MGMT Methylation Status and Glioblastoma Multiforme Outcome

MGMT Methylation Status and Glioblastoma Multiforme Outcome ABSTRACT Background: O6 – methylguanine-methyltransferase (MGMT) promoter methylation has been associated with increased survival among patients with glioblastoma multiforme (GBM) who were treated with various alkylating agents. We examined the relationship between MGMT methylation status and clinical outcome in newly diagnosed GBM patients treated with BCNU wafers (Gliadel ®). Methods: MGMT promoter methylation in DNA from 122 newly diagnosed GBM patients treated with Gliadel was determined by a Quantitative methylation-specific polymerase chain reaction assay (QMSP) and correlated with overall survival (OS) and recurrence-free survival (RFS). Results: The MGMT promoter was methylated in 40 (32.7%) of 122 patients. Overall median survival was 13.5 months (95%CI: 11.0-14.5) and recurrence-free survival (RFS) was 9.4 months (95%CI: 7.8-10.2). After adjusting for age, KPS, extent of resection, temozolomide (TMZ) and radiation therapy (RT), newly diagnosed GBM patients with MGMT methylation who were treated with Gliadel had a 15% reduction in hazard of death compared to patients with unmethylated MGMT (Hazard ratio: 0.85, 95%CI: 0.56-1.31). Patients aged over 70 with MGMT methylation and treated with Gliadel had a significantly longer median survival of 13.5 months compared to 7.6 months in patients with unmethylated MGMT (p=0.027). A similar significant difference was also found in older patients with a median recurrence-free survival of 13.1 versus 7.6 months (p=0.01) for MGMT methylated and unmethylated, respectively. Conclusions: Methylation of the MGMT promoter in newly diagnosed GBM patients who were treated with Gliadel followed by RT and TMZ, was associated with significantly improved survival compared to the non-methylated patient population with similar treatment. For the elderly population, methylation of the MGMT promoter was associated with significantly better OS and RFS. INTRODUCTION Glioblastome multiforme (GBM) is the most common primary brain tumor, with a median survival of less than two years [1]. To date, only two different alkylating agents have been shown to be consistently associated with prolonged survival – temozolomide (TMZ) and the locally delivered BCNU wafers (Gliadel) [1-3]. Gliadel wafers (Eisai Inc. for Arbor Pharmaceuticals, LLC) are implanted and locally deliver Carmustine (also known as (1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU)) at the site of tumor resection, allowing for a higher concentration of local chemotherapeutic doses while minimizing systemic adverse effects [2-4]. These wafers provide a controlled- release form of local chemotherapy for approximately 3 weeks [4, 5]. Methylation of the MGMT promoter in gliomas was found to be an important predictor of the tumor responsiveness after several cytotoxic regimens [6], including BCNU treatment [7]. It was found that expression of the DNA repair protein, O6 – methylguanine-methyltransferase (MGMT), results in GBM resistance to alkylating agents. Alkylating agents cause cell death by binding to DNA, most commonly to the O6 position of guanine, and forms cross-links between adjacent DNA strands. This cross-linking of double strand DNA is inhibited by the cellular DNA-repair protein MGMT. In this study, through a unique analysis of 122 patients with newly diagnosed GBM who were treated with Gliadel, we retrospectively examined the association between MGMT promoter methylation status and survival. METHODS Patients and Tumor Specimens We retrospectively reviewed 185 patients with newly diagnosed GBM who received Gliadel after tumor resection, at Johns Hopkins Hospital in Baltimore, USA, between July 1997 and December 2006. Of these patients, only 122 patients had stored samples that were available for MGMT analysis. The clinical, radiological and hospital course of these patients were retrospectively reviewed. Age and gender were recorded, as well as Karnofsky performance score (KPS) at time of diagnosis, tumor location, time to recurrence and dates of death were recorded. Overall survival (OS) was calculated from the time of surgery to death, and recurrence free survival (RFS) was calculated from the time of surgery to time of recurrence or censored at the last time of follow-up. GBM was histologically confirmed in all cases. Extent of surgical resection was determined based on a postoperative MRI performed Treatment Algorithm Gliadel wafers were typically not implanted in patients after tumor resection when the tumor largely extended into the ventricles or was multifocal. DNA Extraction After initial patient de-identification, all original histologic slides from the GBM specimens were reviewed to reconfirm the diagnosis of GBM by a senior neuropathologist (PB). A representative block with tumor was retrieved for DNA extraction. Histologic slides from the formalin-fixed, paraffin-embedded tissue were obtained. One representative slide was stained with HE and the tumor was marked by the senior neuropathologist (PB). An additional five correlating unstained 10 micron slides were also obtained. The tumor cells in the unstained slides were microdissected according to the marked HE stained reference slide. DNA was extracted from paraffin embedded tissue after xylene deparaffinization. The microdissected tissue was digested with 1% sodium dodecyl sulfate (SDS) and 200ug/mL proteinase K (Roche, Nutley, NJ) at 48 °C for 48 hours, followed by phenol/chloroform extraction and ethanol precipitation of DNA. Extracted DNA was dissolved in either LoTE (2.5 mM EDTA, 10 mM Trisâ⠂¬â€œHCl [pH 8]) or distilled water. Bisulfite Treatment Extracted DNA was subjected to bisulfite treatment, to convert unmethylated cytosine residues to uracil residues. Briefly, 2  µg genomic DNA from each sample was treated with bisulfite using the EpiTect Bisulfite kit (Qiagen, Valencia, CA) according to the manufacturer’s instructions. Converted DNA was stored at -80oC. Methylation Analysis Bisulfite-modified DNA was used as a template for fluorescence-based real-time PCR. Amplification reactions were carried out in triplicate in a final volume of 20  µL that contained 3  µL bisulfite-modified DNA; 600 nmol/L concentrations of forward and reverse primers; 200 nmol/L probe; 0.6 units platinum Taq polymerase (Invitrogen); 200  µmol/L concentrations each of dATP, dCTP, dGTP, and dTTP; and 6.7 mmol/L MgCl2. Primers and probes were designed to specifically amplify the promoter of MGMT and the promoter of a reference gene, ACTIN B; primer and probe sequences and annealing temperatures are provided in Table 1. Amplifications were carried out using the following profile: 95 °C for 3 min followed by 50 cycles at 95 °C for 15 s and 60 °C for 1 min. Amplification reactions were carried out in 384-well plates in a 7900 sequence detector (Perkin-Elmer Applied Biosystems) and analyzed by a sequence detector system (SDS 2.2.1; Applied Biosystems). Each plate included patie nt DNA samples, positive controls (Bisulfite-converted Universal Methylated Human DNAStandards (Zymo Research) in serial dilutions 20ng to 2pg) and molecular grade water was used as a non-template control. The ÃŽ ²-actin gene was used to normalize and act as an internal loading control. The methylation ratio was the ratio of values for the gene-specific PCR products to those of the ACTIN B and then multiplied by 1,000 for more efficient tabulation. Statistical Methods The overall survival (OS) time was defined from the date of initial diagnosis of the disease (surgery) to the time of death or censored at the time last known alive. The recurrence-free survival (RFS) was counted from the date of initial diagnosis of the disease to the time of disease recurrence or censored at the time last known alive and recurrence-free. Probabilities of OS and RFS were estimated using the Kaplan-Meier (KM) method [15] and compared using Log-rank test. Confidence intervals were calculated using the method of Brookmeyer and Crowley[14]. Cox proportional hazards model [16] was used to estimate the association between OS or RFS and MGMT methylation status, treatments and well known prognostic factors. Schoenfeld residuals were used to test the proportionality of factors in Cox proportional hazards models. Radiation status was treated as a stratification factor in the Cox regression model. TMZ has FDA approval for newly diagnosed GBM patients aged between 18-70. Subgro up analyses were performed for patients who were aged over 70. All p values were two-sided. All analyses were performed using the Statistical Analysis System, version 9.2. MGMT was considered as promoter methylated if the methylation ratio was higher than 8, and unmethylated if below 8. RESULTS Patient Population Six hundred patients with newly diagnosed GBM underwent craniotomy between 1997 and 2006, at the Johns Hopkins Hospital. One hundred eighty five patients received Gliadel (30.8%) after tumor resection. Methylation specific PCR was performed in 122 of the 185 patients (66%) because 63 patients did not have sufficient paraffin embedded tumor tissue for MGMT analysis. The characteristics of the patients and type of treatments are shown in Table 2. The clinical course of forty patients who had methylation of MGMT promoter was compared to 82 patients without promoter methylation of MGMT. The similarity of distributions among patients characteristics, and treatments between MGMT methylated and unmethylated is also shown in Table 2. There was a slightly male predominance in both groups. The median age of the MGMT methylated group was 65.5 years compared to 60.5 years in the non-MGMT methylated group (p=0.59). Most of the patients in both groups had KPS score of ≠¤ 80 (p=0.67). Most of the patients in both groups underwent gross total resection (GTR) (85% vs. 74% in the methylated and non-MGMT methylated group, respectively), (p=0.19). Most of the patients in the MGMT methylated and non-MGMT methylated groups received post-operative radiation therapy (RT) (80% and 72% respectively). However, there were 31 patients (25%) without radiation treatment recorded in their medical chart. Only 33% and 29% of MGMT methylated and non-MGMT patients, respectively, were treated with TMZ due to majority of patients was treated prior to 2005 when RT+ TMZ became the stadnadrd of care for the newly diagnosed GBM patients. Overall Survival The Kaplan-Meier estimate of the median OS for the122 patients with newly diagnosed GBM was 13.5 months (95% CI: 11.0, 14.5). Median OS for those with MGMT methylation was 13.9 months (95%CI: 9.5, 17.1) compared to 12.9 months (95%CI: 10.9, 14.5) (p= 0.86) in patients non methylated. Univariate and multivariate association of survival with treatment factor, baseline prognostic factors, and MGMT methylation status are shown in Table 3. There was a 15% reduction in hazard of death (Hazard ratio: 0.85, 95%CI: 0.56-1.31) for patients with MGMT methylated tumor compared to those with MGMT unmethylated tumor after adjusting for age, KPS, extent of resection, TMZ and RT. A subgroup analysis was performed among 35 patients who were 18-70 years old and treated with Gliadel, RT and TMZ ( Gliadel+ Stupp’s regimen) [1]. The median OS was 19.8 months (95% CI, 14.5, 22.2) in this subset of patients. There was no statistically significant difference in OS among these 35 patients with MGMT pr omoter methylation (median OS:20 months,95% CI: 9.2, 37.0), compared to patients without MGMT promoter methylation (median OS: 18.9 months, 95% CI: 11.9, 22.2), (Table 4). Only two out of 30 elderly patients aged above 70 years were treated with TMZ, one was MGMT methylated and another was not. Among these elderly patients, those with MGMT promoter methylation showed a significantly longer median survival of 13.5 months (95% CI, 0.49, 17.1) compared to 7.6 months (95% CI, 2.9, 9.4) when the MGMT promoter was non-methylated (p=0.027). A similar significant difference in median recurrence-free survival was also found in elderly patients where the median survival was 13.1 versus 7.6 months (p=0.01) for MGMT methylated and unmethylated, respectively. The overall median recurrence-free survival was 9.4 months (95%CI: 7.8-10.2) for all patients. There was no difference in RFS between patients 18-70 years old with and without MGMT methylation. DISCUSSION In this study we investigated the significance of MGMT methylation status in a series of 122 patients with newly diagnosed GBM who underwent surgical resection and implantation of Gliadel wafers. The results of our series show a reduction in hazard of death for patients who were MGMT methylated compared to non-methylated. Interestingly, this effect was much more profound in the elderly group of 35 patients who were older than 70 years old when they were diagnosed with GBM. Elderly patients who were MGMT methylated had significantly better OS, compared to non-methylated (13.5 vs. 7.6 months respectively, p=0.027). The methylation of the MGMT promoter region leads to a reduced ability to repair DNA damage induced by alkylating chemotherapeutic agents [7]. Methylation of the MGMT promoter was found to be associated with responsiveness to alkylating chemotherapeutic agents such as temozolomide [6] and BCNU [7], and an increase in OS and progression free survival. The median survival of patients who received the combination of Gliadel, temozolomide and radiation therapy in our cohort ranged between 18.9 to 20 months, six months greater than that for the radiation therapy and temozolomide historic cohort [1] (Figure1). For patients younger than 70 years old, the median survival of the MGMT methylated sub-group was slightly greater that MGMT non-methylated. KPS in a known prognostic factor for patients with brain tumors [8]. Most of the patients in our study cohort had poor KPS of less than 80. Still, our results were in line with the report of Lechapt-Zalcman et al. [9] who assessed the prognostic impact of MGMT promoter methylation in patients with newly diagnosed GBM that received Gliadel in addition to radiation therapy and temozolomide. The OS of their study cohort was 17.5 months. Patients with MGMT methylation had a significantly longer OS of 21.7 months compared with patients without MGMT methylation who had OS of 15.1 months. Two recent phase III clinical trials in the elderly age of patients with malignant astrocytoma, the NOA-08 [10] and Nordic trials [11], demonstrated that temozolomide therapy alone was not inferior to radiotherapy alone, and methylation of the MGMT gene promoter was associated with a benefit from temozolomide. However, there is a concern that combination therapy of radiation therapy and temozolomide may be less active and less well tolerated in the elderly population [12]. European Organization for Research and Treatment of Cancer (EORTC)-26981/National Cancer Institute of Canada (NCIC) CE3 trial have suggested that with increasing age, the relative benefit of addition of temozolomide to radiotherapy decreases and the patients suffer from increased chemotherapy-associated side effect such as neutropenia, lymphocytopenia, thrombocytopenia , raised liver-enzyme concentrations infections and thromboembolic events. As opposed to systemic chemotherapy with its limitations, local delivery of Gliadel wafers may be promising in this subset of patients. Chaichana et al. compared 45 elderly patients who were treated with Gliadel to 88 elderly patients who did not receive Gliadel [13]. The survival for older patients who received Gliadel was significantly longer than for patients who did not receive Gliadel (8.7 months vs. 5.5 months respectively, p=0.007). The median survival of MGMT methylated in elderly patients in the current cohort was doubled. These results may support the use of Gliadel in this sub-population. Limitations There are several limitations to this study. Its retrospective nature carries a potential bias. Moreover, the time period of this study ended in 2006, only one year after temozolomide became the standard of care in the treatment of GBM, thus most of the patients were not treated with the combination of temozolomide and radiation therapy. Furthermore, because this is a tertiary referral center, there is a bulk of patients who were operated in this center, but received further neuro-oncology treatments elsewhere, near their home, and therefore, their complementary oncology treatment is not available. Still, this large and unique cohort of patients with newly diagnosed GBM who were operated in one tertiary center provide novel data that may assist in optimizing and personalizing the treatment for GBM patients.

Cognitive Biases in Entrepreneurial Strategies

The view of the human as a rational being is nowadays heavily questioned (Simon, 1959), UT in science a lot of models and theories still are based on this assumption. When looking at research on entrepreneurship, we notice that it is considered a relatively new field of study, though practice has shown that entrepreneurial activities have a great influence on the market. Schumacher (1934) already linked entrepreneurial Initiatives of Individuals to the creation and destruction of Industries, as well as to economic development.More research has been conducted about entrepreneurship, which questions the classical picture of the economic man – Homo economics – and he classical concept of rationality. This might be because the entrepreneur himself Is one of the most crucial factors of either the success or failure of an entrepreneurial business. This has caused the entrepreneur to be a hot topic and so a lot of research has been dedicated to the phenomenon. An Shame to (200 0) for example different argues that the underlying factor that causes entrepreneur knowledge. Other research has focused on the traits of entrepreneurs.In general, entrepreneurs are considered overconfident (Cooper et al. , 1988), which is a good thing if you want to start-up a company. Without this trait, start-ups would probably not take place as often as we observe (Goodness & Lecher, 2013). However, research has also showed that this overconfidence is associated with failure (Camera & Lovable, 1999). Nobel (2011) argued that although we know 30 to 40 per cent of entrepreneurial firms fail, many other are bought out or never bring expected return on investment, meaning that the real failure rate can be up to 70 or 80 per cent.Overconfidence is one of the known biases that influence human beings in decision making. There are, however, a lot of more biases which an entrepreneur can encounter. This raises the question of whether being aware example of such of the biases could help the bias, entrepreneur in his activities. If we look at the overconfidence overconfidence can lead to wrong decisions. Awareness thus, could be helpful. On the other hand, if the entrepreneur is aware of this bias he could become too careful in the decision making process. This can result in no action being taken when the ‘moment' arrives.Or it could result in the entrepreneur even deciding not to continue due to the risks being too high. This leads us to the question: 3 The following questions will help us answer the main question by shedding some eight on the biases that are out there: Theory of Bounded Rationality As mentioned in the introduction, we assume Homo economics appears to be perfectly rational and has complete knowledge, while the economic choices one makes are clandestine in the economic sphere without affecting other aspects of the individual such as emotions or being influenced by the environment.This is in line with the neoclassical economic theory that assum es full What is a cognitive bias? Why does this article address cognitive biases? What kind of cognitive biases could an entrepreneur encounter? Theory In this section the previously stated substitutions will be answered based on theory of decision-making, cognitive biases and the application to entrepreneurship. Entrepreneurship We accept the definition of entrepreneurship as suggested by Stevenson and Carillon (1990): ‘Entrepreneurship is about individuals who create opportunities through various modes of organizing, without regard to resources currently controlled. Sevens and Carillon moved away from the view of the traits school' which tried to describe how entrepreneurs differed from other people by control, leadership, or propensity for risk-taking. When studies showed that entrepreneurs are as different from one another as they are from school' non- entrepreneurs, the ‘behavioral rationality. This view has been criticized by Simon (1959) who developed an approach based on bounded rationality and problem solving. Simon stated that the assumption of full rationality is unrealistic.In his view, the rationality of individuals is limited by the information they have, the cognitive limitations of their minds and the finite amount of time they have to make decisions. The theory of bounded rationality states that individuals face uncertainty about the future and costs in acquiring information in the present. What is a cognitive bias? Biases and heuristics (mental shortcuts) are decision rules, cognitive mechanisms, and subjective opinions people use to help them making decisions. This is a deviation of the benchmark Cognitive of biases rational prevent decision-making. Individuals to accurately understand reality and interfere with the ability to be impartial, unprejudiced or objective (Goodness and Lecher, 2013). Taverns and Keenan (1974) state that people rely on ‘heuristic principles which reduce the complex tasks of assessing probabilities and predicting values to simpler Judgmental operations. There are specific and systematic biases that move the Judgment away from the perfect rationality of individuals. Argued that the process of creating a new venture, should be the fundamental part of defining someone as an entrepreneur. (Gideon, 2010).This is why we agree on the definition by Stevenson and Carillon, which also implies we will not discuss entrepreneurial traits in this article. 4 Drawing on aspects of both psychology and economics, the operating assumption of behavioral economics is that cognitive biases often prevent people from making rational decisions, despite their best efforts. Why do we focus on cognitive biases? The general opinion about entrepreneurs is that they are risk takers. However, research showed that if entrepreneurs have to choose, they prefer to take moderate risks instead of taking decisions where there is high risk involved (Keenan and Lovable, 1994).This seems a contradiction, because the decision to become an entrepreneur is statistically a highs decision since over half of new ventures fail. In a study conducted by Cooper and colleagues their (1988), 95 per cent of the The interviewed entrepreneurs venture would did not entrepreneurs were convinced succeed. Where there is a complex interplay between feelings and thoughts which have awoken intense emotions. He concludes deal with that these entrepreneurs frequently situations that are new, unpredictable and complex. What kind of cognitive biases could an entrepreneur encounter?When we look at what kind of biases an entrepreneur can encounter, it needs to be known what kind of biases exist. There are dozens of known biases but not all an entrepreneurs will meet. We would like to discuss the biases that came across the most in research of cognitive threats of entrepreneurs. Optimism bias. The decision to become an entrepreneur is a crucial step that only can be taken if the entrepreneur is feeling optimistic about the chances of success. Because the chance of failure is statistically higher than success, entrepreneurs usually have an optimism bias.As mentioned before, 95 per cent of the entrepreneurs perceive the future of their new venture as being successful, while past studies of business survival suggest poor prospects for long-term survival for most new businesses (Cooper et al. , 1988). The optimism bias makes because entrepreneurs they see perceive less risk, more everything receive the new venture as a risk and their perception, rather than objective reality, explained the decision to start a current or future venture. That is why entrepreneurs do not necessarily have a higher risk propensity than other people (Keenan and Lovable, 1994).They simply perceive existing risks smaller than they are which shows that entrepreneurs are biased. Baron (2004) suggests that entrepreneurs are more often exposed to situations that test the limits of their cognitive capacities than other people. This i ncreases their susceptibility to various forms of bias or error. Baron argued that biases occur more frequently when individuals are confronted with more information than they can process at a given time, they face situations that are new to them and involve high degrees of uncertainty, and optimistically.In ‘The Evolution of Cognitive Bias', (2005) Hasten, Nettle, and Andrews state that where biases exist individuals draw inferences or adopt beliefs where the evidence for doing so in a logically sound manner is either insufficient or absent. In the case of 5 entrepreneurs however, we see that even if logical sound manner is sufficient still an entrepreneur can be biased. In the experiment by Cooper and colleagues (1988) 95 percent of the entrepreneurs was thinking that their venture would be a success, disappear when they knew about the objective chances.Business and Barney (1997) have stated that the optimism bias of an entrepreneur could also influence the stakeholders arou nd them as well. If the stakeholders wait until they attain all additional information, the opportunity they seek to exploit could be gone by the time this data is available. This means that the optimism bias of an entrepreneur can even overrule the rationality of other persons involved. Illusion of control The illusion of control gives the entrepreneur a sense of control that increases the likelihood of them acting on an opportunity, but at the same time it may blind them to genuine risks. Simon et al. 2000) The illusion of control states that decision makers often overestimate the personal control they have over the outcomes. This type of bias influences the ability for decision makers to actually make a decision. This could also be the reason many entrepreneurs fail even though they thought they had made a right decision. Belief in the Law of Small Numbers The belief in the law of small numbers is the use small off limited sample of to draw rim are conclusions. The bias makes peo ple believe samples information representative of the entire population from Overconfidence bias.Overconfidence refers to an unwarranted, high level of confidence (Forester and Scratchy, 2007). It is interesting that overconfidence can only be determined in retrospect, after an evaluation of knowledge, predictions and outcomes. Therefore, it will be difficult to notice beforehand if an entrepreneur is dealing with an overconfidence bias. Because of overconfidence, people do not take into account other factors and information that they need for decision-making. Goodness and Lecher optimism (2013), bias and argued distrust. Hat They the overconfidence bias is influenced by both the see overconfidence as a central theme in the failure of entrepreneurial firms with its effects magnified in combination with other cognitive biases. Which they are drawn (Simon et al, 2000). Simon and Houghton (2002) argued that belief in the law of small numbers may explain why entrepreneurs often overesti mate demand. The success of a small number of people in their own environment can make entrepreneurs think that they will also be successful, while the objective probability of success may be very low.Business and Barney (1997) mint out that entrepreneurs often use biased samples from a small number of friends or potential customers. Decision-makers versus Entrepreneurs Business and Barney mentioned that entrepreneurs are influenced by the sorts of cognitive biases that we all as individuals encounter (1997). However, they found that the extent to which people deviate from rational thinking may not be constant and that different individuals may utilize biases and heuristics to different degrees.They argued, and Baron (2004) agrees, that entrepreneurs in general are more susceptible to the use of biases and heuristics in decision-making. For entrepreneurs, the level of uncertainty in making decisions is higher than for general decision-makers (Humpback and Cozier, 1985; Covina and Sl iven, 1989). Also, general managers can approximate the rational ideal more closely because they usually have access to historical trends and past performance, while entrepreneurs do not. Several studies (Covina and Sliven, 1991; Garner et al. 992; Miller and Ferries, 1984) have shown that the context faced in decommissioning by entrepreneurs tends to be more complex than the context faced by managers. Pitfalls, biases and heuristics are likely to have more utility in hose highly complex decision settings faced by entrepreneurs, compared to the less complex context that managers face (Business and Barney, 1997). We find that entrepreneurs in general encounter, and until now no attempt has been done in making such a list. Simon et al. (2000) did make a selection in their research towards risk perception and the start of a new venture.They selected three biases that may lower risk perception when starting a new venture. Their research focused on the overconfidence bias, the illusion o f control and the belief in small numbers (see table 3). In their research optimism did not have a significant relationship with the decision to start a new venture, therefore they left this bias out of the model. Striking is that they left optimism out of their model, because they found a lack of significant relationship between optimism and the decision to start a venture.They mentioned however that other studies did encounter optimism affecting both cognition and behavior and explain that their outcome may have occurred because their survey measured optimism in a specific context. Further research on at least the optimism bias therefore is necessary. What influence can biases have on the success or failure of an entrepreneurial firm? Biases can have great impact on the success or failure of a company. Goodness and Lecher (2013) argued that their research shows that overconfidence can lead to disastrous effects in the entrepreneurial domain.In fact, they even found a strong relati onship between overconfidence and company failure, especially if overconfidence was linked with other biases. Also they found that optimism bias has a negative effect on firm survival, strengthening arguments on low risk perception and resultant propensity to fail. However optimism bias also acted positively on opportunity orientation. This is an important encounter more biases than other types of decision-makers, but no specific research has been done on framing the most common biases faced by entrepreneurs.In the field of strategic decision-making however, Hogwash described the 29 most common separate biases (1980). The ones that he considered most likely to affect strategic decisions are listed in table 1. An overview like this is missing in the field of entrepreneurship. One reason for this might be that most entrepreneurship common biases is hard to frame. Previous research did not mention a list of the that 7 finding, as one of the important aspects of entrepreneurship is find ing opportunities. Effective decision-making by entrepreneurs with respect to actions involving risk could play an important role in the success of new ventures.Empirical findings in literature about entrepreneurship offer support for the possibility that successful entrepreneurs are more effective at this task. Simon et al. (2000) found that effectiveness at decision making is an important factor in the performance of new ventures. Lovable and Keenan (1993) prescribed corrective measures to overcome the biases and achieve optimal behavior in every situation. Also Russo and Shoemaker (1989) reasoned that decision biases can be corrected through training.They have indicated that every decision-maker must, consciously or unconsciously, go through each phase of the decision-making process. They have stated ten most common barriers that entrepreneurs encounter in making good decisions. These barriers show resemblance with the biases described by Hogwash (1980). The availability bias, â €˜Judgments of probability of clearheadedly events are distorted', can be linked to the trusting shortsighted the most shortcuts, readily ‘relying or inappropriately on rules of thumb such as information anchoring too much on invention facts'.Both of them trust the most readily available information and thus the Judgment of probability may be distorted. Conservatism, which is the failure to sufficiently revise forecasts based on new information, can be linked to fooling ourselves about feedback, since in both cases the feedback will not be taken into account when forecasting new decisions, which can also emerge from being overconfident in making a Judgment. Russo and Shoemaker (1989) indicated that good decision-making can be broken down into four main elements: (1) framing; (2) gathering intelligence; (3) coming to a conclusion; (4) learning from feedback.Entrepreneurs have to keep track of what they expected to happen while guarding and against Lecher self-serving (2013) also explanations. Goodness agreed with the effectiveness of training on biases. They stated that for example the training of unrealistic optimists should stimulate the motivation to manage finances, to take advice, not to leave matters up to chance, and to understand the value of healthy distrust in oneself and others in non-routine situations.However, they also warned that training programs for entrepreneurs are not always a good idea. If it was not for the cognitive biases, start-ups would not occur as often as we observe now. Their advice for entrepreneurs is to balance the organization with people that are aware of these biases and can correct the entrepreneur where necessary. As well, Taverns and Keenan (1974) do not consider the biases as something that always should be eliminated.They argued that under conditions of environmental uncertainty and complexity, biases and heuristics sometimes also can be an effective and efficient guide to decision-making, simply because in such settings comprehensive and cautious decommissioning is not always possible. They state that biases and heuristics may even provide an effective way to Training When a bias causes harm, it is of critical importance that it can be addressed properly. Errors in decision-making can be extremely costs at not only the personal but also at the professional and societal level.As this article indicates, there does not seem to be an easy fix. Building further upon his previous work, Fishhook (1982) reviewed four strategies for reducing bias: (1) warning subjects about the potential for bias, (2) describing the likely direction of bias, (3) illustrating bias to the subject, and (4) providing extended training, feedback, coaching and other interventions. Fishhook concluded that these first three strategies yielded limited success, and that ‘even intensive, personalized feedback and training produced only moderate improvements in decision making. This model, derived from Wilson and Breake r (1994), shows how Judgmental biases are created and how they can be reduced. Awareness should first be created, there must be motivation to correct this bias and the direction and magnitude of the bias should be understood. As a final step, the bias should be removed or countered. But what is interesting is to see which techniques can be used to mitigate the bias of concern. We believe this can be done by applying a counter bias or by structuring the decision-making process.If decision makers rely less on intuition and emotion when making a decision, and more on deliberate and structured thinking processes, a decision can be made which approximates rationality. Analysis A list of the most common biases among decision-makers (note this it is not a list of the most common among entrepreneurs) have been framed earlier in this paper by Hogwash (1980). It is known that entrepreneurs are more susceptible to the effects of biases, but it is doubtful whether the most important biases for decision-makers are also the most important ones for entrepreneurs.The optimism bias and overconfidence decision-makers, bias do not appear on in the Hogwash's list of most common biases for while research cognitive biases of entrepreneurs mentions them often. The problem with making an analysis on the cognitive biases that entrepreneurs encounter is that there is no such a list of most common biases among entrepreneurs. Earlier in this paper, we accepted the definition by Stevenson and is Carillon several to (1990) modes that of entrepreneurship opportunities organizing without about creating resources through rage rd currently controlled.This made us not look at the traits of an entrepreneur, but at the processes of decision-making and biases that can occur. There are biases that every person encounters, but there are certain biases that have a more effect on decision-making but also have to be aware of different sorts of biases that can influence their perception of the world. Th is can be of great influence on the future of their new ventures. As Abide (1994) argued, there are three critical elements of successful entrepreneurial approaches.Entrepreneurs 9 have to screen opportunities quickly to weed out unpromising ventures, they have to analyze ideas in which they focus on new important issues and they have to integrate taking action and analysis. His most important conclusion is that entrepreneurs must reflect on the adequacy of their ideas and their capacities to execute them. This comes back to what we are addressing in this article. Can entrepreneurs be aware of adequacy of their ideas? And is it recommendable to create this awareness among entrepreneurs?To be able to have a better perception of the world and thus be better capable of reflecting and making decisions, biases are of great importance. Hen reflecting on the environment of the new venture and when making decisions based upon those reflections. Training programs to become aware of bias do e xist. Russo and Shoemaker (1989) proposed a training system in which good decision- making can be broken down into four main elements. In each element the person involved is encouraged to take the different barriers (table 2) into account so that he or she is guarded against silvering explanations.However, Goodness and Lecher (2013) argued that when entrepreneur are aware of biases, probably less start-ups will be realized. They advise that not the entrepreneurs will follow a raining program, biases. But rather people around the entrepreneur should be aware of existing Conclusion Although there are frameworks of individual cognitive biases in the literature of decision making, like the barriers by Hogwash (1980), there is no clear framework which cognitive biases entrepreneurs commonly encounter and how and if the effects of these biases should be reduced.The biases studied showed however that they can have big influence on the success or failure of a new venture. Goodness and Leche r (2013) found a strong relationship between overconfidence and company failure. Also positive biases strengthen low risk reception and increased the chance of failure. On the other hand, a positive bias in the startup phase of the company could be of great help because it strengthens the entrepreneur in motivation and opportunity finding.If entrepreneurs are aware of their biases, they could take this knowledge into consideration Taverns and Keenan (1974) pointed at the fact that not always should be eliminated. Under conditions of environmental uncertainty and in complexity, biases and simply heuristics because sometimes also can be effective and efficient decision-making, comprehensive and cautious decision-making is not always possible. Being aware of cognitive biases contributes towards obtaining optimal behavior in every situation.However, when we want to answer the question if awareness helps entrepreneurial firms perform better we would like to advise to also create awarenes s among the people around the entrepreneur and not the entrepreneur himself. The bias of an entrepreneur can be crucial in the start-up of a company and the motivation of other people. However, when a bias is harmful people around him can undertake action to 10 eliminate this bias and therefore reduce the chance of a company's failure. As a radical note we would like to mention that research on biases that an entrepreneur can encounter still has not been done.

Physical Therapist College

Since I was a young I have always wanted to have a job that helps out other peoples’ lives for the better. I have gone from wanting to be a cop, fire fighter, EMT (emergency medical technician) and now I have made up my mind to become a physical therapist. After comparing and contrasting the pros and cons of numerous jobs I decided that doing physical therapy fits me best because I am getting to know several types of people. Also, knowing that I am improving the health of patients and uplifting their spirit is the perfect job for me.Although, it is going to be a long journey, I know it will definitely be worth it in the end. Physical therapy is dated back to 460 B. C. when physicians would use water therapy and massage therapy on their patients lower the levels of pain, reduce stress and anxiety, and encoruage healing. However, it was during the World War I (1917 – 1918) that physiotherapy was performed widely as a rehabilitation therapy for people who were injured in t he war. People employred for such rehabilitative work were known as reconstruction aides and they were trained nurses having background of physical education and massage therapy. buzzle Website) Shortly after, physical therapy started to spread across the world. PT’s used hydrotherapy (water therapy) or massage therapy. Now physical therapist can do a lot more thanks to our intelligence of the human body and its functions. What physical therapist do is treat individuals ranging from any age group who have had injuries or unhealthy conditions to health increase their range of motion and ability to move and improve their lives.They examine the person to make a plan that best fits the person according to their age, depth of injury, and many other factors. Such as decreasing the pain and properly regain their strength back to lower the chances of the injury reoccurring. They also â€Å"work with individuals to prevent the loss of mobility before it occurs†¦Ã¢â‚¬  (Bureau o f Labor Statistics Website). In order to do this extensive training and practice is needed. Physical therapist can work in many places and environments.As long as they have the right equipment and tools the job can be performed. They can work from hospitals, outpatient clinics, nursery homes, and many other places. â€Å"About 60 percent of physical therapist worked in hospitals or in offices of other practitioners† (Bureau of Labor Statistics Website). Other physical therapist work in healthcare industries, care centers, or privately. Some PT’s also conduct research to accredit themselves with more knowledge or teach in colleges or institutions.It is estimated that â€Å"Employment of physical therapists is expected to grow by 30 percent from 2008 to 2018† (Bureau of Labor Statistics) and by 2018 there will be 241,700 physical therapist working. The reason why the big percentage jump in a ten year span is because of the baby booming age is getting to about the age where they are more at risk for strokes, heart attacks, and more chances of injuries occurring. Therefore, calling for a higher demand in physical therapist to help aid them in their time of disabling injuries or disliked conditions.

Should Marijuana Be Legal Drinking Age - 1175 Words

â€Å"Since Colonial times, the consumption of alcohol has been part of American culture and its use by young people has been accepted by many as part of growing up. In fact, during the late 1960s and early 1970s, many States lowered the legal drinking age from 21 to 18†, according to the US department of health services. Marijuana is the third most popular recreational drug in America, behind only alcohol and tobacco, and has been used by nearly 100 million Americans. Taboo recreation has been around for years and still continues to be practiced as a pastime all over the globe. As explained in the text, the term taboo comes from the Polynesian word â€Å"tapu†, which refers to a prohibition of a supernatural force. In our case we use the term to represent behaviors restricted by social custom or belief. Examples of taboo recreation include leisure activities such as drinking, recreational drug usage, sex, tattoos, vandalism, gambling, etc. These so called negative pastimes have been part of American culture for years and dates back to the mid to late 1900’s. One of our earliest forms and easiest examples of taboo recreation is underage drinking. Grain, honey and fruit juice have been used to make alcohol for thousands of years. Fermented beverages were around in early Egyptian civilization, and there is said to be evidence of an early alcoholic drink in China around 7000 B.C. At the start of the eighteenth century, the British parliament passed a law promoting the use of grain forShow MoreRelatedMarijuana vs. Alcohol in the United States Essay843 Words   |  4 PagesMarijuana vs. Alcohol In The United States Marijuana and alcohol are the two most threatening drugs used in America today. Marijuana is the most illicit drug while alcohol is the most abused. Both were illegal during the prohibition but when the constitution was ratified in 1933 alcohol was made legal while marijuana remained illegal. It does not mean that because alcohol is still legal it’s less dangerous than marijuana. Both drugs lead to serious risks and should be taken with caution if usedRead MoreAlcohol And Cannabis : The Second And Third Most Consumed Drugs Behind Tobacco For New Zealanders Essay1388 Words   |  6 Pagesfemales 37.9%) of New Zealand youths aged 13-17 have smoked marijuana at least once, with 7.9% of males and 5.7% of females indicating weekly use (Watson, Clark, Sporle, Merry, Adair, et al., 2003). Alcohol use is much more prevalent, with 95% of the New Zealand population aged 16-64 having drunk alcohol before (â€Å"NZADUS†, 2010). 29.5% of people first tried alcohol at 14 years old o r younger, with 23% drinking enough to feel drunk. The median age for first trying alcohol is 15 and 16 for men and womanRead MoreMinimum Limited Drinking Age Law883 Words   |  4 PagesMinimum limited drinking age law in America was passed more than 30 years ago. Therefore, it needed to be altered to catch up with today’s world. Teenagers today are no longer the kind of teenager back in the 1980s. Now, they have access to information on the Internet, they were taught how alcoholic drinks affect to the body, they were supervised by their parents closely. Moreover, teenagers even have legal access to voting, driving, owning a car,...and they can be jailed up if they break the lawRead MoreA Short Note On Social Problems With Youth1551 Words   |  7 PagesHim YEUNG Christopher Cook SOC 201 5 Jun 2015 Social Problems Research Paper Why there are so much alcoholic problems with youth in the United States? United States has the highest legal drinking age in countries that drinking are legal though at the same time, we have one of the worst drinking problem in the world. Why? Alcohol abuse are usually defined as having 5 drinks or more in a short amount of time. Some even drink so much that they can be diagnosed under the guidelines that they have mentalRead MoreBenefits of Medical Marijuana Essay990 Words   |  4 Pages Legalizing Marijuana Marijuana is a very controversial and obtrusive issue in our society today. Although many have made malicious remarks about it in the past, and even still in the present, the truth and beneficial facts of marijuana are finally resurfacing. Unfortunately, our society has become a very critical crowd towards the legalization of marijuana due to the stereotypical view of the kind of people who are considered â€Å"pot smokers†. This contorted perception of a lazy and unmotivated AmericaRead More The Legalization of Marijuana in the USA Essay1063 Words   |  5 PagesLegalization of marijuana is one of the most controversial topics in American society today. Surveys done by the US Government’s Substance Abuse and Mental Health Data Archive showed that 95 million Americans have used marijuana. There are two opposing sides that have strong stances on whether it should become legal or should remain illegal. We have one side that is anti-marijuana and the other is pro-marijuana. Each side provides valid and strong arguments supporting their views. The purpose ofRead MoreShould Marijuana Be Legalized?1535 Words   |  7 Pages Marijuana Legalization Marijuana is the most widely used illicit drug in the United States, according to Jordan Bechtold. It is a cannabis plant intended for use as a psychoactive drug or medicine. Medical marijuana is legal in only 23 states. Many citizens argue that it should be legal for recreational use in all states, though many citizens also disagree. It is mostly compared to alcohol and cigarettes/tobacco. Just like all other drugs, smoking marijuana affects your body in a unique wayRead MoreWhy Marijuana Should Be Illegal1610 Words   |  7 PagesCannabis also known as marijuana, is a plant produced in many countries worldwide. Marijuana was first introduced by the Mexican immigrants for recreational usage, the misconduct of the drug had our whole nation in turmoil so it was voted on to be illegal throughout the whole United States. Marijuana possession is illegal and it is illegal for so many different reason. In fact, there were over 8.2 million marijuana arrest in the united states last yea r according to ACLU’s original analysis drawnRead MoreBefore Delving Into The Economics Of The Proposed Policy,1554 Words   |  7 PagesBefore delving into the economics of the proposed policy, the paper will first show why marijuana is the safer alternative, but as previously mentioned, alcohol and marijuana are still harmful to the body, just in different magnitudes. The World Health Organization (WHO) has been able to directly identify 30 diseases that are attributable to alcohol consumption and although these disorders are not as fatal as other chronic diseases, they still rank fourth among the most disabling diseases in lowRead MoreThe Legal Drinking Age Should Be Lowered1170 Words   |  5 PagesFor a majority of the 20th century, the United States drinking age has been a big issue. After prohibition had concluded in 1933, twenty- one was the new legal drinking age. Meanwhile, during the Vietnam War, eighteen became the new legal drinking age. Finally in 1984, Congr ess passed the National Minimum Drinking Age Act (MLDA). Since then, twenty-one years old has been the legal age to drink in the United States. There are several ways alcohol has been a reason for death such as, alcohol poisoning