Innovation with Innocentive…

Image by jmsmytaste via Flickr

Got ideas that could help produce the next drug,diagnostic test or process.Could you come up with the answer to a company’s research question?
Want to some earn money for solving these problems…then this is for you..

Become a solver:
http://www.nature.com/openinnovation?moreChallenges=true

http://www2.innocentive.com/

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Exmaining processes at the surface of growing crystals

Single Protein crystal of Lysozyme;Image via Wikipedia

Washington, D.C. (September 14, 2010) — Because one of the main bottlenecks in determining the structure of protein molecules is producing good isolated single crystals, improved crystallization techniques would be useful in a wide range of genomics and pharmaceutical research.

Research reported in The Journal of Chemical Physics uses fluorescence correlation spectroscopy (FCS) to investigate the processes at the surface of a growing crystal. By focusing a laser on the crystal surface and measuring the resulting fluorescence, FCS can resolve dimensions as small as a single wavelength of the light.

FCS

Fluorescence correlation spectroscopy (FCS) is one of the many different modes of high-resolution spatial and temporal (relating to time) analysis of extremely low concentrated biomolecules.”In contrast to other fluorescence techniques, the parameter of primary interest is not the emission intensity itself, but rather spontaneous intensity fluctuations caused by the minute deviations of the small system from thermal equilibrium. In general, all physical parameters that give rise to fluctuations in the fluorescence signal are accessible by FCS. It is, for example, rather straightforward to determine local concentrations, mobility coefficients or characteristic rate constants of inter- or intramolecular reactions of fluorescently labeled biomolecules in nanomolar concentrations. FCS is a is a versatile technique that already has demonstrated its vast possibilities for many different problems.It is often used together with other confocal fluorescence readout techniques – one of the standard tools used for high-throughput screening, combining very short data acquisition times with straightforward analysis.[1]

“Another advantage of fluorescence is that it provides a high signal-to-noise ratio,” says author Shinpei Tanaka of Hiroshima University in Japan. “We are able to measure very dilute solutions at the crystal interface.”

Research Findings

The researchers found that when single tetragonal crystals of egg-white lysozyme formed, there was no concentration gradient between the solution and the crystal surface. However, in formation of clumps of needle-like branched crystals, called spherulites, the observed concentration at the surface was several times higher than that of the bulk solution. The authors attributed the difference to aggregates of loosely bound molecules near the interface.

Characterization of the dynamics near the crystal by FCS may provide direction for improving the crystallization process — currently as much an art as a science, based on trial and error — because the spherulites are not usable for structural characterizations.

“Although we knew something was different between the two crystal forms, the degree of concentration of the molecules in spherulites compared to that of the homogeneous state around tetragonal single crystals was surprising,” says Tanaka.

The analytical result could lead to improvements in isolation of good crystals of biomolecules. For example, the results suggest that local heating by a laser could be used to control local concentrations and avoid spherulite formation.

Sources

“Slow molecular dynamics close to crystal surfaces during crystallization of a protein lysozyme studied by fluorescence correlation spectroscopy” by Shinpei Tanaka appears in The Journal of Chemical Physics. http://link.aip.org/link/jcpsa6/v133/i9/p095103/s1

http://www.eurekalert.org/pub_releases/2010-09/aiop-hdy091310.php

References

[1] http://www.biophysics.org/Portals/1/PDFs/Education/schwille.pdf

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Looking for Drug Information?

Image via WikipediaIntroduction

Introduction

I’m writing this post to give advice and include a list of links that I think will be helpful to any college students,businesses,individuals etc who have assignments on various drugs and their manufacturing to do. I know from experience it can be hard to find the exact information you are looking for and nearly impossible to find manufacturing processeses as the details of are generally closely guarded by the drug manufacturers.

Difference Between Generic and Patented Drugs?

One of the first things you may have to figure out is if your drug is still covered by a patent or if the patent has expired and it has now become an off-patent generic drug i.e. many different companies can make the same drug under different trade names.However don’t get confused into thinking a drug is a generic drug  if you see the phrase ‘generic name’ on websites.All drugs have generic names or International Non-Proprietary names (INN‘s),issued by the World Health organization (WHO), which are  the standard names for each drug.INN names are designed to be unique and distinct so as to avoid confusion in prescribing. A similar role is played in Chemistry by IUPAC names to name chemicals in a standard format.

For example,say you are looking for a drug called Panadol. Panadol is a proprietary name i.e. a name owned by someone, for the drug paracetamol which is a generic/INN name.In the United states paracetamol’s non-proprietary generic name is acetaminophen.The American name is known as the United States Adopted Name (USAN).USAN’s are the non-proprietary names that are assigned to pharmaceuticals marketed in the United States.

In summary,the generic name of Panadol is either paracetamol or acetaminophen based on where in the world you are (they are both the same drug).It is an off-patent drug/generic drug (as opposed to an on-patent/proprietary drug) and so it can be manufactured and sold by different companies (since the patent has expired) under various band names such as Panadol,Tylenol,Dolprone,Calpol, and a whole host of other names (see here for a list of paracetamol brand names on Wikipedia).It is also just sold under its generic names which are paracetamol or acetaminophen;it dosen’t have to be sold under a proprietary name.Other generic names for paracetamol are n-acetyl-p-aminophenol and p-acetamidophenol. Knowing the chemical name,other generic names and the formula of a drug are also useful for searching patents.

Sources of Information

Search Engine

Doing a general search using the tradename and then the generic name on search engines like google is a good first port of call.If the drug is marketed under more than one name its a generic drug,if not it is likely to be a drug still covered by a patent although make sure you havent missed any tradenames by accident.

FDA and EMEA websites

If the drug is approved for use in the U.S. and is a generic it will be on the FDA‘s list of generic drugs on their website which is updated on a quarterly basis.The Europen Medicines Agency(EMEA) ,which is the E.U equivalent of the FDA in America, publish European Public Assesment Reports(EPAR’s) on their website which contain summarys and detailed discussions on drugs approved in the E.U. (access list of EPAR’s here).The Scientific Discussions they publish as part of these EPAR’s are also particularly useful as they often contain a brief section on manufature and quality control tests that will be ran on the drug as well as clinical trial data and pharmacology.Just click on the link for the drug you want to learn more about and then click on the individual icon under your selected language (EN) to read the contents.

The ‘Orange Book’

The ‘Orange Book’ is another resource that is available to search on the FDA website (access here) and it can be searched by active ingredient,patent holder, proprietary name,applicant holder and application number.It will provide information on a multitude of different dose forms of various drugs as well as whether or not the drug is on an unexpired patent (propitierary) or not (generic).

Prescribing Information

Getting the Prescribing Information of a drug is also a must,many sites like Rxlist.com provide this kind of data or it can be found on the website of the drug or the company website.

Product Monograph

Product monograhs are a great information source and will often contain more than the prescribing information.However they can be harder and sometimes impossible to find!Good places to start looking are the website of the drug,the company website,by typing the name into google with the words ‘monograph’ or ‘product monograph’ after it.The AHFS website also publishes a book called AHFS Drug Information which describes many drugs.

Pharmacopeias

Pharmacopoeias are a good source of well referenced drug information and iclude data on toxicology,pharmacology ,uses,physical and chemical data and tests to identify the drug.

Patents

For information on the manufacture of a drug you are in most cases going to have to find the patent or patents for the drug.Good places to start looking are the ‘advanced search’ sections of Free Patents Online,Google Patents and patent abstracts at the EBI.If searching by company name (assigne name),check first to see if the company was previously called anything else or it the the company that now sells the drug acquired the company that holds the patent.If any other company names are associated with the drug search these too.Don’t forget to look at related patents too;these are named on the title page of the patent usually and will be referenced in the text also.

Many of the websites named in this text are also listed in my ‘Resources’ links for ease of access.If anyone knows any other resources that they think would be of use to others,please leave a comment about them!

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Overview of some laboratory tests used in the detection of breast cancer

1.0. Introduction to Cancer

Cancer is a genetic disease of the cell. A normal cell transforms to a cancer cell by acquiring an estimated four to seven chromosome mutations which cause the cell to become undifferentiated and undergo tumourigenesis if the alterations confer a selective advantage to the cell. These alterations or mutations can occur spontaneously in the cell due to errors during DNA replication and/or cellular repair mechanisms. They can also be induced by mutagenic agents such as UV light and in most cases these alterations only occur in tumour cells or cells on the verge of becoming cancerous and so are somatic mutations.(1)

Alterations in three types of genes are responsible for tumorigenesis: oncogenes, tumour-suppressor genes and stability genes. Oncogenes can become mutated in ways that render the gene constitutively active or active under conditions in which the wild-type gene is not. Tumour-suppressor genes are targeted in the opposite way by genetic alterations in that mutations reduce the activity of the gene product. The third class of cancer genes called stability or caretaker genes operate in a different way when mutated. Since stability genes keep genetic alterations to a minimum, mutations in other genes occur at higher rates when they are inactivated.(5)

1.1. General Characteristic of Cancer Cells

Cancer cells differ from normal cells in a number of ways. They can operate independently of growth factors thus the cell can proliferate uncontrollably, have unlimited cell division capabilities, can acquire their own blood supply (angiogenesis), can spread via diffusion and metastasis and can avoid apoptotic cell death.(2) The metastatic process is a complex cascade of events in which tumour cells in the primary site must erode the basement membrane, penetrate a blood vessel and spread to distant sites (13)

2.0. Brief introduction to Breast Cancer

Breast cancer is the most common malignancy in women and the second-most common cause of cancer related mortality. (2)It is nearly twice as common in the first-degree relatives of women with the disease, as in the general population.(3) The breast consists of fatty tissue and lobules that are connected to the nipples by ducts. Breast cancer usually begins in a cell lining a duct or a lobule (an epithelial cell).(6)

3.0. Current Diagnostic tests for breast cancer

The goals of breast cancer testing are to identify genetic risk in people with a familial risk, to detect and diagnose breast cancer in its earliest stages, to determine the degree of metastasis if any, to evaluate the cancer characteristics in order to guide treatment and to monitor the effectiveness of treatment or detect cancer recurrences.

Table 1: Some  Laboratory Tests Used in the Detection of Breast Cancer

Test Name	Principal	Use:	Test Sample
BRCA-1 or BRCA-2 gene mutation (7)	A mutation in either gene indicates that the patient has a significantly higher risk of breast cancer (up to 80%)	Used in women who could be at high risk due to a strong personal or family history of ovarian or early onset breast cancer.(However only about 5-10% of familial breast cancer cases are caused by mutations in these genes.)	Blood
Estrogen Receptor/Progesterone Receptor (7,8)	Estrogen and/or receptor positivity indicates sensitivity to these hormones.	Increased levels suggest that patient may be good candidate for anti-hormone therapy	Tissue
CA 15.3 and CA 27.29 (7,11,12)	CA 15-3 and CA 27.29 are well-characterized assays that allow the detection of circulatingMUC-1 antigen in peripheral blood.(12)	Not used to screen for breast cancer but can be used to follow it in patients that have been diagnosed .However low sensitivity has limited its use.(11) (FDA approved).Recommended to use in conjunction with imaging techniques and physical exams i.e. not as a standalone test(12)	Blood
MammaPrint (Agendia) (10,12)	Evaluates gene activity patterns in 70 tumour genes	Used to predict whether a breast cancer will recur or metastasize in women with early stage cancer, who are under 61 and who have cancer-negative lymph nodes.(1st breast cancer predicting tool to get FDA approval)	Tissue
DNA Ploidy (7)	Determines rate of tumour cell growth (S phase)	To determine prognosis and treatment guidelines: Elevated rates of tumour cell growth suggest poorer prognosis. Often indicates need for chemotherapy.	Tissue
Her 2/neu (7,8)	Her2/neu is an oncogene.In about 20-30% of invasive breast cancers, this gene is amplified and its protein (a growth-factor receptor) is over-expressed.	Patients that have this gene amplified respond well to Herceptin (Tastuzumab) that blocks the protein receptors, inhibiting continued replication and tumour growth.	Blood
Tissue Biopsy(7)	Malignant cells show changes in cell shape, size of cell nuclei and evidence of increased cell division.	Tissue stained using immunohistochemical techniques. Screening tool. Also used to determine if cancer is early stage or invasive.	Tissue
Cellsearch System (9)	Detecting elevated numbers of CTC’s in peripheral blood of metastatic breast cancer patients is accompanied by a decreased disease free and overall survival.	Enriches and enumerates circulating tumour cells (CTC’s) from peripheral blood.	Blood
upA +PAI1 (12)	uPA (Urokinase Plasminogen Activator)and PAI-1(Plasminogen Activator inhibitor) are part of the plasminogen activating system, which includes the receptor for uPA and other inhibitors (PAI-2 and PAI-3). This system has been shown experimentally to be associated with invasion, angiogenesis,and metastasis.	Used for the determination of prognosis in patients with newly diagnosed, node-negative breast cancer.  Low levels of both markers are associated with a sufficiently low risk of recurrence (especially in hormone receptor–positive women who will receive adjuvant endocrine therapy).	Tissue

Bibliography:

1.Serre,J.L.,ed, (2006) ‘Diagnostic Techniques in Genetics’,Sussex: John Wiley and Sons Ltd,pgs 139-141

2.Zhong,L., et al, (2008) ‘Autoantibodies as potential biomarkers for breast cancer’ Breast Cancer Research,10(3), available: http://breast-cancer-research.com/content/10/3/R40 [accessed: 27 Feb 2009]

3. Easton, D.F., et al, (2007) ‘Genome-wide association study identifies novel breast cancer susceptibility loci’ Nature,447:1087 1095

4. Venkitaraman,A.R., (2009) ‘Linking the Cellular Functions of BRCA Genes to Cancer Pathogenesis and Treatment’ Annu. Rev. Pathol. Mech. Dis. 4:461–87

5. Vogelstein, B and K.W., Kinzler, (2004) ‘Cancer genes and the pathways they control’ Nature Medicine,10(4): 789-799

6. Breast Cancer Briefsheet,available: http://publications.cancerresearchuk.org/WebRoot/crukstoredb/CRUK_PDFs/CRBSBRC08.pdf [accessed:01 Feb 2009]

7. Lab Tests Online available: www.labtestonline.org/understanding/conditions/breast-3.html [accessed: 20 Feb 2009]

8. Ross,J.S. et al.(2007) ‘Standardizing Slide-Based Assays in Breast Cancer:Hormone Receptors, HER2, and Sentinel Lymph Nodes’ Clin.Cancer.Res., 13(10):2831-2835

9.Riethdorf,S. et al (2007) ‘Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer:A Validation Study of the CellSearch System’ Clin.Cancer.Res. 13(3):920-928

10.Ross,J.S. (2008) ‘Multigene predictors in early stage breast cancer: moving in or moving out?’ Expert.Rev.Mol.Diagn. 8(2):129-135

11. Thorat,M.A. and S.Badve (2007)’Prognostic factors in invasive breast carcinoma: Do new molecular techniques/profiling add significantly to traditional histological factors?’ Curr.Diag.Path.13:116-125

12.Harris,L. Et al (2007) ‘American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumour Markers in Breast Cancer’ J.Clin.Oncol. 25(33):1-26

13. Liotta, L. A., and W. G. ,Stetler-Stevenson,(1992) ‘Cancer: Principles and Practice of

Oncology’ pgs. 98–115. Philadelphia: J. B. Lippincott Co.

Further reading on recent discoverys in breast cancer research and general diagnostic methods e.g mammograms

http://www.technologyreview.com/biomedicine/23621/

http://www.telegraph.co.uk/health/healthnews/6261309/Breast-cancer-gene-discovery-most-important-for-20-years.html

http://www.cancer.gov/cancertopics/factsheet/Detection/breast-cancer

http://blog.oup.com/2009/11/mammography/

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