Presentation on theme: "Presented to Minnesota Futurists 16 January 2010 David Keenan"— Presentation transcript:
1Presented to Minnesota Futurists 16 January 2010 David Keenan Nanotechnology Update Nanomedicine – Fighting Cancer Today’s Focus Nanomaterials – Cleaning Water Rescheduled to later datePresented toMinnesota Futurists16 January 2010David Keenan
2Nanomedicine – Fighting Cancer Futures Methodology – Technology ScanningBackgroundOverview of Approaches & BenefitsExamplesStatus of Developments – Clinic TrialsCautionary StatementsPossible Futures
3Technology Scanning Types of scanning Structured scanning Usually applied by companies to explore opportunities for expansion or threat assessment from competitorsNew markets, new products, new technologiesForesight: Wise anticipation that leads to actionStructured procedures for opportunity searchTypes of scanning(i) Exploratory gazing. (ii) Structured scanning.(iii) Directed viewing. (iv) In depth probingStructured scanningPreparation.Observation.Interpretation.Evaluation.To find(i) Landmark technologies (ii) Targeted technologies (iii) Market ideasVan Wyk, R.J. Copyright 2000, Center for the Development of Technological Leadership, (now Technological Leadership Institute) 1300 South Second Street, Minneapolis, MN 55454
4Seven Pools of Information Macro-map of technological trends: technoscan® Landmark technologies Corporate competenciesTechnology relevance matrixList of targeted technologiesProbes of targeted technologies Roadmaps of selected technologies Used to prepare today’s presentation – review of 56 source articlesVan Wyk, R.J. Copyright 2000, Center for the Development of Technological Leadership, (now Technological Leadership Institute) 1300 South Second Street, Minneapolis, MN 55454
5Cancer Detection - Conventional ImagingCurrent imaging methods can only readily detect cancers once they have made a visible change to a tissue, by which time thousands of cells will have proliferated and perhaps metastasized.And even when visible, the nature of the tumor—malignant or benign—and the characteristics that might make it responsive to a particular treatment must be assessed through biopsies.
6Cancer Detection – Next Generation ImagingImagine if cancerous or even pre-cancerous cells could somehow be tagged for detection by conventional scans.Two things necessary—specifically identify a cancerous cell and something that enables it to be seen.Antibodies that identify specific receptors found to be overexpressed in cancerous cells can be coated on to nanoparticles which produce a high contrast signal on MRI or CT scans.Inside the body, the antibodies on these nanoparticles bind selectively to cancerous cells, effectively lighting them up for the scanner.Nanotechnology will enable the visualization of molecular markers that identify specific stages and types of cancers, allowing doctors to see cells and molecules undetectable through conventional imaging.
7Cancer Screening – Next Generation Screening for biomarkers in tissues and fluids for diagnosis will also be enhanced and potentially revolutionized by nanotechnology.Individual cancers differ from each other and from normal cells by changes in the expression and distribution of tens to hundreds of molecules.As therapeutics advance, it may require the simultaneous detection of several biomarkers to identify a cancer for treatment selection.Nanoparticles such as quantum dots, which emit light of different colors depending on their size, could enable the simultaneous detection of multiple markers. The photoluminescence signals from antibody-coated quantum dots could be used to screen for certain types of cancer. Different colored quantum dots would be attached to antibodies for cancer biomarkers to allow oncologists to discriminate cancerous and healthy cells by the spectrum of light they see.
8Nanotechnology Benefits for Treatment and Clinical Outcomes Cancer therapies are currently limited to surgery, radiation, and chemotherapy. All three methods risk damage to normal tissues or incomplete eradication of the cancer.Nanotechnology offers the means to aim therapies directly and selectively at cancerous cells.NanocarriersPassive TargetingActive TargetingDestruction from Within
9NanocarriersConventional chemotherapy employs drugs that are known to kill cancer cells effectively. But these cytotoxic drugs kill healthy cells in addition to tumor cells, leading to adverse side effects such as nausea, neuropathy, hair-loss, fatigue, and compromised immune function.Nanoparticles can be used as drug carriers for chemotherapeutics to deliver medication directly to the tumor while sparing healthy tissue. Nanocarriers have several advantages over conventional chemotherapy. They can:protect drugs from being degraded in the body before they reach their target.enhance the absorption of drugs into tumors and into the cancerous cells themselves.allow for better control over the timing and distribution of drugs to the tissue, making it easier for oncologists to assess how well they work.prevent drugs from interacting with normal cells, thus avoiding side effects.
10Passive TargetingThere are now several nanocarrier-based drugs on the market, which rely on passive targeting through a process known as "enhanced permeability and retention."Because of their size and surface properties, certain nanoparticles can escape through blood vessel walls into tissues.In addition, tumors tend to have leaky blood vessels and defective lymphatic drainage, causing nanoparticles to accumulate in them, thereby concentrating the attached cytotoxic drug where it's needed, protecting healthy tissue and greatly reducing adverse side effects.
11Active TargetingOn the horizon are nanoparticles that will actively target drugs to cancerous cells, based on the molecules that they express on their cell surface.Molecules that bind particular cellular receptors can be attached to a nanoparticle to actively target cells expressing the receptor. Active targeting can even be used to bring drugs into the cancerous cell, by inducing the cell to absorb the nanocarrier.Active targeting can be combined with passive targeting to further reduce the interaction of carried drugs with healthy tissue.Nanotechnology-enabled active and passive targeting can also increase the efficacy of a chemotherapeutic, achieving greater tumor reduction with lower doses of the drug.
12Destruction from Within Moving away from conventional chemotherapeutic agents that activate normal molecular mechanisms to induce cell death, researchers are exploring ways to physically destroy cancerous cells from within.One such technology—nanoshells—is being used in the laboratory to thermally destroy tumors from the inside. Nanoshells can be designed to absorb light of different frequencies, generating heat (hyperthermia). Once the cancer cells take up the nanoshells (via active targeting), scientists apply near-infrared light that is absorbed by the nanoshells, creating an intense heat inside the tumor that selectively kills tumor cells without disturbing neighboring healthy cells.Similarly, new targeted magnetic nanoparticles are in development that will both be visible through Magnetic Resonance Imaging (MRI) and can also destroy cells by hyperthermia.
13- Gregory Downing, National Cancer Institute “ The science in this area is exploding.The cancer community really gets into this now.”- Gregory Downing, National Cancer InstituteNanotechnology Takes Aim at Cancer – Science Vol Nov05 pp
14Nanotechnology Based Drug Delivery Systems for Cancer Therapy Schematics - Reproduced from Sahoo and Labhasetwar, 2003 with kind permission from Drug Discovery Today.2005
15Nanotechnology Based Drug Delivery Systems for Cancer Therapy NanoparticleDescriptionRecent applicationsReferenceNanocapsulesVesicular systems in which the drug is surrounded by a polymeric membraneStability of the cisplatin nanocapsules has been optimized by varying the lipid composition of the bilayer coatVelinova, 2004NanospheresMatrix systems in which the drug is physically and uniformly dispersedBovine serum albumin nanospheres containing 5-fluorouracil show higher tumour inhibition than the free drugSanthi, 2002MicellesAmphiphilic block copolymers that can self-associate in aqueous solutionMicelle delivery of doxorubicin increases cytotoxicity to prostate carcinoma cellsMcNaealy, 2004Ceramic nanoparticlesNanoparticles fabricated using inorganic compounds including silica, titania…Ultra fine silica based nanoparticles releasing water insoluble anticancer drugRoy, 2003LiposomesArtificial spherical vesicles produced from natural phospholipids and cholesterolRadiation-guided drug delivery of liposomal cisplatin to tumor blood vessels results in improved tumour growth delayGeng, 2004DendrimersMacromolecular compound that comprise a series of branches around an inner coreTargeted delivery within dendrimers improved the cytotoxic response of the cells to methotrexate 100-fold over free drugQuintana, 2002SLN particlesNanoparticles made from solid lipidsSLN powder formulation of all-trans retinoic acid may have potential in cancer chemoprevention and therapeutics.Soo-Jeong, 20042005
16Examples of nanocarriers for targeting cancer A whole range of delivery agents are possible but the main components typically include a nanocarrier, a targeting moiety conjugated to the nanocarrier, and a cargo (such as the desired chemotherapeutic drugs).
17Examples of nanocarriers for targeting cancer Schematic diagram of the drug conjugation and entrapment processes. The chemotherapeutics could be bound to the nanocarrier, as in the use of polymer–drug conjugates, dendrimers and some particulate carriers, or they could be entrapped inside the nanocarrier.
18Mechanisms by which Nanocarriers Can Deliver Drugs to Tumors Polymeric nanoparticles are shown as representative nanocarriers (circles). Passive tissue targeting is achieved by extravasation of nanoparticles (NP) through increased permeability of the tumor vasculature and ineffective lymphatic drainage (EPR effect).Active cellular targeting (inset)can be achieved byfunctionalizing thesurface of NP withligands that promotecell-specific recognitionand binding. The nanoparticles can (i) release their contents in close proximity to the target cells; (ii) attach to the membrane of the cell and act as an extracellular sustained-release drug depot; or (iii) internalize into the cell.
20Quantum DotsRaw quantum dots, 2-8 nm are toxic, CdSe or CdTe cores with ZnS shellBut they fluoresce brilliantly, better than dyes (imaging agents)Coat with tri-n-octyl-phosphine oxide (TOPO), then polymer to prevent toxicityAdd polyethylene glycol (PEG) to improve biocompatibilityAdd other links to attach to target receptorsOnly way of clearance of protected QDs from the body is by slow filtration and excretion through the kidney
21Quantum DotsA research team from Quantum Dot Corporation and Genentech proved the potential of QDs to identify live breast cancer cells that are likely to respond to an anti-cancer drugQD technology helps cancer researchers to observe fundamental molecular events occurring in the tumor cells by tracking the QDs of different sizes and thus different colors, tagged to multiple different biomoleules, in vivo by fluorescent microscopy.QD technology holds a great potential for applications in nanobiotechnology and medical diagnostics where QDs could be used as labels.Use of QDs in humans requires extensive research to determine the long-term effects of administering QDs.
23NanoshellsDeveloped by Drs. Naomi Halas and Jennifer West – Rice University 1994Nanoshells have a core of silica and a metallic outer layer. These nanoshells can be injected safely, as demonstrated in animal models.Because of their size, nanoshells will preferentially concentrate in cancer lesion sites. This physical selectivity occurs through a phenomenon called enhanced permeation retention (EPR).Can further decorate the nanoshells to carry molecular conjugates to the antigens that are expressed on the cancer cells themselves or in the tumor microenvironment. This second degree of specificity preferentially links the nanoshells to the tumor and not to neighboring healthy cells.
24NanoshellsExternally supply energy to these cells. The specific properties associated with nanoshells allow for the absorption of this directed energy, creating an intense heat that selectively kills the tumor cells. The external energy can be mechanical, radio frequency, optical - the therapeutic action is the same.The result is greater efficacy of the therapeutic treatment and a significantly reduced set of side effects.Videos &In clinical trials as AuroLase™of June ‘08 via Nanospectra founded by Halas and West.2Video of AuroLase2
25Review of Trials 2005 Still in trials FDA fast track ’06 2 Approved ‘05In Market 3Nanotechnology Takes Aim at Cancer – Science Vol Nov05 pp23
26Starpharma - Dendrimers Dendrimers can be divided into three sections:the multivalent surface, containing a high number of potential reactive sitesthe outer shell just below the surface,the core in case of higher generation dendrimers. Demonstrated improved solubility of Paclitaxel by 9,000xStarpharma – Melbourne, Australia (SPX:ASL, SPHRY:OTCQX- ADR) Sales ~ $10M ’09, ’08 not yet profitableUS Division – Dendritic Nanotechnologies, Mt. Pleasant, MI2233
28NCI ANC Approaches In Trial or Ready Soon Drs. Caius Radu, Owen Witte and Michael Phelps at the Nanosystems Biology Cancer Center (Caltech/UCLA CCNE) have developed a series of positron emission tomography (PET) imaging agents. These agents are being tested for assigning patients for chemotherapy with drugs such as gemcitabine, cytarabine, fludarabine, and others used to treat cancers including metastatic breast, non-small cell lung, ovarian, and pancreatic, as well as leukemia and lymphomas. Tumors responsive to these drugs show up as bright images in PET scans when patients are first dosed with imaging agent. Biodistribution studies have been conducted in eight healthy volunteers. Clinical development is being conducted by Sofie Biosciences.At the Center of Nanotechnology for Treatment, Understanding, and Monitoring of Cancer (NANO-TUMOR) (UCSD CCNE), Dr. Thomas Kipps developed a chemically engineered adenovirus nanoparticle to deliver a molecule that stimulates the immune system. Phase I clinical trials, being run jointly by Memgen and the Leukemia & Lymphoma Society, are underway in patients with chronic lymphocytic leukemia. An ongoing Phase I dose escalation study is evaluating patients who received direct intranodal injection of the chemically-engineered virus. Systemic clinical effects have been observed with a single injection with significant reductions in leukemia cell counts and reductions in the size of all lymph nodes and spleen. One patient went into complete remission.
29NCI ANC Approaches In Trial or Ready Soon Calando Pharmaceuticals, founded by Dr. Mark Davis at the Caltech/UCLA CCNE, is conducting clinical trials with a cyclodextrin-based nanoparticle that safely encapsulates a small-interfering RNA (siRNA) agent that shuts down a key enzyme in cancer cells. This open-label, dose-escalating trial is testing the safety of this drug in patients who have become resistant to other chemotherapies. Calando is also conducting clinical trials cyclodextrin-based polymer conjugated to camptothecin. This trial is also an open-label, dose-escalation study of IT-101 administered in patients with solid tumor malignancies.At the Siteman Center of Cancer Nanotechnology Excellence (Washington University CCNE), Drs. Gregory Lanza and Samuel Wickline have developed a nanoparticle magnetic resonance imaging (MRI) contrast agent that binds to the αvβ3-intregrin found on the surface of the newly developing blood vessels associated with early tumor development. Kereos, which was founded by Alliance investigators, is conducting Phase I clinical trials with this agent to assess its utility in the early detection of cancer.
30NCI ANC Approaches In Trial or Ready Soon Diagnostic company Nanosphere, founded by Dr. Chad Mirkin to commercialize technology developed at the Nanomaterials for Cancer Diagnostic and Therapeutics Center (Northwestern Univ. CCNE) has already received FDA approval for a nanosensor test for the drug Coumadin. This same technology can be easily adapted to detect important cancer biomarkers, such as prostate specific antigen (PSA) or to measure blood levels of anticancer agents A joint project between Nanosphere, the Northwestern CCNE, and the Robert H. Lurie Comprehensive Cancer Center is conducting a clinical study using human tissue samples to monitor very low levels of PSA to determine if such measurements, which are well beyond the sensivity of conventional PSA assays, can provide early warnings of disease recurrence.Dr. Ralph Weissleder, an investigator at the MIT-Harvard Center for Cancer Nanotechnology Excellence, is leading a clinical trial to determine if lymphotrophic superparamagnetic nanoparticles developed at the CCNE can be used to identify small and otherwise undetectable lymph node metastases.The Integrated Blood Barcode (IBBC) chip, developed by Dr. James Heath at the Caltech/UCLA CCNE, is now undergoing validation tests to measure the levels of approximately 800 miRNAs from 21 melanoma patients before and after therapy.
31NCI ANC Approaches In Trial or Ready Soon Clinical trials - scheduled to begin later this year on a new type of CT scanner, developed by Dr. Otto Zhou at the Carolina Center of Cancer Nanotechnology Excellence (UNC) uses carbon nanotubes as the x-ray source. This new scanner, developed through a joint venture with Xintek, founded by CCNE members, and Siemens, a leader in medical imaging, contains 52 nanotube x-ray sources and detectors arranged in a ring, that eliminates the need to move the x-ray source and increases precision and speed of CT scanning, could be preferred method for detecting small tumors.Discussions with the FDA to start clinical trials using carbon nanotubes to improve colorectal cancer imaging. Imaging agent being developed by Dr. Sanjiv Sam Gambhir from the Center for Cancer Nanotechnology Excellence Focused on Therapy Response Stanford Univ.A nanoparticle designed to cross the blood-brain barrier and specifically target glioblastomas is also nearing clinical trials. This nanoparticle agent can function as both an MRI contrast agent and a drug delivery device. Developed by Dr. Miqin Zhang - Univ. Washington Cancer Nanotechnology Platform Partnership for Pediatric Brain Cancer Imaging and Therapy.
32NCI ANC Approaches In Trial or Ready Soon BIND Biosciences, founded by Drs. Robert Langer and Omid Farokhzad of the MIT-Harvard CCNE, anticipates having its lead compound in clinical trials in BIND’s targeted nanoparticles consist of a polymer matrix, therapeutic payloads, functional surface moieties, and targeting ligands which allow for particle optimization (i.e., accumulation in target tissue, avoidance of being cleared by immune system, and delivery of drug with desired release profile).Liquidia Technologies founded by Univ. North Carolina CCNE Dr. Joseph DeSimone. Liquidia's proprietary PRINT (Pattern Replication In Non-wetting Templates) technology enables the design and manufacture of precisely engineered nanoparticles with respect to particle size, shape, modulus, chemical composition, and surface functionality.
33Similar to BIND Bioscience Triple threat – one example a multi-function nanoparticle combines tumor seeking sensors, imaging agents and toxins to kill cancer cellsNanotechnology Takes Aim at Cancer – Science Vol Nov05 pp
34Doxil - Approved Approved for Ovarian Cancer AIDS-related Karposi’s SarcomaMultiple MyelomaThe STEALTH® liposomemethoxypolyethylene glycol(mPEG) containingAntitumor antibioticInterferes with cell divisionHalf life 55 hours in humans~ 100 nm sizeProduced by Ben Venue Labs, - Bedford, OH, contract mfg Div. of Boeringer IngelheimDistributed by Centocor Ortho Biotech, Inc – Horsham, PA private, Div. of J&JSTEALTH ® and DOXIL ® are trademarks of ALZA Corporation, Div. of J&J
35Abraxane - Approved Approved for Breast Cancer Albumin-bound PaclitaxelPaclitaxel – powerful anticancer drug – not water solubleAbraxane is water soluble – reduces treatment to 30 min from 3 hrs for solvent version & its side effects~130 nmAmerican Pharmaceutical Partners and American BioScience, Inc – approved by FDA 05Jan05Produced by Abraxis BioScience – Los Angeles, CANot yet profitable ABII:NASDAQDrugs are delivered to tumors by leaky junctions in the blood vessels.Drugs also bind to albumin and are transported in the blood and delivered to tumors. This is accomplished first by taking advantage of the transport system (gp60 pathway) across the endothelial cells and then concentrating within the tumor interstitium by its affinity for SPARC (Secreted Protein Acidic and Rich in Cysteine).Finally, the water insolubility of many active chemotherapy agents is overcome by using proteins instead of additional chemicals to dissolve the active drug.
36Coroxane – In Phase 2 Trials Angioplasty, removal of plaque in arteries, short-term solution Next, a bare metal stent is placed to keep the vessel from narrowing. Drug-eluting stents containing either paclitaxel or rapamycin have been approved for treatment of restenosis in the coronary arteries. The drug helps to prevent hardening of the artery in conjunction with the stent.COROXANE™, a microtubule stabilizer, is being developed by Abraxis to be used in conjunction with stents to prevent arterial restenosis.Coronary Artery Restenosis: ~800,000/yr procedures of coronary artery stenting in the US alone. While drug-eluting stents are encouraging, may be complications after surgery, weakening of the artery wall, blood clots, and an increased risk of heart attack when the vessel doesn’t heal completely. COROXANE™ is currently in phase 2 trials for CAR.Peripheral Artery Disease of the lower extremities is common in older adults, caused by thickening of the blood vessel wall that limits blood flow to the legs. Standard treatment is angioplasty alone. Surgical placement of stents in the blood vessel has had limited success. Phase 2 studies are focusing on the use of COROXANE™ along with angioplasty of the affected blood vessel.Produced by Abraxis BioScience – Los Angeles, CA
37Latest News ItemsNewest Breathalyser Knows if You Have Lung Cancer - Israeli Institute of Technology breathalyser works using gold nanoparticles to detect 4 of the 42 volatile organic compounds (VOCs) that indicate lung cancer. Clinical trials expected in 2 years. 1 Sep09Ultra-tiny 'bees' target tumors - tiny particles designed to destroy cancer cells by delivering a synthesized version of a toxin called melittin that is found in bees - Nanobees, are engineered to travel directly to tumor cells without harming any others. They leave the healthy cells alone because the blood vessels around a tumor express a particular protein to which a substance on the nanobees has a chemical affinity. So far tested only on mice, with promising results. therapy could become widely available in humans in 5 to 10 years.2 Aug 09Nano-treatment to torpedo cancer – School of Pharmancy,London Nanotechnology has been used for the first time to destroy cancer cells with a highly targeted package of "tumor busting" genes, which were taken up by cancer cell, but not surrounding healthy cells. 3 Mar 09123
38Latest News ItemsNanotechnology in clinical trials to restore normal gene function to cancer cells - Loss of normal p53 function results in malignant cell growth and has been linked to resistance to radiotherapy and chemotherapy in a number of cancers. Ester Chang, Georgetown Univ. delivered group delivered functional p53 genes to tumor cells and tumor metastases in 16 different types of cancer in animal models. When the job of reinstating a normal p53 suppressor gene is done, the nanoparticle, essentially a little fat droplet wrapped around the gene, simply melts away, unlike non-biodegradable delivery systems. Phase 1 human trials are underway at Baylor Univ - Dallas. 1 Apr09Nanotechnology therapy for brain cancer - Argonne National Laboratory show the first evidence of successful bioconjugated nanoparticles targeting toward cancer and away from normal brain cells. Uses 5 nm TiO2 nanoparticles that are covalently conjugated with an antibody that specifically targets certain tumors, including GBM. A naturally occurring metabolite of dopamin, DOPAC, is used as a linker molecule to tether the antibody to the nanoparticles. The TiO2 absorb energy from light, which is then transferred to molecular oxygen, producing cytotoxic reactive oxygen species (ROS). ROS damages the cell membrane and induces programmed death of the cancer cell. 2 Oct 0912
39Latest News ItemsMultifunctional nanotechnology device for integrated, cell-based nanotherapyDr. Dean-Mo Liu, National Chiao Tung University team developed core/shell drug-delivery nanocapsule – a polymer core covered with a thin layer of single-crystal iron oxide shell and then deposited zinc-copper-indium-sulphur (ZCIS) nanocrystals onto the surface to form a nanoscale multifunctional platform.The iron oxide shell opens with magnetic field in 60 sec. and triggers a color change in the non-toxic quantum dot allowing in-situ monitoring. Nov09
40Latest News ItemsUniversity research teams mix nanomaterials that give tumors a one-two punch in trialsTeams of researchers from three universities are jointly developing a nanotechnology cocktail that should target and kill cancerous tumors.The mixture of two different-sized nanoparticles work with the body's bloodstream to seek out, stick to and kill tumors. The nanomaterials are injected into the patient's vein. One is designed find the cancerous tumor and then adhere to it, while the second is designed to then kill the tumor."This study represents the first example of the benefits of employing a cooperative nanosystem to fight cancer," said Michael Sailor, a lead researcher on the project and a professor of chemistry and biochemistry at the University of California, San Diego.The study, which has been tested on mice, is being conducted by teams of researchers at MIT, the University of California, San Diego, and UC Santa Barbara. 07Jan10
41Cautionary notes Why is x not listed? Success or failure of a clinical trialLots of different cancersWhat about other diseases?
42Summary Cancer Study Cancer Detection Cancer Treatment Quantum dots improve study of cell biology of diseasesCancer DetectionNanoparticle imaging agents improve early detectionNanosensors aid in screeningCancer TreatmentWide variety of nanoparticles as drug or gene delivery vehiclesNanoparticles as absorbers for IR energy for heat deathMulti-function ApproachesEfforts to combine detection, collection at tumor sites, observation and treatment
43Possible FuturesWith first approvals, a few nano-drugs are in the market.Several more will follow.A few will fail – consequences.Insurance reimbursement may lagHigh initial cost may limit who gets to benefitScale-up of new technology drugs may limit availabilitySome early company success stories will fail or wallowDifficult to growDifficult to leverage technologyDifficult to recoup start-up costsDifficult management issues, legal, IP, etcSome cancers will remain unresponsiveSome cancers will be cured
46Nanotechnology for Clean Water Based on ICPC Nanotechnology for Water Purification WebConferences - Dec 2, 8 & 15, 2009ICPCNanoNet is a 4-year project, funded by the European Commission under the 7th Framework ProgrammeAims to provide wider access to published nanoscience and nanotechnology research and opportunities for collaboration between organizations and scientists in the EU and International Cooperation Partner CountriesOnline workshop brought together experts in the field interested in cooperating with their peers in Europe, Africa, Asia, Latin America and other parts of the world.Information available at