PARP and DDR Pathways: Targeting the DNA Damage Response for Cancer Treatment

Our cells, and the DNA they contain, are under constant attack from external factors such as ionizing radiation, ultraviolet light and environmental toxins. Internal cellular processes can also generate metabolites, such as reactive oxygen species, that damage DNA. In most cases, DNA damage results in permanent changes to DNA molecules, including DNA mismatches, single-strand breaks (SSBs), double-strand breaks (DSBs), crosslinking, or chemical alteration of bases or sugars. If left unchecked, DNA damage can cause genome instability, mutations and aberrant transcription, and oncogenic transformation.

PARP DDR pathway for drug discovery

Fortunately, our cells have also evolved multiple pathways to repair damaged DNA, collectively known as the DNA damage response (DDR). The type of repair mechanism depends on the nature of the damage, and whether the damage occurs in mitochondrial or nuclear DNA. These mechanisms have been reviewed extensively (1,2). Recently, considerable attention has focused on pathways for repairing SSBs and DSBs, mediated by the ADP-ribosylating enzyme known as poly (ADP-ribose) polymerase 1, or PARP-1.

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Confronting an Emerging Pathogen: Candida auris

Candida auris illustration
Candida auris is a fungal infection sweeping through healthcare sites across the U.S.

HBO’s The Last of Us has successfully brought fungal pathogens to the forefront of the pandemic discourse, raising questions as to whether a fungus could really pose a significant threat to humans. While scientists agree that the fungus featured in the show, cordyceps, won’t be making the required inter-species jump any time soon, there is a fungal pathogen that has been taking root in hospitals across the U.S. which gives some cause for concern: Candida auris.

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Three Reasons You Should Test Your CRC Patients’ MSI Status

Oncologists, do you know your colorectal cancer patients’ MSI status?

High-frequency microsatellite instability (MSI-H) in tumors is a form of genomic instability where mismatch repair (MMR) proteins fail to properly correct errors in microsatellite regions of the genome. When a patient’s tumor tissue is determined to have MSI-H markers, it’s strongly recommended that they be further tested for Lynch syndrome, a hereditary condition that puts them and their family at a higher risk of developing colorectal and other cancers (1).

Though as many as 1 in 279 people might be carriers for the mutations associated with Lynch syndrome (2), 95% of them don’t know it (3). Furthermore, people with Lynch syndrome have an approximately 80% increased lifetime risk of developing colorectal cancer, compared to a risk of only ~4% for the general population (4, 5).  

On Lynch Syndrome Awareness Day, here are three key reasons why you should test all your colorectal cancer patients’ MSI status.

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T Cells Newly Discovered Role in Alzheimer’s and Related Diseases Could Offer Another Therapeutic Approach

Alzheimer’s disease is a devastating, progressive degenerative brain condition that starts with mild   dementia symptoms like memory issues and gradually worsens to the point where you can no longer communicate or care for yourself. For anyone with personal experience with it, Alzheimer’s looms like a specter over the natural process of aging.

In the beginning phase of Alzheimer’s, abnormal plaques of the protein, amyloid-β, develop. These protein clumps can accumulate for decades with no detectable impact on cognitive ability or brain health. Eventually, a second protein, tau, begins to gather and form intercellular, fibrous, tangles. It is with the formation of these tau tangles that symptoms first appear. The combined presence of these extracellular plaques and intercellular tangles are the hallmarks of Alzheimer’s disease.

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The Largest Maxprep Liquid Handler Installation Ever: Kigali Rwanda, 2022

“It was just a sea of Promega everywhere,” says Rebecca Roberts, a Promega Field Applications Scientist. “Floor to ceiling, piled up with Maxwell instruments, Maxprep Liquid Handlers, all the accessories and consumables…”

In her role on the Field Application Scientists team, Rebecca travels the United States installing the Maxprep Liquid Handler in customer labs and training scientists to operate the system and incorporate it into their workflow. This instrument automates the pre- and post-processing steps in a nucleic acid purification workflow. It’s a large and sophisticated instrument that takes up roughly four feet of lab bench space and weighs up to 220 pounds. It is intended for research use only, but during the COVID-19 pandemic, the Maxprep Liquid Handler, Maxwell RSC 48 Instrument, and several Maxwell purification kits were recommended for nucleic acid extraction protocols in the CDC 2019-Novel Coronavirus Real-Time RT-PCR Diagnostic Panel Emergency Use Authorization (EUA).  

When an instrument is sold, Rebecca and a Service Engineer spend three days on-site installing it and training a small group of staff to use it. One Maxprep instrument at a time is typical. On rare occasions, Rebecca might install two on a single trip. However, in 2022, Rebecca joined a multinational team of Promega scientists and engineers in Kigali, Rwanda for an order that was anything but typical.

Promega field applications scientists install a Maxprep Liquid Handler in a small room that already holds two more liquid handlers.
Field Application Scientists Rebecca Roberts, Ben Cooley and Lucy Swithenbank install a Maxprep Liquid Handler in Kigali, Rwanda

“We knew a large order from this customer was a possibility,” Rebecca says, “But I certainly wasn’t expecting an order of ten.”

This was the largest installation of Maxprep instruments Promega has ever seen from a single order. The customer also had a hard deadline that required delivery, installation and training to be complete in only six weeks – half the time usually quoted for a single instrument.

In the end, ten Maxprep instruments were installed at the National Reference Laboratory in Kigali, and more than twenty people were trained to use the systems for RNA extraction to support COVID-19 testing at a major international meeting. The order was a success, but that six week journey was a wild ride that depended on the hard work and dedication of Promega teams on both sides of the Atlantic.

And the impact of this work is still growing.

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3.14 Ways to Make Pi Day a Piece of Cake!

Celebrated each year on March 14th (3.14), Pi Day commemorates the irrational, transcendent, and never-ending ratio that’s used to represent a mathematical constant. This infinite number is crucial when describing circles because no matter how big or small, the ratio of a circle’s circumference to its diameter will always equal to pi.

In 2009, pi day, also written π or 3.14, was declared an official national holiday–one that’s worth celebrating! We’ll help you kick things off with 3 fun facts, 1 joke, and 4 activities that are certain to get you in the Pi Day spirit.

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Shifting Gears: Repurposing Instruments for Changing Needs

Sarah Teter operates the Tecan Freedom EVO 150 liquid handler
Sarah Teter operates the Tecan Freedom EVO 150

The thought of an expensive instrument falling out of use and gathering dust on the shelf is enough to bring a tear to any lab manager’s eye. An instrument that once served a key purpose and now functions only as a “paperweight” is a tragic waste of valuable resources. Fortunately, it is sometimes possible to breathe new life into neglected tools and to retrofit or repurpose equipment to meet the new needs that will inevitably arise in a changing lab environment.  

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New Vaccine for Honeybees Could Take the Sting Out of Devastating American Foulbrood Disease

Our world is a complex, interdependent system, and invertebrate pollinators such as honeybees play a pivotal role in its survival. Threats to populations numbers of pollinators like honeybees can be equated to threats to the overall health and survival of the ecosystem in which they live. Of the over 20,000 known bee species, one—the western honeybee (Apis mellifera)—acts as the single most frequent pollinator for crops worldwide (1). Found on every continent except Antarctica, the western honeybee owes its status as a top pollinator to its widespread geographic distribution, generalist foraging behavior and competence as pollinators (1).

Deadly American Foulbrood Disease

Honeybees are the most economically valuable pollinators and are threatened by several pathogens (2). Perhaps the biggest threat to honeybee colony health and survival is the bacterial disease, American Foulbrood (AFB; (3). Caused by the spore-forming, Gram+ bacteria, Paenibacillus larvae, the highly contagious AFB disease affects the young brood of colonies.  When newly hatched larvae are fed spore-contaminated food, the spores germinate and replicate causing septicemia and death. P. larvae spores are incredibly resilient and can remain viable for decades (3). Each infected larva can produce over 1 billion new spores.  Thus, a colony can produce large numbers of spores with just a few cases of symptomatic brood (4).

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suPAR: A New Approach to Treating Cardiovascular Disease

Cardiovascular disease (CVD), continues to be the leading cause of death in the United States and worldwide. Many patients with CVD have signs of chronic kidney disease (CKD), and those with CKD are often times disproportionately affected by CVD.

This interconnectedness was further explored in a recent study published in the Journal of Clinical Investigation that identified a new immune target, suPAR, as a protein that causes kidney disease and atherosclerosis, the most common form of CVD. Unlike traditional approaches to treating CVD such as controlling blood pressure and lowering cholesterol, this breakthrough research offers a new approach to treatment from an entirely different perspective.

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The Purr-suit of Happiness: The Science Behind Feline Purring

As any cat person would tell you, one of the greatest joys in life is to be curled up with a feline friend as they purr. Though purring is one of the most widely recognizable and comforting sounds in the animal kingdom—a sound that has come to be virtually synonymous with coziness and contentment—the how and why behind it is still shrouded with some mystery.

Vocal Purr-duction

The scientific community defines purring as a “low-pitched regular sound produced during alternating (pulmonic) egressive and ingressive airstream”. This is a fancy way of saying that sound is continuously produced during both exhales and inhales with no interruptions in between, while keeping their mouths entirely closed. Like fuzzy little ventriloquists.

But how does purring actually work? In the 1960s, it was initially hypothesized that purring was the resulting sound of blood percolating through the inferior vena cava, the blood vessel that returns blood from the body to the heart. However, further research later disproved that theory, indicating that the purring mechanism involves communication between a neural oscillator deep in the feline brain and the larynx, or voice box. As a cat’s laryngeal muscles move, they constrict and dilate the glottis, the part of the larynx surrounding the vocal chords. During inhalation and exhalation, the air passing through the glottis vibrates, resulting in a purr.

Fun Fact: Purring isn’t limited to just domestic house cats! Several wild feline species like bobcats and mountain lions, plus their close relatives mongooses, genets and civets can all purr. But there are a number of other animals that can produce a purr that might surprise you, including rabbits, raccoons, bats, guinea pigs, gorillas and elephants!

Good Vibrations?

Though there is general consensus in the scientific community on the purring process, the question of exactly why cats purr is still up for debate, as studies regarding cat behavior and communication considerably lags behind the efforts for studying dogs. This may be partially due to the fact that dogs are typically more willing study participants (in that they are likely more easily bribed).

Though we most commonly consider a purring cat to be a contented cat, that is not always the case. It turns out that there are actually a number of other emotions and situations that will elicit purring as a response.

Cats first begin to purr when they are only a few days old. As newborn kittens are blind, deaf and overall completely helpless for the first few weeks of their lives, purring serves as a quiet, subtle form of communication and bonding mechanism between mother and offspring. Purring can help kittens communicate their location, and provides a means for mom to affirm her babies’ comfort and safety, as well as signal feeding times.

This behavior sometimes carries over into adulthood, with some cats continuing to purr while they eat or as a means to convince their human that it’s dinner time. A University of Sussex study found that cats even have a solicitous purr that they can employ for exactly this purpose. By embedding a cry similar in frequency to that of a human infant’s cry within a purr, cats can manipulate their owners into taking action and feeding them by triggering and exploiting their innate human nurturing instincts. Even the study participants with no cat experience could hear the difference in urgency between an ordinary and an “I’m hungry” purr.

Purring has also been hypothesized to be a sort of self-soothing mechanism, as cats have been observed to purr in response to nervousness, fear or stressful events, like a trip to the vet, being chased by a dog, or exploring a new environment. Cats have also been observed to purr when they are in pain and dying, leading researchers to postulate about purring’s potential healing properties—for cats and perhaps for humans as well.

Feline Fine

In the early 2000s, researchers dug further into this notion, proposing that purring may have palliative properties that may assist in accelerating the healing process for a cat’s wounds or broken bones.

Given that healers have employed the power of sound and vibrations in their work for centuries, the basis for this notion is not far-fetched. Various studies regarding sound frequencies have demonstrated promising vibratory therapy results in some animals, such as rabbits. Even NASA has explored this therapeutic avenue as a potential means to combat bone density loss and muscle atrophy in astronauts headed to space for long stints.

A 2001 study that recorded and measured the purrs of 44 felids including ocelots, servals, cheetahs, pumas and domestic cats, found that every individual in this study produced strong frequencies between 25 and 150 Hertz (Hz). They discovered that all the species except cheetahs produced frequencies at exactly 25 Hz and 50 Hz, which research suggests are the best frequencies to promote fracture healing and bone growth. Additionally, those same four felids have a strong harmonic either at or within 2 Hz of 100 Hz, a frequency that has been therapeutically used to treat wounds, dyspnea, edema and pain. These findings support the hypothesis that purring may be an advantageous, low energy mechanism that can stimulate feline muscles and bones while sedentary.

Purring releases endorphins in cats and can do the same in people. Endorphins can lower stress hormones, which is beneficial for healing, lowering blood pressure and overall stress, and helping people cope with illness.

Further studies have shown cat ownership in general has demonstrated some physical health benefits. In 2009, a 20 year study of over 4,000 people found that cat owners appeared much less likely to die of a heart attack or stroke, as opposed to people who have never known the love of a cat, with non-cat owners being 40% more likely to die of a heart attack and 30% more likely to die of another cardiovascular disease including strokes than cat owners. Another study by Australia’s Baker Medical Research Institute found that pet owners tend to have lower blood pressure than people who don’t have pets.

Though no research efforts have further explored the direct effects of using purring felines themselves as a mechanism for healing, the overall health effects cat ownership has on people is undeniable. And though the exact purpose and potential physical benefits still elude researchers, purring undoubtedly offers both a soothing psychological balm and gentle medium of communication between a cat and their people.