(An order comes to my pharmacy for a well-known antibiotic. This antibiotic is known to smell exactly like rotten eggs, so most of us just hold our breath while we count it and try not to think about it too much. We dispense it to a woman who is picking it up for her teenage son. Everything is normal and she leaves with the prescription, but about 10 minutes later she comes stomping back into the pharmacy, pretty much shoves the person that I am currently helping out of the way, and throws the bottle of medication on the counter.)
Customer: “I want to speak to your manager right now! You guys gave me rotten medication!”
Me: “Really? Let me look at the expiration date on your bottle. Normally we don’t keep anything that has one less than a year away.”
(I look at the bottle and see that the pharmacist wrote a date of over a year away, and I go over to our stock bottle and check and the numbers correspond with each other.)
Me: “Hmm. Well, ma’am, it doesn’t look like this medication is expired but I will have the phar—”
Customer: “You are just lying! I mean, come on and open that bottle! It smells totally rotten! I can’t believe that you would ever give someone bad medication! My son is very very ill!”
Me: “Oh, that’s just because the active chemical that is in this medication has a bad smell. Trust me, I wish there was something that we could do about it back here, too. Most of us hold our breath while we count it.”
Customer: “Stop ****** lying to me. You just don’t want to admit you did something wrong! I will have your job for this, b****!
(At this point the pharmacist who has been listening the whole time walks over.)
Pharmacist: “Ma’am, while I don’t like the fact that you are calling my staff names like that I will let you know two things. One is, certain chemicals have a bad smell. It’s just a fact of life. So, while I know that smell is unpleasant, it’s just one of those side effects that come with being able to take medications that will help your sick son. I assure you it’s supposed to smell that bad. If it didn’t, it wouldn’t work right. Two, since you don’t seem to want to listen to my employees and call them awful names, this will be the last time that you or any members of your family can shop or fill any type of medication here. Maybe in the future you can learn how to treat people the way you want to be treated.”
(The woman proceeded to turn bright red with embarrassment and tried to apologize, but my boss wouldn’t hear it. That was almost two years ago and he still will not allow her or her family to fill their prescriptions at his pharmacy.)
Standard pathology tests outperform molecular subtyping in bladder cancer
Medical College of Georgia at Augusta University
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IMAGE: Dr. Vinata B. Lokeshwar and graduate students Sarrah S. Lahorewala and Daley S. Morera. view more
Credit: Phil Jones, Senior Photographer, Augusta University
While trying to develop a comparatively easy, inexpensive way to give physicians and their patients with bladder cancer a better idea of likely outcome and best treatment options, scientists found that sophisticated new subtyping techniques designed to do this provide no better information than long-standing pathology tests.
They looked at several sets of data on cancer specimens from patients with muscle invasive bladder cancer, a high-grade cancer associated with high mortality rates. The datasets included the one used to determine emerging molecular subtypes, and had outcome information on patients.
They consistently found that molecular subtyping of bladder tumors, which is currently being offered to patients, was outperformed by standard tests long-used by pathologists to characterize cancer as low- or high-grade and to determine the extent of its invasion into the bladder wall, surrounding fat, lymph nodes, blood vessels and beyond, they report in a study featured on the cover of the Journal of Urology.
"Muscle invasive bladder cancer is aggressive, it often has a very bad prognosis," says Dr. Vinata B. Lokeshwar, chair of the Department of Biochemistry and Molecular Biology at the Medical College of Georgia at Augusta University. "Everyone is trying to find out how to improve diagnosis, treatment and survival."
"Genetic profiling of a patient's tumor definitely has value in enabling you to discover the drivers of growth and metastasis that help direct that individual's treatment, even as it helps to identify new treatment targets," says Lokeshwar, the study's corresponding author and a member of the Georgia Cancer Center. "But using this information to subtype tumors does not appear to add diagnostic or prognostic value for patients."
Rather the investigators suggest that more study is needed before molecular subtypes are used to help guide patient care.
Evolving diagnostic approaches include compiling databanks on gene expression and mutations present in a cancer type to find patterns of gene expression that are then used to subtype tumors that "pathologically look similar" but are molecularly different. The idea is that molecular subtypes are better equipped to indicate which cancer is more or less aggressive and to help steer treatment options like whether chemotherapy before surgery to remove a diseased bladder is better.
It was RNA sequencing, or RNA-Seq, and a federal databank of genetic material from a wide range of cancers that enabled investigators from around the globe to examine gene expression in a particular tumor type, looking for common expression of some genes that correlate with a particular clinical outcome. Two subtypes, luminal, which predicts better survival, and basal, which predicts poor prognosis, were first identified for muscle invasive bladder cancer, and a total of six subtypes have now emerged. The first paper on subtypes in muscle invasive bladder cancer was published in the journal Nature in 2014.
But in their search to find a simpler, cheaper, widely available test to provide similar insight, investigators found that these emerging subtypes were outperformed by the usual clinical parameters like the tumor's grade and its spread to lymph nodes or blood vessels, Lokeshwar says.
Their work began in earnest with an exhaustive review by graduate students Daley S. Morera and Sarrah S. Lahorewala of the datasets on patients and differing classification methods used to identify the molecular subtypes.
They found 11 genes that were common in all subtype classification methods. They thought, if they were going to develop a widely available test, subtyping based on these common genes might suffice. They decided to call their new subtyping panel, MCG-1.
Instead of doing RNA-Seq, which costs several thousand dollars, they used the readily available reverse transcription quantitative PCR method costing less than $10, which also looks at gene expression and is actually used to verify RNA-Seq data, Lokeshwar says.
They first looked at their own cohort of 52 patients with bladder cancer, 39 of whom had muscle invasive disease. They found MCG-1 was only 31-36% accurate at predicting important indicators like likelihood of metastasis; disease specific survival, meaning surviving bladder cancer; or overall survival, meaning survival from all causes of death from the time of cancer diagnosis or beginning of treatment until the study's end.
Recognizing that the dataset they used was comparatively small and that they did not use RNA-Seq for analysis, they then used three patient datasets from the cancer database ONCOMINE which had more patients -- 151 with muscle invasive bladder cancer -- and also used RNA-Seq to look at gene expression.
"We found the same thing: MCG-1 could not predict disease-specific mortality," Lokeshwar says. On some patients in this dataset, information on response to chemotherapy, like commonly used cisplatin-based chemotherapy following surgical removal of the bladder, was available but subtypes could not predict chemotherapy response either, she says.
Next they looked at the dataset that has been used by a large network of investigators to identify the subtypes, The Cancer Genome Atlas, or TCGA. TCGA is a project of the National Cancer Institute and National Human Genome Research Institute that started in 2006, and has collected genetic material for 33 different cancers. The dataset includes routine pathology information on 402 specimens from patients with muscle invasive bladder cancer. It also includes these patients' overall survival and recurrence-free survival - that is when or if their cancer returned or progressed.
"Up until this point, we had been looking at patients that other groups had not looked at," Lahorewala says.
In this dataset MCG-1 predicted overall survival similar to findings reported from subtypes in several high profile publications.
"We were intrigued why MCG-1 could not predict anything in our cohort or the ONCOMINE dataset but predicted overall survival in the TCGA dataset," says Morera.
So they looked again at the 402 patients whose specimens were in the dataset and found that 21 patients' tumors were actually low-grade. Patients with low-grade tumors have higher survivability and a better prognosis than patients with high-grade muscle invasive disease.
When they removed the low-grade cases from the TCGA dataset, MCG-1 accurately predicted essentially nothing, not even overall survival. Then they included some patients with low-grade tumors into their own dataset, which they had looked at originally, and MCG-1 was now able to predict metastasis and disease specific survival, the investigators say.
All the existing subtypes are categorized as bad or better based on the cancer prognosis, the investigators say. The presence of the low-grade tumors in the classification of subtypes skewed the data to make it look like subtypes were predicting overall survival when really it was the grade of the cancer itself that was predictive.
"As investigators the first thing we did was to question our findings, since the results were so different than those reported by others," says Lokeshwar.
With the help of MCG biostatistician and coauthor Dr. Santu Ghosh, they also went back and looked at the same patients in the TCGA datasets and the subtypes they had been assigned by three different classification methods established by a network of bladder cancer researchers.
"Even with these established classification methods, the subtypes were accurate only about 50% of the time in predicting patients' overall survival. And once again, routine pathology parameters like invasion into lymph nodes or blood vessels were more accurate than the established subtypes in predicting patients' prognosis," says Lahorewala.
A recent study by investigators at Sweden's Lund University published in the journal Urologic Oncology supports the MCG investigators' findings. Their study of 519 patients who had their bladders removed because of bladder cancer found subtypes were not associated with cancer-specific survival.
Part of the problem with subtyping may be the inherent heterogeneity of tumors, says Morera. There is tremendous heterogeneity in the gene expression of tumors, even among the same tumor type, like bladder cancer, and within different parts of the same tumor as well. Furthermore, this pattern of heterogeneity can change both during tumor growth and treatment.
"Just because it's bladder cancer does not mean it's the same in all patients. We know that tumors are very dynamic and so there is heterogeneity," Lokeshwar says.
"Because there is heterogeneity, there could be problems when you want to categorize a tumor into a single subtype," says Morera.
As the name indicates, muscle invasive bladder cancer has already spread from the lining of the sac-like organ to its muscular wall. High-grade tumors, if not detected early, will spread into bladder muscle, whereas, low-grade tumors are rarely invasive. Painless blood in the urine is the most common sign of bladder cancer although only a small percentage of the individuals with it have cancer. Smoking is the major risk factor for bladder cancer.
A test of a customized implant for hip replacement
Scientists developed a mathematical model of an 'endoprosthesis-skeleton' system; special attention was paid to the geometry and internal structure of hip bones
Peter the Great Saint-Petersburg Polytechnic University
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IMAGE: General distribution of stresses in the "endoprosthesis-skeleton " model of the biomechanical structure when a patient is standing on two legs. The voltage range is from 1 to 100 MPa. view more
Credit: Peter the Great St.Petersburg Polytechnic University
A team of scientists from the Advanced Manufacturing Technologies Center of the National Technology Initiative (NTI) of Peter the Great St.Petersburg Polytechnic University (SPbPU) (head -- Prof. A.I. Borovkov, the Vice-rector for Advanced Projects of Peter the Great St. Petersburg Polytechnic University) developed a mathematical model of an "endoprosthesis-skeleton" system. Special attention was paid to the geometry and internal structure of hip bones. Using advanced computer modeling technologies, the team assessed the integrity of the biomechanical structure for a typical case (a patient standing on two legs). Currently the team is working on a methodology that would reduce the time of such analysis to several days. The results of the study were published in the Vibroengineering PROCEDIA journal and presented at the 12th All-Russia Congress on Fundamental Issues of Theoretical and Applied Mechanics.
Hip joint arthroplasty is a relatively common procedure today. During arthroplasty the upper part of a patient's hip bone is replaced with a metal stem with a spherical joint element, and a cup to allow the head of the joint to rotate inside the pelvis. Medical companies manufacture standard elements with different parameters for ordinary hip replacement operations. However, after some time a certain share of patients experiences issues with implants and requires their replacement. As a rule, this happens due to the insufficient (or excessive) load the endoprosthesis puts on the hip bone causing its tissue to change. Moreover, bone strength can be affected by osteoporosis and other diseases. By the time of the second surgery (the removal of the initial implant and the installation of a revision one) a part of the hip bone becomes unfit as it is unable to bear the load. Therefore, when a patient comes to a secondary operation with a damaged hip bone, standard implants are of no use for them, and a regular cup (even if it is of a bigger size) might not work.
The manufacturers produce special sets of elements that can be combined with each other in different ways to be used in revision operations as well as in patients with compound fractures or cancer. However, such surgeries have high risk rates: any issue with a revision structure or additional bone tissue loss may cause grave health issues. It is extremely important to understand if the prosthesis is able to bear the load, and if the damage to the patient's bone can be avoided. Virtual testing before installation could help eliminate numerous post-surgical complications. However, there is currently no universal assessment method to do so. It takes a long time to build a model on the basis of bone CT results, while the patient's health parameters keep constantly changing. Therefore, the window between diagnostics and the surgery should be as short as possible.
A team of engineers from the Advanced Manufacturing Technologies Center of the National Technology Initiative (NTI) of Peter the Great St. Petersburg Polytechnic University (SPbPU) analyzed the integrity of an "endoprosthesis-skeleton" system for a case of hip joint revision arthroplasty and assessed the durability of the implanted structure and pelvis bones, as well as the distribution of load when a patient stands on two feet. The work describes the peculiarities of simulation model preparation. Currently, this process takes a long time, but the team is working on a method to reduce the whole calculation to several days.
Other groups tend to entirely ignore pelvic bones in their studies or to consider only their simplified models. However, in this case the researchers paid special attention to detailed description of pelvic bones including their external and porous internal layers. This was done due to the fact that the pelvis is often at risk in its entirety.
"If we consider the work done by us as a virtual test, the article described the load we put on the patient's skeleton and the implant, as if they were tested in reality. Studies like this help reduce the risk of complications in patients with individually designed implants. Hopefully, they would help prioritize prevention over cure," commented Mikhail Zhmaylo, a lead engineer at the Advanced Manufacturing Technologies Center of the National Technology Initiative (NTI) of Peter the Great St. Petersburg Polytechnic University (SPbPU)
New assay assesses multiple cellular pathways at once
Baylor College of Medicine
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IMAGE: Synthetic assembly cloning for inserting multiple luciferase reporters into a single vector. Nature Communications/The Venken lab view more
Credit: Nature Communications/The Venken lab
A novel technological approach developed by researchers at Baylor College of Medicine expands from two to six the number of molecular pathways that can be studied simultaneously in a cell sample with the dual luciferase assay, a type of testing method commonly used across biomedical fields.
Published in the journal Nature Communications, the report shows that multiplexed hextuple luciferase assaying, meaning a testing method that can effectively probe six different pathways. It can also be used to monitor the effects of experimental treatments on multiple molecular targets acting within these pathways. The new assay is sensitive, saves time and expense when compared to traditional approaches, reduces experimental error and can be adapted to any research field where the dual luciferase assay is already implemented, and beyond.
"One of the interests of our lab is to have a better understanding of the processes involved in cancer. Cancer usually originates through changes on many different genes and pathways, not just one, and currently most cell-based screening assays conduct single measurements," said corresponding author Dr. Koen Venken, assistant professor of biochemistry and molecular biology, and pharmacology and chemical biology at Baylor.
To get a more detailed picture of the cellular processes that differentiate normal versus cancer cells, researchers resort to conduct several independent screening assays at the expense of time and additional cost.
"Our goal in this study was to measure multiple cellular pathways at once in a single biological sample, which would also minimize experimental errors resulting from conducting multiple separate assays using different samples," said Venken, a McNair Scholar and member of the Dan L Duncan Comprehensive Cancer Center at Baylor.
Dr. Alejandro Sarrion-Perdigones, first author of the paper, focused on developing a multiplexed method - a method for simultaneously detecting many signals from complex systems, such as living cells. He developed a sensitive assay using luciferases, enzymes that produce bioluminescence. The assay includes six luciferases, each one emitting bioluminescence that can be distinguished from the others. Each luciferase was engineered to reveal the activity of a particular pathway by emitting bioluminescence.
"To engineer and deliver the luciferase system to cells, we used a 'molecular Lego' approach," said co-author Dr. Lyra Chang, post-doctoral researchers at the Center for Drug Discovery at Baylor. "This consists of connecting the DNA fragments encoding all the biological and technological information necessary to express each luciferase gene together sequentially forming a single DNA chain called vector. This single vector enters the cells where each luciferase enzyme is produced separately."
Treating the cells with a single multi-luciferase gene vector instead of using six individual vectors, decreased variability between biological replicates and provided an additional level of experimental control, Chang explained. This approach allowed for simultaneous readout of the activity of five different pathways, compared to just one using traditional approaches, providing a much deeper understanding of cellular pathways of interest.
"In addition to applications in cancer research, as we have shown in this work, our multiplex luciferase assay can be used to study other cellular pathways or complex diseases across different research fields," Venken said. "For instance, the assay can be adapted to study the effect of drugs on insulin sensitivity in different cells types, the immune response to viral infections, or any other combinations of pathways
A test of a customized implant for hip replacement
Scientists developed a mathematical model of an 'endoprosthesis-skeleton' system; special attention was paid to the geometry and internal structure of hip bones
Peter the Great Saint-Petersburg Polytechnic University
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IMAGE: General distribution of stresses in the "endoprosthesis-skeleton " model of the biomechanical structure when a patient is standing on two legs. The voltage range is from 1 to 100 MPa. view more
Credit: Peter the Great St.Petersburg Polytechnic University
A team of scientists from the Advanced Manufacturing Technologies Center of the National Technology Initiative (NTI) of Peter the Great St.Petersburg Polytechnic University (SPbPU) (head -- Prof. A.I. Borovkov, the Vice-rector for Advanced Projects of Peter the Great St. Petersburg Polytechnic University) developed a mathematical model of an "endoprosthesis-skeleton" system. Special attention was paid to the geometry and internal structure of hip bones. Using advanced computer modeling technologies, the team assessed the integrity of the biomechanical structure for a typical case (a patient standing on two legs). Currently the team is working on a methodology that would reduce the time of such analysis to several days. The results of the study were published in the Vibroengineering PROCEDIA journal and presented at the 12th All-Russia Congress on Fundamental Issues of Theoretical and Applied Mechanics.
Hip joint arthroplasty is a relatively common procedure today. During arthroplasty the upper part of a patient's hip bone is replaced with a metal stem with a spherical joint element, and a cup to allow the head of the joint to rotate inside the pelvis. Medical companies manufacture standard elements with different parameters for ordinary hip replacement operations. However, after some time a certain share of patients experiences issues with implants and requires their replacement. As a rule, this happens due to the insufficient (or excessive) load the endoprosthesis puts on the hip bone causing its tissue to change. Moreover, bone strength can be affected by osteoporosis and other diseases. By the time of the second surgery (the removal of the initial implant and the installation of a revision one) a part of the hip bone becomes unfit as it is unable to bear the load. Therefore, when a patient comes to a secondary operation with a damaged hip bone, standard implants are of no use for them, and a regular cup (even if it is of a bigger size) might not work.
The manufacturers produce special sets of elements that can be combined with each other in different ways to be used in revision operations as well as in patients with compound fractures or cancer. However, such surgeries have high risk rates: any issue with a revision structure or additional bone tissue loss may cause grave health issues. It is extremely important to understand if the prosthesis is able to bear the load, and if the damage to the patient's bone can be avoided. Virtual testing before installation could help eliminate numerous post-surgical complications. However, there is currently no universal assessment method to do so. It takes a long time to build a model on the basis of bone CT results, while the patient's health parameters keep constantly changing. Therefore, the window between diagnostics and the surgery should be as short as possible.
A team of engineers from the Advanced Manufacturing Technologies Center of the National Technology Initiative (NTI) of Peter the Great St. Petersburg Polytechnic University (SPbPU) analyzed the integrity of an "endoprosthesis-skeleton" system for a case of hip joint revision arthroplasty and assessed the durability of the implanted structure and pelvis bones, as well as the distribution of load when a patient stands on two feet. The work describes the peculiarities of simulation model preparation. Currently, this process takes a long time, but the team is working on a method to reduce the whole calculation to several days.
Other groups tend to entirely ignore pelvic bones in their studies or to consider only their simplified models. However, in this case the researchers paid special attention to detailed description of pelvic bones including their external and porous internal layers. This was done due to the fact that the pelvis is often at risk in its entirety.
"If we consider the work done by us as a virtual test, the article described the load we put on the patient's skeleton and the implant, as if they were tested in reality. Studies like this help reduce the risk of complications in patients with individually designed implants. Hopefully, they would help prioritize prevention over cure," commented Mikhail Zhmaylo, a lead engineer at the Advanced Manufacturing Technologies Center of the National Technology Initiative (NTI) of Peter the Great St. Petersburg Polytechnic University (SPbPU
Researchers reconstruct spoken words as processed in nonhuman primate brains
Brown University
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VIDEO: Using a brain-computer interface, a team of researchers has reconstructed English words from the brain activity of rhesus macaques that listened as the words were spoken. view more
Credit: Nurmikko Lab / Brown University
PROVIDENCE, R.I. [Brown University] -- A team of Brown University researchers has used a brain-computer interface to reconstruct English words from neural signals recorded in the brains of nonhuman primates. The research, published in the journal Nature Communications Biology, could be a step toward developing brain implants that may help people with hearing loss, the researchers say.
"What we've done is to record the complex patterns of neural excitation in the secondary auditory cortex associated with primates' hearing specific words," said Arto Nurmikko, a professor in Brown's School of Engineering, a research associate in Brown's Carney Institute for Brain Science and senior author of the study. "We then use that neural data to reconstruct the sound of those words with high fidelity.
"The overarching goal is to better understand how sound is processed in the primate brain," Nurmikko added, "which could ultimately lead to new types of neural prosthetics."
The brain systems involved in the initial processing of sound are similar in humans and non-human primates. The first level of processing, which happens in what's called the primary auditory cortex, sorts sounds according to attributes like pitch or tone. The signal then moves to the secondary auditory cortex, where it's processed further. When someone is listening to spoken words, for example, this is where the sounds are classified by phonemes -- the simplest features that enable us to distinguish one word from another. After that, the information is sent to other parts of the brain for the processing that enables human comprehension of speech.
But because that early-stage processing of sound is similar in humans and non-human primates, learning how primates process the words they hear is useful, even though they likely don't understand what those words mean.
For the study, two pea-sized implants with 96-channel microelectrode arrays recorded the activity of neurons while rhesus macaques listened to recordings of individual English words and macaque calls. In this case, the macaques heard fairly simple one- or two-syllable words -- "tree," "good," "north," "cricket" and "program."
The researchers processed the neural recordings using computer algorithms specifically developed to recognize neural patterns associated with particular words. From there, the neural data could be translated back into computer-generated speech. Finally, the team used several metrics to evaluate how closely the reconstructed speech matched the original spoken word that the macaque heard. The research showed the recorded neural data produced high-fidelity reconstructions that were clear to a human listener.
The use of multielectrode arrays to record such complex auditory information was a first, the researchers say.
"Previously, work had gathered data from the secondary auditory cortex with single electrodes, but as far as we know this is the first multielectrode recording from this part of the brain," Nurmikko said. "Essentially we have nearly 200 microscopic listening posts that can give us the richness and higher resolution of data which is required."
One of the goals of the study, for which doctoral student Jihun Lee led the experiments, was to test whether any particular decoding model algorithm performed better than others. The research, in collaboration with Wilson Truccolo, a computational neuroscience expert, showed that recurrent neural networks (RNNs) -- a type of machine learning algorithm often used in computerized language translation -- produced the highest-fidelity reconstructions. The RNNs substantially outperformed more traditional algorithms that have been shown to be effective in decoding neural data from other parts of the brain.
Christopher Heelan, a research associate at Brown and co-lead author of the study, thinks the success of the RNNs comes from their flexibility, which is important in decoding complex auditory information.
"More traditional algorithms used for neural decoding make strong assumptions about how the brain encodes information, and that limits the ability of those algorithms to model the neural data," said Heelan, who developed the computational toolkit for the study. "Neural networks make weaker assumptions and have more parameters allowing them to learn complicated relationships between the neural data and the experimental task."
Ultimately, the researchers hope, this kind of research could aid in developing neural implants the may aid in restoring peoples' hearing.
"The aspirational scenario is that we develop systems that bypass much of the auditory apparatus and go directly into the brain," Nurmikko said. "The same microelectrodes we used to record neural activity in this study may one day be used to deliver small amounts of electrical current in patterns that give people the perception of having heard specific sounds."
Entrectinib effective, well-tolerated against ROS1 and NTRK lung cancers, especially with brain metastases
University of Colorado Anschutz Medical Campus
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IMAGE: Robert C. Doebele, MD, PhD, and colleagues update the effectiveness of entrectinib against ROS1+ and NTRK+ cancers. view more
Credit: University of Colorado Cancer Center
Pooled analysis of three phase 1 and 2 clinical trials published online ahead of print in the journal Lancet Oncology show that the drug entrectinib is effective and well-tolerated against advanced ROS1 and NTRK fusion-positive non-small cell lung cancers (NSCLC). Results of the trials STARTRK-1 (NCT02097810), STARTRK-2 (NCT02568267), and ALKA, show 77 percent response rate to entrectinib in 53 patients with ROS1+ NSCLC, with a median progression-free survival of 19 months and a median duration of response of 24.6 months. In 54 patients with NTRK+ NSCLC, 57 percent responded to entrectinib, with a median progression-free survival of 11.2 months and a median duration of response of 10.4 months. Based on the early promise of these trials, in August 2019 the U.S. Food and Drug Administration granted entrectinib accelerated approval for the treatment of metastatic ROS1+ NSCLC and for advanced tumors across cancer types defined by NTRK fusion. The current journal articles update these findings that led to approval.
"For a drug to get simultaneous approval for use against two different targets is somewhat unique. I don't know of this ever happening before," says Robert C. Doebele, MD, PhD, director of the University of Colorado Cancer Center Thoracic Oncology Research Initiative, senior author on the ROS1 study, and first author on the NTRK study.
About 2 percent of lung cancers are driven by the improper fusion of the gene ROS1 with one of a handful of possible genetic partners, resulting in a cancer-causing ROS1 fusion gene. About 1 percent of all solid tumors, including but not limited to lung cancers, are similarly caused by NTRK fusion genes. The FDA-approved drug crizotinib can silence the action of ROS1 fusion genes in some cases, but can't reach cancers that have metastasized to the brain. And, unfortunately, 36 percent of patients with ROS1+ NSCLC already have brain metastases at the time of advanced disease diagnosis, and many more will go on to develop brain metastases during the course of care.
"For ROS1+ lung cancer, entrectinib represents a new and better standard of care due to entrectinib's effectiveness against ROS1 in the body and especially due to its activity against ROS1+ brain metastases," Doebele says. "For NTRK cancers, the picture is a little more complex and I think it depends on an NTRK+ cancer's chance of developing brain metastases. Personally, if I were a patient and felt there was any chance of me getting brain mets, I would want this brain-penetrating drug."
Included in these phase 1 or 2 studies were adults with locally advanced or metastatic ROS1+ or NTRK+ NSCLC who had received previous treatment not including other ROS1 inhibitors. Patients received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months follow-up. Doebele describes the drug as "well tolerated with a manageable safety profile," with side effects including weight increase (8%) and neutropenia (4%). Eleven percent of patients had serious treatment-related adverse events, the most common of which were nervous system disorders (3%) and cardiac disorders (2%). No treatment-related deaths occurred.
"The genes ROS1 and NTRK are on a growing list of known genetic drivers of non-small cell lung cancer. In addition to showing the benefit of entrectinib against cancers caused by these fusion genes, these results highlight the importance of genetic testing in NSCLC, especially when patients are diagnosed with the condition in the absence of other risk factors," Doebele says. "Only by testing for genes like ROS1 and NTRK can we match these genetic drivers of cancer with drugs like entrectinib."
Rapid tissue donation program offers feasible approach to improve research
Well-preserved postmortem lung cancer specimens allow for genetic and molecular analyses
H. Lee Moffitt Cancer Center & Research Institute
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TAMPA, Fla. - Precision medicine with targeted therapies has led to improved treatment options and patient outcomes. These approaches were developed by studying tumors grown in laboratories and patient samples obtained before and during their treatment. However, there is often a limited supply of patient samples to adequately study, and the samples that exist do not always tell the complete genetic story of how the patient responded to specific drugs and the reasons why they failed treatment. Researchers need a better way to determine how tumors respond to therapies and evolve to resist drug treatment.
In an article published in Cancer Medicine, Moffitt Cancer Center scientists describe a community-based program called the Rapid Tissue Donation (RTD) protocol. It enables patients to consent to donating tumor tissue and blood samples for research purposes after their death. The samples provided by patients postmortem enable researchers to study the genetic and molecular makeup of primary and metastatic tumors after the patient failed treatment, and to compare those finding with what was known about the patient during earlier phases of their therapy.
There were several challenges that the Moffitt team had to overcome before embarking on this program, including ethical considerations and logistical challenges, communication with hospice care facilities, locating autopsy facilities in the community and identifying tumors in postmortem specimens.
During a two-year span from Nov. 2015 to Nov. 2017, Moffitt researchers were able to gain consent from 21 lung cancer patients from Hillsborough, Pinellas and Pasco counties to participate in the RTD study. They collected 180 tumor tissue and blood specimens from nine deceased patients, while the remaining 12 patients were still alive at the time of the article publication.
One of the logistical challenges the researchers faced was the need to preserve the specimens as quickly as possible after death to ensure that the tissue and molecular material remained intact. The average time to collect the specimens for all nine patients was 15.8 hours. Samples were collected within 20 hours of death for eight donors, and by 41 hours from death for one donor due to unavoidable logistic complexities.
Analysis of the specimens found that most of the DNA samples taken from the primary and metastatic tumors of the same patient were similar and contained the same DNA mutations. The researchers also discovered an AGK-BRAF fusion in one patient with a known EML4-ALK fusion and resistance to ALK inhibitor therapy. Activated BRAF can promote tumor growth. "This is a compelling finding because, had the AGK-BRAF fusion been detected during treatment, physicians could have adapted therapy to include a BRAF-targeted agent," said Eric Haura, M.D., medical oncologist and director of Moffitt's Lung Cancer Center of Excellence.
Analysis of tumor tissue samples for protein biomarkers showed that expression of the protein PD-L1 varied up to 55% among samples taken from the primary tumor and metastatic tumors from the same patient. Levels of PD-L1 are used as a diagnostic assay for lung cancer patients to determine if they should receive certain drugs.
"Twenty to sixty percent of individuals in this study would have a different PD-L1 result if different tumor sites were tested," said Haura. "This illustrates the importance of interpreting PD-L1 results with caution because a large number of patients might not be eligible for immunotherapy based on testing of one tumor site but would be eligible based on testing of a tumor in a different location."
Haura is pleased with the progress the RTD program has made and is excited for what is to come. He hopes that it can be expanded into other tumor types and even developed in partnership with other institutions.
Multi-omics approach offers new insights into peanut allergy severity
Findings could improve diagnostics and lead to new treatments
The Mount Sinai Hospital / Mount Sinai School of Medicine
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New York, NY -- Dec 12, 2019 -- Researchers at the Icahn School of Medicine at Mount Sinai have identified novel genes associated with the severity of peanut allergy, as well as ways in which these genes interact with other genes during allergic reactions.
The findings, published December 12 in the Journal of Allergy and Clinical Immunology, could lead to better treatments for peanut allergy.
Peanut allergy varies widely in severity and is the leading cause of fatal food-related anaphylaxis. The tests used to determine the existence of a peanut allergy don't offer any clues as to whether an individual ingesting a peanut could experience a minor rash, major swelling, or life-threatening issues such as difficulty breathing or cardiovascular complications.
The study's senior author, Supinda Bunyavanich, MD, MPH, Associate Professor of Genetics and Genomic Sciences, and Pediatrics, and Associate Director of the Elliot and Roslyn Jaffe Food Allergy Institute at Mount Sinai, was especially curious about why the severity of reactions varies so much, both as a clinician-scientist and as a mother of a child with a peanut allergy.
To help address this question, Dr. Bunyavanich and her team used novel multi-omic approaches (the study of the role, relationships, and actions of a system-wide measure of a given molecular type) to identify genes and networks of activity that might be driving the severity of peanut allergy reactions. The approaches included transcriptomics, the study of gene expression across the genome, and epigenomics, the study of reversible modifications to DNA that affect gene expression.
The study involved 21 children ages 7-17 with peanut allergy, who were given gradually increasing doses of peanut until they displayed an allergic response. The scientists drew blood from the participants at three times: before they ate, as they reacted, and after their reaction. The team confirmed their findings from the initial cohort by repeating the study in another 19 children.
Taking blood samples at multiple times allowed the team to analyze both the transcriptome and epigenome (which can tell scientists which genes are turned on or off through a process called methylation) as the children reacted. Using this genome-wide approach, they identified more than 300 genes and 200 CpG sites (areas where DNA can be activated or inactivated by methylation) associated with reaction severity. Combining these data using integrative networks, the team also characterized key interactions between gene expression, CpG sites, and reaction severity.
Not only did they identify novel genes associated with the severity of peanut allergy, but they also managed to characterize ways in which these genes interact with other genes and CpG sites during allergic reactions to regulate biological processes. "It was very exciting to apply multi-omics to uncover how genes and methylation sites interact to affect reaction severity in these peanut allergic kids," says Anh Do, PhD, lead author of the study and postdoctoral fellow in the Bunyavanich Lab.
Among the insights is that while the findings support recognized roles for adaptive immunity in allergy, they also suggest that neutrophil (a type of white blood cell)-mediated immunity plays a prominent role in reaction severity. "We know neutrophil-mediated immunity is part of immune responses, and this study suggests it may play a central role in the severity of peanut allergic reactions," said Dr. Bunyavanich.
Additionally, one of the reaction severity drivers the team identified, the gene ARG1, can be inhibited by arginase inhibitors, a type of drug under study for many diseases. This study's finding suggests it may be a potential target for treating peanut allergy as well.
Dr. Bunyavanich hopes future studies will identify biomarkers that can predict who is likely to have severe responses without having to expose them to peanuts first. But in the meantime, she states that this study "hopefully challenges people to think about food allergy with a broader lens."
Bone bandage soaks up pro-healing biochemical to accelerate repair
Trapping adenosine at the site of a bone break speeds recovery in mice
Duke University
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IMAGE: This graphic shows the healing progress of a fracture in a mouse treated with a new type of bone bandage that traps native adenosine (top), is preloaded with external adenosine... view more
Credit: Shyni Varghese, Duke University
DURHAM, N.C. -- Researchers at Duke University have engineered a bandage that captures and holds a pro-healing molecule at the site of a bone break to accelerate and improve the natural healing process.
In a proof-of-principle study with mice, the bandage helped to accelerate callus formation and vascularization to achieve better bone repair by three weeks.
The research points toward a general method for improving bone repair after damage that could be applied to medical products such as biodegradable bandages, implant coatings or bone grafts for critical defects.
The results appear online on December 12 in the journal Advanced Materials.
In 2014, Shyni Varghese, professor of biomedical engineering, mechanical engineering and materials science, and orthopedics at Duke, was studying how popular biomaterials made of calcium phosphate promote bone repair and regeneration. Her laboratory discovered that the biomolecule adenosine plays a particularly large role in spurring bone growth.
After further study, they found that the body naturally floods the area around a new bone injury with the pro-healing adenosine molecules, but those locally high levels are quickly metabolized and don't last long. Varghese wondered if maintaining those high levels for longer would help the healing process.
But there was a catch.
"Adenosine is ubiquitous throughout the body in low levels and performs many important functions that have nothing to do with bone healing," Varghese said. "To avoid unwanted side effects, we had to find a way to keep the adenosine localized to the damaged tissue and at appropriate levels."
Varghese's solution was to let the body dictate the levels of adenosine while helping the biochemical stick around the injury a little bit longer. She and Yuze Zeng, a graduate student in Varghese's laboratory, designed a biomaterial bandage applied directly to the broken bone that contains boronate molecules that grab onto the adenosine. However, the bonds between the molecules do not last forever, which allows a slow release of adenosine from the bandage without accumulating elsewhere in the body.
In the current study, Varghese and her colleagues first demonstrated that porous biomaterials incorporated with boronates were capable of capturing the local surge of adenosine following an injury. The researchers then applied bandages primed to capture the host's own adenosine or bandages preloaded with adenosine to tibia fractures in mice.
After more than a week, the mice treated with both types of bandages were healing faster than those with bandages not primed to capture adenosine. After three weeks, while all mice in the study showed healing, those treated with either kind of adenosine-laced bandage showed better bone formation, higher bone volume and better vascularization.
The results showed that not only do the adenosine-trapping bandages promote healing, they work whether they're trapping native adenosine or are artificially loaded with it, which has important implications in treating bone fractures associated with aging and osteoporosis.
"Our previous work has shown that patients with osteoporosis don't produce adenosine when their bones break," Yuze said. "These early results indicate that these bandages could help deliver the needed adenosine to repair their injuries while avoiding potential side effects."
Varghese and Yuze see several other paths forward for biomedical applications as well. For example, they imagine a biodegradable bandage that traps adenosine to help heal broken bones and then decomposes into the body. Or for osteoporotic patients, a permanent bandage that can be reloaded with adenosine at sites that suffer from repeated injuries. They also envision a lubricating gel armed with adenosine that can help prevent bone injuries caused by the wear and tear associated with reconstructive joint surgeries or other medical implants.
"We've demonstrated that this is a viable approach and filed a patent for future devices and treatments, but we still have a long way to go," said Varghese. "The bandages could be engineered to capture and hold on to adenosine more efficiently. And of course we also have to find out whether these results hold in humans or could cause any side effects."
Study probing visual memory, amblyopia unveils many-layered mystery
Picower Institute at MIT
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IMAGE: Researchers used a genetic technique to knock out NMDA receptors in layer 4 of the visual cortex of mice. view more
Credit: Bear Lab/ Picower Institute for Learning and Memory
In decades of studying how neural circuits in the brain's visual cortex adapt to experience, MIT Professor Mark Bear's lab has followed the science wherever it has led, yielding the discovery of cellular mechanisms serving visual recognition memory, in which the brain learns what sights are familiar so it can focus on what's new, and of a potential therapy for amblyopia, a disorder where children born with disrupted vision in one eye can lose visual acuity there permanently without intervention. But this time his lab's latest investigation has yielded surprising new layers of mystery.
Heading into the experiments described in a new paper in Cerebral Cortex, Bear and his team expected to confirm that key proteins called NMDA receptors act specifically in neurons in layer 4 of the visual cortex to make the circuit connection changes, or "plasticity," necessary for both visual recognition memory and amblyopia. Instead, the study has produced unexpectedly divergent results.
"There are two stories here," said Bear, co-senior author and Picower Professor of Neuroscience in The Picower Institute for Learning and Memory. "One is that we have further pinpointed where to look for the root causes of amblyopia. The other is that we have now completely blown up what we thought was happening in stimulus-selective response potentiation, or SRP, the synaptic change believed to give rise to visual recognition memory."
The cortex is built like a stack of pancakes, with distinct layers of cells serving different functions. Layer 4 is considered to be the primary "input layer" that receives relatively unprocessed information that arises from each eye. Plasticity that is restricted to one eye has been assumed to occur at this early stage of cortical processing, before the information from the two eyes becomes mixed. However, while the evidence demonstrates that NMDA receptors in layer 4 neurons are indeed necessary for the degradation of vision in a deprived eye, they apparently play no role in how neural connections, or synapses, serving the uncompromised eye strengthen to compensate, and similarly don't matter for the development of SRP. That's even though NMDA receptors in visual cortex neurons have directly been shown to matter in these phenomena before, and layer 4 neurons are known to participate in these circuits via telltale changes in electrical activity.
"These findings reveal two key things," said Samuel Cooke, co-senior author and a former member of the Bear Lab who now has his own at King's College London. "First, that the neocortical circuits modified to enhance cortical responses to sensory inputs during deprivation or to stimuli that have become familiar reside elsewhere in neocortex, revealing a complexity that we had not previously appreciated. Second, the results show that effects can be clearly manifest in a region of the brain that are actually echoes of plasticity occurring elsewhere, thereby illustrating the importance of not only observing biological phenomena but also understanding their origins by locally disrupting known underlying mechanisms."
'We were stunned'
To perform the study, Bear Lab postdoc and lead author Ming-fai Fong and used a genetic technique to specifically knock out NMDA receptors in excitatory neurons in layer 4 of the visual cortex of mice. Armed with that tool, she could then investigate the consequences for visual recognition memory and "monocular deprivation," a lab model for amblyopia in which one eye is temporarily closed early in life. The hypothesis was that knocking out the NMDA receptor in these cells in layer 4 would prevent SRP from taking hold amid repeated presentations of the same stimulus, and would prevent the degradation of vision in a deprived eye as well as the commensurate strengthening of the unaffected eye.
"We were gratified to note that the amblyopia-like effect of losing cortical vision as a result of closing an eye for several days in early life was completely prevented," Cooke said. "However, we were stunned to find that the two enhancing forms of plasticity remained completely intact."
Fong said that with continued work, the lab hopes to pinpoint where in the circuit NMDA receptors are triggering SRP and the compensatory increase in strength in a non-deprived eye after monocular deprivation. Doing so, she said, could have clinical implications.
"Our study identified a crucial component in the visual cortical circuit that mediates the plasticity underlying amblyopia," she said. "This study also highlights the ongoing need to identify the distinct components in the visual cortical circuit that mediate visual enhancement, which could be important both in developing treatments for visual disability as well as developing biomarkers for neurodevelopmental disorders. These efforts are ongoing in the lab."
The search now moves to other layers, Bear said, including layer 6, which also receives unprocessed input from each eye.
"Clearly this is not the end of the story," Bear said.
IMAGE: A group of banded mongooses (Mungos mungo) enjoying morning sunshine at the study site, the Mweya peninsula in Western Uganda. view more
Credit: Emma Vitikainen
A new study on wild banded mongooses reveals that females may use spontaneous abortion to cope with reproductive competition, and to save their energy for future breeding attempts in better conditions.
Researchers at the University of Exeter, UK, followed a population of wild banded mongooses (Mungos mungo) in western Uganda for 15 years, using ultrasound imaging to track which females became pregnant and which carried to full term. They discovered that there were more abortions during the dry season when food was scarce, and also when more females were competing over reproduction in the same group. Individual females were less likely to carry to term if they were young, in poor condition, or carrying smaller fetuses.
"Reproduction takes a lot of energy, and for a female whose offspring may have slim chances at survival, it makes sense to delay that investment until times are better. Spontaneous abortion may be an adaptive strategy in this species because it enables females to save energy for the next breeding attempt," says researcher, and senior author of the study, Emma Vitikainen from the University of Helsinki.
Banded mongooses are cooperative breeders that live in family groups where several females give birth at the same time to a litter that is jointly cared for by all the group members. Underneath this seemingly harmonious surface, co-breeding females compete over whose offspring do best. Pups that are born bigger have more help from their group members, grow faster and outcompete their littermates.
This study revealed that females adjust their own investment in response to the competition, and that females whose offspring would be more likely to lose out are more likely to cut their losses by aborting their fetuses mid-pregnancy. Banded mongooses also curb competition by evicting younger females. To focus on spontaneous pregnancy loss the researchers only looked at breeding events where no violent eviction events occurred.
"Female competition over reproduction is easily overlooked," explains lead author Emma Inzani from the University of Exeter, UK. "Males fight with horns and antlers over access to females, whereas female competition can be much more subtle. Our study shows that even in the absence of overt aggression, females adjust their reproductive decisions in response to competition from other females. "
All research was done under ethical permits from University of Exeter and Uganda Wildlife Authority and study methods caused no harm to pregnant mongooses
Max Delbrück Center for Molecular Medicine in the Helmholtz Association
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IMAGE: Collage made from single cells expressing titin-GFP and titin-DsRed. view more
Credit: Gotthardt Lab, MDC
Using new high-resolution imaging techniques, MDC researchers and colleagues have tracked titin, the body's largest protein, in real time throughout its entire lifecycle. The method and results could provide new insight into muscle development as well as treating damaged muscles and heart disease.
As twinkling lights brighten the holiday season, Max Delbrueck Center for Molecular Medicine researchers are cheered by red and green lights for an entirely different reason. Using colorful probes, a team has tracked the full lifecycle of titin, the body's largest protein known to play a key role in muscle tissue. Observing titin from synthesis to degradation has provided novel insight into the formation of sarcomeres, the main contractile units of heart and skeletal muscle. The results were reported in the journal Proceedings of the National Academy of Sciences (PNAS).
Titin is such a large molecule that its analysis provides unique challenges. The team attached red and green fluorescent tags to opposite ends of the protein, enabling them to observe titin's precise movements in muscle cells derived from the mouse heart, called cardiomyocytes.
"Cardiomyocytes are highly specialized and cannot skip a beat," said Michael Gotthardt, who heads MDC's Neuromuscular and Cardiovascular Cell Biology Lab and spearheaded the research. "We can watch how titin is made and inserted into the myofilament while everything is still working. It's beautiful to see."
Not just a pretty picture
The insight gained from being able to watch titin in real time is significant. Titin has long been assumed to be the rigid backbone of sarcomeres, the basic functional segments of heart and skeletal muscles that expand and contract. It turns out that titin is much more dynamic than previously thought, Gotthardt said.
Heart muscle cells appear to have a pool of soluble titin spread throughout the sarcomere, ready to replace proteins damaged in the repetitive process of muscle expansion and contraction. Overextended proteins are moved out of the cells and then degraded. All of this happens over the course of a few hours, which sounds fast, but is actually much longer than for any other sarcomeric protein.
The large amount of titin located outside the sarcomere was as surprise, seen for the first time thanks to the new genetic mouse model and imaging technique, Gotthardt said. Another unexpected finding was the diversity of titin molecules, called isoforms, that were observed. Faster moving proteins are likely different isoforms than slower moving ones.
"This is a look at the real life of the sarcomere," Gotthardt said. "We can understand the formation and remodeling of the myofilament structure, which has relevance to human disease and development."
Potential applications
The fluorescent probes can help researchers study how muscles rebuild themselves after exercise, or how heart muscles remodel after a heart attack. They might also help to better understand heart diseases associated with mutations in other sarcomeric proteins, said Franziska Rudolph, first author of the paper.
"This is amazing, to follow endogenous titin variants in real time from start to finish," Rudolph said. "So many experiments are possible with these mouse models and different imaging techniques."
For example, the technique could potentially be used to track implanted cells to see how well they are integrating with the native muscle fiber, and if they properly connect with their new neighbors to work as a unit or not. Such insight could show if cell based therapies are effective.
Validating the novel tools and establishing methods for image analysis was a challenge and required the collaboration with colleagues from MDC's Berlin Institute for Medical Systems Biology, University Medical Center Goettingen, and the University of Arizona. The team worked hard to show how the fluorescent proteins, which are genetically generated, had no unexpected side effects on muscle or titin development and function.
MDC researchers are continuing to investigate titin with the new tools, including how skeletal muscles respond to exercise
The Max Delbrueck Center for Molecular Medicine (MDC)
The Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrueck, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC's mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent and fight it better and more effectively. In these efforts the MDC cooperates with the Charite - Universitaetsmedizin Berlin and the Berlin Institute of Health (BIH ) as well as with national partners such as the German Center for Cardiovascular Research and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers. http://www.mdc-berlin
Lazy/Unhelpful, Non-Dialogue, Pharmacy, Texas, USA |
Healthy | December 16, 2019
I have chronic nausea. I take a prescription nausea medication to keep it under control so I can eat and function. The nausea is related to stress, as well as my diagnosed depression and anxiety.
Six days ago at the time of writing, two days before Thanksgiving, my grandmother, who has to handle most phone calls for me due to my hearing issues, called the pharmacy to request a refill of my meds because I was almost out. Later, we got a call telling us that the refill request had been denied because my doctor’s office said I had to see the doctor before I could get a refill. I called the doctor the next day and was told that they had sent in an approval, but they would send another one to be sure.
Pharmacy still said they had no approvals, only a denial.
Thanksgiving came and the office was closed. I checked the pharmacy again, and they still said they only had a denial and couldn’t fill it.
Black Friday, same deal, but we got a call from someone at my doctor’s office informing us that they’d be closed until Monday. I only had enough of my meds to get me through Black Friday. I ended up skipping my second dose so I would have one for Saturday morning, and was unable to eat dinner on Friday.
Same deal with the pharmacy on both Saturday and Sunday. No approvals received, only one denial, and they still couldn’t fill it even though I was unable to eat or drink without it at this time. I even got on the phone myself and cry and beg the pharmacist to give me an emergency three-day supply that the law allows, and was told no because of the “denial.”
This morning, Cyber Monday, after going the entire weekend feeling like I was in Hell since eating was pretty much impossible, my grandmother called my doctor’s office to set up an appointment for the first time slot they could fit me into today.
She was informed that they absolutely did not send in a denial, I did not need to see my doctor before getting a refill, and that their system says I don’t have to see my doctor for a refill on my medication until sometime next year. My doctor knows that I need the medication every single day to be able to eat, and I’m about twenty pounds underweight right now due to stress-induced illness that lasted for three months solid, so I need to be able to get a refill at any time until I gain some weight back.
It turns out that someone at the pharmacy put it on my file that they were sent a denial and got no approvals whatsoever. A few hours ago, I got a text saying that I had a prescription ready for pickup, which would be done first thing in the morning because we couldn’t get to the store.
I have filed a complaint with corporate for the store the pharmacy is in, and my complaint has been forwarded to the store manager with the assurance that the incident will be investigated and that this absolutely should not have happened. The person I conversed with — via chat — was horrified about it.
I hope that pharmacist gets fired and feels proud of themselves for giving a disabled woman no less than five panic attacks over the course of three days and causing her a lot of unnecessary stress that has likely set back her recovery from illness. I won’t be able to fully enjoy Christmas with my family now because I’ll still be recovering and having trouble eating much food.
Bad Behavior, Hospital, Lazy/Unhelpful, Nurses, USA | Healthy | December 15, 2019
(I have a massive kidney stone trying to pass. I’m in the hospital, waiting for surgery to reduce the size. I suddenly have massive pain, bad enough my vision goes fuzzy. I’m crying, unable to really form words. I press my call button. After a moment, a nurse comes in.)
Nurse: “Can I help you?”
Me: “Pain… bad…”
Nurse: “On a scale of one to ten?”
Me: “Ten!”
(Because of the pain, I practically shout the number.)
Nurse: “You don’t need to raise your voice! I’ll get you something!”
(She leaves and comes back a minute later with a pill.)
Nurse: “Here’s some Tylenol.”
(All I can do is look at her, since that won’t be anywhere near enough for how my pain is.)
Nurse: “Well?! Take it!”
Me: “Need more…”
Nurse: “Ugh, you’re probably just a drug seeker! I’m not giving you anything else!”
(At this point, I just break down sobbing. She storms out. A few minutes later, my doctor comes in.)
Doctor: “Are you okay?!”
Me: “Pain bad… help…”
Doctor: “Okay, sweetie, I just need to know if you can tell me what number you’re at.”
Me: “Ten…”
Doctor: “All right. Do you want me to wait here while I have someone bring you medication?”
Me: “Please!”
(She does stay with me. After she calls the pharmacy, she holds my hand and talks to me to calm me back down. Once the medication is brought up and put into my IV, she makes sure it starts working.)
Doctor: “Your nurse said you were asking for drugs?”
Me: “No, I pushed my call light and told her I was in pain. She yelled at me saying that’s all I wanted and then left.”
Doctor: “She apparently thought you were faking something to get pain meds for an addiction. There’s no way you could fake a kidney stone on the imaging results. I’ll make sure you don’t have to deal with her anymore.”
(True to her word, I didn’t see that nurse for the rest of my stay.)
Health & Body, High School, Jerk, Louisiana, Parents/Guardians, USA | Healthy | December 13, 2019
(This event happens more than halfway through my junior year in high school. It’s important to note that prior to this, I have only missed about four or five days of school during my ENTIRE high school career, half of which were from when my grandmother died unexpectedly last year. This one particular morning, I wake up feeling like complete and utter crap. I also just so happen to have two major presentations today after lunch and my parents know about both of them. They basically have to fight to get me out of bed, accusing me of either lying or exaggerating to get out of my presentations. I manage to power through the first half of the day before breaking down at lunch and having my counselor essentially force my mother to come and get me. Naturally, she isn’t happy about it as she still thinks I’m purposefully trying to avoid my presentations.)
Mom: *in a very condescending tone* “I hope you’re prepared to go to the doctor. I’m bringing you back right after, too.”
(It’s very clear she’s trying to call my “bluff” and scare me into backing down, but I just quietly shrug. And just as she said, she brings me to a walk-in clinic near my school. After going through the standard procedure, the nurse seeing me takes a snot sample for a flu test.)
Mom: “I’m thinking it’s just a little cold at most.”
Nurse: “If that’s the case, we’ll probably just do a steroid shot, but let’s see the test results first.”
(She leaves and returns a few minutes later. To my mother’s surprise, the nurse is now wearing a procedure mask.)
Nurse: “So, he has the flu. We’re lucky y’all caught it within the first two days so we can write him a prescription for some Tamiflu that y’all can pick up at your preferred pharmacy. We’ll also give you a doctor’s note that says he can’t go to school until at least next Monday. Until then, make sure he gets plenty of rest and that he doesn’t have a fever for at least 48 hours prior to Monday.”
(My mother was horrified and ended up asking to have herself tested, too; she was negative. Although I feel bad for all my friends and classmates who sat by me that morning, I can’t help but gleefully remember my mom’s face when she realized that I wasn’t faking s***.)
(When my brother is around nine, he wakes up screaming in pain. As we have no vehicle of our own and no way of getting a taxi or a lift, my mother has to walk with a screaming child two kilometers to the hospital. She went to nursing school, but is not currently working as a nurse.)
Doctor: *after barely poking him* “Well, seems to be just some gas. He’s probably just using the pain to get attention.”
(My mother looks at her like she’s crazy, while my brother still cries and screams.)
Mom: “My son is not like that. Look, I am a nurse. I’m pretty sure he has appendicitis.”
Doctor: “Oh, nonsense. You don’t know what you are talking about.”
Mom: “But I do–”
Doctor: “Listen. I am a doctor. You are just a nurse. He is fine. Now leave.”
(My mother leaves the hospital furious. Not surprisingly, two days later, my brother’s appendix ruptures. My mom manages to get a passing car to take them to the hospital, and my brother has surgery. Because the hospital has no full anesthesia, they have to use local — the kind that only numbs the area — and my brother is operated on while awake and screaming. While he is still in surgery, my mother runs into the doctor in the hallway.)
Doctor: “Oh, you are here again. What, does your son have a headache now? It might be a tumor, don’t you think?”
(My mother almost attacked her, but her father entered the hospital on time and stopped her. My brother survived and made a full recovery, and my mother reported the doctor; unfortunately, nothing came out of it at the time, but a few years later she was forced into retirement for repeatedly misdiagnosing patients.)
California, Health & Body, Los Angeles, Medical Office, USA | Healthy | December 5, 2019
(I work at a non-profit rehab for teens as a counselor. During their lunch, a new resident is having a heated argument with other staff over her dietary restrictions.)
Teen: “I can’t eat this; it has cheese. I’m vegan.”
Staff: “We’re trying to accommodate. The cooks have been made aware and are working on fixing you something else.”
Teen: “You shouldn’t be eating this stuff. Do you know how badly dairy and meat harms your body? You guys are all disgusting.”
Me: *screaming internally* “You shouldn’t lecture anyone when you smoke meth!”
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