Posted by Margaret Donohue on December 20, 2015 at 11:15 AM
You don't know me and as a result my medical history will not be believed until it is. My tests tend to come back normal in spite of obvious symptoms of illness. I have a number of unusual medical conditions going back to birth, literally. Many of these are genetic and rare. They run in my family so I'm familiar with some of them, but the presentations never seem to match text book descriptions. So I'm not believed. I know that. I understand that. That doesn't make it correct. I'm part of a large number of patients with unusual, rare or atypical medical conditions. I am not alone.
So let me explain some things.
- I'm not stupid. If I tell you I'm sick, it's because I believe I am. It doesn't matter what the lab tests say, It doesn't matter what you're training says. Nothing in your experience will prepare you for the likes of me or other people like me. If you don't believe me, I'm not going to believe you. Telling me I can't have the symptoms I have won't help. I remember I was in the process of losing my airway and coughing. The physician at the ER didn't believe a breathing treatment would help. i think he said "it's stupid." After three minutes into a breathing treatment my coughing stopped and I could breath freely. He was surprised. He did the treatment only because I insisted.
- I live with these symptoms. You might want to take some time to understand them. Going with the first thing that pops in your head as a diagnosis doesn't inspire confidence. I had severe vomiting. The tests all came back negative doctor at the ER said "Maybe it's stress." No. Vomiting is not a symptom of stress. I had an atypical life threatening reaction to a medication I'd been on a long time. Not stress.
- Look at me. Get your face out of the computer, the chart and the lab findings, and actually look at me. If you have any understanding of clinical medicine, it might help if you look at the patient. My labs come back normal because I have low blood volume. I've been told I'm not anemic even when I was ghastly pale and fainting. I've been told I have no signs of infection even with pus coming out of my eyes. Look at me it might help you figure out what is wrong.
- I avoid seeing physicians unless I already have a good idea of what's wrong. I don't expect a physician to be able to diagnose me anymore. I have developed a low pain threshhold and a high pain tolerance and a higher tolerance for ambiguity. I started readng medical texts as soon as I could read. It's why I ended up studying medicine and working with a physician after I finished my education in psychology. It's a method for gaining some semblence of control. The alternative is to ignore any symptoms unless something explodes and I can't function any longer. Some people like me do that because it's easier, but we're sicker when we come to see you. We have a greater tendency to shun western medicine and are less likely to see it as helpful.
- Telling me, there's nothing wrong doesn't help. Asking why I waited so long to seek treatment doesn't help. I've had these two responses within 24 hours. I saw a doctor and said I had pneumonia. He said I didn't and sent me home telling me I had a cold. I went home. 18 hours later I went to the emergency room with 103 fever and both lungs full of fluid. The second doctor said I should have come in sooner and not waited so long. The first doctor was the chief physician at the medical group. I showed him the chest x-ray from the second physician.
There are millions of people with rare or unusual medical conditions. I'm not alone. Women with these conditions are more likely to seek treatment than men with these conditions. Women report more trauma as a result of these interactions. Men tend to be more avoidant of treatment and there is a resulting higher mortality rate.


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ask for help and a positive light could be shown on mental health, the world would be a more positive place and suicide would be less of a commonality. Social media and general media should be promoting more positive things, especially surrounding mental health to promote getting help. They should be portraying mental illness as something more positive and less of something that makes those will an illness any less than those without. Schools should be teaching a curriculum to promote the benefits of getting help and empower those who are dealingwith mental illnesses. They should teach better ways to deal with their illnesses and how to cope
with the various symptoms that they might be feeling. Health care should cover mental health to reduce the possibility of their conditions becoming something more. Help should be available to everyone. These changes need to be made to help destigmatize mental health to reduce the statistics of bad mental illnesses, suicides, and school shootings. Reductions in things like this can help cause a more positive, less anxiety-filled society so media can report more positive things.
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CXR: There is a nasogastric tube terminating in the patient's mid-esophagus; repeated attempts failed to pass the tube. The abdomen is distended and gasless.
U/S: There is significant distension of a fluid-filled stomach.
MRI: There is dilatation of the stomach and proximal duodenum, producing a "double bubble" appearance. The distal esophagus also appears distended.
Combined duodenal and esophageal atresia without tracheoesophageal fistula.
The combination of esophageal and duodenal atresia is a rare but well-known association. This combination is most often associated with a tracheoesophageal fistula. Combined esophageal and duodenal atresia with absence of tracheoesophageal fistula, as demonstrated in this case, is even more rare; yet this entity exhibits a constellation of radiographic features considered to be virtually pathognomonic.
Clinically, the diagnosis of esophageal atresia is established by the failure to pass a nasogastric tube. The chest x-ray confirms that the tube tip is in the mid-esophagus, and the gasless abdomen reflects the absence of tracheoesophageal fistula. However, duodenal atresia, which is commonly a plain film diagnosis on the basis of a gas-distended stomach and proximal duodenum (the so-called "double bubble"), cannot be diagnosed on this study because of the lack of communication of the air-filled esophagus with the stomach and duodenum.
Thus, the ultrasound study establishes the additional diagnosis of duodenal atresia, with massive accumulation of secretions within the closed loop involving the distal esophagus to the duodenum. This distension is far greater than would be seen in duodenal atresia alone.
This case is of special interest because of the availability of a prenatal MRI study. Could the diagnosis have been made prenatally? The MRI clearly demonstrates duodenal atresia with "double bubble" distension of the stomach and proximal duodenum. However, the diagnosis of esophageal fistula is difficult to make prospectively on MRI. In this case the proximal esophagus is not dilated, as one might expect in esophageal atresia, although a review of fetal thoracic MRI by Levine et al. suggests that distension of the proximal esophagus is not a reliable finding for esophageal atresia. Perhaps more useful in this case is the observation of distal esophageal distension, reflecting reflux of secretions into the blind-ending lower segment of esophagus. However, the specificity of this finding is uncertain. To our knowledge, no case of prenatal MR imaging of combined esophageal and duodenal atresia has been reported in the literature.
In summary, the combination of duodenal and esophageal atresia without tracheoesophageal fistula is a rare but known clinical entity. The diagnosis is important to make because of significant associated morbidity and mortality; this patient had no associated congenital abnormalities and underwent successful staged surgical repair. From an imaging standpoint, the case is of particular interest because of the need for multimodality imaging to establish the complete diagnosis.
Crowe JE, Sumner TE. Combined esophageal and duodenal atresia without tracheoesophageal fistula: characteristic radiographic changes. Am J Roentgenol. 1978 Jan;130(1):167-8.
Hayden CK Jr, Schwartz MZ, Davis M, Swischuk LE. Combined esophageal and duodenal atresia: sonographic findings. Am J Roentgenol. 1983 Feb;140(2):225-6.
Levine D, Barnewolt CE, Mehta TS, Trop I, Estroff J, Wong G. Fetal thoracic abnormalities: MR imaging. Radiology. 2003 Aug;228(2):379-88.
McCook TA, Felman AH. Esophageal atresia, duodenal atresia, and gastric distention: report of two cases. Am J Roentgenol. 1978 Jul;131(1):167-8.
We welcome your feedback, please send questions and comments to Marcel Maya, MD


Our Emergency Medical Team has flown to Malawi to provide assistance to the Malawi Ministry of Health, after a major cholera outbreak. One of the poorest countries in the world, the healthcare system in Malawi needs extra support to increase capacity as cases rise.
Health professionals are concerned about the impact cyclone season will have on the outbreak. There is a significant risk that the next two months could bring extreme weather, leading to destruction of health infrastructure and large numbers of displaced people without access to medical care.
Cholera is endemic in Malawi with seasonal outbreaks reported regularly, but this instance is rapidly becoming the most devastating in over 20 years. The latest outbreak began in the southern region following a tropical storm in January 2022. Flooding led to population displacement and a lack of adequate access to safe water and sanitation, creating ideal conditions for the spread of the disease.
Since then, the outbreak has grown in case numbers as well as geographical spread, despite vaccination campaigns taking place across the country. As of February 2023, a total over 1000 deaths have been reported. Mortality rates are particularly high in the capital of Lilongwe, where roughly 50% of nationwide deaths have occurred over the last few days.
UK-Med, as partners of the UK EMT, is providing emergency medical support alongside partners already working to address the critical needs brought on by the cholera outbreak.
Our team is providing early detection and identification of cholera cases and delivering care to patients with the disease.
We are strengthening local staff and health facilities to better manage and respond to the outbreak by providing training and mentoring in case management, water and sanitation practices, and infection prevention
We are providing local health teams with specialist cholera kits and essential supplies, to ensure they are well equipped to tackle this ongoing emergency.
We’re grateful to the Foreign, Commonwealth & Development Office (FCDO) for UK Aid funding from the British people to fund this important response.


Bangalore has become a favoured destination not only for IT / BT but also international patients who need high risk procedures. The confidence in the medical community is high and it works out very cheap for them. Added to it is the advantage of the great weather. A Case report to highlight this.
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Disclosures Drs Hayes and Jacober are employees and stockholders of Eli Lilly and Company. Dr Fitzgerald is a consultant to Eli Lilly and Company.
Primary care physician beliefs about insulin initiation in patients with type 2 diabetes
Article first published online: 3 APR 2008
© 2008 Eli Lilly & Company. Journal compilation © 2008 Blackwell Publishing Ltd
International Journal of Clinical Practice
Volume 62, Issue 6, pages 860–868, June 2008
How to Cite
Hayes, R. P., Fitzgerald, J. T. and Jacober, S. J. (2008), Primary care physician beliefs about insulin initiation in patients with type 2 diabetes. International Journal of Clinical Practice, 62: 860–868. doi: 10.1111/j.1742-1241.2008.01742.x
Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2·5, which does not permit commercial exploitation.
- Issue published online: 3 APR 2008
- Article first published online: 3 APR 2008
- Paper received January 2008, accepted February 2008
Background: Insulin is the most effective drug available to achieve glycaemic goals in patients with type 2 diabetes. Yet, there is reluctance among physicians, specifically primary care physicians (PCPs) in the USA, to initiate insulin therapy in these patients.
Aims: To describe PCPs’ attitudes about the initiation of insulin in patients with type 2 diabetes and identify areas in which there is a clear lack of consensus.
Methods: Primary care physicians practicing in the USA, seeing 10 or more patients with type 2 diabetes per week, and having > 3 years of clinical practice were surveyed via an internet site. The survey was developed through literature review, qualitative study and expert panel.
Results: Primary care physicians (n = 505, mean age = 46 years, 81% male, 62% with > 10 years practice; 52% internal medicine) showed greatest consensus on attitudes regarding risk/benefits of insulin therapy, positive experiences of patients on insulin and patient fears or concerns about initiating insulin. Clear lack of consensus was seen in attitudes about the metabolic effects of insulin, need for insulin therapy, adequacy of self-monitoring blood glucose, time needed for training and potential for hypoglycaemia in elderly patients.
Conclusions: The beliefs of some PCPs are inconsistent with their diabetes treatment goals (HbA1c ≤ 7%). Continuing medical education programmes that focus on increasing primary care physician knowledge about the progression of diabetes, the physiological effects of insulin, and tools for successfully initiating insulin in patients with type 2 diabetes are needed.


10 Key Questions About Lupus
How does lupus progress?
Some people with lupus will live a fairly normal life while others may face more life-threatening situations. Since the disease varies greatly from one person to the next, it is difficult to say how the disease will progress over time.
Most people with lupus experience a relapsing and remitting disease course where symptoms appear again or get worse and then go away for a period of time. It is difficult to predict whether each case will be relatively harmless or produce life-threatening complications.
Some of the more serious complications of lupus include:
- Kidney disease that might require dialysis
- Heart inflammation (myocarditis), which can lead to chronic heart failure
- Lung disease called pulmonary hypertension
- Hardening of the arteries (atherosclerosis), which can lead to heart attack
- Involvement of the brain, which can cause a variety of neurologic problems
Last Updated: 12/13/2007 |
Last Reviewed: 05/05/2008
This section created and produced exclusively by the editorial staff of HealthTalk. © 2009 EverydayHealth.com; all rights reserved.


A large Canadian cohort provides insights into the genetic architecture of human hair colour
Researchers performed genome-wide association studies and meta-analyses to garner insight on regulatory mechanisms of hair colour variation and pigmentation biology. 12,996 genotyped CanPath participants were included in this study, along with their self-reported natural hair colour. The researchers fine-mapped significant loci throughout the genome, identifying multiple novel causal variants for hair colour.
Metabolomics and cancer preventive behaviors in the BC Generations Project
To better understand links between behaviours and cancer, researchers measured metabolites in blood samples from 1,319 BC Generations Project participants. The study found a large number of metabolites were different between health behaviours. Highlights include lower levels of metabolites that are involved in pathways that play a role in cancer development among participants who consumed more fruits and vegetables and had a healthy body weight.
The National Cancer Institute Cohort Consortium: An International Pooling Collaboration of 58 Cohorts from 20 Countries
The NCI Cohort Consortium was founded in 2001 and brings together 58 cancer epidemiology cohorts from 20 countries to undertake large-scale pooling research. This article outlines the structure, governance, methods of working, and the participating cohorts (including CanPath), publications and activities of the consortium.
Metabolic profiling of adherence to diet, physical activity and body size recommendations for cancer prevention
This study examined cross-sectional associations between metabolites and cancer preventive behaviors as well as the relevance to cancer-related pathways among 120 participants with no history of smoking or cancer. Cancer preventive behaviors were associated with complex metabolic signatures, including alterations in pathways known to be involved in cancer pathogenesis.
Allele-specific expression reveals interactions between genetic variation and environment
Combining whole-blood RNA-seq with extensive environmental annotations collected from 922 human individuals, we identified 35 GxE interactions, compared with only four using standard GxE interaction testing. EAGLE provides new opportunities for researchers to identify GxE interactions using functional genomic data.
Dietary assessment is a critical element of health research – Perspective from the Partnership for Advancing Nutritional and Dietary Assessment in Canada
This was an opinion based paper which argued that while assessing dietary intakes is difficult, it`s not impossible. They believe that building capacity and funding opportunities should be readily available in order to build research. If they were to have these, there would be better understanding in Canada and elsewhere.
Cohorts and consortia conference: a summary report (Banff, Canada, June 17–19, 2009)
This discussed how various cohort studies can build a strong network of research.


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A concept that deals with dysfunctions affecting several central organs, such as the heart, brain lungs, muscles, and joints, which are long overdue to develop symptoms and illness—examples of techniques from Facial Reflexology and additional techniques to balance.
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Recent years have witnessed transformative advances in the ability to profile distinct biological features at the resolution of single-cells, which has reverberated across biology and medicine. These breakthroughs encompass new microfluidic techniques, molecular advances in next-generation sequencing approaches, and the development of computational platforms to analyse sequencing information at massive scale. All these gave us the ability to profile the genome (DNA sequencing), transcriptome (RNA-Sequencing), epi-genome (ATAC-Sequencing, DNA methylation sequencing) at single cell resolution leading to a deluge of novel information on the biological make up of a number of cell types, tissues and even whole organisms. The field of human health has used such sequencing and analytic approaches to start profiling normal and disease states, leading to significant breakthroughs in our understanding of how disease loos at the single cell level. Such tools are now applied to human genetics, immunity, infection and the understanding of cancer, to mention just a few areas of intense interest. The main focus of this conference will be to explore of how these methodological advances in single cell biology can impact our understanding of human disease, and lead to the introduction of novel therapies. Our goal is to bring together both single cell biologists and human health leaders, to spark new interactions, collaborations and generate ideas that will lead to future clinical trials and cures. We also aim to highlight new technical breakthroughs in the areas of sequencing and protocol development, sample preparation, and data analysis. As the field is progressing at warp speed it will important to hear from leaders in the field of single cell technology development and understand new directions and future applications. Finally, our objective is to see how such new technical developments can be applied to the study of human disease, opening a window on genomic medicine of tomorrow.
Chaired by: Iannis Aifantis (NYU School of Medicine) and Rahul Satija (New York Genome Center)


Potential Side Effects from a Stem Cell Transplant for Non-Hodgkin Lymphoma
The early side effects of a stem cell transplant aren’t from the transplant, but rather from the high-dose chemotherapy and radiation. These can be serious, but they should go away over time while you are recovering from the transplant. You may also experience a strange taste in your mouth from the preservative used to freeze the stem cells. These are some common side effects. They vary depending on whether or not you received your stem cells from a donor. Ask your doctor which ones may be most likely for you:
Other side effects may appear years later or be long-lasting. These are possible long-term side effects:
Graft-versus-host disease (GVHD), a possible side effect only of allogeneic (donor) transplants. This condition occurs if the immune cells in the donor’s stem cells attack your skin, liver, gastrointestinal tract, mouth, or other organs. The symptoms include severe skin rashes with itching, severe diarrhea, fatigue, and muscle aches. Mild GVHD can be a good thing as it attacks any remaining lymphoma cells as well, but more severe GVHD may be debilitating or even life-threatening.


A doctor aide in the USA, Canada as well as several other nations name themselves a Doctor Aide or PA. Some likewise work as a clinical biller. This project calls for referring to as people for the insurance provider to refine cases. The task explanation of a medical professional aide differs through condition yet typically is composed of aiding doctors, registered nurses and physicians. Some additionally provide companies such as teaching individuals on their medical condition and therapies, clearing away sutures used on wounds and helping them along with dressing themselves.
Lots of people are wanting to load this ranking as the task market in this particular nation is not good. Various other nations all over the world are making the transition coming from private practice to the public field as well as are experiencing far better development in their economic situations. As additional medical care professionals begin to focus on a specific place of medicine, the necessity for aides will raise. Some PAs will begin functioning directly along with physicians while others will certainly be actually advertised by means of instruction to become a doctor’s associate or a nurse’s aide.
They are typically the very first point of contact for individuals as well as their families. If they do not possess a lot instruction in nursing or medicine, PAs will frequently function as the major connect with individual for both people and also their family members.
A physician aide assists medical professionals do their obligations and aids make certain that clients obtain high quality healthcare. The scope of their job varies greatly relying on where they work. Some operate in medical facilities, while others concentrate on private practice. Private practices could be either hospital or even private practice depending on the environment.
Some positions demand passing a qualified requirements exam. These examinations are actually likewise needed of all members of the clinical field as well as this physical examination is actually called for of PAs too. If you want to assist pass this assessment, PAs must know as high as they can easily about the daily operations of the physician’s office. They will definitely also need to show that they have the capacity to adhere to the medical professional’s instructions and also assistance individuals along with their issues.
PAs can also deliver a support group for the healthcare crew. Their part is actually incredibly crucial to the overall health care group. They are usually the basis of the healthcare staff and may be counted on to aid supply clients along with fundamental solutions. This consists of supporting physicians along with necessary indicators as well as keeping an eye on clients’ drugs. Associates can also aid deal with the individual’s drugs at home. They can ask for prescriptions or even have chats with pharmacists on people’ drugs.
Along with some training, a doctor aide can easily additionally concentrate in a specific location of medication. PAs may likewise get proceeding education and learning credit histories each year, which enables all of them to extend their ability collection as well as become even much more knowledgeable about the health and wellness treatment market.
If they choose to seek this career, doctor aides may damage into the health care field swiftly and also effortlessly. A lot of colleges possess lots of opportunities for these kind of graduates. Once they finish, many additionally possess progress courses standing by for all of them. This allows all of them to discover a task as soon as they feel prepared as well as to carry on a healthcare career that is actually monetarily gratifying and also meeting.
Although a medical professional associate can easily execute numerous responsibilities, they are actually primarily referred to as call individuals for doctors, doctors, and also other qualified medical care experts Therefore, there is commonly a big demand for their services, both in terms of hrs as well as kind of company required. An associate might be hired to manage rings regarding their people, response inquiries coming from people, or merely give their people paths on where to opt for procedure.
As a medical doctor aide, patients usually assume you to become helpful and reliable. You are going to likely communicate with a few of one of the most necessary folks in a patient’s daily life. You are heading to must get along and client, but you must also reveal your expertise of the health care area concurrently. This will take some skill, and also your personality should be comfortable with dealing with tough clients. The potential to work without bacteria is actually necessary at the same time, given that you will likely handle patients that have a variety of conditions, and it is your duty to maintain them well-balanced. Karl Simon
If this sounds like a wonderful job for you, take a look at some university systems to get a tip of what the requirements are actually. You should have the ability to locate a healthcare occupation that suits your finances and passions, given that this is actually an expanding field. The future seems intense for this impressive job, and also many people have actually begun their personal effective medical technique after specializing as an aide. This can be actually a fantastic selection for you if you have a passion and an enthusiasm for aiding individuals.
A medical professional assistant in the U.S., Canada as well as a lot of various other countries decide on physician assistant or accredited qualified medical doctor aide as their profession. This is actually given that it gives them a functional experience that may be applied in the place of work or even in the several medical care organizations. Additionally, this sort of expert associate likewise has the possibility to function abroad to enable all of them to know the society of the nation they are actually functioning in.
Medical professional aides are the ones that offer consultation to medical professionals and specialists during the course of client examinations and also surgical procedures. If the surgeon determines that the individual calls for surgical procedure, they will certainly handle the information of supplying the required medication to the person or aiding the patient while they are being run upon.
A traditional day of work for this kind of worker is made up of delivering consultation to doctors, doctors and also other medical team and also recording essential signs of the individuals. They have to aid the medical doctors to relocate people to the surgery region.
The role of a medical care aide is not limited to helping medical professionals in their job but they can broaden their scope of work. They can increase their scope of process by conducting various other jobs connected to individual treatment. This can easily be actually carried out through operating along with clinics, medical centers and also outpatient health care. The healthcare assistants may use their solutions to any sort of person who needs their support. Although some aides are actually needed to partner with patients only, they can also function independently and in alliance with other healthcare professionals.


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Amonafide is an investigational drug.
There have been 5 clinical trials for Amonafide. The most recent clinical trial was a Phase 2 trial, which was initiated on June 1st 2007.
The most common disease conditions in clinical trials are Leukemia, Myeloid, Leukemia, and Leukemia, Myeloid, Acute. The leading clinical trial sponsors are Antisoma Research, Xanthus Pharmaceuticals, Inc., and Memorial Sloan Kettering Cancer Center.
Recent Clinical Trials for Amonafide
|A Pharmacokinetic and Efficacy Study of Amonafide L-malate (AS1413) in Combination With Cytarabine in Patients With Acute Myeloid Leukemia (AML)||Antisoma Research||Phase 2|
|Phase III Randomized Study of Amonafide (AS1413) and Cytarabine Versus Daunorubicin and Cytarabine in Patients With Secondary Acute Myeloid Leukemia (AML)- the ACCEDE Study||Antisoma Research||Phase 3|
|Amonafide in Combination With Cytarabine in Secondary AML||Xanthus Pharmaceuticals, Inc.||Phase 2|


The involvement of P2Y receptors, which are activated by extracellular nucleotides, in proliferative regulation of human lung epithelial cells is unclear. Here we show that extracellular ATP and UTP stimulate bromodeoxyuridine (BrdU) incorporation into epithelial cell lines. The nucleotide efficacy profile [ATP = ADP > UDP ≥ UTP > adenosine ≥ 2-methylthioadenosine-5′-diphosphate, with α,β-methylene adenosine 5′-triphosphate, 2′,3′-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate, AMP, UMP, and ATPαS inactive] and PCR analysis indicate involvement of P2Y2 and P2Y6 receptors. The signal transduction pathway, which, via the P2Y2 receptor, transmits the proliferative activity of ATP or UTP in A549 cells downstream of phospholipase C, depends on Ca2+/calmodulin-dependent protein kinase II and nuclear factor-κB, but not on protein kinase C. Signaling does not involve the mitogen-activated protein kinases extracellular signal-regulated kinases-1 and -2, the phosphatidylinositol 3-kinase pathway, or Src kinases. Thus nucleotides regulate proliferation of human lung epithelial cells by a novel pathway. The stimulatory effect of UTP, but not ATP, in A549 cells is attenuated by preincubation with interleukin-1β and interleukin-6, but not tumor ncerosis factor-α. This indicates an important role for the pyrimidine-activated P2Y receptor in the inflammatory response of lung epithelia. ATP antagonizes the antiproliferative effect of the anticancer drugs paclitaxel and etoposide, whereas it enhances the activity of cisplatin about fourfold. Thus pathways activated by extracellular nucleotides differentially control proliferation of lung epithelial tumor cells.
- purinergic receptors
- extracellular nucleotides
extracellular nucleotides activate epithelial cells in many organs and tissues under physiological and pathological conditions (2, 37, 46). The nucleotides ATP and UTP are released from airway epithelial cells on the apical and basolateral sides in response to cell swelling (43) or mechanical stimuli (11, 27, 48). The released ATP or UTP, in an autocrine or paracrine fashion, controls cell volume through Cl- and fluid secretion (17, 22, 41, 43), mucociliary clearance (mucin, salt, and water secretion) (28, 33), or intracellular Ca2+ oscillations (8) and coordinates responses of distant airway cells by modulating intercellular communication (12, 18) and ciliary beat frequency (35).
The effects of ATP and UTP are mediated through the metabotropic P2Y receptor family. The subtypes, P2Y1, P2Y2, P2Y4, P2Y6, and P2Y13 receptors, are expressed in human lung (37, 50). In airway epithelial cells, extracellular nucleotides regulate physiological functions via phospholipase C activation and subsequent inositol 1,4,5-trisphosphate formation, mainly through P2Y2 and P2Y1 receptors (8, 12). The P2Y2 receptor, which responds equally to extracellular UTP and ATP, is expressed at the apical side of human airway epithelial cells (26). Moreover, diadenosine polyphosphates can activate a Ca2+ increase in human lung epithelial cells via purinergic receptors (24, 25). There is no direct evidence of a role for P2X receptors in regulation of airway ion transport activities. However, it has been proposed that, in tubes and sacs of gallbladders and in the lung, tension leads to release of ATP from the lining epithelium, which then acts on P2X2 and P2X3 receptors of subepithelial sensory nerves to convey information to the central nervous system (2).
Recently, extracellular nucleotides have emerged as regulators of tumor proliferation and possible effectors of neoplastic transformation. In carcinoma tissues, not only is ATP released during chemotherapy (23), it also controls proliferation of various tumor cells. Depending on the subtype(s) of P2Y receptor expressed, P2Y receptors facilitate proliferation, as in C6 glioma cells (44) and breast cancer cells (47), or inhibit cell proliferation, as reported for endometrial cells (20), colon (13), or esophageal cancer cells (31). However, the mitogenic actions of extracellular nucleotides on airway epithelial cells have not been investigated. This is especially important for understanding lung tumorigenesis. Moreover, the actions of the extracellular nucleotides, in concert with cytokines and epidermal growth factor (EGF), which are known to tightly control proliferation of tumor cells, remain to be clarified.
Extracellular nucleotides have been reported to regulate proliferation of several cancer cell lines (13, 31, 47). ATP inhibits weight loss in tumor-bearing murine hosts (38). Moreover, clinical studies have indicated that, in patients with advanced lung cancer, ATP 1) may inhibit weight loss and suppress tumor growth and 2) displays protective effects against radiation tissue damage (reviewed in Ref. 3).
We therefore examined the effect of extracellular nucleotides on proliferation of tumorigenic and nontumorigenic human lung epithelial cell lines. Proliferation of the tumorigenic A549 cells and the nontumorigenic BEAS-2B cells is stimulated by the purine nucleotide ATP and the pyrimidine nucleotides UTP and UDP through activation of the P2Y receptor subtypes P2Y2 and P2Y6 receptors. P2Y2 receptor-induced A549 tumor cell proliferation depends on activation of phospholipase C, Ca2+/calmodulin-dependent kinase II (CaMKII), nuclear factor-κB(NF-κB), and, possibly, EGF receptor (EGFR) tyrosine kinase. This new pathway directly stimulates cell cycle progression, as indicated by the specific interference of ATP with the cytostatic actions of paclitaxel, etoposide, and cisplatin.
MATERIALS AND METHODS
Cell culture and reagents. The human lung cancer cell line A549 was obtained from the German Collection of Micro-organisms and Cell Cultures (DSMZ, Braunschweig, Germany), and the noncarcinogenic human lung cell line BEAS-2B was kindly provided by Dr. F. Bühling (Otto-von-Guericke University). A549 human non-small cell lung cancer cells were cultured in DMEM (Biochrom) supplemented with 5% fetal calf serum, 100 IU/ml penicillin, and 100 μg/ml streptomycin in a 10% CO2 incubator at 37°C. The BEAS-2B cells were cultured in DMEM supplemented with 10% fetal calf serum, 100 IU/ml penicillin, and 100 μg/ml streptomycin in a 10% CO2 incubator at 37°C.
The anticancer drugs paclitaxel, etoposide, and cisplatin were purchased from Calbiochem (Bad Soden, Germany). U-73122 and its inactive enantiomer U-73343, N-nitro-l-arginine, chelerythrine, SB-203580, wortmannin, AG-1478, NS-398, 8-cyclopentyl-1,3-dipropylxanthine, CGS-15943, alloxazine, suramin, reactive blue-2 (RB-2), pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), ARL-67156, adenosine 3′-phosphate 5′-phosphate (A3P5P; Sigma), KN-62, GF-109203X, PD-908059, PP-2, methyl arachidonyl fluorophosphonate (Bio-Trend), genistein, SKF-96365, indomethacin, and NF-κB SN-50 (Calbiochem) were dissolved according to the recommendations of the manufacturer in dimethylsulfoxide or in phosphate-buffered saline to give a stock concentration of 10 or 100 mM. The cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were obtained from Roche.
RNA extraction and RT-PCR for detection of P2Y receptor subtypes. Total RNA was isolated from A549 and HEK-293 cells with the RNeasy kit (Qiagen). HEK-293 cells were used to verify the usefulness of the primers chosen for PCR and to control the RT-PCR conditions, because HEK-293 cells endogenously express P2Y1, P2Y2, and P2Y4 receptors. The isolation included a DNase treatment to remove contaminating DNA. RT was performed with 1 μg of total RNA using oligo(dT) primer with the Omniscript kit (Qiagen). For amplifying the P2Y receptor cDNAs, sets of specific oligonucleotide primers were synthesized on the basis of the published sequences for P2Y1, P2Y2, P2Y4, and P2Y6 receptors (see below). Because the P2Y4 receptor has only one exon and the P2Y6 receptor has two exons, primers were defined, flanking the intron of P2Y6 (exon 1 = 156–242, exon 2 = 243–1,563). PCR without the RT step was used as control to exclude amplification of genomic DNA. Amplification was performed with 1 μl of cDNA, and the conditions were as follows: 98°C for 2 min, 94°C for 1 min, 55°C for 90 s, 72°C for 2 min, and a final extension step of 10 min at 72°C for 30 cycles.
The primers were 5′ GCC GCC GTC TCC TCG TCG TT 3′ (forward, position 146–166) and 5′ CCA TTC TGC TTG AAC TCA G 3′ (reverse, position 1133–1152) with 1,006 bp for hP2Y1 (accession no. U42029), 5′ CGA GGA CTT CAA GTA CGT GC 3′ (forward, position 329–349) and 5 ′GTT CTC GCT ACC AGC CGG CG 3′ (reverse, position 1338–1358) with 1,030 bp for hP2Y2 (accession no. U07225), 5′ GCT GCC TGT GAG CTA TGC AG 3′ (forward, position 110–140) and 5′ GAG CTG ACG GAG CTG ACG TCG′ (reverse, position 939–960) with 850 bp for hP2Y4 (accession no. X91852), and 5′ GTT CAG GCT GAG GAG ATG 3′ (forward, position 201–219) and 5′ GGA AGC TGA TGC AGG TGA 3′ (reverse, position 623–643) with 442 bp for hP2Y6 (accession no. U52464).
Determination of cell proliferation. Cell proliferation was measured by luminometric immunoassay based on BrdU incorporation during DNA synthesis using a cell proliferation enzyme-linked immunosorbent assay BrdU kit (Roche, Mannheim, Germany) according to the manufacturer's protocol. Briefly, A549 or BEAS-2B cells were seeded at a density of 3 × 103 cells/well on 96-well plates and incubated for 24 h. Cells were then incubated with the different nucleotides or nucleotide analogs at 100 μM (standard conditions) for 1 h in a final volume of 100 μl/well. For each concentration as well as the controls, three wells were used. Subsequently, 10 μl of BrdU-labeling solution were added to each well, and the cells were incubated again for 12 h. The different antagonists were added to the cells 1 h before addition of the nucleotides. After removal of the BrdU-labeling solution, cells were washed with 100 μl of phosphate-buffered saline, dried for 1 h at 60°C, and then incubated with the kit's FixDenat solution for 45 min at room temperature. Denaturation of the DNA is necessary to improve the accessibility of the incorporated BrdU for detection by antibody. Samples were incubated for 90 min with peroxidase-conjugated anti-BrdU antibody, which binds to BrdU incorporated into newly synthesized cellular DNA. After the unbound peroxidase-conjugated anti-BrdU-antibody was washed off the samples, 100 μl of the luminescence substrate was added, the generation of the signal was allowed to develop for 3–5 min under gentle shaking, and the luminescence was quantified using a microplate luminometer (Spectrafluorplus, Tecan).
Data analysis. Proliferation data refer to the chemiluminescence values of BrdU-labeled cellular DNA content per well. Stimulation is expressed as x-fold proliferation over basal value, where basal growth of the untreated control was set at 1.0, or as percentage of nucleotide-stimulated proliferation. In the latter case, the difference between the values of the untreated control and the values of the nucleotide-stimulated samples was taken as 100%. Unless indicated otherwise, values are means ± SD from at least three independent experiments.
Regulation of epithelial lung tumor cell proliferation by extracellular nucleotides. To investigate the effects of extracellular nucleotides on proliferation of human lung tumor cells, proliferating A549 cells were pulse stimulated with ATP or UTP. Then cell proliferation was measured by monitoring BrdU incorporation into newly synthesized DNA for 12 h after addition of nucleotides. ATP and UTP induced a concentration-dependent increase in proliferation of A549 cells. The maximal stimulation, which was seen at 100 μM nucleotide, was 3.2-fold for ATP and 1.8-fold for UTP (Fig. 1A). Despite the difference in maximal stimulation, the potency of both nucleotides to stimulate proliferation was very similar, with EC50 of 26.0 ± 2.8 μM(n = 3) for ATP and 31.3 ± 4.1 μM (n = 3) for UTP.
The effect of the nucleotides on BrdU incorporation into A549 cells was time dependent. The maximal stimulatory effect by ATP and UTP was reached at 1 h after addition of the nucleotides and lasted for 3–6 h (Fig. 1B). Incorporation of BrdU into newly synthesized DNA rapidly declined to baseline values at >6 h after nucleotide addition. This indicates that extracellular nucleotides stimulate DNA synthesis by direct interaction with cell cycle progression.
Besides ATP and UTP, the diphosphate nucleotides ADP and UDP also stimulated BrdU incorporation into proliferating A549 cells with an efficacy nearly identical to that of the respective triphosphate nucleotides (Fig. 2A). At 100 μM, ADP and UDP enhanced proliferation of A549 cells 3.1- and 2.2-fold, respectively.
To determine whether the stimulatory effect of extracellular nucleotides on proliferation of A549 lung tumor cells was associated with neoplastic transformation of the cells, we also investigated the effect of nucleotides on proliferation of the nontumorigenic human epithelial lung cell line BEAS-2B. BEAS-2B and A549 cells serve as in vitro models for bronchiolar and alveolar cells, respectively.
Enhancement of proliferation by extracellular nucleotides was even stronger in the BEAS-2B cells than in the A549 cells. Here, 100 μM ATP and 100 μM ADP stimulated BrdU incorporation into newly synthesized DNA 7.1- and 6.5-fold, respectively (Fig. 2B). The pyrimidine nucleotides UTP and UDP exhibited identical efficacy and induced a 3.2- and 3.4-fold stimulation, respectively (Fig. 2B). Thus purine and pyrimidine nucleotides may regulate human lung epithelial cell proliferation in vivo. Moreover, control of proliferation by nucleotides is not due to transformation of lung epithelial cells, because proliferation of tumorigenic and nontumorigenic airway cells is equally affected.
To evaluate whether the trophic actions of the extracellular nucleotides on the human lung cells were mediated by the P2Y or the P2X receptors, proliferative regulation of A549 and BEAS-2B cells was investigated by using different nucleotides, nucleotide analogs, and P2 receptor antagonists. Characterization of A549 cell proliferation revealed that only ATP, ADP, UTP, and UDP, which stimulate different P2Y receptor subtypes, were active, but the P2Y1 receptor-selective analogs 2-methylthioadenosine 5′-diphosphate (2-MeS-ADP) and ATPαS and the P2X receptor-activating nucleotides α,β-methylene adenosine 5′-triphosphate (α,β-MeATP) and 2′,3′-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate (BzATP) were inactive (Fig. 2). AMP and UMP at up to 100 μM also had no effect on proliferation (data not shown).
The efficacy of the different nucleotide ligands was as follows: ATP = ADP > UDP ≥ UTP > 2-MeS-ADP, whereas α,β-MeATP, BzATP, AMP, UMP, and ATPαS were inactive. This clearly shows that stimulation of A549 cell proliferation is mediated by P2Y, but not by P2X, receptors, inasmuch as α,β-MeATP and BzATP, which, in addition to ATP, can activate P2X receptors (P2X1, P2X2, P2X3, P2X7) (21), have no influence on proliferation (Fig. 2). In addition, the lack of activity of 2-MeS-ADP and ATPαS indicates that in A549 cells no functional P2Y1 receptors are involved. However, the pharmacological profile suggests involvement of more than one P2Y receptor in stimulation of A549 cell proliferation, because the profile is not consistent with the properties of a single P2Y receptor subtype (46).
We further attempted to identify the P2Y receptor subtypes involved by applying the P2 receptor-selective antagonists PPADS, suramin, RB-2, and ARL-67156. Preincubation of A549 cells with 100 μM suramin or RB-2 inhibited ATP-stimulated proliferation to 37 ± 8.4% (n = 4) and 45 ± 4.5% (n = 3), respectively (Table 1). There was no significant inhibition of ATP-stimulated proliferation by PPADS, which predominantly inhibits the human P2Y1 and P2Y4 receptors or the P2Y1 receptor-selective antagonists ARL-67156 and A3P5P (Table 1). Thus this approach also did not identify a single P2Y receptor subtype (see discussion).
Adenosine did not mimic ATP-stimulated proliferation. At 100 μM, where ATP is maximally effective, adenosine enhanced proliferation only marginally by 35 ± 4.3% and 57 ± 12.1% in A549 and BEAS-2B cells, respectively (Fig. 2), excluding the possibility that the stimulatory effect of ATP was caused by the metabolic breakdown product adenosine. Furthermore, to rule out the possibility that adenosine-mediated signaling partly contributed to the ATP-stimulated proliferative response, the effect of different adenosine receptor antagonists (i.e., P1 antagonists) on ATP-stimulated proliferation of A549 cells was investigated (Table 1). Neither the nonselective adenosine receptor antagonist CGS-15943 nor the A1 and A2B receptor-selective antagonists 8-cyclopentyl-1,3-dipropylxanthine and alloxazine, respectively, inhibited ATP-stimulated proliferation. We did not test specific inhibitors of A3 receptors, inasmuch as this receptor subtype is not expressed in A549 cells (42). Thus, clearly, P1 receptors are not contributing to the signaling of extracellular nucleotides in the proliferative response of A549 cells. Therefore, characterization of A549 cell proliferation using agonists and antagonists of P2 and P1 receptors reveals that only P2Y receptors, but not P2X or P1 receptors, mediate stimulation of lung epithelial cell proliferation.
Furthermore, we examined expression of different P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, and P2Y6 receptors) by RT-PCR. In A549 cells, only mRNA specific for the P2Y2 receptor, which is activated with identical potency by ATP and UTP, and the UDP-selective P2Y6 receptor was detected by RT-PCR, whereas no transcripts for the P2Y1 or P2Y4 receptor could be found (Fig. 3). In the same experiment, we employed HEK-293 cells to control the RT-PCR conditions. HEK-293 cells endogenously express P2Y1, P2Y2, and P2Y4 receptors. These results indicate that primarily the P2Y2 and P2Y6 receptors mediate nucleotide-stimulated proliferation of A549 cells.
Signal transduction pathways of nucleotide-stimulated proliferation of A549 cells. We next investigated the signaling pathways involved in P2Y receptor-stimulated proliferation. A549 or BEAS-2B cells were pretreated with different inhibitors of signaling cascades that mediate proliferation of other cell types. Basal DNA synthesis of proliferating cells was not blocked by these inhibitors at the concentrations used. ATP-stimulated proliferation of A549 cells was almost completely attenuated by preincubation for 1 h with U-73122 (10 μM), an inhibitor of phospholipase C, whereas the inactive control derivative U-73343 was not effective (Fig. 4A). Also, inhibition of CaMKII activity with KN-62 (10 μM) and of the influx of extracellular Ca2+ through receptor-operated Ca2+ channels with SKF-96365 (50 μM) strongly decreased ATP-stimulated BrdU incorporation to 34.6 ± 8.7% (n = 6) and 33.3 ± 5.2% (n = 5), respectively (Fig. 4A). However, the following drugs did not influence the ability of ATP or UTP to stimulate proliferation of A549 cells (Table 2): chelerythrine (20 μM) and GF-109203X (1 μM), which inhibit different protein kinase C (PKC) isoforms, the mitogen-activated protein kinase (MAPK) kinase (MEK1/2) inhibitor PD-98059 (20 μM), the p38 kinase inhibitor SB-203580 (20 μM), the phosphatidylinositol 3-kinase pathway inhibitors wortmannin (0.1 μM) and LY-294002 (25 μM), and Nω-nitro-l-arginine (10 μM), which blocks generation of nitric oxide.
To identify components of the signal transduction pathway resulting in DNA synthesis, we evaluated pathways that can be activated by CaMKII or tyrosine kinases. Pretreatment of A549 cells with an inhibitory peptide specific for the p50 form of NF-κB (NF-κB SN-50; 20 μM) or with AG-1478 (500 nM), specifically inhibiting EGFR tyrosine kinase activity, significantly reduced ATP stimulation of DNA synthesis to 42.8 ± 5.9% and 43.0 ± 4.6%, respectively (Fig. 4B, Table 2). Inhibition of Src kinase, which can also be activated by G protein-coupled receptors, with PP-2 (500 nM), inhibition of general tyrosine kinase activity (genistein at 100 μM), inhibition of cytosolic phospholipase A2 (methyl arachidonyl fluorophosphonate, 10 μM), or inhibition of cyclooxygenases with indomethacin (20 μM) or NS-398 (10 μM) did not abolish the effect of ATP and UTP on proliferation of A549 cells (Fig. 4B, Table 2).
Interestingly, similar results were derived for BEAS-2B cells. In the analysis of signal transduction, we obtained identical inhibition by the various drugs for the bronchial epithelial BEAS-2B cells, except for genistein, which only in BEAS-2B cells decreased ATP- and UTP-stimulated proliferation to 60 and 68%, respectively (Table 2). This indicates that, in the immortalized bronchial BEAS-2B cells, additional tyrosine kinases are involved in the proliferative regulation.
Modulation of nucleotide-regulated proliferation of lung tumor cells by cytokines. Airway epithelial cells are a major source of proinflammatory cytokines and, thus, play an important role in the pathophysiology of lung diseases. Therefore, we investigated the effect of cytokines on nucleotide-regulated proliferation. Moreover, cytokines had also been found to upregulate P2Y2 receptors in vascular smooth muscle cells (15). Preincubation of A549 cells for 24 h with IL-1β (10 ng/ml) or IL-6 (50 ng/ml), at concentrations that are detected under inflammatory conditions, attenuated UTP-stimulated proliferation to 59.7 ± 10.3% and 34.7 ± 12.1%, respectively, compared with the untreated stimulation (Fig. 5, Table 3). However, proliferation of A549 cells induced by the purine nucleotide ATP was clearly not affected by pretreatment with the cytokines. TNF-α had no effect at concentrations up to 50 ng/ml. Moreover, pretreatment of BEAS-2B cells with the cytokines IL-1β, IL-6, and TNF-α did not influence ATP- or UTP-stimulated proliferation (Table 3).
Interaction of anticancer drugs with nucleotide-stimulated proliferation of lung tumor cells. Inasmuch as control of proliferation is a key target in cancer therapy, we also examined the effect of anticancer drugs on the nucleotide-regulated proliferation. BrdU incorporation into proliferating A549 cells was inhibited dose dependently by the anticancer drugs cisplatin, etoposide, and paclitaxel, with IC50 of 2.7 ± 1.1 μM (n = 5), 19.8 ± 2.2 μM (n = 5), and 17.6 ± 3.8 nM (n = 4), respectively (Fig. 6). The simultaneous addition of 100 μM ATP enhanced the antiproliferative potency of cisplatin 3.6-fold, shown by reduction of IC50 to 0.75 μM (Fig. 6). The effect of ATP was most obvious at low concentrations of the anticancer drugs. At 1 μM, cisplatin was twice as effective in reducing proliferation in the presence of ATP than in its absence.
The antiproliferative activity of etoposide and paclitaxel was antagonized by the simultaneous presence of 100 μM ATP, resulting in 1.6-fold (IC50 = 31 ± 2.9 μM, n = 5) and 2.6-fold (IC50 = 46.2 ± 4.8 nM, n = 4) lower inhibitory potency, respectively (Fig. 6). ATP still stimulated proliferation 80% above control in the presence of 1 μM etoposide. Addition of 100 μM UTP did not change the potency of the three anticancer drugs (data not shown). These results support the notion that ATP regulates proliferation of human lung tumor cells by direct control of the cell cycle.
This is the first study showing that extracellular nucleotides stimulate proliferation of human lung epithelial cells by activation of the P2Y2 and P2Y6 receptors, which are detected by RT-PCR to be expressed in A549 cells. The identical EC50 values for ATP- and UTP-stimulated proliferation of A549 cells indicate that both nucleotides stimulate A549 cell proliferation through activation of P2Y2 receptors, because this receptor is equally sensitive to ATP and UTP. This conclusion is also supported by the activity profile of the P2 receptor antagonists. The significant, but not complete, inhibition of ATP- and UTP-stimulated proliferation by 100 μM suramin or 100 μM RB-2 and the lack of activity of 100 μM PPADS are characteristic of the human P2Y2 receptor (46).
Furthermore, our results showing that UTP and UDP stimulate BrdU incorporation in A549 cells with equal efficacy indicate that, in addition to the P2Y2 receptor, the P2Y6 receptor can also mediate stimulation of proliferation. At the human P2Y6 receptor, UDP is ∼100-fold more potent than UTP (46). Thus, as in vascular smooth muscle cells, where for the first time UDP-stimulated growth via the P2Y6 receptor had been reported (14), the P2Y6 receptor is likely to be involved in the control of proliferation in lung epithelial cells.
However, the efficacy profile (ATP = ADP > UDP ≥ UTP) found for A549 cells indicates involvement of some additional receptor, other than the P2Y2 or P2Y6 receptor subtypes (46). ADP activated proliferation of A549 cells with a potency similar to that of ATP. The identity of the receptor, which mediates the action of ADP, is not known. ADP has been found to be considerably less active at the P2Y2 and P2Y6 receptors than the preferred agonists ATP/UTP and UDP, respectively (46). ADP preferentially activates the P2Y1 receptor, which, however, is not expressed in A549 cells. The absence of P2Y1 receptor expression in A549 cells is also pharmacologically underlined by the inactivity of 2-MeS-ADP. 2-MeS-ADP activates the P2Y1 receptor to an even greater degree than ADP.
An alternative possibility explaining the effectiveness of ADP implies that ADP may be converted to ATP by an ectonucleoside diphosphokinase or by an extracellular adenylate kinase, similar to cardiac endothelial cells (4) and nasal airway cells (7), thereby activating the P2Y2 receptor. Both kinases are secreted from human nasal epithelia and are suggested to play an important role in the interconversion and metabolism of extracellular nucleotides on airway surfaces (7). The mechanism in the proliferative response of ADP in A549 cells remains to be examined.
The two lung cell lines used in our study, bronchiolar BEAS-2B cells and alveolar A549 epithelial airway cells, originate from two distinct lung regions. These regions respond distinctly to different stimuli, such as steroids, inflammatory cytokines, or chemotherapy. Nevertheless, ATP/UTP and UDP stimulated proliferation of both cell lines, suggesting a common mechanism of action in the physiological responses of human lung cells to extracellular nucleotides. The maximal concentrations of extracellular nucleotides achieved on stimulation of epithelial cells were calculated to be 5–10 μM (see Ref. 40 and references therein). These concentrations, determined for the release of ATP from resting cells, appear to be sufficient to stimulate proliferating epithelial cells, as detected in our experiments. It is conceivable that even higher ATP concentrations, i.e., 50–100 μM, can be reached under conditions where the epithelial cell layer is disrupted (ventilation injury) or under inflammatory conditions, where proliferation of these cells is necessary to regain an intact barrier. BEAS-2B and A549 cells serve as in vitro models for bronchiolar and alveolar cells, respectively. Therefore, a further in-depth analysis, similarly studying the regulation of BEAS-2B cell proliferation by extracellular nucleotides, will be important for understanding bronchiolar physiology.
The P2Y2 receptor has been described to have an important role in control of proliferation of different cell types. Interestingly, activation of the P2Y2 receptor has been reported to exert contrasting effects. It can lead to proliferation, as in MCF-7 breast cancer cells (47) and C6 glioma cells (44), or to apoptosis, as in colon carcinoma cells (13), endometrial cells (20), and esophageal cancer cells (31). In these cells, the P2Y2 receptor signals through the MAPK pathway.
Our results indicate that, in A549 and BEAS-2B human lung cells, the Gq protein-initiated signaling by nucleotides eliciting proliferation is via NF-κB activation and does not involve the classical Ras-Raf-MAPK pathway, as in astrocytes or C6 glioma cells (36, 44), because the specific MEK1/2 inhibitor PD-98059 did not block nucleotide-mediated proliferation. In addition, inhibition of the phosphatidylinositol 3-kinase pathway with wortmannin or LY-294002 also did not affect nucleotide-stimulated lung cell proliferation. This pathway had been shown to play an important role in P2Y2 receptor-mediated activation of MAPK in human monocytes (39) and renal mesangial cells (16).
Furthermore, in A549 cells, P2Y2 receptor-mediated proliferation is not dependent on PKC activation and general tyrosine kinase activity, because the PKC inhibitors chelerythrine and GF-109203X and the tyrosine phosphorylation inhibitor genistein were ineffective. In A549 cells, a Ca2+-dependent activation of NF-κB or CaMKII-triggered phosphorylation of the EGFR may be one of the main signaling pathways. Alternatively, CaMKII may directly translocate to the nucleus, thereby acting as a trigger for centrosome duplication or coordinating centrosome formation and DNA replication (34). CaMKII and NF-κB activation in A549 cells, however, do not involve PKC activation or an intermediate tyrosine kinase, which has been found for the P2Y2 receptor-stimulated proliferation of C6 glioma cells (44).
Signaling of the P2Y receptor through activation of NF-κB or CaMKII during regulation of proliferation has not been reported. CaMKII has only been found to be involved in the P2Y receptor-mediated enhancement of lipopolysaccharide-induced activation of IκB kinase in macrophages (5). Involvement of NF-κB in P2Y receptor signaling was detected in UTP-induced activation of nuclear factor of activated T cells, initiating IL-6 expression in vascular smooth muscle cells (1), and in UTP-initiated prostaglandin E2 release from macrophages (5). NF-κB activation was found for P2X7 receptor-mediated apoptosis of endothelial cells (45) and microglia cells (9). Thus the extracellular nucleotides ATP and UTP stimulate proliferation via a novel pathway in A549 and BEAS-2B cells. EGFR transactivation, suggested by the inhibitory effect of AG-1478, may also contribute to ATP-stimulated proliferation by activation of NF-κB. It is important to note that our results were obtained with proliferating cells. Whether this mechanism is also active in resting cells remains to be examined.
To further understand the mechanism of control of proliferation of lung epithelial cells by nucleotide receptors, we investigated the effects of the cytostatic drugs cisplatin, etoposide, and paclitaxel. These substances inhibit cell cycle progression and form the basis of current chemotherapeutic regimens in lung cancer treatment. The concentrations of the three anticancer drugs used in our study match those used for investigation of cell cycle inhibition of A549 cells (6). Paclitaxel and etoposide cause cell cycle arrest in A549 cells at the G2/M phase through interference with disassembly of microtubules (paclitaxel) or inhibition of spindle formation and topoisomerase II (etoposide) (6, 30). A consistent block in 40% of the cells at the G2/M phase after 24 h of application was found with 10–30 nM paclitaxel, and an induction of apoptotis was found in 20% of the cells with the higher concentration (30). Etoposide at 5–30 μM exerted a block at the G2 phase in A549 cells without significant apoptosis (6). In contrast, cisplatin does not induce G2 arrest in A549 cells but cross-links with DNA, forming intra- and inter- strand adducts (6). Cell death is believed to be mediated by recognition of the cisplatin-DNA adducts by cellular proteins (19).
We found a specific interaction of ATP, but not UTP, with control of proliferation by the anticancer drugs in A549 cells. ATP selectively potentiated the effect of cisplatin and most effectively antagonized the cell cycle-blocking activity at low paclitaxel and etoposide concentrations, where no significant apoptotic or cytotoxic activity of the anticancer drugs at A549 cells was found (6, 30). The antagonistic effects of ATP on the action of paclitaxel/etoposide are consistent with the assumption that ATP stimulates growth by directly promoting cell cycle progression from the G1/S phase to beyond the G2/M phase. Furthermore, stimulation of cells to progress into the S phase leads to more DNA in the uncoiled state, which then forms adducts with cisplatin. This might explain enhancement of the antiproliferative activity of cisplatin by ATP. The present results using these drugs are supportive but do not provide definitive evidence for direct control of cell cycle progression by extracellular nucleotides in A549 cells. The molecular mechanisms or the proteins mediating the action of ATP are not known. Possible candidates, which are known to be regulated in A549 cells by low concentrations of paclitaxel or etoposide, include proteins regulated by the tumor suppressor protein p53 and c-jun (p21WAF1 and cyclin B1) and the metastasis suppressor gene KAI1 (6, 32).
Cytokines influence UTP-stimulated, but not ATP-stimulated, proliferation of A549 cells. Thus pyrimidine nucleotides preferentially interact with the signal transduction of inflammatory cytokines. Different interactions of extracellular nucleotides with cytokines have been described for macrophages, monocytes, and dendritic cells, where cytokines regulate inflammatory or immune responses. In other cells, such as fetal human astrocytes, P2 receptors modulate IL-1β- and TNF-α-stimulated activation of NF-κB and activator protein-1 (29), supporting a regulatory role for the P2 receptors in inflammatory reactions in the human central nervous system. Moreover, in human bronchial epithelia, activation of Cl- channels by UTP is enhanced by IL-4 (10), and in vascular smooth muscle cells, IL-1β induces upregulation of the P2Y2 receptor (15).
In conclusion, our results, for the first time, show that extracellular nucleotides exert mitogenic effects on human lung epithelial cells through ATP/UTP-mediated activation of the P2Y2 receptor and the UDP-activated P2Y6 receptor. Stimulation of the P2Y2 receptor leads to activation of CaMKII and NF-κB. This novel pathway is modulated by extracellular Ca2+ and, possibly, involves EGFR transactivation. Understanding the mechanisms of interactions of extracellular nucleotides with anticancer drugs, growth factors, and cytokines will be an important task, because non-small cell lung cancer cells, such as A549 cells, rapidly develop resistance to conventional chemotherapy.
This work was supported by Deutsche Krebshilfe Project 10-1754, Land Sachsen-Anhalt, and Fonds der Chemischen Industrie.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2003 the American Physiological Society


In this webinar, Dr. Smoller describes the current status of psychiatric genetic research with a focus on depressive and anxiety disorders. Dr. Smoller reviews implications of this work for clinical practice, including the prospects and limitations of genetic or pharmacogenetic testing. He describes the potential for extending a precision medicine approach to the realm of depression and anxiety disorders.
At the end of this session, participants will be able to:
- Summarize progress in identifying the genetic basis of psychiatric disorders;
- Understand the implications of psychiatric genetics for clinical practice
- Discuss the current status of pharmacogenetic testing for psychiatric drug use.
This webinar is sponsored by the Genetics and Neuroscience Special Interest Group.
CE Credit Information:
Learners must complete an evaluation form to receive a certificate of completion. You must participate in the entire activity as partial credit is not available. If you are seeking continuing education credit for a specialty not listed below, it is your responsibility to contact your licensing/certification board to determine course eligibility for your licensing/certification requirement.
This course is co-sponsored by Amedco and Anxiety and Depression Association of American (ADAA). Amedco is approved by the American Psychological Association to sponsor continuing education for psychologists. Amedco maintains responsibility for this program and its content. 1.0 hours.
New York Board for Social Workers
Amedco SW CPE is recognized by the New York State Education Department’s State Board for Social Work as an approved provider of continuing education for licensed social workers #0115. 1.0 hours.
The Anxiety and Depression Association of American (ADAA) has been approved by NBCC as an Approved Continuing Education Provider, ACEP No. 6872. Programs that do not qualify for NBCC credit are clearly identified. ADAA is solely responsible for all aspects of the programs.
The CAMFT board accepts credits from providers approved by the American Psychological Association (APA).
Amedco, #1346, is approved as a provider for social work continuing education by the Association of Social Work Boards (ASWB) www.aswb.org, through the Approved Continuing Education (ACE) program. Amedco maintains responsibility for the program. ASWB Approval Period: 6/24/2016 to 6/24/2019. Social workers should contact their regulatory board to determine course approval for continuing education credits.
Social workers participating in this course may receive up to 1 clinical continuing education clock hours.
Dr. Jordan Smoller is the MGH Trustees Endowed Chair in Psychiatric Neuroscience, Professor of Psychiatry at Harvard Medical School and Professor in the Department of Epidemiology at the Harvard School of Public Health in Boston. He is Associate Chief for Research in the MGH Department of Psychiatry and Director of the Psychiatric and Neurodevelopmental Genetics Unit in the MGH Center for Genomic Medicine. Dr. Smoller is a Tepper Family MGH Research Scholar and also serves as Director of the Omics Unit of the MGH Division of Clinical Research and co-Director of the Partners HealthCare Biobank at MGH. He is a Principal Investigator of All of Us New England as part of the NIH All of Us Research Program. Dr. Smoller is an author of more than 300 scientific publications and is also the author of The Other Side of Normal (HarperCollins/William Morrow, 2012).


The Philippine Red Cross (PRC) said on Monday that the saliva reverse transcription polymerase chain reaction (RT-PCR) test for COVID-19 was as accurate as swab testing.
In a media briefing, the PRC saliva test lead researcher Michael Tee said that the testing method was at par with the swab test as it was 98.23% accurate.
“Ibig sabihin kung may 100 tayong tinest, kung positive sa saliva, positive din ang swab. Kung negative ang saliva, negative din ang swab, 98% of the time,” Tee explained.
He added that over 1,000 samples were used during the pilot study to determine the accuracy of the saliva test.
The PRC on Monday publicly launched the saliva RT-PCR test after getting the approval of the Department of Health (DOH).
PRC Chairman and Senator Richard Gordon said the saliva test can be availed through online booking via the PRC website.
He added that the turnaround time for the saliva test was three to 11 hours depending on the samples being tested.
A saliva test currently costs P2,000, but Gordon said it may become cheaper if more people got tested.
“‘Pag marami na nagte-test, papatunayan ko na kaya natin babaan ‘yan dahil bawas na tayo sa PPE,” he said.
Meanwhile, testing czar Vince Dizon said under the approval of the DOH, the saliva test should be covered by the Philippine Health Insurance Corp. (PhilHealth).
Over the weekend, Health Undersecretary Maria Rosario Vergeire said the DOH had approved the use of saliva as an alternative specimen in COVID-19 tests in PRC laboratories.
Vergeire, however, noted that the DOH will wait for the validation test results from the Research Institute for Tropical Medicine before allowing saliva tests in other laboratories in the country.
Earlier, PRC molecular laboratory head Dr. Paulyn Ubial said saliva testing was also used in the United States, Japan, Hong Kong, and Singapore.
The PRC said this COVID-19 testing method was a faster, easier, and cheaper alternative to the swab testing.
Gordon earlier said the saliva test for the detection of COVID-19 will still use the same RT-PCR technology that is being used for the swab test. — DVM, GMA News


Good pet dental care is essential to the well-being of your pets. Regular dental care, including daily brushing and professional cleaning promote a longer, healthier life by protecting your pet’s mouth from harmful bacteria that can affect the heart, kidneys and liver.
All dogs and cats need dental care throughout their lives. Our dental services include:
- Tooth extractions
- Minor oral surgery


Gait analysis is not new. Clinicians have long wanted reliable and objective ways of documenting movement in health and disease. Insole X is designed to make gait analysis practical for clinical use. As a portable and unobtrusive footwear, Sennotech InsoleX has high-resolution sensors to measure foot movement data and transfer data to a coupled cloud service for further analysis. You can get a comprehensive understanding of gait data and adjust body behaviors in time.


Oral Microbial Species and Virulence Factors Associated with Oral Squamous Cell Carcinoma
Torralba MG, Aleti G, Li W, Moncera KJ, Lin YH, Yu Y, Masternak MM, Golusinski W, Golusinski P, Lamperska K, Edlund A, Freire M, Nelson KE
The human microbiome has been the focus of numerous research efforts to elucidate the pathogenesis of human diseases including cancer. Oral cancer mortality is high when compared with other cancers, as diagnosis often occurs during late stages. Its prevalence has increased in the USA over the past decade and accounts for over 40,000 new cancer patients each year. Additionally, oral cancer pathogenesis is not fully understood and is likely multifactorial. To unravel the relationships that are associated with the oral microbiome and their virulence factors, we used 16S rDNA and metagenomic sequencing to characterize the microbial composition and functional content in oral squamous cell carcinoma (OSCC) tumor tissue, non-tumor tissue, and saliva from 18 OSCC patients. Results indicate a higher number of bacteria belonging to the Fusobacteria, Bacteroidetes, and Firmicutes phyla associated with tumor tissue when compared with all other sample types. Additionally, saliva metaproteomics revealed a significant increase of Prevotella in five OSCC subjects, while Corynebacterium was mostly associated with ten healthy subjects. Lastly, we determined that there are adhesion and virulence factors associated with Streptococcus gordonii as well as from known oral pathogens belonging to the Fusobacterium genera found mostly in OSCC tissues. From these results, we propose that not only will the methods utilized in this study drastically improve OSCC diagnostics, but the organisms and specific virulence factors from the phyla detected in tumor tissue may be excellent biomarkers for characterizing disease progression.


Unlike just just what numerous may think, whenever a female has a good intimate appetite, it does not always mean this woman is a nymphomaniac. This term encompasses a comprehensive infection or condition, where a lady is affected with an intercourse addiction and it has a compulsion for intimate behavior that will be impractical to get a handle on. This signifies having a dependence that is great intimate tasks which, more often than not, makes someone not able to lead a standard life and social relationships may be significantly impacted. Because of this, it really is imperative that medical assistance is wanted so the appropriate mental therapy can be were only available in each instance. The question how to know if I am a nymphomaniac in this OneHowTo article, all the signs and symptoms will be explained which answer.
Even though the factors behind nymphomania are not completely clear, professionals have actually remarked that hyper sexuality or intercourse addiction might be inspired by different factors and that many of these factors coinciding could possibly be responsible because of this condition.
Among the list of facets which could make clear something concerning the origins of compulsive behaviour that is sexual there are the annotated following:
- Alterations in biochemical substances when you look at the mind: some research reports have suggested that lesions into the mind’s medial prefrontal cortex or high degrees of serotonin, dopamine, and norepinephrine could boost the likelihood of this disorder occurring.


An EU-funded task carried out an ‘advance care planning’ trial on people with late-stage most cancers in a bid to strengthen their welfare and improve their involvement in care-providing conclusion-building.
© ipopba #341152297, resource:stock.adobe.com 2020
Sophisticated most cancers affects a patients bodily and mental ailment, whilst also obtaining a significant impression on the patients high-quality of lifetime, with depression and anxiousness staying typical challenges . Preparing a patients care tactic, with the patients participation, is envisioned to strengthen their well-staying. On the other hand, the result of these kinds of progress care scheduling (ACP) had not formerly been widely examined.
The EU-funded task Motion has aided bridge this information gap by discovering the impression of formalised ACP on the high-quality of lifetime of people with state-of-the-art most cancers as a result of an worldwide, multi-centre affected person-dependent clinical trial.
Open interaction can be a significant challenge for health care professionals, people and family. We adapted the US-dependent Respecting Decisions method into a European progress care scheduling programme to facilitate interaction between the distinctive teams involved with patients care choices. We then as opposed this method with care as the ordinary circumstance as a result of our trial, points out Agnes van der Heide, Professor of Care and conclusion-building at the end of lifetime, at the Erasmus Universitair Medisch Centrum, Rotterdam and Motion task coordinator.
Motion carried out a clinical trial with 1 117 people in 23 hospitals across six EU nations with the aim of evaluating the high-quality of lifetime amid people who followed ACP and these who followed care as usual approaches.
The people, identified with state-of-the-art lung or stage-4 colorectal most cancers, ended up questioned to fill in questionnaires at two.five months and then four.five months into the trial. A relative loaded in a questionnaire if the affected person died for the duration of the trial. The sixty-query surveys ended up employed to judge no matter whether or not the care provided matched every single patients choices, how the affected person evaluated the conclusion-building approach, the high-quality of dying and the cost-performance of care.
ACTION identified that correct scheduling for care for the duration of state-of-the-art-stage most cancers is hard. On the other hand, analyses of the concluded types exhibit that staying independent, sustaining a ordinary lifetime, obtaining significant relations and staying free of charge from suffering are essential subjects for people with state-of-the-art most cancers in Europe, suggests Van der Heide.
Sophisticated care scheduling discussions could outcome in people filling out a medically, ethically and lawfully suitable kind, named My preferences. This kind can help describe the patients ambitions for health care treatment and care, their worries and fears, their beliefs and hopes. It also handles their choices on questions about the use, or not, of most likely lifetime-prolonging therapies, about resuscitation and about no matter whether concentrating on dealing with the ailment or maximising convenience was much more essential to the affected person. People can also use the kind to state where their most popular final put of care would be.
Factors of ACP are staying built-in into the treatment of state-of-the-art most cancers in some European nations for case in point, people can express their care choices. On the other hand, ACP goes deeper into their needs and choices and gives them increased authority to refuse or ask for therapies and tactics.
Our task has elevated consciousness of the need to entirely foresee the foreseeable future deterioration of the patients well being and the great importance to program for it in an inclusive way, Van der Heide adds.
The tools and techniques designed by Motion are now available for researchers, health care professionals, policymakers and many others to use.