Study sheds light on how ovarian cancer spreads

With 20,000 diagnoses each year, ovarian cancer is the ninth most common cancer and fifth leading cause of cancer death among women in the United States. So many women die from ovarian cancer because it often goes undetected until it has spread within the pelvis and abdomen, by which point it is difficult to treat and usually fatal. A team of researchers from the University of California, Riverside and the University of Notre Dame are studying the molecular mechanisms by which ovarian cancer spreads — or metastasizes — to uncover new therapeutic opportunities.

In their latest paper, published in the journal Oncogene, they used live imaging and electron microscopy to study the cellular activities associated with successful metastasis, including the expression of a group of proteins called cadherins, which help cells bind together. Since these proteins enable cancer cells to anchor to new sites in the body, it may be possible to disrupt metastasis by blocking cadherin-mediated binding.

The research was led by Mark Alber, a distinguished professor of applied mathematics at UC Riverside, and M. Sharon Stack, a Kleiderer-Pezold professor of biochemistry and director of Notre Dame Harper Cancer Research Institute.

As primary ovarian tumors metastasize, they shed both single cells and clusters of cells, called multicellular aggregates (MCAs), into the pelvis and abdomen. To study exactly how metastasis occurs, the researchers quantified the interactions between epithelial ovarian cancer (EOC) cells and three-dimensional models of the abdomen wall. They showed when EOC cells acquired N-cadherin (Ncad), an event that occurs in human EOC tumors, they could penetrate and attach to the abdomen wall. Furthermore, MCAs dispersed prior to invasion as a large cohort of cells, showing that cell to cell junctional integrity (i.e. attachment at the single cell level) was needed for successful metastasis.

Alber said unlike results observed in other cancers, ovarian cancer cells do not appear to exhibit a ‘leader-follower’ type of collective cell invasion.

“Interestingly, co-culture of Ncad-expressing cells with cells expressing E-cadherin (Ecad) did not promote invasion of the Ecad-expressing cells, demonstrating that Ncad-expressing cells do not simply lead the way for other cell populations to follow,” Stack said.

The findings emphasize the importance of Ncad in ovarian cancer metastasis and provide the rationale to support pre-clinical studies using Ncad-blocking molecules as a therapeutic strategy to suppress EOC metastatic anchoring.

The group is using these results to develop computational models of cancer cell invasion. Future studies will also use patient samples, which will be provided by collaborators from the City of Hope, in Duarte, Calif. for combined modeling and experimental approaches to obtain novel insights into the cellular mechanisms of ovarian cancer metastasis.

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Materials provided by University of California – Riverside. Original written by Sarah Nightingale. Note: Content may be edited for style and length.

Human enzyme can reduce neurotoxic amyloids in a mouse model of dementia

A naturally occurring human enzyme -called cyclophilin 40 or CyP40- can unravel protein aggregates that contribute to both Alzheimer’s disease and Parkinson’s disease, according to a study publishing June 27 in the open access journal PLOS Biology by Jeremy Baker, Laura Blair, and Chad Dickey of the University of South Florida in Tampa, and colleagues. The finding may point toward a new therapeutic strategy for these diseases.

In most neurodegenerative diseases, misfolded proteins aggregate to form an insoluble clump called amyloid. Many amyloid-forming proteins, including tau in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease, contain the amino acid proline, whose unique structure induces a bend in the amino acid chain. Those bends contribute to stacking of adjacent regions of the protein, thus promoting amyloid formation. During normal protein folding, CyP40 latches on to prolines, orienting them into their characteristic chain-bending conformation, but like most enzymes, it can also operate in reverse, helping to unbend the chain.

The researchers found that CyP40 could reduce the amount of aggregated tau, converting it into a more soluble form. In a mouse model of an Alzheimer’s-like disease, experimental expression of CyP40 preserved brain neurons and rescued cognitive deficits. The same enzyme also disaggregated alpha-synuclein, an aggregate associated with Parkinson’s disease. This is the first time that CyP40 has been shown to disaggregate an amyloid responsible for a neurodegenerative disease.

Exactly how CyP40 reduces aggregation is not yet clear, and the authors provide two possibilities. The enzyme may bind to aggregated protein and, by reversing the proline bend, help unstack and separate the amino acid chain. Support for this model comes from the observation that the enzyme was less effective at reducing aggregates when its action was inhibited. Alternatively, the enzyme may bind to the protein before it forms aggregates, sequestering it and thus preventing it from clumping.

Understanding more about the exact mechanism of the enzyme may help point toward a therapeutic strategy centered on proline’s role in amyloid formation. “The finding that Cyp40 can untangle clumps of tau and alpha-synuclein suggests that it, or one of the more than 40 other human proteins with similar activity, may have a role to play in treating neurodegenerative disease,” Blair said.

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Materials provided by PLOS. Note: Content may be edited for style and length.

Biologist looks at butterflies to help solve human infertility

When insects skip the light fandango their romantic foreplay often involves some pretty crazy things like hypnotic dance moves and flashy colors. In some species it ends with a complex ejaculate package that does more than fertilize offspring.

In the case of butterflies, the cabbage white Pieris rapae in particular, scientists have found male butterfly ejaculate — a complex package designed to deliver sperm — also contains a dose of valuable life-extending nutrients that female butterflies devour like candy.

But receiving this parcel of goodness comes at a cost — male dominance.

It comes covered in a hard shell that takes three days to digest, during which time the female cannot mate again, says University of Cincinnati biologist Nathan Morehouse.

Recent interdisciplinary research led by Morehouse in the Morehouse Research Lab and Nathan Clark, biologist in the Clark Research Lab at the University of Pittsburgh looked closer at the complex structures and mechanisms within male butterfly ejaculates and the adaptive responses in the female butterfly reproductive tract.

The researchers hope these study findings will aid in understanding the complex human reproductive cycle and the occasional problems that originate on a molecular level. The authors published their co-evolutionary results in the June journal Proceedings of the National Academy of Sciences.

“As scientists, we already knew that male butterfly ejaculates were three-fold complex structures we call spermatophores — composed of an outer envelope, an inner matrix of fluids and a bolus of sperm,” says UC’s Morehouse. “What we didn’t know and found through our research is that these three structures are distinctly different in protein composition, are separately stored in the male reproductive tract and are transferred sequentially to the female reproductive tract during mating.”

Why such an elaborate process for such a tiny butterfly? Control over female reproduction, Morehouse says.

Because the spermatophore occupies much of the female reproductive tract, she cannot mate again until it is gone. Males make it tough for her by encasing the spermatophore in a hard shell. This delay benefits the male by assuring more of his sperm fertilize her eggs.

Method behind his madness

“In this set of species, and in many insects, they have what’s called last male sperm precedence,” says Clark. “When another male comes in and mates, his sperm either displaces the first male’s sperm or pushes them to the back.”

Occasionally, individual male seminal fluids and female enzymes won’t work together efficiently, creating an imbalance that can result in low egg fertilization. The researchers say looking at how female butterflies have resolved this obstacle may open the curtain for correcting similar protein-enzyme imbalances in human infertility.

Using high-tech computerized technology such as mass spectrometry and older standard biochemical processes, the researchers determined that the tiny winged macho-men transfer 13 percent of their total body weight through their spermatophore complex during the mating process. But surprisingly, only 2 percent of that is actually sperm.

The rest of the complex goody bag of proteins, carbohydrates, lipids and other compounds play all sorts of other important roles in reproduction — not the least of which is a way for the males to prevent the female from mating again for about three to four days, says Morehouse.

On the flip side, he says females benefit much more by mating often for a number of reasons:

Females like a variety in the genetics of the offspring they produce, as some male genotypes are better than others and this assures her the most successful outcome.

Females crave the delicious protein nutrients males pass along during mating that provide life-extending cell repair — sort of like going to a butterfly spa — so the more the better.

These protein nutrients also help females build eggs. We estimate that a female who mates 2-3 times may build 30-40 percent of the eggs she lays from proteins the male transfers during copulation. So male mates are actually funding her reproduction.

“To keep a female from remating, the males have developed a hard outer shell around the precious nutrients that are especially desirable by females to repair their cells and live longer,” says Clark. “This hard outer shell gets transferred behind the bolus of sperm and acts as a copulatory plug that prevents the female from being able to mate again with other males — hopefully insuring his sperm as the cocktail that fertilizes the female’s eggs when she lays them.”

Wait! Not so fast

“I was fascinated to discover that females are actually very well equipped to quickly digest the nuptial gift from the male,” says Camille Meslin-Auclair, post-doctoral biologist who performed most of the analysis working at the University of Pittsburgh. “Even more fascinating are the mechanical and biochemical tools she possesses to dissolve this outer shell.”

In an evolutionary twist of fate, these clever little females have developed an extraordinary way to break free from the male’s control.

“We discovered a surprising mechanical chewing device inside the female reproductive tract lined with a spectacular array of tooth-like structures that can gnaw through the hard outer shell in a matter of hours,” says Morehouse. “Without this mechanism we affectionately call the ‘vagina dentata,’ it would likely take a week or more to dissolve the hard protective shell with just her enzymes alone.”

By looking at reproduction as both a source of cooperation and conflict between the sexes, the researchers are finding clues from this study on a behavioral and molecular level that can be an important link for solving certain unexplained causes of human infertility.

“Reproduction is a very interesting social interface where males and females have a conversation,” says Morehouse. “That conversation often begins with courtship, but doesn’t stop after mating happens.

“It becomes a negotiation between the molecules of both sexes for the shared goal of producing offspring.”

As the researchers understand incompatibilities between butterflies on a molecular level, they plan to track how these creatures evolve and develop certain enzymes and proteins to solve this tug of war.

Morehouse and Clark hope new findings eventually unlock some of the mysteries of human infertility that exist on a similar stage between male seminal fluids and female reproductive enzymes.

“These cabbage white butterflies are one of the most common butterflies in the world and very common in Cincinnati,” says Morehouse.

“There is magic all around us and the lovely thing about science is that sometimes clues that might actually help with health issues like human infertility can come from a butterfly in your own backyard.”

Health24.com | How to communicate with your kids about nutrition

Most parents will agree that they just want their kids to eat healthy, nutritious foods.

Even if you manage to navigate the barrage of junk food advertising aimed at children, most kids are fussy eaters and it can be an exhausting exercise negotiating with them to eat their vegetables every night after a long day of work.

The good news is that you’re not alone. And the earlier you start implementing healthy eating habits, the less of a battle you should have on your hands when they’re older.

Here are some tips for parents on how to lay the foundations for basic healthy eating and nutrition in young children:

Be the adult: You oversee what food is available to your child. If it’s not in the cupboard or the fridge, they can’t have it, so don’t buy it.

Instead stock up fruit, yoghurts, dried fruit, cheeses and wholegrain breads as snack options. 

Read food labels: The Nutrition Facts label on packaged foods lists everything you need to know about that product, from the calories, to the fat, protein and carbohydrate content. Aim for products with the lowest number of ingredients and as little sugar as possible.

Vary your offerings: especially in the case of young children and toddlers who are notoriously fussy eaters. Don’t give up; keep presenting a variety of healthy foods. Children are generally reluctant to try new foods and textures, but keep presenting these, giving them the choice.

Don’t use food as a reward: As difficult as it is, using treats or junk food as a reward or a comfort when they’re in pain will subconsciously make the child place more value on these foods.

Eat together: Eating together as a family at a table and not in-front of the TV allows the children to see what everyone else eats and is encouraged to eat the same.

This article is provided through a sponsorship from Pfizer in the interests of continuous medical education. Notwithstanding Pfizer’s sponsorship of this publication, neither Pfizer nor its subsidiary or affiliated companies shall be liable for any damages, claims, liabilities, costs or obligations arising from the misuse of the information provided in this publication. Readers are advised to consult their health care practitioner for specific information on personal health matters as this is not the intention or purpose of the publication. Specific medical advice or recommendations on the clinical management of patients will not be provided by Pfizer. In this regard Pfizer does not support the use of products for off label indications, nor dosing which falls outside the approved label recommendations and readers must refer to the Package Insert of any product for full prescribing guidelines.

Health24.com | When is it safe to take opioids?

Codeine – an opioid medication used for the relief of mild to moderate pain – is said to be the most abused over-the-counter drug in South Africa, according to a Health24 article.

Many people in pain are apprehensive about taking an opioid painkiller to ease their suffering, and rightfully so.

Widespread use of opioids for pain has led to an epidemic of addiction in the United States. Forty lives are lost to prescription drug overdose every day, according to the US Centers for Disease Control and Prevention (CDC).

Opioids not bad all the time

But an opioid painkiller, such as oxycodone (Oxycontin, Percocet) or hydrocodone (Vicoprofen) can sometimes be the best option for treating pain in the short term, particularly right after surgery or during a severe pain flare-up, pain experts say.

In those instances, patients and doctors need to work together to make sure a patient’s pain is treated while managing their risk of addiction and overdose.

“You have to individualise care,” said Dr Edward Michna, an anaesthesiologist and pain specialist at Brigham and Women’s Hospital in Boston. “Obviously you’re not going to torture people when the severity of their pain is such that they should be treated with an opioid. The question is, should that be maintained for a long-term period? That can be debated.”

Prescription guidelines

The CDC has recommended a three-day limit on prescription painkillers for patients, said Dr Anita Gupta, an anaesthesiologist and pain specialist who serves as the American Society of Anaesthesiologists’ co-chair on prescription and opioid abuse.

“The reason why they chose three days is because dependency begins within three days,” Gupta said. “There are clear signs of that. If you put people on opioids beyond three days, you are putting them at risk for dependency.”

There are exceptions to that rule, according to the CDC. People with active cancer or those who need palliative care at the end of their lives should not worry about using opioids to ease pain.

Questions to ask

In general, all other patients should ask themselves and their doctor some tough questions if they’ve been prescribed an opioid, says the American Society of Anesthesiologists (ASA):

  • Why was I prescribed opioids? Did the doctor assume opioids are the strongest and most effective pain relief for my pain, without considering other options?
  • How long should I take prescription painkillers? If you continue to have pain after a few days on an opioid, you should ask your doctor about alternatives.
  • Are opioids affecting my quality of life? Using prescription opioids can affect a person in many different ways, including mental fogginess, severe constipation, nausea or depression.

The CDC and ASA recommend trying other pain management techniques to treat chronic pain before resorting to opioids. These options include over-the-counter medications such as acetaminophen (Tylenol) or ibuprofen (Advil, Motrin), physical therapy, injections with local anaesthetics, electrical stimulation, acupuncture and meditation.

Consider all options

Doctors should consider opioids only if the benefits regarding pain relief and daily ability to function outweigh the risks of addiction and overdose, the CDC says.

Even then, the lowest possible dosage should be used for the shortest period possible, and doctors should closely monitor patients for signs of addiction, the agency advised.

The problem is that opioids become less effective over time, as patients build up tolerance, Michna said.

“The data, particularly for low back pain, seems to show the longer you’re on it the less effective it is, and the more of the drug you need to get an effect,” Michna said. “When they’ve studied it, it appears that people on the opioids aren’t any better off than those who aren’t, in terms of functionality and their overall pain levels.”

Warning signs

Michna said red flags for opioid addiction include:

  • Taking painkillers more often or at larger doses than prescribed.
  • Getting less pain relief when you take the dosage prescribed to you.
  • Taking the drugs for something other than pain relief, for example, to ease anxiety.
  • Hearing from people around you that you regularly seem sedated, sleepy, uneasy, troubled or unable to function.

Good to know

People taking opioids should remain in regular contact with their doctor, Gupta said. They also should ask for a prescription for naloxone (Evzio), a drug that can reverse an overdose if injected quickly enough.

An opioid overdose can happen even if people are taking their recommended dose, Gupta said. Kidney disease, another illness or an interaction with another drug can bring on an overdose.

“It doesn’t always happen because you take too much of the drug,” Gupta said. “Everyone’s different. Everybody’s condition is different. That’s why you need a doctor you trust by your side, as someone you can call upon.”

Read more:

The reason why opioids are so addictive

Opioid Dependence – is something we should all know about

Backache patients with depression get more opioids