Landing site - Faxbroadcasting Essay Example | Topics and Well Written Essays - 250 words

Landing site - Faxbroadcasting - Essay Example You definitely know from your own experiences that people have a tendency to throw direct mail in waste basket very often without having a quick glance on the contents. But this kind of incident can not happen to a fax. Hence, the rate of response to fax is much greater than the response rate to direct mail. Due to the low cost of fax and higher response rate fax is becoming more and more popular. (INFAX, 2010; FAXMAILBROADCASTING, 2010; BROADFX, 2010). You just need to spend a fraction of money that you require to purchase a postage stamp. You will save your time as well as cost by sending your message through fax. Fax broadcasting also provides you higher return on your invested money. (FAXMAILBROADCASTING, 2010) IF you are running a business, they it is essential for you to build strong connection with your partners, customers, suppliers, etc. If you want to build an inexpensive, fast and effective communication with your clients or other people, fax broadcasting service will come to your great help. (ACCELERO Communications, 2010) You can also use fax broadcasting as an effective marketing tool of your products or services. As faxes can not get unnoticed by the recipients, your promotional messages will surely be noticed by your targeted customers. Since response rate is higher to fax, then it can be expected that marketing through fax broadcasting will bring you great response at very low cost.

No topc Essay Example | Topics and Well Written Essays - 750 words - 1

No topc - Essay Example Sometimes women are the suppressed gender in our society. Conflict arises relating to what are the socially accepted roles for women. What are the typical gender issues in our society today? Why do gender issues focus on women? Historical accounts about women’s societal roles can be traced back during the time of Abraham and Jesus. We can see how women were treated during those times based on the Bible. Men’s societal roles during this time were outside the home, as dictated by the traditional society. They work mostly in the plantation, work as carpenters, palace guards, while women nurse their children and always stay at home to do household chores. During the early colonial period where galleon trade started conquering the world, women remained domesticated. Education was only given to men who will be part of this trade. During the 19th century, different types of government began to emerge, yet these governments were not aware of gender inequality because they only continue the same norm and culture of men dominating women. The establishment of these governments was created through elections. However, women were not given the right to suffrage / vote until 1920s. Suffrage issues began to alarm some women who can’t bear the unequal rights given to women. They believe that they are also part of the success of the society and can decide whom to vote. Because of some uprisings of these women in the 19th century, women were persecuted for fighting for their rights. Men believed that women are not yet ready to take on responsibilities outside their home. Still, more women fought against these socially constructed norms about them. Some women were not fully recognized for their contributions in the society. Mostly men were given credits and privileges. We can call this kind of society as patriarchal, for believing men are more sufficient and rational as women. Economies of European countries before were ruled by men

HR Issues in Google Inc Essay Example for Free

HR Issues in Google Inc Essay 26 March 2009, 200 Layoffs â€Å"So today we have informed Googlers that we plan to reduce the number of roles within our sales and marketing organizations by just under 200 globally. The recession makes the timing even more difficult for the Googlers concerned. We had to restructure our organizations in order to improve our effectiveness and efficiency as a business. We will give each person time to try and find another position at Google, as well as outplacement support, and provide severance packages for those who leave the company. Finally, I would like to take this opportunity to thank everyone affected for all they have contributed to Google. † * Omid Kordestani, Senior VP, Global Sales and Business Development (2009) From this article, google would cut 200 would cut about 200 employees from its sales and marketing organization. It would reduce the overlap between different groups and speed up decision making. Omid Kordestani, Senior VP, Global Sales and Business Development said, the cut meant to address the mistakes that the company had done before. In some areas we’ve created overlapping organizations which not only duplicate effort but also complicate the decision-making process,† Mr. Kordestani wrote on Google’s corporate blog. â€Å"That makes our teams less effective and efficient than they should be. In addition, we over-invested in some areas in preparation for the growth trends we were experiencing at the time. † 4 January 2009, 100 Layoffs â€Å"Given the state of the economy, we recognized that we needed fewer people focused on hiring e need to go further and reduce the overall size of our recruiting organization by approximately 100 positions. We know this change will be very difficult for the people concerned, and we hope that many of them will be able to find new roles at Google. They helped build this company, new hire by new hire, and we are enormously grateful for everything they have done. † * Laszlo Bock, Vice President, People Operations (2009 In January, google laid off 100 recruiters which is that deeper cuts were â€Å"unlikely†. In February, company cut another 40 positions when it closed its radio advertising efforts. About 100 of the eliminated positions will be in the United States and the rest overseas, said Matt Furman, a Google spokesman. Mr. Furman said the company continued to hire new workers, albeit at a slow rate. In the fourth quarter of 2008, the company grew by 99 workers, ending the year with 20,222 full-time employees. In previous years, Google had added more than 2,000 people in a single quarter. Laid-off workers will be given time to apply for other jobs within the company. How a Giant Company Aims to Remain Intimate. Google have a good track record in management. It routinely ranks first or near the top in â€Å"best places to work† reports. Google’s value proposition as an employer combines a laser focus on innovation and smart business practices with a small-company feel that includes direct access to top management. For instance, no one hesitates to pose questions directly to the founders at the weekly all-hands meetings. The HR management system plays a critical role in keeping this value proposition well tuned and relevant for each successive generation of employees by embedding Google’s mission into daily work life. As Laszlo Bock, vice president of people operations at Google, said in an interview with BCG: â€Å"If you talk to anybody at Google and ask them what the mission is, they’ll say, ‘To organize the world’s information and make it universally accessible and useful. ’ It’s rare to find a place where everyone knows the mission—and then actually believes it. † Google’s benefits and compensation packages, renowned for their largess, have a threefold purpose, Bock pointed out. First, to create a community—hence the microkitchens sprinkled around the offices, where people can interact informally. Second, to drive innovation: the more people interact, the higher the likelihood of creating serendipitous sparks of innovation. And third, to promote efficiency: on-site oil changes and dry-cleaning services help hard-working employees save time in their personal lives. To keep a pulse on how â€Å"Googlers† are feeling, which informs talent-management and development programs, HR undertakes a variety of analyses, Bock said. The company monitors retention and attrition and looks for patterns. An annual employee survey plus focus groups throughout the year provide ample qualitative feedback. On the basis of this analysis, upward management feedback gets put into practice. â€Å"Every member of our executive team has goals for the year,† Bock said. â€Å"These are not amorphous goals, like ‘make the company feel more engaged,’ but very specific, like ‘there were three issues in the sales organization that we will address this year. ’† Recruitment group Randstad Chooses Google Apps for its 29,000 Employees. Randstad consist of four large Dutch cities (Amsterdam, Rotterdam, The Hague, and Utrecht) and the surrounding areas. It is one of the biggest staffing companies in the world and has some 29,000 employees working from more than 4,500 branches in 40 countries around the world. They help companies and candidates connect in industries such as engineering, finance and accounting, healthcare, human resources, managed services, pharma and technology. To give an idea, they place on average well over 500,000 people per day. It have grown to become quite large since it began as a small company started in a student dorm room in 1960 and the business has changed quite a bit in that time. But at its core, it still the same. All about people. Their decision making process involved several companies, but ultimately they decided on Google for a few different reasons. They have a workforce of younger, and heard the feedback that are quite familiar with Google tools like Gmail, Google Calendar, Google Drive and Google+ Hangouts in user personal lives, and theyd like to use them at work too. Also, because the Google tools are all integrated, they wouldnt run into the problem of having employees across offices and countries having to work with several different pieces of technology that don’t work well together. Lastly, we wanted to provide our employees with as much training as they needed and G-company were able to provide that. Their rollout will eventually include all 29,000 Randstad employees, 5,000 of whom are located in the Netherlands. Their employees in France, Japan and India, approximately 8,000, are already on Google.

Management of Melanoma Brain Metastases (MBM)

Management of Melanoma Brain Metastases (MBM) Abstract: Melanoma is the third most common cause of brain metastases, after lung and breast cancer. Common clinical manifestations include headache, neurologic deficits, cognitive impairment and seizures. The management of melanoma brain metastases (MBM) can be broadly divided into symptom control and therapeutic strategies. Supportive treatment includes corticosteroids to reduce peritumoral edema, antiepileptics for seizure control and medications to preserve cognitive function. Until recently the therapeutic strategies focused on local treatment including surgery, whole brain radiation therapy (WBRT), and stereotactic radiation (SRS). Historically, systemic therapy has had limited utility. Immunotherapeutic drugs like anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD1) and agents targeting BRAF- MEK pathway have revolutionized the systemic treatment of MBM. Recent clinical trials with these agents have shown activity against MBM and incre asingly being used in clinical practice. In this article, we will discuss epidemiology, biology of MBM and the role of surgery, WBRT, SRS in this patient population. An overview of the currently available systemic therapeutic agents that includes immunotherapy and targeted tyrosine kinase inhibitors (TKIs) and a practical multidisciplinary management algorithm to guide the practicing oncologist will be outlined. Introduction: Recent advances in the management of advanced melanoma have resulted in improved 5-year survival rates, however, MBM remain a significant cause of morbidity and mortality. Approximately 20% of metastatic melanoma patients have brain metastases at diagnosis.   Overall about 50% of stage IV melanoma patients will develop symptomatic brain metastases (1-3). Cerebral hemispheres are the site of 80% of brain lesions from melanoma followed by the cerebellum (15%) and brainstem (5%)(4).Common clinical manifestations include headache, neurologic deficits, cognitive impairment and seizures. Until recently, patients with MBM had a dismal prognosis with a median overall survival (OS) of 6 months (5). The management of MBM can be broadly divided into supportive management and therapeutic strategies. Supportive treatment includes steroids to reduce peritumoral edema, antiepileptics for seizure control and medications to preserve cognitive function. Traditionally, therapeutic strategies focused on local treatment including surgery, WBRT, and SRS. Historically, systemic therapy has had limited utility in the management of MBM. However, the treatment paradigm has changed considerably with the advent of targeted therapy and immunotherapy. Approximately 50% of advanced melanoma patients harbor a BRAF mutation and a number of targeted agents for this mutation and downstream pathway have shown promise in the management of metastatic melanoma. Immunotherapeutic agents like anti- CTLA-4 and anti- PD-1 have shown clinical efficacy in MBM and now constitute first line treatment options for metastatic melanoma. Biology of brain metastases: Until recently MBM were believed to have the highest mutational discordance compared to the primary site (6).   However, Chen et al. reported molecular profiling that included hot spot mutations, global mRNA expression patterns, quantitative analysis of protein expression and activation by reverse protein array (RPPA) analysis of 16 patients (7). In this study, authors reported complete concordance in mutational profile between intracranial and extracranial sites. Despite these similarities crucial differences in the expression of PI3K/AKT pathway were noted by RPPA. Another study compared the expression of BRAF mutation in different sites of metastases in advanced melanoma and showed greater mutational concordance (16/20 patients) in brain compared to other visceral/subcutaneous metastases (8). These studies provide an initial understanding of the molecular characteristics of MBM. With the advent of immunotherapy, tumor microenvironment and immune infiltration has been a focus of intense research. Brain has been traditionally thought of as an immune privileged organ but recent studies have established the existence of a neuro-immune axis and questioned this belief(9). Our understanding of this unique interplay between the immune system and central nervous system has dramatically evolved over time. Berghoff et al. investigated the expression of PD-1, PD-L1, CD3, CD8, CD45RO, forkhead box protein 3 (FoxP3), CD20, and BRAF V600E by immunohistochemistry in MBM samples (10). Varying degrees of tumor infiltrating lymphocytes (TILs) were reported in this study, 33 out of 43 specimens stained positive for CD3(+) T-lymphocytes, 39 for CD8(+) T-lymphocytes, 32 for CD45RO (+)memory T-lymphocytes, 27 for PD-1(+), 21 for FoxP3(+) T regulatory lymphocytes, and 19 for CD20(+) lymphocytes.   Significant tumoral PD-L1 expression (>5%) was observed in 9 specimens while 22 sam ples stained positive for PD-L1 suggesting role of immunotherapeutic agents in MBM. Prognostic indices Although the median OS of MBM is dismal, approximately 5% patients are long term survivors(2). Hence prognostic factors that predict outcomes and can guide the treatment decisions and enrollment in clinical trials are of value. Several large single center series have examined various primary tumor, brain metastases, and patient characteristics predictive of survival (2, 11, 12). Age, performance status, number of brain metastases, extra-cranial metastases, time from primary tumor diagnosis, presence of neurologic symptoms and elevated LDH are factors that determine survival. (13). Sperduto et al proposed a new disease basedscoring index based on 483 newly diagnosed MBM patients from 8 different centers (14). On multivariate analysis, performance status and number of BMs were prognostic for survival in MBM. The outcomes of ds-GPA MBM varied from GPA class I with survival of 3.4 months to GPA class IV with survival of 13.2 months. These prognostic indices have inherent limitations. All of them were evaluated retrospectively, had only overall survival as the end point, did not include molecular and genetic profile of the primary malignancy, and did not take systemic therapy into consideration (15). A large single institutional experience of 366 patients treated to 1,336 brain metastases has also shed some light on the interplay of important prognostic variables in patients with MBM. In this series, characteristics associated with survival included younger age, lack of extracranial metastases, performance status, and treatment with BRAF inhibitors or immunotherapies. This work specifically highlights the importance of modern out outcomes in patients who are eligible for and receive newer targeted therapies. For example, the 12-month survival estimate for patients treated with BRAF inhibitors was 37% compared to 23% for those patients who did not receive these therapies (p=0.01). Moreover, the 12-month survival e stimate for patients treated with immunotherapies was 47% compared to 22% for those patients who did not receive these therapies (p=0.04). Clearly, further work is needed to define the impact of mutation, targeted drugs and immunotherapy in the current era. Diagnosis: The neurologic symptoms associated with brain metastases include headaches, seizures, cranial nerve deficits to motor or sensory deficits. All melanoma patients with neurologic symptoms worrisome for MBM should undergo a gadolinium enhanced magnetic resonance imaging (MRI) of the brain, if no contraindications exist. Guidelines recommend routine MRI of brain with and without gadolinium contrast for patients with stage IV melanoma due to the high prevalence of asymptomatic brain metastases(16). Computed tomography of brain with and without contrast can be used as an alternate imaging. Management: The options available for management of brain metastases include surgery, WBRT, SRS, systemic therapy and symptom management. The management plan to treat these patients should take into account the overall prognosis, performance status and morbidity associated with the treatment. 5.1 Management of symptoms: Supportive care for patients with brain metastases is typically to control the cerebral edema with steroids. Due to minimalmineralocorticoid effect and long half-life, dexamethasone is the steroid of choice, however, other steroids at an equivalent dose can be used and tapered gradually over a two week period(17). A randomized trial in 1990s compared different doses of dexamethasone ranging from 4 mg/day to 16 mg/day and concluded that 4-8 mg/day would provide same degree of clinical improvement in 1 week (18). Routine use of prophylactic anti-epileptics in patients with brain metastases is not recommended(19). When patients have seizures several anti-epileptics are available including phenytoin, carbamazepine, valproic acid and levetiracetam. Non-enzyme inducing agents like levetiracetam are preferred to avoid interactions with systemic agents. 5.2 Neurosurgical Options: Surgery has traditionally been used for management of solitary brain metastases, or large symptomatic brain lesions. Multiple retrospective studies have reported improved survival with surgery compared to best supportive care(13, 20-22). Younger patients with good performance status, fairly well-controlled extracranial disease, solitary brain metastasis, lesions in accessible locations and of small size generally have better outcomes with surgery (21, 23). Surgery is usually followed by radiation boost to the surgical bed by either WBRT or SRS, with an intention of sterilizing the surrounding tissues and preventing local recurrence. Two randomized trials comparing adjuvant WBRT to surgery alone have shown improvement in outcomes(24, 25). Patchell et al. evaluated the role of WBRT post-resection of a single brain metastasis compared to surgery alone(25). Postoperative WBRT resulted in a significant reduction in local and distant intracranial failure. However, no difference in the over all survival or time duration of functional independence was noted. Similar results were seen in the EORTC 22952-26001 study with decreased 2-year intracranial and resection site recurrence without significant survival benefit. Multiple retrospective reports of post-operative SRS have shown improved patient outcomes however prospective data is awaited (26, 27). Bindal et al. showed benefit of resection in select group with multiple metastases in a retrospective review of 56 patients(28).   In practice, surgery plays an important role in debulking or removal of life-threatening lesions. Surgery also provides immediate relief from intracranial hypertension by eliminating the mass effect, and symptomatic hydrocephalus by reestablishing the flow of cerebrospinal fluid (CSF). 5.3 Whole brain radiation therapy: Melanoma brain metastases lesions are generally considered radio-resistant compared to other histologies (29). Randomized trials with WBRT have reported survival in the range of 2.4 to 4.8 months.(30) The ideal dose and number of fractions, balancing the intracranial control and cognitive decline, has been subject to intense debate.   WBRT fraction sizes of ≠¤ 3 Gy do not lead to significant neuro-cognitive decline. A retrospective study compared higher dose of radiation, 40 Gy in 20 fractions with 30 Gy in 10 fractions(31). The 40 Gy group had overall survival of 5.6 months compared to 3.1 months. However most of these trials were not melanoma specific and included patients with all tumor types. Patients who are symptomatic with change in mentation, headaches and seizures but are deemed unfit for surgery or SRS due to large number of metastases, poor performance and uncontrolled extracranial metastases are generally treated with WBRT(32). 5.4 Stereotactic radiation therapy: Stereotactic radiation has been increasingly used in the management of MBM in the last two decades. SRS in MBM results in local control rates of 50-75% at 1 year(33-35). SRS is generally limited to lesions smaller than 4 cm in diameter (36).   In a retrospective review of 333 patients treated with SRS showed a sustained tumor control rate of 73%(35). The 12-month cumulative incidence of local failure was 14% in another single institution experience of 191 patients treated to 793 MBM.   Number of brain metastases that can be treated with SRS has been intensely investigated. SRS for solitary brain metastasis was compared to surgery plus WBRT in a phase III trial that closed prematurely due to poor accrual. The overall survival, freedom from local recurrence and neurological death rates were similar in both groups(37).   Several studies have evaluated the role of SRS in patients with 1-3 brain metastases (38, 39). Aoyama et al. compared SRS alone with SRS followed by WBRT in patie nts with 1-4 brain metastases(38). No difference in neurocognitive function and survival was observed. SRS-alone arm had increased local and distant intracranial failure. A phase III trial compared WBRT followed by SRS to WBRT alone, in 333 patients with 1-3 brain metastases from different histologies that included only 13 MBM patents (40). Performance status at six months improved significantly with addition of SRS to WBRT. SRS for patients with 5-10 brain lesions was evaluated in a multi-institution prospective observational Japanese study of 1194 patients(41). The overall survival, neuro-cognitive function and post SRS complications did not differ for patients with 5-10 brain lesions compared to 2-4 brain lesions(42). 5.5 Systemic therapy: Traditional systemic therapy had a limited role in MBM due to challenges of drug delivery in the brain from blood brain barrier (BBB) with its tight junctions and efflux pumps (P-gp and MRP transport proteins) (43). The concept of localized disruption of BBB at the site of brain metastases has been proposed, as demonstrated on MRI by contrast enhancement (44). Chemotherapy: Chemotherapy agents have not shown good activity in MBM. Dacarbazine which is the approved chemotherapy for metastatic melanoma does not cross the BBB(45). A number of studies evaluated the role of alkylating agents with good BBB penetration such as temozolomide (TMZ), lomustine and fotemustine in MBM patients. In a phase II trial Agarwala et al. enrolled 151 MBM patients with no local radiation therapy for BM to receive TMZ (46). TMZ use showed a modest intracranial response of 6%, median PFS of 4.3-5.2 weeks and median OS of 3.2 months. Two phase II trials of WBRT with TMZ(47, 48); or thalidomide, WBRT with TMZ (49) failed to improve the response rates significantly. Lomustine in combination with TMZ showed modest efficacy in a phase I/II study(50).   Intracranial activity of fotemustine was first reported in a phase III trial of fotemustine versus dacarbazine for metastatic melanoma (51). This led to a randomized phase III trial that compared fotemustine plus WBRT to fotemustine alone in MBM (52). The response rates were 7.4% for fotemustine alone and 10% for fotemustine plus WBRT. Fotemustine is not currently approved by FDA for use in MBM due to delayed thrombocytopenia and leukopenia(53). Targeted therapy: BRAF, NRAS and KIT are three common, mutually exclusive driver mutations seen in metastatic melanoma (54, 55). Of these three, BRAF mutation is the most common mutation seen in approximately 40-50% of patients with advanced melanoma. The presence of BRAF, NRAS increases the risk of CNS metastases seen in patients with   advanced melanoma. Prior studies have reported 24% CNS metastases rate in BRAF and 23% CNS metastases incidence in NRAS mutant melanoma compared to 12% rate in those who lack these mutations(56). Dabrafenib and vemurafenib target BRAF V600 mutation and FDA approved for metastatic melanoma. A phase I trial of dabrafenib in ten patients with untreated asymptomatic brain metastases, intracranial response was seen in 8 patients (four CR, four PR) (57). This impressive 80% response rate prompted the phase II trial of dabrafenib in BRAF mutant melanoma brain metastases (BREAK-MB) (58). This multicenter open label study accrued 172 patients asymptomatic brain metastases with BRAFV600E or BRAFV600K mutation and one measurable lesion (defined as atleast 1 cm in diameter). Cohort A consisted of 89 patients who were radiation naive and cohort B consisted of 83 patients who had failed prior radiation therapy for BM. BRAFV600E patients had an intracranial response rate (IRR) of 39% (29/74) in cohort A and 31% (20/65) in cohort B, PFS of 16.1 weeks in cohort A and 16.6 weeks in cohort B with OS of 33.1 weeks in cohort A and 31.4 weeks in cohort B. BRAFV600K patients had a lower IRR of 7%(1/15) in cohort A and 22% (4/18) in cohort B. This trial supports the efficacy of dabrafenib in BRAF mutant MBM patients, especially those with BRAFV600E mutations with acceptable toxicity. In an open label study of 24 non-resectable, untreated MBM patients harboring BRAFV600 mutation, treatment with vemurafenib resulted in tumor regression of more than 30% (7/19)and partial response was seen in 3 patients. Median PFS and OS was 3.9 and 5.3 months respectively in this study. In a phase II study, 146 BRAF mutant MBM patients were treated with vemurafenib(59). The first cohort included 90 patients with untreated BM, the second cohort comprised of 56 patients with previously treated BM.   Complete response was noted in 2 patients, with 14 PRs, and a best objective response rate of 18%. In previously untreated MBM, the median intracranial PFS and OS were 3.7 months and 8.9 months respectively. Previously treated MBM had similar PFS and OS of 4.0 months and 9.6 months respectively. There is no prospective data of safety and efficacy of combination of BRAF inhibitors and radiation therapy. Most reports are retrospective in nature with increased incidence of dermatitis seen in extracranial skin associated with concurrent use of BRAF inhibitors and radiation (60). Rompoti et al. reported five patients with MBM treated with combined radiation and BRAF inhibitor(61). Two patients underwent SRS and three received WBRT. Patients treated with SRS did not experience any skin adverse effects while all three patients treated with WBRT noted grade1/2 dermatitis. A retrospective analysis evaluated effectiveness of vemurafenib and radiation in BRAFV600 MBM (62). All of them received vemurafenib, six patients underwent SRS, two received WBRT, one received SRS and WBRT and three underwent surgery and radiation. Thirty-six of the 48 index lesions responded with 23 (48%) CRs and 13(27%) PRs. Major limitations were the retrospective nature of the study, small number, and pretreat ed patients with radiation and systemic therapy including ipilimumab. Several small retrospective case series have reported outcomes of MBM treated with targeted agents and SRS/WBRT (Table-1). A recent study of 19 patients with BRAF mutations undergoing SRS and concurrent BRAF directed therapies has shown impressively few local failures (12-month cumulative incidence of 1%). Additional studies of combination therapy are clearly warranted. Immunotherapy: Melanoma is an immunogenic malignancy (63) with a high mutational burden that results in high number of neo-antigen(64). It has been proposed that the relatively high neo-antigen burden makes this malignancy more susceptible to immunotherapy. However, the brain has traditionally been considered an immunologically privileged site due to the presence of the BBB. Recent studies on the intracranial tumor microenvironment as elucidated above have suggested otherwise, showing CD8 T-cells, CD 20+ cells, T-regulator cells and PD-L1 expression within intracranial tumor(10). The intracranial activity of interleukin-2 (IL-2, one of the first immune modulatory agents) was reported in two retrospective reviews(65, 66).   A response rate of 5.6% was seen in 37 patients with untreated brain metastases within a larger group of 1069 metastatic melanoma and renal cell carcinoma patients treated with high dose IL-2(65). In a second report, two of the 15 brain metastases patients treated with high dose IL-2 showed CR (66). No prospective trials were initiated with high dose IL-2 due to concerns for cerebral edema and neurotoxicity. Two pathways that have revolutionized the management of advanced melanoma are those involving CTLA-4 and PD-1/PD-L1.   The CTLA-4 receptor is expressed exclusively on T-cells and downregulates the interaction between antigen presenting cells and T-cells. Ipilimumab is a fully human monoclonal antibody against the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)(67). The pivotal phase III trial that compared ipilimumab with or without gp 100 peptide vaccine to gp 100 vaccine as a single agent allowed enrollment of patients with asymptomatic and/or previously treated MBM (68). A non-significant trend towards better survival in the MBM subgroup was noted among the patients treated with either ipilimumab alone or ipilimumab plus gp 100 compared to gp 100 alone(69). In an expanded access program (EAP) in Italy, 146 MBM patients received ipilimumab and a global response rate of 12% was seen (70). An American EAP reported a 1-year overall survival rate of 20% among 165 MBM patients tr eated with ipilimumab (71). Margolin et al. conducted an open label phase II clinical trial of ipilimumab for MBM (72). The trial enrolled 72 patients 51 patients in cohort A (those who were not on steroids for cerebral edema) and cohort B of 21 patients (on treatment with steroids). According to the WHO criteria, the response rate was 18% (9/51) in cohort A compared to 5% (1/21) in cohort B, and by immune-related response criteria the response rate was 25% (12/51) in cohort A and 10% (2/21) in cohort B. The median OS was 7.0 months and 3.7 months in cohort A and cohort B respectively. The study concluded that ipilimumab can be used safely in MBM patients. An Italian phase II trial tested a combination of ipilimumab and fotemustine in patients with advanced melanoma including asymptomatic MBM patients (73). A total of 20 patients (out of 83 patients) had asymptomatic MBM, and among these patients the study reported a PFS of 3.0 months and 3-year OS rate of 27.8% (74). A randomized, 3 arm, phase III trial of fotemustine, versus fotemustine plus ipilimumab, versus ipilimumab plus nivolumab (NIBIT-M2) is currently recruiting patients (75). Several retrospective studies have evaluated the safety of combining ipilimumab and radiation therapy (SRS or WBRT), and prospective trial data is forthcoming (76-78). PD-1 receptors are expressed on several cells including T-cells and antigen presenting cells. Their interaction with PD-L1 ligands on tumor cells leads to T-cell exhaustion and downregulation of tumor-specific immune response(79). Nivolumab and pembrolizumab are two anti-PD-1 antibodies that are currently approved for the management of advanced melanoma, and several others are under evaluation. An open label, single-center, phase II clinical trial is currently enrolling patients with untreated brain metastases from melanoma or non-small cell lung cancer (80). In a published early analysis, a response rate of 22% (4 patients) was reported in a total of 18 MBM patients and the responses were durable. Authors noted a high concordance between systemic and brain metastasis responses. Additionally, 11% (2 patients) had stable disease. Intriguingly all responders lacked a BRAF mutation. Relatedly, 4 patients were not evaluable either due to rapid progression necessitating BRAF-targeted ther apy (3 patients), or intralesional hemorrhage (1 patient). Toxicities in the MBM cohort included grade 3 transaminitis (1 patient), as well as grade 1-2 seizures (3 patients) and grade 3 cognitive dysfunction (1 patient) from peritumoral edema. Leptomeningeal disease in melanoma   Leptomeningeal disease (LMD) is a subset of metastatic with extraordinarily poor prognosis and median survival of 8 weeks(81, 82). About 5% of malignant LMD originates from melanoma (Kesari) and up to 23% of melanoma cases develop LMD(1, 83). Primary leptomeningeal melanoma also exists as a separate clinical entity and should be a consideration in the context of a person with multiple congenital melanocytic nevi(84). Diagnosis of LMD is usually made based on the combination of neurologic symptoms along with corresponding leptomeningeal enhancement on MRI. While cytology from cerebrospinal fluid (CSF) is considered to be the gold standard for LMD diagnosis, sensitivity of this testing ranges from 50% to 80%, depending on number of lumbar punctures performed (85). Like with MBM, treatment of LMD with chemotherapy has low response rates(86). The clinical course of LMD is more treacherous in melanoma in other malignancies given the propensity for melanoma LMD to hemorrhage(87). Molec ular characterization of melanoma LMD suggests a higher percentage of BRAF mutations in comparison to the general melanoma population (68% v 45%), based on a single center melanoma LMD cohort of 60 patients(76). Several case reports have been published highlighting complete and partial responses as well as prolonged ongoing survival beyond 15-18 months with BRAF inhibitors (86). Immunotherapy approaches, including intrathecal IL-2, adoptive cell therapies with tumor infiltrating lymphocytes (TILs) and cytotoxic T-lymphocytes (CTLs), and immune checkpoint inhibitors, have also reported prolonged survival in comparison to historic medians (86). A single center study of 38 patients with melanoma LMD who were treated with intrathecal IL-2 reported a median survival of 9.1 months, and the best 15% of patients reached a median survival over 24 months(88). Ongoing survival over 18 months in a melanoma LMD case was reported with WBRT followed by ipilimumab, an immune checkpoint CTLA-4 inhib itor; in this case, treatment with ipililumab resulted in complete radiologic response(89). A phase II trial of combination immunotherapy with ipilimumab and nivolumab, a PD-1 inhibitor, in melanoma LMD has recently opened to accrual(90). In summary, these early data suggest that both targeted therapy and immunotherapy have efficacy in melanoma LMD and can result in durable responses well over a year. Upcoming trials addressing melanoma LMD with newer therapies will likely yield significantly improved survival data over the next decade. Conclusion: Despite significant recent improvement in the outcomes of patients with melanoma, brain metastases remain a major determinant of mortality and morbidity in melanoma patients, and patients with MBM remain in the worst prognostic category. The vast majority of clinical trials with newer agents exclude patients with MBM, thus data on the effectiveness of new drugs in the context of MBM is still lacking. Understanding the biology of MBM and its clinical response to newer agent and particularly combinations of agents and strategies is crucial to increasing the longevity of the poorest-risk melanoma. Appropriate care of MBM begins with diagnosis. In melanoma, the brain is a common site of metastatic spread, both early and late. It is crucial to begin screening patients for MBM at diagnosis, and NCCN guidelines have recently been updated to reflect this changing diagnostic paradigm. The frequency at which to repeat imaging is still not known. Several therapeutic options now exist for the treatment of MBM (A proposed algorithm is provided in Figure-1). Surgical resection, radiation therapy, targeted therapy and immunotherapy all show some degree of efficacy with MBM.   Even in cases of LMD, perhaps the worst subset of MBM in terms of survival, treatment with targeted therapy and immunotherapy can induce prolonged survivals from historic means. Initial reports involving combinations of these therapies, such as radiotherapy with either targeted therapy or immunotherapy, appear promising, but will need to be systematically studied in cohorts with larger numbers. Equally important will be the parallel investigation of predictive markers in MBM with these therapies and combinations. Thus, whenever possible, patients with a new diagnosis of brain metastases should be enrolled in appropriate clinical trials. If an appropriate clinical trial is unavailable, treatment decisions should be made with input from a multidisciplinary t eam including radiation oncologists, neurosurgeons, and medical oncologists.

Physics of Paintball :: physics sport paint paintball gun

There are three main areas of paintball that I will be analyzing. First the way in which a paintball leaves the barrel of a paintball marker. Second the way in which a paintball fly's through the air and lastly how to determine optimum ranges for paintballs. Firing a paintball As you fire the trigger, the paintball is being pushed down the barrel of the marker by the difference in pressure between the CO2 from a tank attached to the marker which builds up behind the ball and the air in front of the ball. There are several other forces which act on the paintball besides the air resistance and the CO2. One is the friction of the ball against the barrel. This frictional force is in no way constant because the shape and the smoothness of the inside of the barrel is not always constant. Likewise, the surface of the paintball is not always smooth. A second force is A spinning force that the C02 imparts on the ball causing a rotational acceleration and also a rolling motion. Once the ball has cleared the barrel there is a significant change in the forces that are acting on the paintball. The imbalance of the pressure behind the ball is gone. So that there is no longer any force pushing the ball in the direction that the muzzle is pointing in. It should be noted that there are many different ways that are employed to get a marker to shoot a paintball out of the marker. Nearly every brand of marker has a different firing system. All have several things in common. They all have some sort of tank with compressed air or C02 or Nitrogen. Then they usually have sort of bolt and hammer system which is cocked back and held in place by a sear which compresses a spring. When the trigger is pulled it releases the sear. The restoring force of the spring pushes the bolt and the hammer forward starting the paintball moving then the C02 is released propelling the ball outward. The flight of a Paintball Once a paintball gets into the air its flight is much like that of a golf ball. There are a verity of forces that act upon the ball once its in the air. The ball always has the force of gravity acting on it. This causes the paintball to travel in an arc and return to the earth.

6 Months Later :: essays research papers

6 Months Later Now that Lennie is out of the way, I guess that I can actually do something with my life. But, It's been 6 months since leaving the farm and I still don't have a job. Oh, here's a sign. A mentally handicapped hospital needs an attendant. I can do that, and it pays well too. $150 a month. "At that rate, I'll be able to get that land soon enough. Ain't that right," I asked Candy? "We sure are," he replied with enthusiasm. As we stepped into the complex, the first thing I saw was the reception desk with a young, pretty, receptionist sitting behind the desk, polishing her nails. Lennie would have enjoyed watching her I pondered. She asked us what we wanted, and I told her that we were just here to find out 'bout the job. After getting a quick overview and job description, I was ready to work right away. Candy was also lucky enough to get hired as a nurse for $100 a month. I stepped into the bedroom and I saw about 25 kids sitting around a middle-aged man, listening to a story. As I stepped in, the story teller stepped over to me and told me what I had to do. Educate them and talk to them. That was it. I was getting paid $150 just to teach a group of handicapped kids. I sat down next to the story teller, Bob, and I looked around and carefully observed them. As I did this, I could see Lennie's face flashing in my mind. What was happening to me. Why couldn't he just leave me alone. I survived through my first day of work, reluctantly. The hospital also provided housing. That night, I had the most horrible dream of my life. I could see Lennie petting hundreds of rabbits, one at a time. But he was crying and screaming in rage. The rabbits were dying. "George, why do they die? Don't let them die George, please. Can I still tend the rabbits? I know I done a bad thing," exclaimed Lennie. I got up, screaming. "Lennie, please leave me alone, please," I asked. It was silent. Nobody was awake. I looked like a complete nut with all those kids, including Candy, staring at me. Candy just went back to sleep. He was the only one that could understand the pain that I was going through. This happened to me several nights after the first nightmare. Each one would consist of rabbits, lots of them, and Lennie.

Coping with Death

Existentialists and intellectuals relatively have similar views about certain things. Existentialists are intellectuals while some intellectuals can be existentialists. However, there are instances when their philosophies can reveal differences which make them stand out and identify themselves. This paper aims to discuss how one is likely to cope with the issue of death in an existential and intellectual point of view. Coping with Death Death has been the most absolute event that is bound to happen to human beings even before they were born.It is one constant thing that will be waiting at the end no matter how well or bad we live our lives. Throughout life, there are inevitable instances when we are forced to cope with the death of someone, whether a stranger’s, relative’s, or plainly, the thought of ours. Since existential views root from the idea of existentialism and intellectual views from intellectualism, let us first identify the distinction between these two phil osophies. One of the most famous existentialists in history is the French philosopher Jean-Paul Sartre.He defined existentialism as a philosophy which focuses on the existence of man alone and not on his essence or for any other purpose. He argued that man exists without meaning or definition. However, he stated that essence and meaning only manifest later in our lives. It is through our decisions that we come to begin the definition of our existence (Earnshaw, 2006, p. 74). Clearly, it is evident in his argument that religion is out of the picture. In the book Existentialism, Steven Earnshaw quoted Sartre’s (2006) claim:If man as the existentialist sees him is not definable, it is because to begin with he is nothing. He will not be anything until later, and then he will be what he makes of himself (p. 74). Based on the definition by Sartre, it is now reasonable to say that existentialists view death as something that just happens without any meaning at all. If we are to cope with it existentially, it can be claimed that death is a fearful event because it does not provide a sensible reason.It does not label our meaning; rather, death ends it. On the other hand, there are also existential arguments with regard to death which claims that death is necessary to remind us of â€Å"possibilities. † Without death, one would not be obliged to be cautious in his/her decisions because that individual has all the time in the world to do them in â€Å"trial and error. † Now, we move on to intellectualism. This philosophy is actually quite self-explanatory in nature. An intellectual acts in accordance to reason.Similar to existentialism, intellectualism also disregards the involvement of religion, for religion is based on faith which is unfounded with solid evidences. Nonetheless, intellectuals can have different ways of coping with death. Since reason is more complex than the idea of â€Å"existence comes first† by Sartre, intellectuals can va ry in their opinion of death. As for me, if I am to cope with death intellectually, I can start off by going back to the theory of evolution.As rational and mortal animals, we are capable of deteriorating because of several conditions such as diseases, old age, natural disaster, etc. Hence, death is a cycle which is scientifically normal and inevitable. Most likely, if one is to view the concept of death either existentially or intellectually, he or she is still subject to fear its arrival. However, there is a loophole in both of the arguments because the root of our existence is still questionable. They can bring up the Big Bang or the Theory of Evolution, but as far as I am concerned, there is no solid evidence of the first inhabitants on earth.As long as theories have not been proved with concrete evidence, there is no way that we can reach the answers about life and death. In any case, existentialism and intellectualism do not provide the perfect way to cope with issues like dea th. What they can only provide is the flailing argument that we are considered materials which have the capability to break down and crash at any point in time. Would it not be better to accept death knowing that something unimaginable is waiting for us?