MODIFIED VITAMIN D SHOW PROMISE AS TREATMENT FOR PANCREATIC CANCER

A synthetic derivative of vitamin D was found by Salk Institute researchers to collapse the barrier of cells shielding pancreatic tumors, making this seemingly impenetrable cancer much more susceptible to therapeutic drugs.

The discovery has led to human trials for pancreatic cancer, even in advance of its publication today in the journal Cell. By attacking a wound repair mechanism called fibrosis, the findings may also have implications for other tough-to-treat tumors, such as lung, kidney and liver cancer.

"While the success of this drug in humans with pancreatic cancer is still unclear, the findings in animal studies were strong, raising hope that ongoing clinical trials will give people with this terrible disease hope for a truly new type of therapy," says Ronald Evans, director of Salk's Gene Expression Laboratory and senior author of the new paper.

Pancreatic cancer is one of the deadliest forms of cancer, a fact highlighted in recent years by the deaths of well-known figures such as Steve Jobs and Patrick Swayze. About 46,000 people are diagnosed in the United States each year and about 40,000 people die from the disease, according to the National Institutes of Health.

"For pancreatic cancer, the five-year survival rate is the lowest of all cancers," says Evans, holder of Salk's March of Dimes Chair and a Howard Hughes Medical Institute investigator. "Part of the problem is that the science of pancreatic cancer and its renowned resistance to therapy has not been understood and that's why the work that we're doing is so important."

Evans and his colleagues knew that the ability of the pancreatic tumor to communicate with nearby cells -- called the tumor microenvironment -- is key to its growth. Tumor cells send out signals that make the microenvironment inflamed and dense; this "living shield" around a tumor not only helps the cancer grow, but blocks the access of immune cells and chemotherapeutic drugs, making the cancer particularly hard to treat.

Evans -- in collaboration with researchers around the country involved in an interdisciplinary initiative supported by Stand Up to Cancer -- wanted to figure out how to restore this inflamed microenvironment to its normal or "quiescent" state and weaken the wall around the tumor.

"There was evidence that the activation of the microenvironment was theoretically reversible, but nobody knew exactly what was responsible for the activation, making it hard to turn off," says Salk postdoctoral research fellow Mara Sherman, first author of the new paper.

Sherman, Evans and their collaborators focused their attention on one component of this wall: pancreatic stellate cells, which usually respond to small injuries by briefly switching to an activated state, spurring new cell growth. In the case of cancer, however, the stellate cells near a tumor -- in response to signals from the tumor -- are constantly turned on. This chronic activation of the stellate cells provides the tumor cells with extra growth factors and therefore helps them proliferate, but also forms a wall-like barrier around the tumor that protects it from chemotherapeutics and other cancer-fighting drugs.

In 2013, Evans' group discovered that stellate cells in the liver could be inactivated by a chemically modified form of vitamin D. They wondered whether the same could hold true in the pancreas, despite the fact the vitamin D receptor was not thought to be present in pancreatic tissue.

But indeed, when the group of researchers examined the differences between activated and inactivated stellate cells in the pancreas, they found that activated stellate cells near a tumor had high levels of the vitamin D receptor. And when the researchers then added modified vitamin D to activated stellate cells the cells quickly reverted back to a healthy, inactivated state, stopping production of signals that spur growth and inflammation.

"This was a big surprise because vitamin D has been tried multiple times as a therapy for pancreatic cancer and never worked," says Evans.

It turns out that activated stellate cells rapidly break down normal vitamin D, preventing the vitamin from binding to the receptor, Evans explains. But systematic analysis of vitamin D analogues allowed the team to discover a modified form of vitamin D that is more stable, resilient and effective in vitro.

To see whether this new vitamin D-like compound could halt the growth of a tumor, Evans and the team next studied its effectiveness in mice. The researchers found that combining the drug with existing chemotherapeutics gave a 50 percent increase in lifespan compared to chemotherapy alone.

"It's really remarkable considering that vitamin D itself is not attacking the cancer cells," says Michael Downes, a senior staff scientist at Salk and co-corresponding author of the new work. "It's changing the environment to a more favorable setting needed for the chemotherapy drugs to work."

Studies have shown that people deficient in vitamin D are more likely to develop pancreatic cancer. Based on the new results, Evans thinks that healthy levels of vitamin D may help keep vitamin D receptor signaling in stellate cells normal and squash a cancer's growth -- at least until a tumor itself forces the stellate cells to "turn on."

"Recently, other research groups have explored the idea of destroying the microenvironment altogether to weaken a tumor," says Downes. "Our approach is very different. Instead of destroying, we simply want to reprogram the tumor microenvironment to a healthy state. This has the dual effects of delivering more drugs to the tumor as well as replenishing the tissue with normal stellate cells."

Evans group has already teamed up with clinicians at the University of Pennsylvania to launch a clinical trial testing the effectiveness of using their vitamin D-like drug in cancer patients before pancreatic surgery. "Previous trials with vitamin D failed because they didn't understand the need for a special form of vitamin D and that for pancreatic cancer it must be used in combination with chemotoxic drugs," Evans says. "So, by re-thinking the problem, have been able to open up a new route to the treatment of pancreatic cancer and, looking forward, hopefully other diseases as well."

RESTROOMS NOT AS UNHEALTHY AS YOU MIGHT THINK

Microbial succession in a sterilized restroom begins with bacteria from the gut and the vagina, and is followed shortly by microbes from the skin. Restrooms are dominated by a stable community structure of skin and outdoor associated bacteria, with few pathogenic bacteria making them similar to other built environments such as your home.

The research is published ahead of print in Applied and Environmental Microbiology.

In the study, the investigators characterized the structure, function, and abundance of the microbial community, on floors, toilet seats, and soap dispensers, following decontamination of each surface. They analyzed the surfaces hourly at first, and then daily, for up to eight weeks. "We hypothesized that while enteric bacteria would be dispersed rapidly due to toilet flushing, they would not survive long, as most are not good competitors in cold, dry, oxygen-rich environments," says corresponding author Jack A. Gilbert of San Diego State University. "As such, we expected the skin microbes to take over--which is exactly what we found."

"Reproduceable successional ecology is remarkable," says Gilbert, who has conducted similar studies of the home, and the hospital. "Most systems have the potential to have multiple outcomes. The restroom surfaces, though, were remarkably stable, always ending up at the same endpoint."

Indeed, the communities associated with each surface became more similar in species and abundance within five hours following initial sterilization, and the resulting late-successional surface community structure remained stable for the remainder of the 8 weeks' sampling. Floor communities showed a rapid reduction in abundance of Firmicutes and Bacteroidetes, while the relative abundance of Proteobacteria, Cyanobacteria, and Actinobacteria declined over the course of a day. Cyanobacteria are likely derived from dietary plant biomass or from plant material tracked in from outdoors.

Toilet seat samples, alone, clustered according to restroom gender, with Lactobacillus and Anaerococcus--vaginal flora--dominating ladies' room toilet seats, while the gut-associated Roseburia and Blautia, were more copious on toilet seats in men's rooms.

Ultimately, skin and outdoor-associated taxa comprised 68-98 percent of cultured communities, with fecal taxa representing just 0-15 percent of these. And out-door-associated taxa predominated in restrooms prior to sterilization, as well as in long-term post-sterilization communities, suggesting that over the long term, human-associated bacteria need to be dispersed in restrooms in order to be maintained there.

Overall, the research suggests that the restroom is no more healthy or unhealthy than your home, says Gilbert."A key criterion of of healthy or unhealthy might be the presence or relative abundance of pathogens. While we found cassettes associated with methicillin-resistant Staphylococcus aureus (MRSA) the predominant Staph organisms didn't harbor those genes, so MRSA may be there but it is very rare." Restrooms, he says, are not necessarily unhealthy, but classifying them as healthy would not necessarily be accurate.

The research, he says, is very important for understanding the environmental ecology of the built environment, and will likely help in building restrooms and buildings generally that are healthier for humans.

ARE YOU AS OLD AS WHAT YOU EAT

Researchers from UCL (University College London) have demonstrated how an interplay between nutrition, metabolism and immunity is involved in the process of aging

The two new studies, supported by the Biotechnology and Biological Sciences Research Council (BBSRC), could help to enhance our immunity to disease through dietary intervention and help make existing immune system therapies more effective.

As we age our immune systems decline. Older people suffer from increased incidence and severity of both infections and cancer. In addition, vaccination becomes less efficient with age.

In previous BBSRC funded work, Professor Arne Akbar's group at UCL showed that aging in immune system cells known as 'T lymphocytes' was controlled by a molecule called 'p38 MAPK' that acts as a brake to prevent certain cellular functions.

They found that this braking action could be reversed by using a p38 MAPK inhibitor, suggesting the possibility of rejuvenating old T cells using drug treatment.

In a new study published in Nature Immunology the group shows that p38 MAPK is activated by low nutrient levels, coupled with signals associated with age, or senescence, within the cell.

It has been suspected for a long time that nutrition, metabolism and immunity are linked and this paper provides a prototype mechanism of how nutrient and senescence signals converge to regulate the function of T lymphocytes.

The study also suggests that the function of old T lymphocytes could be reconstituted by blocking one of several molecules involved in the process. The research was conducted at UCL alongside colleagues from Complejo Hospitalario de Navarra, Pamplona, Spain.

The second paper, published in The Journal of Clinical Investigation, showed that blocking p38 MAPK boosted the fitness of cells that had shown signs of aging; improving the function of mitochondria (the cellular batteries) and enhancing their ability to divide.

Extra energy for the cell to divide was generated by the recycling of intracellular molecules, a process known as autophagy. This highlights the existence of a common signaling pathway in old/senescent T lymphocytes that controls their immune function as well as metabolism, further underscoring the intimate association between aging and metabolism of T lymphocytes.

This study was conducted by researchers from UCL, Cancer Research UK, University of Oxford and University of Tor Vergata, Rome, Italy.

Professor Arne Akbar said: "Our life expectancy at birth is now twice as long as it was 150 years ago and our lifespans are on the increase. Healthcare costs associated with aging are immense and there will be an increasing number of older people in our population who will have a lower quality of life due in part to immune decline. It is therefore essential to understand reasons why immunity decreases and whether it is possible to counteract some of these changes.

"An important question is whether this knowledge can be used to enhance immunity during aging. Many drug companies have already developed p38 inhibitors in attempts to treat inflammatory diseases. One new possibility for their use is that these compounds could be used to enhance immunity in older subjects. Another possibility is that dietary instead of drug intervention could be used to enhance immunity since metabolism and senescence are two sides of the same coin."

Nerve Damage As A Result Of Cancer Treatment

Today's post from cancernetwork.com (see link below) discusses the neurological consequences of cancer treatment, especially neuropathy, which seems to be occurring more and more frequently according to which chemotherapy drugs are administered. Unfortunately, whatever other medical complications we may have, we're all at risk of cancer of one form or another, therefore neuropathy is showing up more and more as a co-morbidity problem in that area. That said, once it is established that you have nerve damage, the treatment progression is pretty much the same whatever the cause of the nerve problems. This is why neuropathy patients are such a diverse group - there are over 100 causes and over 100 forms but in the end we all face the same treatment regimes, which won't cure the nerve damage but may keep the symptoms under control.
 

Managing Treatment-Related Neurotoxicity
By Michelle Bragazzi, BS, RN May 01, 2015 | ONS 2015
 
Understanding treatment-induced neurotoxicity can be difficult when treating patients with central nervous system (CNS) malignancies. This was a topic of discussion at the Oncology Nursing Society (ONS) 40th Annual Congress, held April 23-26, in Orlando, Florida.

Using a case-based approach, clinical nurse specialist’s Mary Elizabeth Davis, RN, MSN, AOCNS, and Wayne Quashie, MSN, RN, ACNS-BC, AOCNS, both from the Memorial Sloan Kettering Cancer Center in New York, explained how nurses can effectively manage the signs and symptoms of CNS toxicity and disease.

Surgery, radiation, and/or chemotherapy may cause acute or delayed CNS issues such as necrosis, encephalopathy, intracranial hemorrhage, and myelopathy. Neuropathy—a common symptom associated with chemotherapy—would be considered a peripheral nervous system (PNS) disorder. While all require intervention, treatment options may vary, depending on the extent of the toxicity.

How do you distinguish between toxicity and disease symptomology?

It can be tricky to distinguish tumor recurrence from neurotoxicity. Metabolic imaging and perfusion scans may help decipher between the two. Pathological analysis would be the best way to confirm this, but obtaining another biopsy in a patient with brain cancer can be risky.

Radiation necrosis of the cerebral hemispheres and spinal cord is related to the administration of radiation treatment—especially with higher doses. Patients generally present with cognitive dysfunction, personality changes, increased intracranial pressure (which may result in brain herniation), paresis, and other neurological deficits. While radiation necrosis can be difficult to manage, there are treatment options available:

• Corticosteroid therapy (standard of care)

• Surgery

• Hyperbaric oxygen therapy

• Bevacizumab

It’s important to keep in mind that while steroid use in patients with CNS tumors is the standard, patients can develop what’s commonly referred to as, “steroid psychosis.” Patients receiving high doses of steroids, those with a psychiatric history, blood-brain barrier damage, and cytochrome P450 inhibition are at risk.

Another toxicity to consider is chemotherapy- and radiation-induced neuropathy. Many patients experience peripheral neuropathy from drugs such as bortezomib, vinca alkaloids, taxanes, and platinum-based therapies. Patients typically complain of a numbness and tingling sensation in the extremities, specifically in the fingers, toes, and feet. Autonomic neuropathy can also occur and causes symptoms such as constipation, erectile dysfunction, bladder retention, and orthostatic hypotension.

Radiation patients may experience neuropathic side effects as well. For patients receiving radiation, specifically to the sacral plexus (colorectal cancer, gynecological cancers) or to the brachial plexus (upper airway cancers), are at risk for developing radiating neuropathic pain.

Currently, there are no established agents available to prevent neuropathic toxicity, but there are pharmacological and non-pharmacological treatment options available:

• Duloxetine

• Anticonvulsant drugs (gabapentin, pregabalin)

• Tricyclic antidepressant drugs (nortriptyline, amitriptyline)

• Compounded topical gel containing baclofen, amitriptyline, HCL, and ketamine)

• Refer patients to occupational medicine

• Cognitive and behavioral modifications such as guided imagery for pain control

• Educate patients on safety measures in the home such as water temperature, clutter, and wearing shoes

Lastly, another neurotoxic adverse event that’s referred to as, “chemo brain/chemo fog,” is a form of cognitive dysfunction that healthcare practitioners generally relate to cancer treatment. These patients have difficulty resuming their precancer lifestyle, and it can significantly impact their quality of life. Fatigue, the inability to concentrate and learn new skills, and memory loss are the typical symptoms. Pre-existing conditions and direct neurotoxic effects are associated with chemo brain.

Research studies suggest that cancer patients with undiagnosed, pretreatment cognitive impairment via imaging studies (white and gray matter abnormalities) are at a higher risk of developing chemo brain—especially those receiving high-dose chemotherapy. Pre-existing conditions (existing comorbidities, cognitive dysfunction) are some of the indirect factors contributing to chemo brain. The direct effects from treatment, such as chemical toxicity, inflammatory factors, vascular injury, blood clots, and defects in neural repair, are other possible etiologies.

Nurses need to be diligent about screening cancer patients for chemo brain. Imaging studies and neuropsychological testing should be performed at all patient visits. There are treatment options to also consider for these patients:

• Investigate confounding factors (medications, nutrition, sleep disorders)

• Consider neuropsychiatric evaluation

• Consult occupational therapy

• Administer psychostimulant drugs if necessary (last line of therapy if other interventions have failed)

• Encourage physical activity, but rest periods as well

• Urge patients to limit alcohol or other substances that may alter cognition

• Encourage patients to use memory aids (planners, to-do lists, etc)

Oncology nurses are in a great position to help identify signs and symptoms of neurotoxicity early on. Immediate intervention will maximize the patient’s quality of life, and possibly reduce the need for excessive drug administration.

http://www.cancernetwork.com/ons-2015/managing-treatment-related-neurotoxicity

MAKING SURE ANTIBIOTICS AS THEY SHOULD

Researchers at ETH Zurich are decoding the structure of the large ribosomal subunit of the mitochondria at an atomic level, thereby providing insight into the molecular architecture of this ribosome with implications for a better understanding of the mode of action of antibiotics.

A team of ETH Zurich researchers led by professors Nenad Ban and Ruedi Aebersold have studied the highly complex molecular structure of mitoribosomes, which are the ribosomes of mitochondria. Ribosomes are found in the cells of all living organisms. However, higher organisms (eukaryotes), which include fungi, plants, animals and humans, contain much more complex ribosomes than bacteria. In eukaryotes, ribosomes can also be divided into two types: those in the cytosol -- which comprises the majority of the cell -- and those found in the mitochondria or "power plants" of cells. Mitochondria are only found in eukaryotes.

Ribosomes serve as translation devices for the genetic code and produce proteins based on the information stored in DNA. Every ribosome consists of two subunits. The smaller subunit uses transfer ribonucleic acids (transfer RNA or tRNA) to decode the genetic code it receives in the form of messenger RNA, while the larger subunit joins the amino acids delivered by the transfer RNA together like a string of pearls.

Even higher resolution, even more details

Mitochondrial ribosomes are especially difficult to study because they are found only in small amounts and are difficult to isolate. At the beginning of the year, ETH researchers had shed light on the molecular structure of the large subunit of the mitoribosome in mammalian cells to a resolution of 4.9 Å (less than 0.5 nm). However, this resolution was not adequate to reliably build a complete atomic model of this previously unknown structure. The team lead by ETH Professor Nenad Ban has now succeeded in this task and was able to map the entire structure at a resolution of 3.4 Å (0.34 nm). The researchers recently published their findings in the scientific journal Nature.

The scientists used high-resolution cryo-electron microscopy at the Electron Microscopy Center of ETH Zurich (ScopeM) and state-of-the-art mass spectrometry methods in their experiments. Thanks to recent technical advances in cryo-electron microscopy and the development of direct electron detection cameras that can correct for specimen motion during the exposure, it only recently became possible to capture images of biomolecules at a resolution of less than four angstroms.

Improving the effect of antibiotics

In particular, the new images show the details of the peptidyl transferase centre (PTC), which is where the amino acid building blocks are combined. The proteins synthesised in this way then pass through a tunnel, where they finally exit the large subunit of the ribosome.

"This process is medically relevant," said Basil Greber, lead author of the study and postdoctoral researcher in Nenad Ban's group. The reason is that this tunnel is a target for certain antibiotics. The antibiotic becomes lodged in the tunnel and prevents the proteins that have just been synthesized from leaving the tunnel. However, antibiotics should only inhibit protein synthesis in the ribosomes of bacteria.

"For an antibiotic to be used in humans, it must not attack human ribosomes," explains Greber. Antibiotics must inhibit protein synthesis only in bacterial ribosomes. The problem is that mitochondrial ribosomes resemble those of bacteria, which is why certain antibiotics also interfere with mitoribosomes. "This can lead to serious side effects." The ETH researchers' findings will make it possible in the future to design antibiotics that inhibit only bacterial and not mitochondrial ribosomes. This is one basic requirement for using them in clinical applications.

A surprising discovery

The ETH researchers also made an unexpected discovery. They found that mitoribosomes use transfer RNA in two fundamentally different ways. Firstly, the tRNA is used to select the right amino acid for peptide synthesis in the PTC. Secondly, one tRNA is a fixed part of the structure, unlike in all other ribosomes. Although it has been known for quite some time that mitochondrial ribosomes integrated new proteins into their structure over the course of their development, this is the first time that the use of an entirely new RNA molecule was observed. "This demonstrates the great evolutionary plasticity of mitoribosomes," underscored Greber.

The ETH team is now faced with a major, still unresolved task in its research: determining the structure of the smaller subunit of the mitochondrial ribosome. The fact that it is more flexible than the large subunit renders this undertaking an even greater challenge.