Nanoparticles used to enhance chemotherapy


University of Georgia researchers have developed a new formulation of cisplatin, a common chemotherapydrug, that significantly increases the drug’s ability to target and destroy cancerous cells.

Cisplatin may be used to treat a variety of cancers, but it is most commonly prescribed for cancer of the bladder, ovaries, cervix, testicles and lung. It is an effective drug, but many cancerous cells develop resistance to the treatment.

Shanta Dhar, assistant professor of chemistry in the UGA Franklin College of Arts and Sciences, and Rakesh Pathak, a postdoctoral researcher in Dhar’s lab, constructed a modified version of cisplatin called Platin-M, which is designed to overcome this resistance by attacking mitochondria within cancerous cells. They published their findings recently in the Proceedings of the National Academy of Sciences.

“You can think of mitochondria as a kind of powerhouse for the cell, generating the energy it needs to grow and reproduce,” said Dhar, a member of the UGA Cancer Center and principal investigator for the project. “This prodrug delivers cisplatin directly to the mitochondria in cancerous cells. Without that essential powerhouse, the cell cannot survive.”

Sean Marrache, a graduate student in Dhar’s lab, entrapped Platin-M in a specially designed nanoparticle 1,000 times finer than a human hair that seeks out the mitochondria and releases the drug. Once inside, Platin-M interferes with the mitochondria’s DNA, triggering cell death.

Dhar’s research team tested Platin-M on neuroblastoma – a cancer commonly diagnosed in children-that typically originates in the adrenal glands. In preliminary experiments using a cisplatin-resistant cell culture, Platin-M nanoparticles were 17 times more active than cisplatin alone.

“This technique could become a treatment for a number of cancers, but it may prove most useful for more aggressive forms of cancer that are resistant to current therapies,” said Pathak.

Both Dhar and Pathak caution that their experimental results are preliminary and they must do more work before Platin-M enters any clinical trials. However, their early results in mouse models are promising, and they are currently developing safety trials in larger animals.

“Cisplatin is a well-studied chemotherapy, so we hope our unique formulation will enhance its efficacy,” said Dhar, who is also a member of UGA’s Nanoscale Science and Engineering Center, Center for Drug Discovery, and Regenerative Bioscience Center. “We are excited about these early results, which look very promising.”

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“Big data” technique improves monitoring of kidney transplant patients


A new data analysis technique could radically improve monitoring of kidney transplant patients, according to new research published this week in PLOS Computational Biology.

The research, carried out by a team comprising physicists, chemist and clinicians at the University of Leeds, provides a method for making sense out of the huge number of clues about a kidney transplant patient’s prognosis contained in their blood.

By applying a sophisticated “big data” analysis to the samples, scientists were able to process hundreds of thousands of variables into a single parameter to indicate how a kidney transplant was faring. This allowed them to predict poor function of a kidney after only two days in cases that may not have been previously detected as failing until weeks after transplant.

These extra few days are vital in the early stages after transplant and would give doctors a better chance to intervene to save the transplant and improve patient recovery periods. In some cases, the team were able to predict failure from patients’ blood samples taken before the transplant operation.

Dr Sergei Krivov, in the University of Leeds’ Astbury Center, said: “If you put a blood sample through Nuclear Magnetic Resonance analysis you get data down to the molecular level. You can identify chemical fingerprints left behind by specific cellular processes and you get a very large number of different parameters in those samples that vary with the outcome for a patient.

“These are vital clues. But, if you have got thousands of variables all moving in different ways in a complex system, how does a doctor bring all that information together and decide what to do? It is not possible to do this with the human mind; there are just too many variables. We have to do it with computers and find a way to weigh those variables and produce an intelligible output describing where, overall, the patient is heading.”

The study, which analysed data from daily blood samples from 18 patients immediately before and in a week-long period after kidney transplants, showed that it was possible to pick out pieces of information that varied with the overall likelihood of a patient either rejecting a kidney or recovering kidney function.

Given enough data, the technique could even be used to quantify very complex and extended processes affecting the whole population.




Increased risk of rare, deadly condition faced by obese, older, Caucasian women on dialysis


Obese, Caucasian females over age 50 with diabetes and on dialysis because their kidneys have failed are among those at highest risk for the rare and deadly condition calciphylaxis, according to an analysis of the United States Renal Data System.

Calciphylaxis occurs when calcium and phosphorus bind to form a biological cement that blocks and inflames small blood vessels, putting patients at risk for major infection and skin ulcers as well as patches of dying skin, said Dr. Lu Huber, nephrologist at the Medical College of Georgia at Georgia Regents University.

“It’s all about balance, and our kidneys help regulate that balance,” said Huber, who scoured the national database of 2.1 million patients with failed kidneys to better define incidence and risk factors with the goal of better identifying and managing those at highest risk.

Her findings were cited as one of eight best abstracts submitted to the 51st European Renal Association – European Dialysis and Transplant Association Congress in Amsterdam.

Huber found the condition occurred in 459, or 0.02 percent, of the patients, who were mostly white, older women on traditional hemodialysis, where an external machine filters the total blood volume typically three times a week rather than the continuous efforts of healthy kidneys.

The median time from the first dialysis treatment to a diagnosis of calciphylaxis was less than four years, median survival time was 176 days, and 50 percent of deaths were within 87 days. Being over age 65, Caucasian, and diabetic are significant risk factors for death from calciphylaxis.

“We are not completely sure why calciphylaxis happens, but mostly it’s in dialysis patients,” Huber said. While dialysis is literally a lifesaver, it does not completely replace all the filtering work of the kidney, never mind other major functions, such as making the active form of vitamin D, Huber said. Vitamin D increases absorption of calcium, which is essential to strong bones and teeth as well as muscle function, including the heart.

Physicians give patients vitamin D while they are receiving dialysis to keep bone strong. Ironically, vitamin D also increases absorption of phosphorus, which, without functioning kidneys, begins to accumulate in the blood.

“In end-stage renal disease, we tend to see low calcium and high phosphorus,” Huber said. The dysregulation somehow prompts the two to bind in the blood and ‘basically make cement,” Huber said. The material deposits in small blood vessels, valves and soft tissue, contributing to the vascular complications of life on dialysis.

“When we do X-rays of patients, their small vessels actually light up because of the calcium/phosphorus deposition,” Huber said. With the calcium-phosphorus deposition, vessels quickly become stiff and narrowed, which leads to inadequate blood supply, contributing to tissue death, and paving the way for infection.

To try and balance things out, all dialysis patients take phosphorus binders before eating that grab excess phosphorus, found in high levels in animal protein and processed foods, so more will be eliminated from the gut and less absorbed into the blood. Dietitians help patients minimize phosphorus intake, and blood levels of phosphorus and calcium are regularly monitored, often as kidneys are failing and before dialysis has even begun.

However, physicians may need to be even more diligent and aggressive particularly in these high-risk populations, Huber said. This may include additional diet changes, taking more phosphorus binders, and more frequent dialysis. She notes that no prospective studies have measured the effectiveness of these current interventions.

A specific diagnostic code for calciphylaxis – currently, it shares one with multiple other conditions resulting from calcium-phosphorus abnormalities – could ease future studies of this relatively small population of patients, Huber said. This could include examining more detailed clinical information that is currently housed at countless dialysis centers across the country.

Diabetes and hypertension are major causes of kidney failure, although Huber notes that many kidney failure patients are not obese.

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Anxiety and depression linked to physical impairments in dialysis patients

May_Part 2_Nephrology_Urology

With the rate of chronic kidney disease on the rise among older Americans, researchers seeking to improve patients’ quality of life studied a group of adults undergoing hemodialysis and found their higher rates of depression andanxiety could be associated with their impaired physical exercise capability and reduced daily physical activity, according a new study published online by the Journal of Renal Nutrition.

The researchers studied 72 relatively healthy maintenance hemodialysis patients and compared them to 39 healthy adults who were not on dialysis. They found significantly higher rates of anxiety and depression among the dialysis patients, than among the adults who were not on dialysis. They also found the dialysis patients suffering from depression and anxiety had the greatest impairments in physical exercise performance and daily physical activity.

“Adults undergoing dialysis often have less daily physical activities than other adults, but little was known about what, if any, effect this reduced activity had on their mental state,” said Joel D. Kopple, MD, Los Angeles Biomedical Research Institute (LA BioMed) lead researcher. “Our study found an association between reduced daily physical activities and depression and anxiety. Also, the capacity to perform physical exercise was diminished in these patients. These findings provide a strong rationale for studying whether increased daily physical activity can reduce depression and anxiety among adults undergoing dialysis.”

Each person enrolled in the study took walks, climbed stairs and engaged in other physical activities so that researchers could determine their physical abilities. The researchers gauged their depression and anxiety using standardized tests and found 43% of the dialysis patients had anxiety and 33% suffered from depression. In comparison, only 2.5% of the adults who were not on dialysis had anxiety and only 5% of them suffered from depression.

Approximately one in 10 Americans has some form of chronic kidney disease, and the incidence of chronic kidney disease among people ages 65 and older more than doubled between 2000 and 2008, according to the Centers for Disease Control and Prevention.

Hemodialysis is a life-preserving treatment for hundreds of thousands of Americans with kidney failure. It is a medical procedure to remove fluid and waste products from the blood and to correct electrolyte imbalances. This is accomplished using a machine and a dialyzer, which is sometimes described as an “artificial kidney.”

“Research is important to improve the quality of life of patients undergoing dialysis,” said Dr. Kopple. “With the growing population of people undergoing dialysis, this research is growing in importance.”

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Unplanned Visits After Urinary Stone Treatment Defined

May_Part 1_Urology

Researchers have found that, overall, 1 in 7 patients who undergo a procedure to treat urinary stones make unplanned, high-acuity, follow-up visits, defined as presentation to an emergency department or a hospital admission within 30 days of the procedure.

Charles D. Scales, MD, of Duke University in Durham, N.C., and colleagues identified 93,523 initial procedures to fragment or remove urinary stones.

Unplanned visits occur less frequently after shockwave lithotripsy (12% of cases) and occurred with similar frequency after ureteroscopy and percutaneous nephrostolithotomy (15%), the investigators reported in Surgery (2014;155:769-775). Procedures at high-volume facilities were substantially less likely to result in an unplanned visit.




Muscle mass of dialysis patients linked with physical function and quality of life

April_Part 2_Urology_Nephrology

Dialysis patients with more muscle mass had better scores on a 6-minute walking test as well as better scores on physical and mental health questionnaires in a study appearing in an upcoming issue of the Clinical Journal of the American Society of Nephrology (CJASN). The findings suggest that physical activity that builds muscle mass may help improve the health and quality of life of dialysis patients.

Physical functional ability is often significantly impaired in patients on maintenance hemodialysis. Srinivasan Beddhu, MD (University of Utah), Macy Martinson, MD (University of Utah), T. Alp Ikizler (Vanderbilt University), and their colleagues wondered whether modifiable factors such as body size and body composition could influence dialysis patients’ physical function and quality of life.

To investigate, the researchers assessed 105 maintenance dialysis patients’ body mass index (BMI), waist circumference, and measurements of mid-thigh muscle area and intra-abdominal fat area. They also tested how far patients could walk in 6 minutes, and they examined other measures of physical and mental health through questionnaires. Assessments were made at the start of the study, after 6 months, and after 12 months.

The investigators found that higher BMI levels at the start of the study were linked with shorter 6-minute walking distances measured at both at the start of the study and at later time points. Results were similar for waist circumference and intra-abdominal fat. On the other hand, higher levels of mid-thigh muscle – which indicates higher muscle mass – were linked with longer 6-minute walking distances. After adjusting for BMI, increases in mid-thigh muscle were also strongly linked with higher physical and mental health scores at the start of the study, but only weakly so at later time points.

“Because this study shows that higher muscle mass is associated with better physical function and quality of life in dialysis patients, interventions such as increased physical activity that decrease fat mass and increase muscle mass are likely to improve physical function, quality of life, and survival in dialysis patients,” said Dr. Beddhu. “Such interventions need to be tested in clinical trials.”

The findings may help explain the “obesity paradox” associated with dialysis patients, which relates to the prolonged survival sometimes seen in obese patients compared with normal-weight patients. “The obesity paradox has been interpreted in earlier studies as fat is good. Some have even argued that weight loss should be discouraged in dialysis patients,” said Dr. Beddhu. “But the situation is more nuanced. This study provides a better understanding of the role of body composition in dialysis patients.”

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Quick, simple blood test for solid cancers looks feasible


The idea of a general, quick and simple blood test for a diverse range of cancers just came closer to reality with news of a new study published in Nature Medicine.

Researchers from Stanford University School of Medicine have devised an ultra-sensitive method for finding DNA from cancer tumors in the bloodstream.

Previous research has already shown circulating tumor DNA holds promise as a biomarker for cancer, but existing methods for detecting it are not sufficiently sensitive and do not cover a diverse range of cancers.

Ways to increase the sensitivity and coverage of such tests exist, but these are cumbersome and time-consuming, and need lots of steps to customize for individual patients, so they are not feasible for use in clinics.

The new approach promises to change that. It is highly sensitive and specific and should be broadly applicable to a range of cancers, say the researchers.

Their new test identified around half of patients with stage 1 lung cancer and all patients with stage 2 or higher disease. They also showed the circulation tumor DNA was highly correlated with tumor volume estimated using CT and PET scans.

This suggests an approach based on CAPP-Seq could monitor tumors at a fraction of the cost of present methods that rely on imaging studies.

Team faced two major hurdles

In developing the test, they faced two major hurdles, as Maximilian Diehn, co-senior author and assistant professor of radiation oncology, explains:

“First, the technique needs to be very sensitive to detect the very small amounts of tumor DNA present in the blood. Second, to be clinically useful it’s necessary to have a test that works off the shelf for the majority of patients with a given cancer.”

Co-senior author, Ash Alizadeh, assistant professor of medicine, explains why they are interested in developing a general way to detect and measure disease burden in solid cancers, and how they are approaching it:

“Blood cancers like leukemias can be easier to monitor than solid tumors through ease of access to the blood. By developing a general method for monitoring circulating tumor DNA, we’re in effect trying to transform solid tumors into liquid tumors that can be detected and tracked more easily.”

Cancer cells divide and die, even without treatment. When a cancer cell dies, the DNA in its nucleus escapes into the bloodstream. This is present in small concentrations; something like 1 in 1,000 or 10,000 bits of DNA in the blood can be from a dead cancer cell in a person with cancer.

Even in patients with advanced cancer, the vast majority of DNA circulating in their blood is from healthy, normal cells.

So a test that can quickly and non-invasively monitor the tiny concentrations of cancer cell DNA would be really useful to clinicians who need to estimate the size of the tumor, how it changes over time, and monitor a patient’s response to treatment.

New test boosts existing methods for analyzing DNA

The team found a way to do this by boosting existing methods for extracting, processing and analyzing the DNA. They called their approach CAPP-Seq (which is short for Cancer Personalized Profiling by deep Sequencing).

CAPP-Seq is sensitive enough to detect one molecule of tumor DNA among 10,000 DNA molecules from healthy cells in the blood.

In their study, they tested blood from patients with non-small-cell lung cancer (this includes most lung cancers, like adenocarcinomas, squamous cell carcinoma and large cell carcinoma). But they say the approach should also work with solid cancers that occur in other parts of the body.

And while they see the test one day being used to follow the progress of tumors in patients already diagnosed with cancer, the researchers say it also has potential as a cancer screening tool for healthy and at-risk populations.

Although the test is described as a general test for cancer, it by no means just looks for one pattern of DNA. Each cancer is genetically different in different patients, but there are certain sets of DNA mutations that are the same across patients with the same cancer.

So the challenge was to find which DNA sequences were the ones most likely to indicate the presence of a given cancer across a diverse range of patients.

Test looks for as many of the known mutations for a given cancer as possible

This is why the team decided to take a population-based approach. They looked in national databases that contain DNA sequences of tumors from thousands of patients, and identified the points on the cancer DNA that are different from normal DNA.

From this information, they were able to compile a fingerprint for each cancer type made up of all the DNA mutations recorded – these include insertions or deletions of short pieces of genetic material, plus where sequences of DNA have been shuffled around or even flipped over.

But while no patient will have all these mutations, nearly all of them will have at least one of them. This makes it possible to compile a test that looks for as many of the known mutations for a given cancer as possible. But it only has to find one of them to strike a positive.

The next stage of the study was to examine the genome of the 407 patients with non-small-cell lung cancer recruited for the study.

Prof. Alizadeh explains how, using an approach called bioinformatics, they looked for regions in the genome enriched for cancer-associated mutations:

“We looked for which genes are most commonly altered, and used computational approaches to identify what we call the genetic architecture of the cancer. That allowed us to identify the part of the genome that would be best to identify and track the disease.”

They identified 139 genes that only represent 0.004% of the human genome but are recurrently mutated in non-small-cell lung cancer.

“By sequencing only those regions of the genome that are highly enriched for cancer mutations, we’re able to keep costs down and identify multiple mutations per patient,” Prof. Diehn says.

Other approaches tend to look for single, well-known mutations that occur frequently, but not necessarily in every patient, with a particular cancer. Because it looks for more than one mutation, the CAPP-Seq approach is more sensitive and gives researchers more flexibility in how to track the cancer over time.

Prof. Diehn explains that there are currently no reliable biomarkers for lung cancer, a cancer that claims the most lives. He says they are “very excited” about the study results because “a personalized, clinically useful biomarker could revolutionize how we detect and manage this devastating disease.”

The team is now working on ways to quickly home in on patient-specific mutations and methods to suppress background noise in a sample so they can identify even very tiny amounts of cancer DNA that might be in it.

CAPP-Seq may also have possibilities as a prognostic tool

The researchers say CAPP-Seq may also have potential as a prognostic tool. When they tested one patient thought to have been successfully treated for lung cancer, they found low levels of circulating tumor DNA. The cancer came back in that patient, and they died.

Conversely, scans of another patient who was treated for early stage disease showed a mass that was thought to indicate disease was still present. But CAPP-Seq found no circulating tumor DNA in that patient’s blood, and they remained disease-free for the rest of the study period.

And in a third patient, CAPP-Seq found a mutation that makes non-small-cell lung cancer resistant to the drug that is commonly used to treat it.

Prof. Diehn says this suggests another use for the approach – to monitor how the tumor progresses and look out for the emergence of treatment resistance early on, giving enough time to switch therapy to target the resistant cells.

“It’s also possible we could use CAPP-Seq to identify subsets of early stage patients who could benefit most from additional treatment after surgery or radiation, such as chemotherapy or immunotherapy,” he adds.

Funds from a number of sources helped finance the study, including the Department of Defense and the National Institutes of Health.

Meanwhile, Medical News Today recently learned how another US study led by The Scripps Research Institute (TSRI) found a new biomarker for head and neck cancer and non-small-cell lung cancer. That study focused on CCTα – an antigen that prompts the immune system to make specific antibodies – and concluded it was a better predictor of patient outcomes than expression of ERCC1, which is involved in DNA repair.

Written by Catharine Paddock PhD