Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study)

Background Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. Methods/Design Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs. We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. Discussion Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

Impaired immune evasion in HIV through intracellular delays and multiple infection of cells

With its high mutation rate, HIV is capable of escape from recognition, suppression and/or killing by CD8(+) cytotoxic T lymphocytes (CTLs). The rate at which escape variants replace each other can give insights into the selective pressure imposed by single CTL clones. We investigate the effects of specific characteristics of the HIV life cycle on the dynamics of immune escape. First, it has been found that cells in HIV-infected patients can carry multiple copies of proviruses. To investigate how this process affects the emergence of immune escape, we develop a mathematical model of HIV dynamics with multiple infections of cells. Increasing the frequency of multiple-infected cells delays the appearance of immune escape variants, slows down the rate at which they replace the wild-type variant and can even prevent escape variants from taking over the quasi-species. Second, we study the effect of the intracellular eclipse phase on the rate of escape and show that escape rates are expected to be slower than previously anticipated. In summary, slow escape rates do not necessarily imply inefficient CTL-mediated killing of HIV-infected cells, but are at least partly a result of the specific characteristics of the viral life cycle.

AN EXPERIMENTAL EVALUATION OF THE PERFORMANCE OF A VORTEX-DRIVEN AIR LIFT PUMP

A prototype vortex-driven air lift pump was developed and experimentally evaluated. It was designed to be easily manufactured and scalable for arbitrary riser diameters. The model tested fit in a 2 inch diameter riser with six air injection nozzles through which airwas injected helically around the perimeter of the riser at an angle of 70º from pure tangential injection. The pump was intended to transport both water and sediment over a large range of submergence ratios. A test apparatus was designed to be able to simulate deep water or oceanic environments. The resulting test setup had a finite reservoir; over the course of a test, the submergence ratio varied from 0.48 to 0.39. For air injection pressures ranging from 10 to 60 psig and for air flow rates of 6 to 15 scfm, the induced water discharge flow rates varied only slightly, due to the limited range of available submergence ratios. The anticipated simulation of deep water environment, with a corresponding equivalent increase in thesubmergence ratio, proved unattainable. The pump prototype successfully transported both water and sediment (sand). Thepercent volume yield of the sediment was in an acceptable range. The pump design has been subsequently used successfully in a 4 inch configuration in a follow-on project. A computer program was written in Matlab to simulate the pump characteristics. The program output water pressures at the location of air injection which were physicallycompatible with the experimental data.

The Supreme Court Confirmation Process and Its Implications

In recent history, there has been a trend of increasing partisan polarization throughout most of the American political system. Some of the impacts of this polarization are obvious; however, there is reason to believe that we miss some of the indirect effects of polarization. Accompanying the trend of increased polarization has been an increase in the contentiousness of the Supreme Court confirmation process. I believe that these two trends are related. Furthermore, I argue that these trends have an impact on judicial behavior. This is an issue worth exploring, since the Supreme Court is the most isolated branch of the federal government. The Constitution structured the Supreme Court to ensure that it was as isolated as possible from short-term political pressures and interests. This study attempts to show how it may be possible that those goals are no longer being fully achieved. My first hypothesis in this study is that increases in partisan polarization are a direct cause of the increase in the level of contention during the confirmation process. I then hypothesize that the more contention a justice faces during his or her confirmation process, the more ideologically extreme that justice will then vote on the bench. This means that a nominee appointed by a Republican president will tend to vote even more conservatively than was anticipated following a contentious confirmation process, and vice versa for Democratic appointees. In order to test these hypotheses, I developed a data set for every Supreme Court nominee dating back to President Franklin D. Roosevelt¿s appointments (1937). With this data set, I ran a series of regression models to analyze these relationships. Statistically speaking, the results support my first hypothesis in a fairly robust manner. My regression results for my second hypothesis indicate that the trend I am looking for is present for Republican nominees. For Democratic nominees, the impacts are less robust. Nonetheless, as the results will show, contention during the confirmation process does seem to have some impact on judicial behavior. Following my quantitative analysis, I analyze a series of case studies. These case studies serve to provide tangible examples of these statistical trends as well as to explore what else may be going on during the confirmation process and subsequent judicial decision-making. I use Justices Stevens, Rehnquist, and Alito as the subjects for these case studies. These cases will show that the trends described above do seem to be identifiable at the level of an individual case. These studies further help to indicate other potential impacts on judicial behavior. For example, following Justice Rehnquist¿s move from Associate to Chief Justice, we see a marked change in his behavior. Overall, this study serves as a means of analyzing some of the more indirect impacts of partisan polarization in modern politics. Further, the study offers a means of exploring some of the possible constraints (both conscious and subconscious) that Supreme Court justices may feel while they decide how to cast a vote in a particular case. Given the wide-reaching implications of Supreme Court decisions, it is important to try to grasp a full view of how these decisions are made.

Aging and mental health in the decade ahead: What psychologists need to know

Until relatively recently, most psychologists have had limited professional involvement with older adults. With the baby boomers starting to turn 65 years old in 2011, sheer numbers of older adults will continue to increase. About 1 in 5 older adults has a mental disorder, such as dementia. Their needs for mental and behavioral health services are not now adequately met, and the decade ahead will require an approximate doubling of the current level of psychologists' time with older adults. Public policy in the coming decade will face tensions between cost containment and facilitation of integrated models of care. Most older adults who access mental health services do so in primary care settings, where interdisciplinary, collaborative models of care have been found to be quite effective. To meet the needs of the aging population, psychologists need to increase awareness of competencies for geropsychology practice and knowledge regarding dementia diagnosis, screening, and services. Opportunities for psychological practice are anticipated to grow in primary care, dementia and family caregiving services, decision-making-capacity evaluation, and end-of-life care. Aging is an aspect of diversity that can be integrated into psychology education across levels of training. Policy advocacy for geropsychology clinical services, education, and research remains critical. Psychologists have much to offer an aging society

The Permanent Income Hypothesis: A Test on Czech Privatisation

Since the late eighties, economists have been regarding the transition from command to market economies in Central and Eastern Europe with intense interest. In addition to studying the transition per se, they have begun using the region as a testing ground on which to investigate the validity of certain classic economic propositions. In his research, comprising three articles written in English and totalling 40 pages, Mr. Hanousek uses the so-called "Czech national experiment" (voucher privatisation scheme) to test the permanent income hypothesis (PIH). He took as his inspiration Kreinin's recommendation: "Since data concerning the behaviour of windfall income recipients is relatively scanty, and since such data can constitute an important test of the permanent income hypothesis, it is of interest to bring to bear on the hypothesis whatever information is available". Mr. Hanousek argues that, since the transfer of property to Czech citizens from 1992 to 1994 through the voucher scheme was not anticipated, it can be regarded as windfall income. The average size of the windfall was more than three month's salary and over 60 percent of the Czech population received this unexpected income. Furthermore, there are other reasons for conducting such an analysis in the Czech Republic. Firstly, the privatisation process took place quickly. Secondly, both the economy and consumer behaviour have been very stable. Thirdly, out of a total population of 10 million Czech citizens, an astonishing 6 million, that is, virtually every household, participated in the scheme. Thus Czech voucher privatisation provides a sample for testing the PIH almost equivalent to a full population, thus avoiding problems with the distribution of windfalls. Compare this, for instance with the fact that only 4% of the Israeli urban population received personal restitution from Germany, while the number of veterans who received the National Service Life Insurance Dividends amounted to less than 9% of the US population and were concentrated in certain age groups. But to begin with, Mr. Hanousek considers the question of whether the public percieves the transfer from the state to individual as an increase in net wealth. It can be argued that the state is only divesting itself of assets that would otherwise provide a future source of transfers. According to this argument, assigning these assets to individuals creates an offsetting change in the present value of potential future transfers so that individuals are no better off after the transfer. Mr. Hanousek disagrees with this approach. He points out that a change in the ownership of inefficient state-owned enterprises should lead to higher efficiency, which alone increases the value of enterprises and creates a windfall increase in citizens' portfolios. More importantly, the state and individuals had very different preferences during the transition. Despite government propaganda, it is doubtful that citizens of former communist countries viewed government-owned enterprises as being operated in the citizens' best interest. Moreover, it is unlikely that the public fully comprehended the sophisticated links between the state budget, state-owned enterprises, and transfers to individuals. Finally, the transfers were not equal across the population. Mr. Hanousek conducted a survey on 1263 individuals, dividing them into four monthly earnings categories. After determining whether the respondent had participated in the voucher process, he asked those who had how much of what they received from voucher privatisation had been (a) spent on goods and services, (b) invested elsewhere, (c) transferred to newly emerging pension funds, (d) given to a family member, and (e) retained in their original form as an investment. Both the mean and the variance of the windfall rise with income. He obtained similar results with respect to education, where the mean (median) windfall for those with a basic school education was 13,600 Czech Crowns (CZK), a figure that increased to 15,000 CZK for those with a high school education without exams, 19,900 CZK for high school graduates with exams, and 24,600 CZK for university graduates. Mr. Hanousek concludes that it can be argued that higher income (and better educated) groups allocated their vouchers or timed the disposition of their shares better. He turns next to an analysis of how respondents reported using their windfalls. The key result is that only a relatively small number of individuals reported spending on goods. Overall, the results provide strong support for the permanent income hypothesis, the only apparent deviation being the fact that both men and women aged 26 to 35 apparently consume more than they should if the windfall were annuitised. This finding is still fully consistent with the PIH, however, if this group is at a stage in their life-cycle where, without the windfall, they would be borrowing to finance consumption associated with family formation etc. Indeed, the PIH predicts that individuals who would otherwise borrow to finance consumption would consume the windfall up to the level equal to the annuitised fraction of the increase in lifetime income plus the full amount of the previously planned borrowing for consumption. Greater consumption would then be financed, not from investing the windfall, but from avoidance of future repayment obligations for debts that would have been incurred without the windfall.

Impact of Holocene climate changes on alpine and treeline vegetation at Sanetsch Pass, Bernese Alps, Switzerland

In order to infer reactions of treeline and alpine vegetation to climatic change, past vegetation changes are reconstructed on the basis of pollen, macrofossil and charcoal analysis. The sampled sediment cores originate from the small pond Emines, located at the Sanetsch Pass (connecting the Valais and Bern, Switzerland) at an altitude of 2288 m a.s.l. Today's treeline is at ca. 2200 m a.s.l. in the area, though due to special pass (saddle) conditions it is locally depressed to ca. 2060 m a.s.l. Our results reveal that the area around Emines was covered by treeless alpine vegetation during most of the past 12,000 years. Single individuals of Betula, Larix decidua and possibly Pinus cembra occurred during the Holocene. Major centennial to millennial-scale responses of treeline vegetation to climatic changes are evident. However, alpine vegetation composition remained rather stable between 11,500 and 6000 cal. BP, showing that Holocene climatic changes of +/− 1 °C hardly influenced the local vegetation at Emines. The rapid warming of 3–4 °C at the Late Glacial/Holocene transition (11,600 cal. BP) caused significant altitudinal displacements of alpine species that were additionally affected by the rapid upward movement of trees and shrubs. Since the beginning of the Neolithic, vegetation changes at Sanetsch Pass resulted from a combination of climate change and human impact. Anthropogenic fire increase and land-use change combined with a natural change from subcontinental to more oceanic climate during the second half of the Holocene led to the disappearance of P. cembra in the study area, but favoured the occurrence of Picea abies and Alnus viridis. The mid- to late-Holocene decline of Abies alba was primarily a consequence of human impact, since this mesic species should have benefitted from a shift to more oceanic conditions. Future alpine vegetation changes will be a function of the amplitude and rapidity of global warming as well as human land use. Our results imply that alpine vegetation at our treeline pass site was never replaced by forests since the last ice-age. This may change in the future if anticipated climate change will induce upslope migration of trees. The results of this study emphasise the necessity of climate change mitigation in order to prevent biodiversity losses as a consequence of unprecedented community and species displacement in response to climatic change.

Ocular manifestations in congenital toxoplasmosis

BACKGROUND: Retinochoroiditis is the most common ocular manifestation of congenital toxoplasmosis, but other associated ophthalmological pathologies can also occur. The aim of this study was to determine the nature of the latter in treated cases of the disease and to assess their impact on visual function. METHODS: Four hundred and thirty consecutive children with serologically confirmed congenital toxoplasmosis were included in this study. Data were prospectively collected using standardized ophthalmological assessment forms. The presence of retinochoroiditis and of associated pathologies was ascertained, and their impact on visual function was assessed. RESULTS: After a median follow-up of 12 years [range 0.6-26 years], 130 children manifested retinochoroiditis. We detected 22 foci of retinochoroiditis at birth and 264 additional ones during the follow-up period. Of these, 48 (17%) were active when first diagnosed. Twenty-five of the 130 children (19%) had other associated ocular pathologies. Of these, 21 (16%) had a strabismus, which was due to macular lesions in 86% of the cases; 7 (5.4%) presented with unilateral microphthalmia, and 4 (3%) with cataracts. Most of these events were detected after the onset of retinochoroiditis. None of the children presented with ocular involvement in the absence of chorioretinal lesions. Macular lesions occurred more frequently in children with associated pathologies (p<0.0001), and associated pathologies were likewise more common in individuals with macular lesions (p=0.0003). Visual impairment occurred in 31/130 cases, and in all but 3 of these eyes it was due not to an associated pathology but to macular retinochoroiditis. CONCLUSIONS: At the end of the follow-up period, ocular involvement existed in 30% of the treated children with congenital toxoplasmosis. Associated eye pathologies were manifested less frequently than anticipated. They may occur later in life and are an indirect marker of the severity of congenital toxoplasmosis, but they do not have a direct impact on visual acuity. The overall functional prognosis of congenital toxoplasmosis is better than would be expected on the basis of literature findings, with only 2 of the 130 children suffering bilateral visual impairment.

"What is the Value of Youth Work?" Symposium Booklet

As a group of experienced and novice youth workers, we believe that youth work is fundamentally about building trust-filled, mutually respectful relationships with young people. We create safe environments for young people to connect with other supportive adults and peers and to avoid violence in their neighborhoods and their homes. We guide those harmed by oppressive community conditions such as racism, sexism, agism, homophobia, and classism through a process of healing. As we get to know more about young people’s interests, we help them develop knowledge and skills in a variety of areas including: academic, athletic, leadership/civic, the arts, health and wellbeing, and career exploration. In short, we create transformative experiences for young people. In spite of the critical roles we play, we have largely been overlooked in youth development research, policy, and as a professional workforce. We face challenges ‘moving up’ in our careers. We get frustrated by how little money we earn. We are discouraged that despite our knowledge and experience we are not invited to the tables where youth funding, programming, and policy decisions are made. It is true—many of us do not have formal training or degrees in youth work—a reality which at times we regret. Yet, as our colleague communicates in the accompanying passage (see below), we resent that formal education is required for us to get ahead, particularly because we question whether we need it to do our jobs more effectively. Through the “What is the Value of Youth Work?” symposium, we hope to address these concerns through a dialogue about youth work with the following objectives: • Increase awareness of the knowledge, skills, contributions, and professionalism of youth workers; • Advance a youth worker professional development model that integrates a dilemma-focused approach with principles of social justice youth development; • Launch an ongoing Worcester area Youth Worker network. This booklet provides a brief overview of the challenges in ‘professionalizing’ youth work and an alternative approach that we are advancing that puts the knowledge and expertise of youth workers at the center of professional development.

Ischemic muscle necrosis leading to life-threatening hyperkalemia. Case report and review of the literature

Objective: Description of a cat with ischemic muscle necrosis that suffered from cardiopulmonary arrest due to hyperkalemia. Pathogenesis, clinical signs and therapy of ischemic muscle necrosis are discussed and possible causes, symptoms and treatment of hyperkalemia are shown. Material and methods: case report of a four-year-old male castrated domestic shorthair cat. Results: The cat was successfully resuscitated and hyperkalemia was treated with different treatment modalities. Conclusion: Ischemic muscle necrosis can lead to severe live-threatening hyperkalemia which has to be anticipated, monitored and treated adequately. Aggressive fluid therapy might be responsible for a higher risk of hyperkalemia in predisposed cases. Clinical relevance: Potassium concentrations and acid-base disturbances must be closely monitored in patients with ischemic muscle necrosis

Effects of Silvicultural Practices on Soil Carbon and Nitrogen in a Nitrogen Saturated Central Appalachian (USA) Hardwood Forest Ecosystem

Silvicultural treatments represent disturbances to forest ecosystems often resulting in transient increases in net nitrification and leaching of nitrate and base cations from the soil. Response of soil carbon (C) is more complex, decreasing from enhanced soil respiration and increasing from enhanced postharvest inputs of detritus. Because nitrogen (N) saturation can have similar effects on cation mobility, timber harvesting in N-saturated forests may contribute to a decline in both soil C and base cation fertility, decreasing tree growth. Although studies have addressed effects of either forest harvesting or N saturation separately, few data exist on their combined effects. Our study examined the responses of soil C and N to several commercially used silvicultural treatments within the Fernow Experimental Forest, West Virginia, USA, a site with N-saturated soils. Soil analyses included soil organic matter (SOM), C, N, C/N ratios, pH, and net nitrification. We hypothesized the following gradient of disturbance intensity among silvicultural practices (from most to least intense): even-age with intensive harvesting (EA-I), even-age with extensive harvesting, even-age with commercial harvesting, diameter limit, and single-tree harvesting (ST). We anticipated that effects on soil C and N would be greatest for EA-I and least with ST. Tree species exhibited a response to the gradient of disturbance intensity, with early successional species more predominant in high-intensity treatments and late successional species more predominant in low-intensity treatments. Results for soil variables, however, generally did not support our predictions, with few significant differences among treatments and between treatments and their paired controls for any of the measured soil variables. Multiple regression indicated that the best predictors for net nitrification among samples were SOM (positive relationship) and pH (negative relationship). This finding confirms the challenge of sustainable management of N-saturated forests.

Chronic thromboembolic pulmonary hypertension - assessment by magnetic resonance imaging

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe disease that has been ignored for a long time. However, with the development of improved therapeutic modalities, cardiologists and thoracic surgeons have shown increasing interest in the diagnostic work-up of this entity. The diagnosis and management of chronic thromboembolic pulmonary hypertension require a multidisciplinary approach involving the specialties of pulmonary medicine, cardiology, radiology, anesthesiology and thoracic surgery. With this approach, pulmonary endarterectomy (PEA) can be performed with an acceptable mortality rate. This review article describes the developments in magnetic resonance (MR) imaging techniques for the diagnosis of chronic thromboembolic pulmonary hypertension. Techniques include contrast-enhanced MR angiography (ce-MRA), MR perfusion imaging, phase-contrast imaging of the great vessels, cine imaging of the heart and combined perfusion-ventilation MR imaging with hyperpolarized noble gases. It is anticipated that MR imaging will play a central role in the initial diagnosis and follow-up of patients with CTEPH.

Anticipatory cognitive stress appraisal and the acute procoagulant stress response in men

OBJECTIVE: Acute mental stress elicits blood hypercoagulability. Following a transactional stress model, we investigated whether individuals who anticipate stress as more threatening, challenging, and as exceeding their coping skills show greater stress reactivity of the coagulation activation marker D-dimer, indicating fibrin generation in plasma. METHODS: Forty-seven men (mean age 44 +/- 14 years; mean blood pressure [MBP] 101 +/- 12 mm Hg; mean body mass index [BMI] 26 +/- 3 kg/m(2)) completed the Primary Appraisal Secondary Appraisal (PASA) scale before undergoing the Trier Social Stress Test (combination of mock job interview and mental arithmetic task). Heart rate, blood pressure, plasma catecholamines, and D-dimer levels were measured before and after stress, and during recovery up to 60 minutes poststress. RESULTS: Hemodynamic measures, catecholamines, and D-dimer changed across all time points (p values <.001). The PASA "Stress Index" (integrated measure of transactional stress perception) correlated with total D-dimer area under the curve (AUC) between rest and 60 minutes poststress (r = 0.30, p = .050) and with D-dimer change from rest to immediately poststress (r = 0.29, p = .046). Primary appraisal (combined "threat" and "challenge") correlated with total D-dimer AUC (r = 0.37, p = .017), D-dimer stress change (r = 0.41, p = .004), and D-dimer recovery (r = 0.32, p = .042). "Challenge" correlated more strongly with D-dimer stress change than "threat" (p = .020). Primary appraisal (DeltaR(2) = 0.098, beta = 0.37, p = .019), and particularly its subscale "challenge" (DeltaR(2) = 0.138, beta = 0.40, p = .005), predicted D-dimer stress change independently of age, BP, BMI, and catecholamine change. CONCLUSIONS: Anticipatory cognitive appraisal determined the extent of coagulation activation to and recovery from stress in men. Particularly individuals who anticipated the stressor as more challenging and also more threatening had a greater fibrin stress response.

Erosive tooth wear - a multifactorial condition of growing concern and increasing knowledge

Dental erosion is often described solely as a surface phenomenon, unlike caries where it has been established that the destructive effects involve both the surface and the subsurface region. However, besides removal and softening of the surface, erosion may show dissolution of mineral underneath the surface. There is some evidence that the presence of this condition is growing steadily. Hence, erosive tooth wear is becoming increasingly significant in the management of the long-term health of the dentition. What is considered as an acceptable amount of wear is dependent on the anticipated lifespan of the dentition and, therefore, is different for deciduous compared to permanent teeth. However, erosive damage to the permanent teeth occurring in childhood may compromise the growing child's dentition for their entire lifetime and may require repeated and increasingly complex and expensive restoration. Therefore, it is important that diagnosis of the tooth wear process in children and adults is made early and adequate preventive measures are undertaken. These measures can only be initiated when the risk factors are known and interactions between them are present. A scheme is proposed which allows the possible risk factors and their relation to each other to be examined.

Outside-in signaling through integrins and cadherins: a central mechanism to control epidermal growth and differentiation?

The process of epidermal renewal persists throughout the entire life of an organism. It begins when a keratinocyte progenitor leaves the stem cell compartment, undergoes a limited number of mitotic divisions, exits the cell cycle, and commits to terminal differentiation. At the end of this phase, the postmitotic keratinocytes detach from the basement membrane to build up the overlaying stratified epithelium. Although highly coordinated, this sequence of events is endowed with a remarkable versatility, which enables the quiescent keratinocyte to reintegrate into the cell cycle and become migratory when necessary, for example after wounding. It is this versatility that represents the Achilles heel of epithelial cells allowing for the development of severe pathologies. Over the past decade, compelling evidence has been provided that epithelial cancer cells achieve uncontrolled proliferation following hijacking of a "survival program" with PI3K/Akt and a "proliferation program" with growth factor receptor signaling at its core. Recent insights into adhesion receptor signaling now propose that integrins, but also cadherins, can centrally control these programs. It is suggested that the two types of adhesion receptors act as sensors to transmit extracellular stimuli in an outside-in mode, to inversely modulate epidermal growth factor receptor signaling and ensure cell survival. Hence, cell-matrix and cell-cell adhesion receptors likely play a more powerful and wide-ranging role than initially anticipated. This Perspective article discusses the relevance of this emerging field for epidermal growth and differentiation, which can be of importance for severe pathologies such as tumorigenesis and invasive metastasis, as well as psoriasis and Pemphigus vulgaris.