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8 Rejected Papers That Won the Nobel Prize

Nobel prize winning ideas are not always accepted by the community. By definition, they are paradigm shifting, revolutionary. Accordingly, many breakthroughs that are in our textbooks today were initially rejected, if not ridiculed, by the scientific community. Howard Temin proposed a reversal of the central dogma, wherein RNA could create DNA. It was called "ludicrous" and his Nobel "came after a lonely battle to overcome derisive criticism from scientific leaders who refused to believe in his theory that some viruses carry their genetic information in the form of RNA, which is then copied into DNA in infected cell." Similarly, Werner Arber, the scientist who discovered restriction enzymes worked, "in a climate of almost total indifference, notably that of the committees and organizations tasked with allocating funds for research" Jacob 1998.

Here we outline 8 Nobel prize papers that were initially rejected by anonymous pre-publication peer review and ask, "What Nobel ideas are we rejecting and/or delaying today?"

1. Nobel Prize in Chemistry (1997) awarded to Paul Boyer for: Identification of the mechanism for the synthesis of adenosine triphosphate (ATP)

Rejection: Boyer had been greeted with disbelief when he theorized that the previously mysterious process is the work of a "beautiful little machine" that operates within enzymes on the molecular level. His proposed resolution of a major unsolved problem in biochemistry threatened to "change the paradigm," Boyer remembers, and "the leading journal" in his field -The Journal of Biological Chemistry-declined to publish his work. 

Paul Boyer

2. Nobel Prize in Chemistry (1991) awarded to Richard Ernst for: The development of high resolution nuclear magnetic resonance (NMR) spectroscopy

Rejection: "The paper that described our achievements was rejected twice by the Journal of Chemical Physics to be finally accepted and published in the Review of Scientific Instruments"

Richard Ernst

3. Nobel Prize in Physics (1969) awarded to Murray Gell-Mann for: "for his contributions and discoveries concerning the classification of elementary particles and their interactions"

Rejection: That was not my title, which was : Isotopic Spin and Curious Particles. Physical Review rejected "Curious Particles". I tried "Strange Particles", and they rejected that too. They insisted on : "New Unstable Particles". That was the only phrase sufficiently pompous for the editors of the Physical Review. I should say now that I have always hated the Physical Review Letters and almost twenty years ago I decided never again to publish in that journal, but in 1953 I was scarcely in a position to shop around.

Murray Gell-Mann

4. Nobel Prize in Medicine (1953) awarded to Hans Krebs for: The discovery of the citric acid cycle (aka the Krebs cycle)

Rejection letter from Nature to Hans Krebs. 

5. Nobel Prize in Physics (2000) awarded to Herbert Kroemer for: "Developing semiconductor heterostructures used in high-speed and opto-electronics"

Rejection: "I wrote up the idea and submitted the paper to Applied Physics Letters, where it was rejected. I was talked into not fighting the rejection, but to submit it to the Proceedings of the IEEE, where it was published, but ignored. I also wrote a patent, which is probably a better paper than the one in Proc. IEEE."

Herbert Kroemer

6. Nobel Prize in Chemistry (1986) awarded to John Polanyi for: elucidating the dynamics of chemical elementary processes.

Rejection: "Physical Review Letters rejected the paper as lacking scientific interest. Shortly thereafter they rejected T. Maiman's report of the first operating laser, on the same grounds. Polanyi read about this second rejection, quite by chance, while holidaying on an island in Georgian Bay. On returning to Toronto in September of 1960 he submitted the identical manuscript to the Journal of Chemical Physics, where it was promptly published."

John Polanyi

7. Nobel Prize in Chemistry (1993) awarded to Kary Mullis for: invention of the polymerase chain reaction (PCR) method

Rejection: "And Dan Koshland would be the editor of Science when my first PCR paper was rejected from that journal and also the editor when PCR was three years later proclaimed Molecule of the Year."

8. Nobel Prize in Medicine (1977) awarded to Rosalind Yalow for: invention of the radioimmunoassay (RIA).

Rejection: "For years after winning the Nobel Prize, Yalow proudly showed this rejection letter in her public presentations."

Rejection letter received by Dr. Bradley and Dr. Yalow. 

Today, authors have the ability to upload their manuscript to places like Authorea and communicate their ideas prior to formal publication. This allows new and potentially breakthrough ideas to be discussed transparently. We think good science is science that can be scrutinized transparently--we're facilitating that. Join us!

References: François Jacob. Of flies, mice, and men. 158 p. (1998).

Which Drug Interactions Matters a lot in Older Adults?

Conventional wisdom has it that the elderly are at greater risk for adverse drug interactions, and the published evidence supports this view. Older patients take more medications and experience physiologic changes that may affect drug disposition, making them potentially more susceptible to the adverse outcomes from drug interactions. 

Over the past decade or so, we have also accumulated some useful data on which specific drug interactions increase the risk of serious reactions in older patients. In a recent paper, Hines and Murphy from the University of Arizona reviewed population-based studies over the past 10 years, and discussed those that detected serious adverse outcomes due to particular drug interactions. The Table lists the interactions found to result in either increased risk of hospitalization or death. It is important to remember that the interactions in the Table are the ones that were chosen for study, and other related interactions involving these drugs are also likely to increase the risk of serious adverse outcomes. For example, angiotensin receptor blockers may also increase the risk of hyperkalemia when combined with potassium-sparing diuretics or co-trimoxazole; combining calcium-channel blockers with cytochrome P450 (CYP) 3A4 inhibitors other than macrolides may increase the risk of hypotension or shock; digoxin toxicity may occur with concurrent use of many P-glycoprotein inhibitors other than macrolides; and phenytoin toxicity can be produced by CYP2C9 inhibitors other than co-trimoxazole.

Clinical evidence also suggests that a number of other oral antidiabetic agents are metabolized by CYP2C9 and CYP3A4, and hypoglycemia may occur when inhibitors of these isozymes are given concurrently; CYP2D6 inhibitors other than paroxetine may inhibit the efficacy of tamoxifen in breast cancer; CYP1A2 inhibitors other than ciprofloxacin can cause theophylline toxicity; and any CYP2C9 inhibitor would be expected to increase the anticoagulant response to warfarin. Moreover, the elderly may take many other drugs that have substantial risk of drug interactions, especially psychotherapeutic drugs, but also drugs such as colchicine, statins, drugs for Parkinson’s disease, cholinesterase inhibitors for Alzheimer’s disease, and nonsteroidal anti-inflammatory drugs. The vast majority of publications on drug–drug interactions are either case reports or pharmacokinetic studies in healthy subjects. Such data provide evidence that a drug interaction exists, but seldom give us information on how often adverse consequences occur or how severe they are likely to be. The value of the population-based studies discussed above is that they help us determine which drug interactions actually can result in severe adverse consequences, and give us some idea of the incidence of the adverse outcomes. 

References:

1. Drs. Horn and Hansten are both professors of pharmacy at the University of Washington School of Pharmacy. 
2. For an electronic version of this article, including references if any, visit www.hanstenandhorn.com.

Drug Interactions : An addition to Beer's Criteria

In 1991, the first “Beers Criteria” were published to alert clinicians to drugs that are potentially inappropriate for use in older adults. Updates to the list have appeared periodically, and the most recent (November 2015) includes drug– drug interactions (DDIs) for the first time. The expert panel included primarily pharmacists, physicians, and nurses, and they used a modified Delphi method to compile the criteria. 

Criteria for the Inclusion of DDIs:

The panel members made it clear that the DDI list is not intended to be comprehensive, and that individuals should not assume that these are the only DDIs worth considering in older adults. The panel selected DDIs it felt were particularly problematic in the elderly, regarding the potential for adverse outcomes. The panel did not include anti-infective agents or address drug therapy in individuals receiving palliative and hospice care. 

Drug Interactions that Were Included:

The DDIs the panel added to the Beers Criteria fell into several categories, but the most prevalent was an increased risk of falls due to combined use of 2 or more central nervous system (CNS) drugs (eg, antidepressants, antipsychotics, benzodiazepines, hypnotics, opioid analgesics). 

Unfortunately, despite the fact that these additive pharmacodynamic effects are well known and predictable, they are still too often overlooked in the elderly. Also included in the list were the following: 

• Lithium toxicity from concurrent angiotensin-converting enzyme (ACE) inhibitors or loop diuretics 

• Hyperkalemia from ACE inhibitors with amiloride or triamterene • Cognitive decline from multiple anticholinergics 

• Peptic ulcers and gastrointestinal (GI) bleeding from nonsteroidal anti-inflammatory drugs (NSAIDs) plus systemic corticosteroids 

• Urinary incontinence in older women from peripheral alpha-1 blockers plus loop diuretics 

• Theophylline toxicity due to cimetidine 

• Increased bleeding risk from warfarin when combined with amiodarone or NSAIDs 

Evaluation:

The expert panel appears to have achieved its goal of preparing a list of DDIs that can be particularly dangerous in the elderly. It would not be difficult for pharmacists to commit these to memory given that there are only 13 DDIs on the list. When alerted to these DDIs by a computerized screening system, pharmacists could pay particular attention to the alert for elderly patients. In general, the DDIs on the list should be avoided in older adults when possible; therefore, action by a pharmacist may well be warranted. It is important to keep in mind that this list is not comprehensive. The risk of GI bleeding due to NSAIDs can be increased by drugs other than corticosteroids (eg, spironolactone). The risk of lithium toxicity can be increased by drugs other than ACE inhibitors or loop diuretics (eg, angiotensin receptor blockers, NSAIDs). Many drugs other than cimetidine inhibit CYP1A2 and can cause theophylline toxicity. In addition, dozens of drugs other than amiodarone and NSAIDs can increase the risk of bleeding in patients on warfarin, usually through inhibition of CYP2C9 or by inhibitory effects on platelet function. Moreover, many other important DDIs were not included, as the expert panel pointed out. Leaving out antiinfective agents was probably prudent, but many anti-infectives have properties that result in clinically important DDIs. It is important to note that the new Beers Criteria DDIs are not intended to be applied to patients in palliative and hospice care. These patients, for example, may well need therapy with various combinations of CNS-active drugs that can be problematic in other older adults. For most of the 13 DDIs on the list, the expert panel recommended that they should be avoided if possible, but for one of the interactions (theophylline plus cimetidine), the panel simply said “Avoid.” This is appropriate because other histamine2 -receptor antagonists have little effect on theophylline and there is no reason to use cimetidine. 

Summary:

The American Geriatrics Society 2015 Updated Beers Criteria included DDIs for the first time. The panel listed 13 DDIs that may be particularly dangerous in older adults. It would be prudent for pharmacists to pay particular attention to these DDIs in all patients, but especially in the elderly. 

References: 

1. Drs. Horn and Hansten are both professors of pharmacy at the University of Washington School of Pharmacy. 
2. For an electronic version of this article, including references, visit hanstenandhorn.com.

Drug–Disease Interactions : Lot to Know

This column usually deals with interactions that occur when one drug directly affects the pharmacokinetics or pharmacodynamics of a second drug. It is possible, however, for a precipitant drug to indirectly affect the object drug. A common example would be drug-induced renal or hepatic dysfunction that reduces the elimination of another drug. It is also possible for effective drug therapy to enhance the elimination of an object drug by treating a disease that inhibits drug elimination.

Effect of Disease on Drug Metabolism:

The activity of several cytochrome P450 enzymes (eg, CYP1A2, CYP3A4, CYP2C19, CYP2C9) can be inhibited by disease states that are characterized by infection or inflammation. These disease states increase cytokine concentrations in response to infection, trauma, ischemia, immune-activated T cells, and toxins. Cytokines associated with this CYP inhibitor effect include interleukin-6 (IL-6), IL-1, tumor necrosis factor, and interferon. During active disease periods, the metabolism of drugs may be reduced by the elevated cytokine concentrations; however, it is unknown if these cytokines reduce CYP activity in the liver or the intestinal enterocytes, or both. 

Treatment of the disease may reduce cytokine production and the suppressant effect on CYP enzymes. Schmitt et al reported on the simvastatin plasma concentrations in 12 patients with rheumatoid arthritis (RA) before and after treatment with tocilizumab (Actemra). Patients were administered a single 40-mg dose of simvastatin before and at 7 and 35 days after a single dose of tocilizumab 10 mg/kg. Following treatment with the IL-6 antagonist, the mean simvastatin peak plasma concentration and area under the concentration time curve (AUC) were reduced by close to 60% compared with baseline values. The reduction in simvastatin AUC following tocilizumab administration correlates to approximately a doubling of its oral clearance. At 35 days after the tocilizumab dose, simvastatin plasma concentrations were still 40% less than levels prior to the tocilizumab dosing. The inhibition of CYP3A4 activity by cytokines is likely responsible for the increased simvastatin concentration observed prior to tocilizumab treatment. There was no observable change in the half-life of simvastatin after treatment, suggesting that the change in simvastatin AUC may have been due to increased first-pass effect rather than a change in systemic clearance. It appears that cytokine inhibition of metabolism is rapidly reversed by agents that reduce the inflammatory response (Table). 

A decrease in omeprazole plasma concentration was noted following tocilizumab administration to patients with RA.5 The decrease was about 40% in extensive metabolizers of CYP2C19, but less than 20% in poor metabolizers. These data suggest that the activity of both CYP2C19 and CYP3A4 is reduced in patients with RA and this inhibition is reversed by IL-6 inhibition. Clinical Perspective The magnitude of the change in a drug’s elimination following the administration of a cytokine inhibitor will likely be limited to the degree of cytokine-induced inhibition of the CYP enzymes. Based on the limited data available, cytokine induced inhibition may approach a 50% reduction in drug clearance. In disease states with chronic inflammation, drug dosages may be adjusted downward to avoid adverse events. Treating the inflammation with a cytokine inhibitor will result in an increase in drug clearance and reduction in drug concentration. For drugs with a narrow therapeutic range (eg: warfarin, theophylline, cyclosporine) or in cases in which low plasma concentrations pose a risk of therapeutic failure (eg, antivirals, immunosuppressants, antineoplastics), the increase in clearance may result in an altered patient response. Drug dosage may require an increase when cytokine inhibitors are administered. Patients treated with tocilizumab or other cytokine inhibitors should be monitored for altered response to long-term medications that undergo CYP metabolism. 

References: 

1. Drs. Horn and Hansten are both professors of pharmacy at the University of Washington School of Pharmacy.
2. For an electronic version of this article, including references, visit hanstenandhorn.com.

UNICEF Internship Programme 2016 - Generic Vacancy Announcement

Purpose of the UNICEF Internship Programme

If you are a committed, creative professional and are passionate about making a lasting difference for children, the world's leading children's rights organization would like to hear from you.

The UNICEF Internship Programme offers qualified and eligible students at both Headquarters (HQ) and Country Offices (CO) the unique opportunity to acquire direct practical experience in UNICEF's work and the United Nations system under the direct supervision of experienced UNICEF staff.

Internships are offered depending on the availability of meaningful assignments and the needs and capacity of units/offices to receive and supervise interns. UNICEF is active in various functional areas related to its mandate, which can be categorized in three main pillars: Programme and Policy, External Relations and Operations. 

Eligibility Requirements

1. At the time I would like to start my internship with UNICEF, I will be enrolled in a graduate (Master's) degree or undergraduate (Bachelor's) degreel; and
2. I will have completed at least two years of full-time studies towards completion of my undergraduate degree.
3. I have excellent academic performance and can demonstrate it by my recent university or other academic institution records.
4. I am proficient in at least one of UNICEF's working languages (English, French or Spanish) and fluent in the working language of the office I am interested to work in.

Please note: Additional consideration will be given to any past professional experience.

If you could answer 'yes' to all the above listed requirements, you are highly encouraged to apply now to UNICEF's internship database!

If you would like to be eligible to start your internship in 2017, please apply between 1 November 2016 and 30 September 2017.

Please keep in mind: Even if you meet these qualifications, there is no guarantee of placement. Qualified candidates will be placed in UNICEFs Internship database which is accessed by UNICEF managers globally. If you are applying for more than one location, the online application will allow you to choose the New York Headquarters location as well as up to three other field locations outside New York. If an exciting opportunity matching to your profile and interests arise, you will be contacted directly.

Internship dates and duration

To be eligible for an internship with UNICEF, you have to apply to its internship database. When completing your application, you will be asked to indicate:

1. A time period in the current year when you are available to start your internship,
2. Your preferred functional areas; and
3. The location you would like to be considered for.

Please make sure to always keep the information in your profile up-to-date, as the database is being refreshed every year.

Incomplete applications will not be considered.

The duration of an internship with UNICEF is between six weeks and six months.

More information : For more details on the Internship Programme, please see the section's FAQ.

Advertised: 04 Apr 2016 Eastern Standard Time

Applications close: 30 Sep 2016 Eastern Standard Time

Work type: Internship (Apply Here)

Location: United States of America