referral elsewhere (current standard), and 3) routine referral of all patients for HIV testing. TB-related data were from the World Health Organization. HIV prevalence among TB patients was 9.0% in the highest prevalence states, 2.9% in the other states, and 4.9% overall. The selective referral strategy, beginning from age 33.50 years, had a projected discounted life expectancy of 16.88 years and a mean lifetime HIV/TB treatment cost of US$100. The current standard increased mean life expectancy to 16.90 years with additional per-person cost of US$10; the incremental cost-effectiveness ratio was US$650/year of life saved (YLS) compared to selective referral. Routine referral of all patients for HIV testing increased life expectancy to 16.91 years, with an incremental cost-effectiveness ratio of US$730/YLS compared to the current standard. For HIV-infected patients cured of TB, receiving antiretroviral therapy increased survival from 4.71 to 13.87 years. Results were most sensitive to the HIV prevalence and the cost of second-line antiretroviral therapy.

Conclusions

Referral of all patients with active TB in India for HIV testing will be both effective and cost-effective. While effective implementation of this strategy would require investment, routine, voluntary HIV testing of TB patients in India should be recommended.     

Single-dose mucosal immunization with a candidate universal influenza vaccine provides rapid protection from virulent H5N1, H3N2 and H1N1 viruses

Background

The sudden emergence of novel influenza viruses is a global public health concern. Conventional influenza vaccines targeting the highly variable surface glycoproteins hemagglutinin and neuraminidase must antigenically match the emerging strain to be effective. In contrast, “universal” vaccines targeting conserved viral components could be used regardless of viral strain or subtype. Previous approaches to universal vaccination have required protracted multi-dose immunizations. Here we evaluate a single dose universal vaccine strategy using recombinant adenoviruses (rAd) expressing the conserved influenza virus antigens matrix 2 and nucleoprotein.

Methodology/Principal Findings

In BALB/c mice, administration of rAd via the intranasal route was superior to intramuscular immunization for induction of mucosal responses and for protection against highly virulent H1N1, H3N2, or H5N1 influenza virus challenge. Mucosally vaccinated mice not only survived, but had little morbidity and reduced lung virus titers. Protection was observed as early as 2 weeks post-immunization, and lasted at least 10 months, as did antibodies and lung T cells with activated phenotypes. Virus-specific IgA correlated with but was not essential for protection, as demonstrated in studies with IgA-deficient animals.

Conclusion/Significance

Mucosal administration of NP and M2-expressing rAd vectors provided rapid and lasting protection from influenza viruses in a subtype-independent manner. Such vaccines could be used in the interval between emergence of a new virus strain and availability of strain-matched vaccines against it. This strikingly effective single-dose vaccination thus represents a candidate off-the-shelf vaccine for emergency use during an influenza pandemic.     

Evidence for a Novel Marine Harmful Algal Bloom: Cyanotoxin (Microcystin) Transfer from Land to Sea Otters

“Super-blooms” of cyanobacteria that produce potent and environmentally persistent biotoxins (microcystins) are an emerging global health issue in freshwater habitats. Monitoring of the marine environment for secondary impacts has been minimal, although microcystin-contaminated freshwater is known to be entering marine ecosystems. Here we confirm deaths of marine mammals from microcystin intoxication and provide evidence implicating land-sea flow with trophic transfer through marine invertebrates as the most likely route of exposure. This hypothesis was evaluated through environmental detection of potential freshwater and marine microcystin sources, sea otter necropsy with biochemical analysis of tissues and evaluation of bioaccumulation of freshwater microcystins by marine invertebrates. Ocean discharge of freshwater microcystins was confirmed for three nutrient-impaired rivers flowing into the Monterey Bay National Marine Sanctuary, and microcystin concentrations up to 2,900 ppm (2.9 million ppb) were detected in a freshwater lake and downstream tributaries to within 1 km of the ocean. Deaths of 21 southern sea otters, a federally listed threatened species, were linked to microcystin intoxication. Finally, farmed and free-living marine clams, mussels and oysters of species that are often consumed by sea otters and humans exhibited significant biomagnification (to 107 times ambient water levels) and slow depuration of freshwater cyanotoxins, suggesting a potentially serious environmental and public health threat that extends from the lowest trophic levels of nutrient-impaired freshwater habitat to apex marine predators. Microcystin-poisoned sea otters were commonly recovered near river mouths and harbors and contaminated marine bivalves were implicated as the most likely source of this potent hepatotoxin for wild otters. This is the first report of deaths of marine mammals due to cyanotoxins and confirms the existence of a novel class of marine “harmful algal bloom” in the Pacific coastal environment; that of hepatotoxic shellfish poisoning (HSP), suggesting that animals and humans are at risk from microcystin poisoning when consuming shellfish harvested at the land-sea interface.     

应用红外相机技术研究秦岭观音山自然保护区内野猪的行为和丰富度

2009年7月,在陕西观音山自然保护区凉风垭小区域（中高海拔）和西沟小区域（低海拔）安装18台红外相机,2009年8月至2013年4月共收集野猪照片1 195张。定义9种野猪行为,分别为站立、走动、跑动、采食、饮水、修饰、发情、拱土、坐着休息,并逐一比对照片中野猪的行为,统计各种行为所占的比例;引入月相对丰富度和时间段相对丰富度两个指数分别研究野猪的年活动规律和日活动规律;利用一个种群估测模型探讨野猪密度的年际变化。结果表明：（1）春季野猪以走动、采食和站立为主,分别占总行为次数的36%、25.6%和17.4%;夏季野猪以走动、站立、采食和跑动为主,分别占总行为次数的35.7%、23.6%、17%和16.5%;秋季野猪以采食、走动和发情为主,分别占总行为次数的50.3%、19.3%和17.8%;冬季野猪以采食、走动和站立为主,分别占总行为次数的53.7%、26.7%和11.9%。（2）野猪在8月、9月和12月活动较为频繁;全年日活动高峰出现在午后14:00-16:00,低谷出现在22:00-04:00,四季显示活动规律不同。（3）2009-2012年野猪密度呈逐年上升趋势。这些研究结果有助于了解野猪的行为活动和种群动态,并采取针对性的措施对野猪进行有效管理。