What is tumor necrosis factor (TNF)?

Cancers treated: Breast cancers, ovarian cancers, colon cancers, kidney cancers, and liver cancers, as well as melanomas; tests carried out with a variety of other tumors

Delivery routes: Tumor necrosis factor is generally delivered as an injection in a vein or muscle. Injection may also be under the skin. A colloidal form of TNF bound to small particles of gold has also been tested for improved specificity for cancer tissue, reducing the ability of the drug to bind normal tissue and possibly permitting systemic delivery.

How this drug works: The term TNF actually refers to a family of trimeric proteins produced by certain types of white blood cells that can attack blood vessels in tumors, thereby destroying certain types of cancer cells. The most common forms are TNF-α and TNF-β. TNF-α is the form used for cancer therapy. Its existence was discovered fortuitously in the early twentieth century when physicians observed that certain types of tumors would spontaneously regress in the presence of bacterial infections. It was subsequently discovered that TNF production is a part of the immune response and is induced in the presence of bacterial endotoxin (lipopolysaccharide).

The response to TNF is dose-dependent and can result either in inflammation, augmenting the immune response, or in binding to a cell surface, inducing the destruction of that cell. The induction of apoptosis, or “cell suicide,” appears to be the primary mechanism by which TNF may cause tumor regression. Depending upon the state of the particular cell, either tumor cells or the cells of the blood vessels that feed those tumors may express receptors on their respective surfaces for the drug. Binding of TNF sets in motion a series of intracellular signals that results in the death of the cell.

Testing has also been carried out using a human recombinant form of TNF (rTNF), as well as treatments utilizing a combination of chemotherapies in conjunction with TNF.

Side effects: Like other forms of chemotherapy, TNF has the potential to interact with other medications. Since TNF may interact with other cells of the immune system, vaccinations should be avoided during the course of treatment. Specific side effects of TNF may include a mild fever, chills or sweating, fatigue, and vomiting. Since most cells in the body have surface receptors to which TNF may bind, the drug is potentially toxic if given systemically.

Despite its potential as an anticancer agent, TNF has also been investigated for its possible role in cancer proliferation. It also can contribute to other diseases including autoimmune disorders.

Bibliography

Escarra, Agueda. Tumor Necrosis Factor: Structure, Enzyme Regulation, and Role in Health and Disease. New York: Nova Science, 2013. Print.

Chu, Wen-Ming. "Tumor Necrosis Factor." Cancer Letters 328.2 (2013): 222–25. PMC. Web. 6 Jan. 2015.

"TNF Tumor Necrosis Factor [Homo Sapiens (Human)]." Natl. Center for Biotechnology Information. Natl. Center for biotechnology Information, Natl. Lib. of Medicine, 4 Jan. 2015. Web. 6 Jan. 2015.

"Tumor Necrosis Factor." Natl. Cancer. Inst. Natl. Cancer Inst., Natl. Institutes of Health, n.d. Web. 6 Jan. 2015.

Van Horssen, R., T. L. Ten Hagen, and A. M. Eggermont. "TNF-alpha In Cancer Treatment: Molecular Insights, Antitumor Effects, and Clinical Utility." Oncologist 11.4 (2006): 397–408. PubMed. Web. 6 Jan. 2015.

"Waters, John P., Jordan S. Pober, and John R. Bradley. "Tumor Necrosis Factor and Cancer." Journal of Pathology 230.3 (2013): 241–48. Print.

What are corticosteroids?

Structure and Functions

Corticosteroids are steroid hormones produced by the cortex of the adrenal glands. They have several physiological actions, including regulation of glucose, lipid and protein metabolism, regulation of inflammation and the immune response, maintenance of homeostasis during stress, and control of water and electrolyte balance and blood pressure.

Corticosteroids that have their primary effects on glucose metabolism are glucocorticoids, whereas those that have the control of electrolyte and water balance as their main functions are mineralocorticoids. Cortisol is the primary glucocorticoid, although significant amounts of corticosterone and cortisone are secreted. Aldosterone is the primary mineralocorticoid.

Glucocorticoids promote an increase in blood glucose by stimulating the synthesis of glucose (gluconeogenesis). They also stimulate the catabolism of lipids and proteins. Thus, glucocorticoids increase blood glucose and are antagonistic to insulin.

The synthesis of corticosteroids is controlled by adrenocorticotropic hormone (ACTH)
produced by the pituitary gland. corticotropin-releasing hormone (CRH)
produced by the hypothalamus controls the secretion of ACTH. A feedback loop exists so that when cortisol levels are high, the release of CRH and ACTH is inhibited, and when cortisol levels are low, CRH and ACTH are released.

Aldosterone is primarily responsible for the control of salt and water balance by promoting the excretion of potassium and the retention of sodium and water. Through its effect on salt and water balance, aldosterone can increase blood pressure. Plasma levels of aldosterone are controlled by a variety of mechanisms, including plasma volume and potassium ion concentration.

Disorders and Diseases

Addison’s disease results from adrenal insufficiency (hypocortisolism). Although most cases are caused by a disorder of the adrenal glands (primary adrenal insufficiency), some cases are caused by a disorder of the pituitary gland (secondary adrenal insufficiency). An autoimmune disorder that destroys the adrenal cortex is the major cause of primary adrenal insufficiency. Secondary adrenal insufficiency is usually caused by a lack of ACTH. Pituitary tumors, surgical removal of the pituitary, and loss of blood flow to the pituitary are the major causes of secondary adrenal insufficiency. Major symptoms of adrenal insufficiency include loss of appetite, weight loss, fatigue, muscle weakness, and hypotension. Addison’s disease can be diagnosed by administering ACTH and monitoring the adrenal gland’s response by measuring serum and urine cortisol levels. Adrenal insufficiency is treated by oral administration of
hydrocortisone, a synthetic form of cortisol. If aldosterone is also deficient, then fludrocortisone is administered.

Adrenal insufficiency is often caused by a mutation in one of the enzymes synthesizing cortisol. These cases are referred to as congenital adrenal hyperplasia (CAH). Since serum cortisol is low or absent, the pituitary gland stimulates the adrenal gland to produce more cortisol. The precursor steroids and their metabolic products that accumulate can cause varying degrees of virilization of female fetuses and infants. Replacement therapy is the treatment of choice. Surgery to reconstruct the genital organs may be necessary in severe cases.

Hypercortisolism can lead to Cushing’s syndrome. Major symptoms include obesity, osteoporosis, fatigue, hypertension, hyperglycemia, and amenorrhea (absence of menstruation). Cushing’s syndrome may be caused by prolonged use of glucocorticoids or by an overproduction of glucocorticoids by the adrenal glands. The major causes of an overproduction of glucocorticoids are pituitary and adrenal tumors. Diagnosis of Cushing’s syndrome is most commonly made by determining the amount of cortisol in the urine. Cushing’s syndrome can be treated by reducing administered glucocorticoids or by treatment of the tumor causing the disease through surgical removal, radiation, and/or chemotherapy.

Hypoaldosteronism is a condition in which the adrenal cortex does not produce an adequate amount of aldosterone, which results in an inability to control and regulate blood volume and blood pressure. Blood pressure can fall to dangerously low levels.

Synthetic corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and dexamethasone have an immunosuppressive effect and are used to treat a variety of chronic autoimmune and inflammatory diseases. They can reduce the pain, swelling, itching, inflammation, and redness associated with arthritis, bursitis, asthma, dermititis, eczema and psoriasis, lupus erythematosus, Crohn’s disease, and various ear, eye, and skin infections and allergic reactions.

Prolonged use of corticosteroids can lead to medically induced Cushing’s syndrome, suppression of the immune system, hypertension, hypokalemia (low serum potassium), and hypernatremia (high serum sodium).

Perspective and Prospects

In 1855, Thomas Addison became the first physician to describe the clinical symptoms of adrenal insufficiency. In the early 1930s, Frank Hartman, Wilbur Swingle, and Joseph Pfiffner were the first to prepare active adrenal extracts capable of treating the symptoms of adrenal insufficiency. By the mid-1930s, Pfiffner, Edward Calvin Kendall, Oskar Wintersteiner, and Tadeus Reichstein had isolated and crystallized some of the adrenal hormones. In 1944, Lewis Sarett became the first to synthesize cortisone. In the late 1940s, Philip Showalter Hench discovered that the administration of cortisone could alleviate the symptoms of arthritis.

In recent years, it has been shown that corticosteroids express their effect by modulating the expression of a variety of genes involved in many physiological functions, including metabolism and the immune or inflammatory response.

Bibliography

"Corticosteroids." NHS, April 18, 2013.

Griffin, James E., and Sergio R. Ojeda, eds. Textbook of Endocrine Physiology. 5th ed. New York: Oxford University Press, 2004.

Lüdecke, Dieter K., George P. Chrousos, and George Tolis, eds. ACTH, Cushing’s Syndrome, and Other Hypercortisolemic States. New York: Raven Press, 1990.

Riedemann, Therese, Alexandre Patchev, Kwangook Cho, and Osborne F. X. Almeida. "Corticosteroids." Molecular Brain 3 (2010): 2–21.

Vaughan, Darracott E., and Robert M. Carey. Adrenal Disorders. New York: Thieme Medical, 1989.

Vinson, Gavin P., Barbara Whitehouse, and Joy Hinson. The Adrenal Cortex. Englewood Cliffs, N.J.: Prentice Hall, 1992.

"What Are Corticosteroids?" healthychildren.org, May 11, 2013.

How were nuclear submarines used in the Cold War?

There were two main uses for nuclear submarines in the Cold War.  One was as hard-to-track launch platforms for nuclear missiles.  The other was as hunters who tried to find those launch platforms so as to be in position to destroy them if there was a threat of war.

During the Cold War, the most important weapon in the US and Soviet arsenals was the nuclear missile.  Each side felt that it needed to have the ability to strike the other with nuclear missiles.  Each side had many missiles based on land, but they were afraid that the other side could target those missile installations and destroy them in case of war.  Therefore, “boomer” submarines, those that could launch ballistic nuclear missiles from underwater, were an important weapon.  The idea was that these subs could launch nuclear missiles at the enemy even if the enemy somehow managed to destroy all of a country’s land-based missiles.  Nuclear submarines were good for this because they could stay underwater for extended periods of time.  This meant, hopefully, that the enemy could not know where they were.

The second function of nuclear submarines was to try to hunt the boomers.  If a country could keep tabs on all of the enemy’s boomers, that threat could be neutralized.  The country could then, if it chose to go to war, destroy all the enemy boomers so the enemy could not launch missiles from those subs.  Therefore, both the US and the Soviet Union had fast attack subs that tried to detect and track the boomers.

In these ways, nuclear submarines were important parts of the Cold War.

In the book Night, what does Eliezer mean when he refers to his father as " his weak point"? Why has he come to view love as a weakness?

It might seem odd to refer to love and connection as a "weak point," but when you are in a survival situation, concern for anyone other than yourself, of necessity, dilutes your resources -- both physical and mental.  Thus, for example, when the selection was announced in Chapter Five, Elie had to concern himself with the question of whether or not his father would be selected, rather than simply worrying about his own chances.  Likewise, when his father appeared weak, Elie would periodically share his food rations, rather than using them to grow as strong as possible.

Yet, as Elie ultimately admits and understands, it is precisely his love and connection with his father that keeps Elie alive in the end.  During their final run from camp to camp, Elie and his father keep each other awake in the snow, and it is thoughts of wanting to stay on in support of his father that ultimately drive Elie.  Thus, while his father may be a "weak point," their connection also serves as motivation in the end.

Why did Catherine Petkoff lie to Major Petkoff about his old coat?

There are two major reasons. The first, and most pressing, is that Catherine doesn't want Sergius, who is present, to hear the truth about Bluntschli.

Telling the truth about the coat would mean revealing that Bluntschli had visited Raina in her bedroom, and this would likely end the engagement between Sergius and Raina. Catherine notes this explicitly in an aside to her daughter:

If Sergius finds out, it will be all over between you.

And we see later in the play, Catherine's fears were justified. When Sergius discovers that Bluntschli had visited that night, he is quick to interpret this as evidence that Raina has been "trifling with another man behind [his] back" and he is ready to denounce her.

Second, telling the truth would mean confessing that she and Raina were the anonymous women depicted in the story that Sergius had recounted to them. Even if there had been no engagement between Sergius and Raina, Catherine wouldn't have liked this revelation to come out. She is very concerned with her image as a dignified, cultured, high-status woman. In Sergius's gossipy account, the women who sheltered Bluntschli had shown a lack of aristocratic judgment. The women are depicted in a way that makes them seem amusing or ridiculous. They were credulous, easily flattered and taken in by a lower class man unworthy of their esteem:

SERGIUS [with bitter irony] Oh yes: quite a romance! He was serving in the very battery I so unprofessionally charged. Being a thorough soldier, he ran away like the rest of them, with our cavalry at his heels. To escape their attentions, he had the good taste to take refuge in the chamber of some patriotic young Bulgarian lady. The young lady was enchanted by his persuasive commercial traveller's manners. She very modestly entertained him for an hour or so, and then called in her mother lest her conduct should appear unmaidenly. The old lady was equally fascinated; and the fugitive was sent on his way in the morning, disguised in an old coat belonging to the master of the house, who was away at the war.

Note the derisive tone, and the digs at everyone concerned. The soldier "ran away," which is inconsistent with the idealized image of a gentleman that Sergius and his cultural circle favor. The young woman entertained the soldier for an hour before deciding -- too late, by this same cultural standard -- that she needed a chaperone. And the mother, described as an "old lady" (which can't have pleased Catherine), is equally credulous.

The stage directions suggest that every compliment paid to the characters is ironic, indicating that Sergius really means to say the affair wasn't a heroic romance, but something ridiculous and low. The women were silly to have treated the soldier as a gentleman worthy of such hospitality, and their actions suggest they are not true elites. True elites would have known better.

So Catherine doesn't want to be identified in this way. It would open her to derision on a point that is dear to her self-image.

`int_0^(pi/4) tan^4(t) dt` Evaluate the integral

`int_0^(pi/4) tan^4(t) dt`

Express the integrand in factor form.

`= int _0^(pi/4) tan^2(t) *tan^2(t) dt`

Plug-in the trigonometric identity `tan^2(t) = sec^2(t)-1` to one of the factors.

`= int_0^(pi/4) tan^2(t)*(sec^2(t)-1) dt`

`= int_0^(pi/4) (tan^2(t)sec^2(t)-tan^2(t)) dt`

`= int _0^(pi/4) tan^2(t)sec^2(t) dt - int_0^(pi/4)tan^2(t) dt`

Plug-in again the trigonometric identity  `tan^2(t) =sec^2(t) - 1` to the second integral.

`= int_0^(pi/4) tan^2(t)sec^2(t)dt- int_0^(pi/4) (sec^2(t) - 1) dt`

`= int_0^(pi/4) tan^2(t) sec^2(t) dt - int_0^(pi/4) sec^2(t)dt + int_0^(pi/4) dt`

For the first integral, apply the u-substitution method.

     `u=tan (t)`

     `du = sec^2(t) dt`

>> `int tan^2(t) sec^2(t)dt = int u^2du=u^3/3 = (tan^3(t))/3`

For the second integral, apply the formula `int sec^2 x dx = tanx` .

>> `int sec^2(t)dt = tan (t)`

And for the third integral, apply the formula `int adx = ax` .

`gtgt int dt = t`

So the integral becomes:

`int_0^(pi/4) tan^2(t) sec^2(t) dt - int_0^(pi/4) sec^2(t)dt + int_0^(pi/4) dt`

`= ((tan^3(t))/3 -tan(t) + t) |_0^(pi/4)`

`=((tan^3(pi/4))/3 - tan(pi/4) + pi/4) - ((tan^3(0))/3 - tan(0) + 0)`

`= (1/3 - 1 + pi/4) - 0`

`=pi/4 - 2/3`

Therefore,   `int_0^(pi/4) tan^4(t) dt = pi/4 - 2/3` .

What are government warnings for addictive substances?

Purpose and Functions

The primary function of a government warning is to increase public knowledge about unsafe use of substances, particularly tobacco and alcohol products that can be purchased without a prescription by adults who have proper identification. These health warnings attempt to minimize dangerous substance activity by discouraging drug misuse and overuse. Warning label goals include the complete cessation of tobacco use and total abstinence from alcohol during any stage of pregnancy.

The first alcohol and tobacco warning labels developed as a result of acts by the US Congress. The Alcoholic Beverage Labeling Act of 1988 was passed in response to birth defects connected with alcohol use during pregnancy. Similarly, tobacco use has been tracked by the Office of the Surgeon General (OSG) since the 1920s. In the 1960s, tobacco use became a public health issue that resulted in government warnings because of early reports about the health damage to nonsmokers from exposure to secondhand smoke.

Government warning labels on alcohol and tobacco are intended to call separate attention to multiple risks. Label text may be decided by the OSG but enforcement is often implemented by affiliate agencies, such as the Alcohol and Tobacco Tax and Trade Bureau (TTB). One goal of the TTB is to protect public safety through oversight of federal laws about alcohol and tobacco product-labeling.

Label Formats

Product health warnings require text introductions of “Warning” or “Government Warning” in bold type on every package. To ensure visibility, all statements must be placed prominently on high-contrast sections of the package label, separate from other information.

Warning texts expand as evidence builds on the dangers of alcohol and tobacco use. Since 1989, the US government has mandated two warnings on alcoholic products. These warnings are “According to the Surgeon General, women should not drink alcoholic beverages during pregnancy because of the risk of birth defects” and “Consumption of alcoholic beverages impairs your ability to drive a car or operate machinery, and may cause health problems.”

In 2001, horizontal boxed text and conspicuous statements with surrounding white space were encouraged on beverage labels to increase attention to the warnings. In 2005, the OSG supplemented alcohol label warnings with an online news advisory to recommend total avoidance of any amount of alcohol during all stages of pregnancy, as evidenced by expanded research on fetal alcohol syndrome disorders.

Like alcohol warnings, tobacco warnings were initiated in Congress and adapted in time. Government warnings about tobacco changed little since the 1960s, until the statements were strengthened by the US Food and Drug Administration in response to the Family Smoking Prevention and Tobacco Control Act of 2009. The new warnings, effective September 2012, comprise nine separate statements, a resource site (1-800-QUIT-NOW), and images of harmful tobacco effects on the body. Each warning contains one statement, one image, and the toll-free quit hotline.

The plain-language warnings, identified through literature review and public commentary, are as follows: cigarettes are addictive, tobacco smoke can harm your children, cigarettes cause fatal lung disease, cigarettes cause cancer, cigarettes cause strokes and heart disease, smoking during pregnancy can harm your baby, smoking can kill you, tobacco smoke causes fatal lung disease in nonsmokers, and quitting smoking now greatly reduces serious risks to your health. These changes, especially the new graphics, are negative reminders to heighten risk awareness, increase quit rates, and empower youth to avoid smoking.

Label Efficacy

Government warnings are updated infrequently, and public awareness of the standard labeling may introduce complacency. Government warnings on alcohol and tobacco are acknowledged by consumers, but effects on behavior are variable. For example, in the Alcoholic Beverage Label Evaluation survey from 1989 to 1995 (which surveyed persons in the Midwest), alcohol risks were noted by participants, but no significant changes in alcohol use resulted. Positive changes, such as lower rates of alcohol use while driving, appeared to level off after approximately three years. Thus, although awareness appears commonplace, the warnings do not appear to affect any long-term behavioral change.

Strategies for calling greater attention to the health risks include point-of-purchase notices, graphic images to supplement text labels, and even more prominent placement of warnings on the products. For example, cigarette products now require warning label placement on the top half of the front and back of each package or advertisement to pointedly display potential consequences of use. The use of graphics to transmit any health information is known to increase knowledge of risks, increase quit rates, and prevent new smokers.

Even greater distribution of warnings is available through state-regulated point-of-purchase programs, which require establishments that sell alcohol and tobacco to display warning signs at checkouts. For example, businesses that sell liquor must post the government warning about pregnancy and birth defect risks, and tobacco warning signs must be present where the tobacco products are sold.

Bibliography

Alemanno, Alberto, and Amandine Garde, eds. Regulating Lifestyle Risks: The EU, Alcohol, Tobacco and Unhealthy Diets. New York: Cambridge UP, 2015. Print.

Centers for Disease Control and Prevention. How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease. Rep. Washington, DC: DHHS, 2010. Print.

Hammond, David, et al. “Text and Graphic Warnings on Cigarette Packages: Findings from the International Tobacco Control Four Country Survey.” American Journal of Preventive Medicine 32.3 (2007): 202–9. Print.

MacKinnon, David P., and Liva Nohre. “Alcohol and Tobacco Warnings.” Handbook of Warnings. Ed. M. Wogalter. Mahwah: Erlbaum, 2006. Print.

Thomas, Gerald, Ginny Gonneau, Nancy Poole, and Jocelynn Cook. "The Effectiveness of Alcohol Warning Labels in the Prevention of Fetal Alcohol Spectrum Disorder: A Brief Review." International Journal of Alcohol and Drug Research 3.1 (2014): 91–103. Print.

Voon, Tania, Andrew D. Mitchell, and Jonathan Liberman, eds. Regulating Tobacco, Alcohol, and Unhealthy Foods: The Legal Issues. New York: Routledge, 2014. Print.