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Category Archives: Femtomedicine

Femtomedicine : Femto Medicine | Femto Medicine News

Posted: November 24, 2017 at 9:42 am

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femtomedicine.com is 7 years 9 months old. It has a global traffic rank of #1,196,668 in the world. It is a domain having .com extension. This website is estimated worth of $ 480.00 and have a daily income of around $ 2.00. As no active threats were reported recently by users, femtomedicine.com is SAFE to browse.

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Venta, manejo y distribucion de medicamento especializado para diversas patologias

Domain Name: FEMTOMEDICINE.COMRegistry Domain ID: 1585166248_DOMAIN_COM-VRSNRegistrar WHOIS Server: whois.meshdigital.comRegistrar URL: http://www.domainbox.comUpdated Date: 2014-05-08T00:00:00ZCreation Date: 2010-02-12T00:00:00ZRegistrar Registration Expiration Date: 2023-02-12T00:00:00ZRegistrar: MESH DIGITAL LIMITEDRegistrar IANA ID: 1390Registrar Abuse Contact Email: [email protected] Abuse Contact Phone: +1.8779770099Reseller: Domainmonster.comDomain Status: clientDeleteProhibitedDomain Status: clientUpdateProhibitedDomain Status: clientTransferProhibitedRegistry Registrant ID:Registrant Name: Domainmonster.com Privacy ServiceRegistrant Organization: Identity Protect LimitedRegistrant Street: PO Box 795Registrant City: GodalmingRegistrant State/Province: SurreyRegistrant Postal Code: GU7 9GARegistrant Country: GBRegistrant Phone: +44.1483307527Registrant Phone Ext:Registrant Fax: +44.1483304031Registrant Fax Ext:Registrant Email: [email protected] Admin ID:Admin Name: Domainmonster.com Privacy ServiceAdmin Organization: Identity Protect LimitedAdmin Street: PO Box 795Admin City: GodalmingAdmin State/Province: SurreyAdmin Postal Code: GU7 9GAAdmin Country: GBAdmin Phone: +44.1483307527Admin Phone Ext:Admin Fax: +44.1483304031Admin Fax Ext:Admin Email: [email protected] Tech ID:Tech Name: Domainmonster.com Privacy ServiceTech Organization: Identity Protect LimitedTech Street: PO Box 795Tech City: GodalmingTech State/Province: SurreyTech Postal Code: GU7 9GATech Country: GBTech Phone: +44.1483307527Tech Phone Ext:Tech Fax: +44.1483304031Tech Fax Ext:Tech Email: [email protected] Server: ns1.managementserver.netName Server: ns2.managementserver.netDNSSEC: unsignedURL of the ICANN WHOIS Data Problem Reporting System: http://wdprs.internic.net/>>> Last update of WHOIS database: 2014-12-11T09:56:26Z

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Femtomedicine : Femto Medicine | Femto Medicine News

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Torrents.fm

Posted: October 15, 2016 at 8:41 pm

Free traffic, earnings, ip, location, rankings report for torrents.fm torrents.fm snoop summary

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dotFM – 404 Error dotFM – The .FM Top-Level Domain Registry HomeDomain AppsManage DomainsLog OutLog InRenew DomainsRegister DomainsTransfer DomainsDomain PricingWHOISBuy DomainsSearch DomainsPremiumPlus DomainsDropped DomainsRetail RegistrarsSell DomainsICANN Registrar ProgramiRRP Reseller ProgramAffiliate [email protected] [email protected] [email protected] EmailSupportKnowledgebaseManage DomainsSubmit a TicketView TicketAnnouncementsAbout UsContact Us http://www..fm.am.radio.am.radio.fm.tv.com.net.org dotFM 404 Error – Document Not Found The page you arelooking for may have been removed, had its name changed, or is temporarily unavailable. Please return to the dotFM Home Page: http://www.dot.fm dotFM – .FM Top-Level Domain 55 New Montgomery St. Ste 622 San Francisco CA 94105-3432 Toll Free US/CA: 1.888.DOT.AMFM (1.888.368.2636) Intl/Tel: +1.415.424.4663 Home | About Us | Whois | Legal | Contact Us 1995-2016 dotFM is a registered trademark of BRS Media Inc., All rights reserved. Please read our Domain, Dispute, Trademark,and Privacy PolicyStatements. Registrant Rights and Responsibilities (ICANN document)

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Torrents.fm

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Research in biochemistry and molecular biology | Institute …

Posted: August 27, 2016 at 12:45 pm

Marc Aucoin Process dynamics of virus-based systems for the production of complex biologics such as viral vectors and vaccines, and the development of strategies using multiple viruses to obtain recombinant products in cell culture. Michael Beazely How growth factor receptors and G protein-coupled receptors modulate ion channels involved in excitatory neurotransmission, neuroprotective mechanisms, and neuronal development; intracellular signaling pathways downstream of GPCRs such as the 5-HT7 receptor and growth factor receptors such as the PDGF receptor. Niels C. Bols Animal cell culture, in vitro toxicology, and biotechnology. Differentiated fish cell lines and culture systems. Hormones and polypeptide growth factors. Toxicology of dioxin-like compounds and polycyclic aromatic to cultured cells. Barb Butler Undergraduate teaching in microbiology, the way microorganisms function and interact with surrounding habitat; microbial ecology; biodegradation of organic contaminants, particularly in groundwater and soil environments. Trevor C. Charles Molecular genetic studies of plant-associated bacteria. Rhizobium carbon metabolism. Genetics of polyhydroxyalkanoate metabolism. General environmental microbiology. Jeff Z.Y. Chen Computer simulations of protein folding and protein-protein interaction. Specialization in molecular dynamics and Monte-Carlo simulations. C. Perry Chou Recombinant protein production, biofuel production, and bioprocessing technology. Applied biological sciences and engineering theories to develop novel and effective bioprocesses for the production of recombinant proteins (including industrial enzymes and therapeutic proteins) and metabolites (including biohydrogen, biodiesel, and biobutanol). Such bioprocess development includes upstream technology for biological strain construction, midstream technology for bioreaction (i.e. cultivation), and downstream processing for bioproduct recovery and purification. Thorsten Dieckmann NMR-spectroscopy, RNA and protein structure, RNA-protein interactions, RNA catalysis, viral infections, cellular defense mechanisms. Brian Dixon Characterization of fish immune system at the molecular level. Cytokines and receptors in fish immune systems. Defining fish populations using polymorphism of immune system genes. Cold-blooded vertebrate immunotoxicology. D. George Dixon Effects of toxic chemicals on aquatic organisms. Biotic modifying factors of toxicity. Development of methods for environmental effects monitoring. Physiologically based pharmacokinetic modelling of contaminant levels in fish. Gary I. Dmitrienko Enzyme structure and function. Bernard P. Duncker Genetics and DNA replication. Use of the budding yeast Saccharomyces cerevisiae to investigate protein factors that control the initiation of DNA replication. Heidi Engelhardt The dialogue between the developing fetus and the mother during mammalian pregnancy, and the role of the placenta as the mediator; the ability of the placenta to protect the developing organism from sub-optimal maternal environments through adaptive changes in structure, vasculature or functional exchange capacity. Moira Glerum Mitochondrial myopathies, mitochondrial biogenesis, assembly of cytochrome oxidase in yeast and humans, mitochondrial copper transport, mitochondrial peroxide metabolism, heme A biosynthesis. Bernard R. Glick Isolation and manipulation of microbial genes involved in microbial stimulation of plant growth. Use of bacteria as biocontrol agents. Biochemical consequences of the genetic transformation of plant growth-promoting bacteria. Bruce M. Greenberg Environmental Chemistry and Biology: Photochemistry and photobiology of xenobiotic contamination and ultraviolet radiation. Frank Gu Nanotechnology, Nanomedicine, Cancer Therapy, Drug Delivery, Biomaterials, Bioconjugated Chemisry and Bioinformatics. Guy Guillemette Nitric Oxide Synthase: Function, structure, catalysis, and regulation. Analysis of enzyme activity, mechanism and inhibition. Cytochrome c: Function, structure, stability, redox potential, and protein folding. John J. Heikkila

The use of recombinant DNA methodology to examine the molecular response of amphibian embryos and tissue culture cells to environmental stress. Isolation and expression of heat shock genes.

My laboratorys research interests lie in the areas of enzyme structure, mechanism, inhibition and allostery. In light of these general interests our research currently focuses on the role that conformational plasticity plays in these areas of enzymology and how these dynamic aspects of enzyme structure can be exploited in the regulation of enzyme function.

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Waterloo researcher discovers molecules that could kill …

Posted: July 23, 2016 at 12:46 pm

Researchers have identified new molecules that kill cancer cells while protecting healthy cells and that could be used to treat a variety of different cancers. The research shines a light on what happens to cells at the moment they become cancerous.

The research and pre-clinical trial results were published this month as an open access article in EBioMedicine, a new joint research-clinical journal from the editors of Cell and The Lancet.

Professor Qing-Bin Lu, from the University of Waterloos Faculty of Science, initiated a novel molecular-mechanism-based program to discover a new class of non-platinum-based-halogenated molecules that kill cancer cells, yet prevent healthy cells from being damaged.

The most effective cancer drugs today may kill cancer cells, but they also kill healthy cells, causing severe side effects for patients in the process.

Femtosecond time-resolved laser spectroscopy is a technique traditionally applied to study chemical reactions as they occur on a molecular level. The laser takes a series of rapid snapshots of molecules as they interact and change structure over time. The technique is part of a potential new field of science developed by Professor Lu called femtomedicine (FMD), which integrats the ultrafast laser with molecular biology and cell biology.

Professor Lu has applied the tool to understand the molecular mechanisms that cause cancer at the very moment when the DNA becomes damaged. He has also used it to investigate how radiation therapy and chemotherapy using chemical agents, in particular the widely used platinum chemotherapeutic Cisplatin, work in treating a variety of cancers.

We know DNA damage is the initial step, said Professor Lu. With the novel femtomedicine approach we can go back to the very beginning to find out what causes DNA damage in the first place, then mutation, and then cancer.

By understanding more about the fundamental mechanisms of the diseases, Professor Lu pre-selected molecules most likely to be effective as anti-cancer agents. In this case, he discovered a new family of non-platinum-based molecules similar in structure to Cisplatin but containing no toxic platinum.

Pre-clinical studies with various cultured human cells as well as on rodents show that these new molecules are effective against cervical, breast, ovarian, and lung cancers.

Cisplatin, discovered more than 40 years ago, is an important, widely used platinum-based anti-cancer agent. Unfortunately, the inclusion of platinum in the molecule causes serious side effects like neurotoxicity, kidney damage, hearing loss, nausea and vomiting.

It is extremely rare to discover anti-cancer agents that can selectively kill cancer cells and protect healthy cells, as well as being effective in treating many different types of cancer and having a novel molecular mechanism of action. These candidate drugs should have a high potential to pass through clinical trials and could ultimately save lives, said Professor Lu.

Professor Lu has already applied for patents on the new family of non-platinum-based-halogenated molecules that he has discovered and hopes to start clinical trials soon.

The papers co-authors include Professor Lus team members from Waterloo Qin-Rong Zhang, Ning Ou, Chun-Rong Wang, and Jenny Warrington. Professor Lu is a University Research Chair in the Department of Physics and Astronomy and holds cross-appointments in the departments of Biology and Chemistry.

In just half a century, the University of Waterloo, located at the heart of Canada’s technology hub, has become one of Canada’s leading comprehensive universities with 35,000 full- and part-time students in undergraduate and graduate programs. A globally focused institution, celebrated as Canadas most innovative university for 23 consecutive years, Waterloo is home to the world’s largest post-secondary co-operative education program and encourages enterprising partnerships in learning, research and discovery. In the next decade, the university is committed to building a better future for Canada and the world by championing innovation and collaboration to create solutions relevant to the needs of today and tomorrow. For more information about Waterloo, please visit uwaterloo.ca.

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Nick Manning University of Waterloo 519-888-4451 226-929-7627 http://www.uwaterloo.ca/news @uWaterlooNews

Attention broadcasters: Waterloo has facilities to provide broadcast quality audio and video feeds with a double-ender studio. Please contact us to book.

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Femtocell – Wikipedia, the free encyclopedia

Posted: July 12, 2016 at 5:17 am

In telecommunications, a femtocell is a small, low-power cellular base station, typically designed for use in a home or small business. A broader term which is more widespread in the industry is small cell, with femtocell as a subset. It connects to the service providers network via broadband (such as DSL or cable); current designs typically support four to eight active mobile phones in a residential setting depending on version number, and eight to 16 active mobile phones in enterprise settings. A femtocell allows service providers to extend service coverage indoors or at the cell edge, especially where access would otherwise be limited or unavailable. Although much attention is focused on WCDMA, the concept is applicable to all standards, including GSM, CDMA2000, TD-SCDMA, WiMAX and LTE solutions.

Use of femtocells benefits both the mobile operator and the consumer. For a mobile operator, the attractions of a femtocell are improvements to both coverage, especially indoors, and capacity. Coverage is improved because femtocells can fill in the gaps and eliminate loss of signal through buildings. Capacity is improved by a reduction in the number of phones attempting to use the main network cells and by the off-load of traffic through the user’s network (via the internet) to the operator’s infrastructure. Instead of using the operator’s private network (microwave links, etc.), the internet is used.

Consumers benefit from improved coverage since they have a base-station inside their building. As a result, the mobile phone (user equipment) achieves the same or higher data rates using less power, thus battery life is longer. They may also get better voice quality. The carrier may also offer more attractive tariffs, e.g., discounted calls from home.

Femtocells are an alternative way to deliver the benefits of Fixedmobile convergence (FMC). The distinction is that most FMC architectures require a new (dual-mode) handset which works with existing unlicensed spectrum home/enterprise wireless access points, while a femtocell-based deployment will work with existing handsets but requires installation of a new access point that uses licensed spectrum.

Many operators have launched femtocell service, including Vodafone, SFR, AT&T, Sprint Nextel, Verizon, T-Mobile US, Zain, Mobile TeleSystems, and Orange.

In 3GPP terminology, a Home Node B (HNB) is a 3G femtocell. A Home eNode B (HeNB) is an LTE femtocell.

Typically the range of a standard base station may be up to 35 kilometres (22mi), a microcell is less than two kilometers wide, a picocell is 200 meters or less, and a femtocell is in the order of 10 meters,[1] although AT&T calls its product, with a range of 40 feet (12m), a “microcell”.[2] AT&T uses “AT&T 3G MicroCell” as a trade mark and not necessarily the “microcell” technology, however.[3]

Femtocells are sold or loaned by a mobile network operator (MNO) to its residential or enterprise customers. A femtocell is typically the size of a residential gateway or smaller, and connects to the users broadband line. Integrated femtocells (which include both a DSL router and femtocell) also exist. Once plugged in, the femtocell connects to the MNOs mobile network, and provides extra coverage. From a users perspective, it is plug and play, there is no specific installation or technical knowledge requiredanyone can install a femtocell at home.

In most cases,[4] the user must then declare which mobile phone numbers are allowed to connect to his femtocell, usually via a web interface provided by the MNO.[5] This needs to be done only once. When these mobile phones arrive under coverage of the femtocell, they switch over from the macrocell (outdoor) to the femtocell automatically. Most MNOs provide a way for the user to know this has happened, for example by having a different network name appear on the mobile phone. All communications will then automatically go through the femtocell. When the user leaves the femtocell coverage (whether in a call or not) area, his phone hands over seamlessly to the macro network. Femtocells require specific hardware, so existing WiFi or DSL routers cannot be upgraded to a femtocell.

Once installed in a specific location, most femtocells have protection mechanisms so that a location change will be reported to the MNO. Whether the MNO allows femtocells to operate in a different location depends on the MNOs policy. International location change of a femtocell is not permitted because the femtocell transmits licensed frequencies which belong to different network operators in different countries.

The main benefits for an end user are the following:

Femtocells can be used to give coverage in rural areas.

The standards bodies have published formal specifications for femtocells for the most popular technologies, namely WCDMA, CDMA2000, LTE and WiMAX. These all broadly conform to an architecture with three major elements:

The key interface in these architectures is that between the femtocell access points and the femtocell gateway. Standardisation enables a wider choice of femtocell products to be used with any gateway, increasing competitive pressure and driving costs down. For the common WCDMA femtocells, this is defined as the Iuh[expand acronym] interface. In the Iuh architecture, the femtocell gateway sits between the femtocell and the core network and performs the necessary translations to ensure the femtocells appear as a radio network controller to existing mobile switching centres (MSCs). Each femtocell talks to the femtocell gateway and femtocell gateways talk to the Core Network Elements (CNE)[expand acronym] (MSC for circuit-switched calls, SGSN for packet-switched calls). This model was proposed by 3GPP and the Femto Forum.[6] New protocols (HNBAP [Home Node B Application Part] and RUA[7] [RANAP User Adaptation]) have been derived; HNBAP is used for the control signaling between the HNB and HNB-GW[8] while RUA[7] is a lightweight mechanism to replace the SCCP[expand acronym] and M3UA[expand acronym] protocols in the RNC[expand acronym]; its primary function is transparent transfer of RANAP[expand acronym] messages.[9]

In March 2010, the Femto Forum and ETSI conducted the first Plugfest to promote interoperability of the Iuh standard.[10]

The CDMA2000 standard released in March 2010[11] differs slightly by adopting the SIP protocol to set up a connection between the femtocell and a femtocell convergence server (FCS). Voice calls are routed through the FCS which emulates an MSC. SIP is not required or used by the mobile device itself. In the SIP architecture, the femtocell connects to a core network of the mobile operator that is based on the SIP/IMS architecture. This is achieved by having the femtocells behave toward the SIP/IMS network like a SIP/IMS client by converting the circuit-switched 3G signaling to SIP/IMS signaling, and by transporting the voice traffic over RTP as defined in the IETF standards.

Although much of the commercial focus seems to have been on UMTS, the concept is equally applicable to all air-interfaces. Indeed, the first commercial deployment was the cdma2000 Airave in 2007 by Sprint.

Femtocells are also under development or commercially available for GSM, TD-SCDMA, WiMAX and LTE.

The H(e)NB functionality and interfaces are basically the same as for regular HSPA or LTE base stations except few additional functions. The differences mostly to support differences in access control to support closed access for residential deployment or open access for enterprise deployment, as well as handover functionality for active subscribers and cell selection procedures for idle subscribers. For LTE additional functionality was added in 3GPP Release 9 which is summarized in.[12]

The placement of a femtocell has a critical effect on the performance of the wider network, and this is the key issue to be addressed for successful deployment. Because femtocells can use the same frequency bands as the conventional cellular network, there has been the worry that rather than improving the situation they could potentially cause problems.

Femtocells incorporate interference mitigation techniquesdetecting macrocells, adjusting power [13] and scrambling codes accordingly. Ralph de la Vega, AT&T President, reported in June 2011 they recommended against using femtocells where signal strength was middle or strong because of interference problems they discovered after widescale deployment.[14] This differs from previous opinions expressed by AT&T and others.

A good example is the comments made by Gordon Mansfield, Executive Director of RAN Delivery, AT&T, speaking at the Femtozone at CTIA March 2010:

We have deployed femtocells co-carrier with both the hopping channels for GSM macrocells and with UMTS macrocells. Interference isnt a problem. We have tested femtocells extensively in real customer deployments of many thousands of femtocells, and we find that the mitigation techniques implemented successfully minimise and avoid interference. The more femtocells you deploy, the more uplink interference is reduced

The Femto Forum has some extensive reports on this subject, which have been produced together with 3GPP and 3GPP2.[15][16]

To quote from the Summary Paper Summary of Findings:

The simulations performed in the Femto Forum WG2 and 3GPP RAN4 encompass a wide spectrum of possible deployment scenarios including shared channel and dedicated channel deployments. In addition, the studies looked at the impact in different morphologies, as well as in closed versus open access. The following are broad conclusions from the studies:

The conclusions are common to the 850 MHz and 2100 MHz bands that were simulated in the studies, and can be extrapolated to other mobile bands. With interference mitigation techniques successfully implemented, simulations show that femtocell deployments can enable very high capacity networks by providing between a 10 and 100 times increase in capacity with minimal deadzone impact and acceptable noise rise.

Femtocells can also create a much better user experience by enabling substantially higher data rates than can be obtained with a macro network and net throughputs that will be ultimately limited by backhaul in most cases (over 20 Mbps in 5 MHz).

Access point base stations, in common with all other public communications systems, are, in most countries, required to comply with lawful interception requirements.

Other regulatory issues[17] relate to the requirement in most countries for the operator of a network to be able to show exactly where each base-station is located, and for E911 requirements to provide the registered location of the equipment to the emergency services. There are issues in this regard for access point base stations sold to consumers for home installation, for example. Further, a consumer might try to carry his base station with him to a country where it is not licensed. Some manufacturers are using GPS within the equipment to lock the femtocell when it is moved to a different country;[18] this approach is disputed[citation needed], as GPS is often unable to obtain position namely indoors because of weak signal.

Access Point Base Stations are also required, since carrying voice calls, to provide a 911 (or 999, 112, etc.) emergency service, as is the case for VoIP phone providers in some jurisdictions.[17] This service must meet the same requirements for availability as current wired telephone systems. Simply the phones must work if the AC mains grid is blacked out. There are several ways to achieve this, such as alternative power sources or fall-back to existing telephone infrastructure.

When using an Ethernet or ADSL home backhaul connection, an Access Point Base Station must either share the backhaul bandwidth with other services, such as Internet browsing, gaming consoles, set-top boxes and triple-play equipment in general, or alternatively directly replace these functions within an integrated unit. In shared-bandwidth approaches, which are the majority of designs currently being developed, the effect on quality of service may be an issue.

The uptake of femtocell services will depend on the reliability and quality of both the cellular operators network and the third-party broadband connection, and the broadband connections subscriber understanding the concept of bandwidth utilization by different applications a subscriber may use. When things go wrong, subscribers will turn to cellular operators for support even if the root cause of the problem lies with the broadband connection to the home or workplace. Hence, the effects of any third-party ISP broadband network issues or traffic management policies need to be very closely monitored and the ramifications quickly communicated to subscribers.

A key issue recently identified is active traffic shaping by many ISPs on the underlying transport protocol IPSec.[citation needed]

To meet Federal Communications Commission (FCC) / Ofcom spectrum mask requirements, femtocells must generate the radio frequency signal with a high degree of precision. To do this over a long period of time is a major technical challenge. The solution to this problem is to use an external, accurate signal to constantly calibrate the oscillator to ensure it maintains its accuracy. This is not simple (broadband backhaul introduces issues of network jitter/wander and recovered clock accuracy), but technologies such as the IEEE 1588 time synchronisation standard may address the issue. Also, Network Time Protocol (NTP) is being pursued by some developers as a possible solution to provide frequency stability. Conventional (macrocell) base stations often use GPS timing for synchronization and this could be used,[18] although there are concerns on cost and the difficulty of ensuring good GPS coverage.

Standards bodies have recognized the challenge of this and the implications on device cost. For example, 3GPP has relaxed the 50ppb parts per billion precision to 100ppb for indoor base stations in Release 6 and a further loosening to 250ppb for Home Node B in Release 8.

At the 2013 Black Hat hacker conference in Las Vegas, NV, a pair of security researchers detailed their ability to use a Verizon femtocell to secretly intercept the voice calls, data, and SMS text messages of any handset that connects to the device.

During a demonstration of their exploit, they showed how they could begin recording audio from a cell phone even before the call began. The recording included both sides of the conversation. They also demonstrated how it could trick Apples iMessage which encrypts texts sent over its network using SSL, rendering them unreadable to snoopers, including the NSA into defaulting to SMS, allowing the femtocell to intercept the messages.

They also demonstrated it was possible to clone a cell phone that runs on a CDMA network by remotely collecting its device ID number through the femtocell, in spite of added security measures to prevent against cloning of CDMA phones.[19]

The impact of a femtocell is most often to improve cellular coverage, without the cellular carrier needing to improve their infrastructure (cell towers, etc.). This is net gain for the cellular carrier. However, the user must provide and pay for an internet connection to route the femtocell traffic, and then (usually) pay an additional one-off or monthly fee to the cellular carrier. Some have objected to the idea that consumers are being asked to pay to help relieve network shortcomings.[20] On the other hand, residential femtocells normally provide a personal cell which provides benefits only to the owners family and friends.[21]

The difference is also that while mobile coverage is provided through subscriptions from an operator with one business model, a fixed fibre or cable may work with a completely different business model. For example, mobile operators may imply restrictions on services which an operator on a fixed may not. Also, WiFi connects to a local network such as home servers and media players. This network should possibly not be within reach of the mobile operator.

According to market research firm Informa and the Femto Forum,[22] as of December 2010 18 operators have launched commercial femtocell services, with a total of 30 committed to deployment.

At the end of 2011, femtocell shipments had reached roughly 2 million units deployed annually, and the market is expected to grow rapidly with distinct segments for consumer, enterprise, and carrier-grade femtocell deployments.[23] Femtocell shipments are estimated to have reached almost 2 million at the end of 2010.[24] Research firm Berg Insight estimates that the shipments will grow to 12 million units worldwide in 2014.[25]

Within the United States, the most significant deployments up to December 2010 were by Sprint Nextel, Verizon Wireless and AT&T Wireless. Sprint started in the third quarter of 2007 as a limited rollout (Denver and Indianapolis) of a home-based femtocell built by Samsung Electronics called the Sprint Airave that works with any Sprint handset.[26] From 17 August 2008, the Airave was rolled out on a nationwide basis. Other operators in the United States have followed suit. In January 2009, Verizon rolled out its Wireless Network Extender, based on the same design as the Sprint/Samsung system.[27] In late March 2010, AT&T announced nationwide roll-out of its 3G MicroCell, which commenced in April. The equipment is made by Cisco Systems and ip.access, and was the first 3G femtocell in US, supporting both voice and data HSPA.[28] Both Sprint[29] and Verizon[30] upgraded to 3G CDMA femtocells during 2010, with capacity for more concurrent calls and much higher data rates. In November 2015, T-Mobile US began deployment of 4G LTE femtocells manufactured by Alcatel Lucent.

In Asia, several service providers have rolled out femtocell networks. In Japan, SoftBank launched its residential 3G femtocell service in January 2009[31] with devices provided by Ubiquisys. In the same year, the operator launched a project to deploy femtocells to deliver outdoor services in rural environments where existing coverage is limited. In May 2010, SoftBank Mobile launched the first free femtocell offer, providing open access femtocells free of charge to its residential and business customers. In Singapore, Starhub rolled out its first nationwide commercial 3G femtocell services with devices provided by Huawei Technologies, though the uptake is low, while Singtels offering is targeted at small medium enterprises. In 2009, China Unicom announced its own femtocell network.[32] NTT DoCoMo in Japan launched their own femtocell service on 10 November 2009.

In July 2009, Vodafone released the first femtocell network in Europe,[33] the Vodafone Access Gateway provided by Alcatel-Lucent.[34] This was rebranded as SureSignal in January 2010,[35] after which Vodafone also launched service in Spain, Greece, New Zealand,[36][37] Italy, Ireland,[38] Hungary[39] and The Netherlands.[40] Other operators in Europe have followed since then.

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In Vitro and In Vivo Studies of a New Class of Anticancer …

Posted: at 5:17 am

There is a compelling need to develop anticancer therapies that target cancer cells and tissues. Arising from innovative femtomedicine studies, a new class of nonplatinum-based halogenated molecules (called FMD molecules) that selectively kill cancer cells and protect normal cells in treatments of multiple cancers has been discovered. This article reports the first observation of the radiosensitizing effects of such compounds in combination with ionizing radiation for targeted radiotherapy of a variety of cancers. We present in vitro and in vivo studies focused on combination with radiotherapy of cervical, ovarian, head and neck, and lung cancers. Our results demonstrate that treatments of various cancer cells in vitro and in vivo mouse xenograft models with such compounds led to enhanced efficiencies in radiotherapy, while the compounds themselves induced no or little radiotoxicity toward normal cells or tissues. These compounds are therefore effective radiosensitizers that can be translated into clinical trials for targeted radiotherapy of multiple types of cancer. This study also shows the potential of femtomedicine to bring breakthroughs in understanding fundamental biologic processes and to accelerate the discovery of novel drugs for effective treatment or prevention of a variety of cancers. Mol Cancer Ther; 15(4); 64050. 2016 AACR.

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Scientists discover new molecules that kill cancer cells …

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Research in mice suggests molecules could treat cervical, breast, ovarian, and lung cancers

A new family of molecules that kill cancer cells and protect healthy cells could be used to treat a number of different cancers, including cervical, breast, ovarian and lung cancers. Research published in EBioMedicine shows that as well as targeting and killing cancer cells, the molecules generate a protective effect against toxic chemicals in healthy cells.

Cells can become cancerous when their DNA is damaged. Many different things can cause DNA damage, including smoking, chemicals and radiation; understanding exactly what happens at the point of DNA damage can help scientists develop new cancer treatments. By studying this mechanism, researchers from the University of Waterloo in Canada could identify new molecules that selectively target cancer cells.

The researchers studied the process of DNA damage using a sort of molecular filming technique called femtosecond time-resolved laser spectroscopy. The technique is like a high-speed camera, which uses two pulses of light: one to start a reaction, and the other to monitor the way the molecules react. This technique let researchers watch how molecules interact in real-time, revealing how cells become cancerous.

Researchers have been using femtosecond laser spectroscopy to study biological molecules for decades, in fields called femtochemistry and femtobiology. More recently, this technique was fused with molecular biology and cell biology techniques to advance our understanding of human diseases, notably cancer, and how their treatments work. This potential new field is being dubbed femtomedicine (FMD).

We know DNA damage is the initial and crucial step in the development of cancer, said Professor Qing-Bin Lu, lead author of the study from the University of Waterloo, Canada. With the FMD approach we can go back to the very beginning to find out what causes DNA damage in the first place, then mutation, then cancer. FMD is promising as an efficient, economical and rational approach for discovering new drugs, as it can save resources required to synthesize and screen a large library of compounds.

Taking advantage of the FMD approach, Professor Lu and his colleagues discovered a new family of molecules called nonplatinum-based halogenated molecules, or FMD compounds. These are similar to cisplatin a drug used to treat ovarian, testicular, lung, brain and other cancers. However, while cisplatin is highly toxic, the new FMD compounds are not harmful to normal cells.

When the FMD compounds enter a cancer cell, they react strongly and form reactive radicals, which cause the cell to kill itself. When the FMD compounds enter a healthy cell, the cell starts to increase the amount of a protective molecule called glutathione (GSH) in the cell. This protects the cell against chemical toxins, so it is not damaged.

The researchers tested the molecules on human cells and in mice, and found very consistent results. They treated human cells various normal and cancer cells with the FMD compounds and tested them to see whether the cells were killed. They also tested the levels of GSH in the cells, revealing that the amount of protective molecule increased in the normal cells, while it decreased in cancer cells.

They then tested the FMD compounds on a range of tumors in mice, representing cervical, ovarian, breast and lung cancers. They measured the extent to which the FMD compounds slowed down tumor growth, and found it was effective at slowing or halting the growth of all tumors.

Were very excited about our discovery; we can see that the FMD compounds are just as effective as cisplatin in mice but without being toxic, said Professor Lu. We believe that it could potentially be used to treat a very wide rage of cancers, without making patients suffer the toxic side effects that some existing drugs have.

We want this discovery to help patients, and we plan to move it into clinical trials as soon as possible, added Professor Lu.

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Article details In Vitro and In Vivo Studies of Non-Platinum-Based Halogenated Compounds as Potent Antitumor Agents for Natural Targeted Chemotherapy of Cancers by Qing-Bin Lu, Qin-Rong Zhang, Ning Ou, Chun-Rong Wang and Jenny Warrington (doi: 10.1016/j.ebiom.2015.04.011). The article appears in online EBioMedicine, published by Elsevier.

The article is available as open access paper: http://www.sciencedirect.com/science/article/pii/S235239641500105X http://www.ebiomedicine.com/article/S2352-3964(15)00105-X/abstract

For more information or to schedule an interview with the authors, contact Elseviers Newsroom at [email protected] or +31 20 4853564

About EBioMedicine The effective translation of insights gained from biomedical research into improved human health is a global priority. To this end, Elsevier has looked to the leadership of its two leading brands, Cell and The Lancet, to guide the launch of a new comprehensive, online-only open access, rapid publication Elsevier journal, EBioMedicine, focused on forming a community that spans this interface and creates a valuable opportunity for dialogue and collaboration between their respective audiences. As the communities that border this interface are large and diverse, the scope of EBioMedicine covers the entire breadth of translational and clinical research within all disciplines of life and health sciences, ranging from basic science to clinical and public/global health science. The journal is committed to facilitating and incentivizing a robust and successful pipeline for improved human health globally (www.ebiomedicine.com).

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Electron transfer-based combination therapy of cisplatin …

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Electron-transfer reactions play key roles in diverse processes in chemistry, physics, and biology, ranging from photo-induced reactions (1, 2), electron tunneling in proteins (3), and electron transport in DNA (4) to the ozone hole formation (5) and reductive DNA damage (6, 7). Electron-transfer reactions in molecular systems have therefore been the subject of intense experimental and theoretical studies. Following the pioneering contribution of Zewail (8), the advent of femtosecond time-resolved laser spectroscopy (fs-TRLS; 1fs=10-15s) provided an unprecedented capacity in techniques of observing molecular reactions, including electron transfer. Its application to the study of chemical and biological systems led to the birth of new scientific subfields: femtochemistry and femtobiology (8). Recently, Lu (9) further proposed that integrating ultrafast laser techniques with biomedical methods to advance fundamental understandings and treatments of major human diseases might lead to the opening of a new frontier called femtomedicine. Regarding the latter, we have recently unraveled unique dissociative electron-transfer (DET) mechanisms of reductive DNA damage (6, 7) and several anticancer agents for radiotherapy and chemotherapy (1014). In this paper, we present results of experimental studies on a unique combination therapy based on the DET mechanism of cisplatin to enhance the efficacy of human ovarian-, cervical-, and lung-cancer therapies.

Ovarian and cervical cancers are leading causes of cancer deaths in women, while lung cancer is the deadliest type of cancer for both men and women (15). The standard treatment is surgery followed by platinum-based chemotherapy, which generally yields a positive response in the initial treatment. In many cases, however, cancer cells become refractory with time (1620), and 7090% of patients with serious cancers die of progressive chemoresistant disease (19). Successful treatment strategies are still lacking, especially for ovarian and lung cancers (1520).

Cisplatin [Pt(NH3)2Cl2] (CDDP) is the first and most widely used platinum-based chemotherapy drug (2124). CDDP is now the cornerstone agent in treating a variety of cancers, including ovarian, testicular, cervical, bladder, lung, head and neck, lymphoma, and brain cancers (1618, 2224). However, its application is often limited by toxic side effects and resistance of various cancers (1618, 2224). The cytotoxicity of CDDP is well known to arise from its capacity to damage DNA by binding the cis-[Pt(NH3)2] unit to DNA. The conventional understanding of the initial action of CDDP was the hydrolysis mechanism (17, 2224). Based on this mechanism, many studies in the past 40years attempted to circumvent the drawbacks of CDDP. Over 3,000 CDDP analogues were designed, synthesized, and tested, but only two have been approved by the US Food and Drug Administration: oxaliplatin and carboplatin. This might imply that a precise understanding of the molecular mechanism of the cytotoxicity of CDDP was lacking.

Moreover, recent advances in cancer research have shown that even the most successful targeted therapies lose potency with time; attaining permanent cures for most cancers would require a combination therapy of two or more drugs simultaneously (25). Indeed, the combinations of cisplatin with another therapy/agent have shown promising results in treating lung, cervical, and head and neck cancers (2631). In most cases, however, the combined therapies/agents act via different mechanisms of action or target different pathways, thereby achieving an additive therapeutic effect. Thus, there have been no or limited synergetic effects in the combinations. It is desirable to develop a synergetic combination therapy of low-dose CDDP with another agent.

Through the femtomedicine approach, we have recently obtained the precise molecular mechanisms of cisplatin in combination with radiotherapy (13) and chemotherapy (14) of cancer. First, we found that CDDP is extremely effective for the DET reaction with ultrashort-lived (540fs) prehydrated electrons () generated in radiotherapy to produce a [Pt(NH3)2Cl] or cis-[Pt(NH3)2] radical that then causes DNA strand breaks (13). The latter will lead to apoptosis and final clonogenic cell kill (32). Second, we found that, for chemotherapy, the DET reaction of CDDP occurs preferentially with two neighboring G bases (the most favorable electron donor among the four bases in DNA), while the DET with base A is much weaker and there is no DET with C and T (14). This DET mechanism has directly unraveled the long-existing mystery regarding why Pt drugs result in the preferential binding of the cis-[Pt(NH3)2] to two neighboring G bases in DNA. The high reactivity of cisplatin with electrons has been confirmed subsequently by Kopyra et al. (33) in studying dissociative attachments of low-energy free electrons to gas-phase CDDP. It is well known that in liquid water, free electrons produced by ionizing radiation will rapidly become on the fs timescale and finally form the nonreactive solvated electrons (6, 7, 9). Most recently, quantum chemical calculations by Kuduk-Jaworska et al. (34) have confirmed the DET mechanism of CDDP. The authors presented results on delicate electronic-structure calculations of model systems for cis-and trans-platin with free electrons, hydrated electrons, and water by using density functional theory approach. Their results are consistent with our DET mechanism involving electrons trapped in water, though the hydrolysis of CDDP was not excluded in the study. The DET mechanistic insight into the cytotoxicity mechanism of CDDP obtained through our fs-TRLS studies (13, 14) has potential to improve existing therapies using CDDP and enable new combination treatments for challenging cancers.

Based on the DET mechanism, it is expected that CDDP may be administered in combination with a biological electron donor (mimicking the generated in radiotherapy) to enhance the chemotherapeutic efficacy. Aromatic amines like N,N,N,N-tetramethyl-p-phenylenediamine (TMPD) are well-known biological electron donors (35). Thus, the expected strong DET reaction between cisplatin and TMPD will form reactive radicals to kill cancer cells. In this study, we conducted both absorption and fluorescence spectroscopic measurements to confirm the DET reaction. Furthermore, we measured the DET-induced strand breaks of plasmid DNA by gel electrophoresis. We used a CDDP-sensitive human cervical cancer (HeLa) cell line and highly CDDP-resistant human ovarian cancer (NIH:OVCAR-3) and lung cancer (A549) cell lines to evaluate the combination therapy of CDDP with the exemplary electron-donating molecule TMPD. The NIH:OVCAR-3 cell line has been established by Hamilton and coworkers (3639) as a model system for in vitro and in vivo studies of the resistance of CDDP and other chemotherapy drugs.

We first show time-series changes of the absorption spectrum of TMPD in pure water. A shows that after 100M TMPD was dissolved for a few hours, a pronounced absorption band appeared at 500650nm, which is the well-known characteristic absorption of the cation TMPD+. This band was observed in many studies of photoionization of TMPD in polar solvents and photo-induced DET from TMPD to halogenated molecules as solvents or solutes (40, 41). In contrast to those previous studies, no extra photo-excitation was applied in our present experiments. This indicates the effective autoionization of TMPD into a TMPD+ and a solvated electron in water. As a strong electron-donating agent, TMPD has a low ionization potential of 6.10.1eV in the gas phase (42), which can be lowered by more than 3eV due to the solvent polarization in some polar solvents (40). Thus, the ionization energy of TMPD in some solvents can be lower than the binding energy of the solvated electron, which is approximately 3.23.5eV in water. As a result, the autoionization of TMPD occurs in water. More interestingly, the results in B show that adding CDDP increased the TMPD+ yield, indicating an effective electron transfer from TMPD to CDDP. B also shows that when the samples were irradiated by a laser at 266nm for 1h, the TMPD+ yield was additionally enhanced. This is consistent with the previous observations of photo-induced electron transfer reactions of TMPD (40, 41).

Spectroscopic observations of the DET reaction between cisplatin (CDDP) and TMPD. Absorption spectra (AD) and fluorescence spectra (E, F) of TMPD in water or EtOH with and without the presence of CDDP. In B, spectra are also shown for the samples …

By contrast, the observed results for 100M TMPD in pure EtOH are shown in C. No changes in the absorption spectrum were observed up to 48h or longer, giving direct evidence of no autoionization of TMPD in EtOH. This is consistent with the observation that the ionization energy of TMPD in alcohols is higher than in water, which is approximately 4.75eV in methanol (40). Thus, the autoionization of TMPD cannot occur in EtOH. Interestingly, however, adding 100M CDDP caused no changes in the absorption spectrum of 100M TMPD in EtOH initially, but the strong absorption band of the TMPD+ at 500650nm appeared after a few hours (D). The results for mixing 100M TMPD with various concentrations of CDDP are plotted in Fig.S1, showing that the delay time to observe the pronounced TMPD+ absorption band decreased with rising CDDP concentrations. An additional absorption band at 300350nm was also observed in the spectra shown in A,B, and D and Fig. S1. This extra band appeared simultaneously with that of TMPD+ at 500650nm, both having an identical growth rate either in pure water or in mixtures with CDDP in H2O or EtOH. Thus, it may be attributed to TMPD+ as well. These data clearly demonstrate the effective DET reaction between TMPD and CDDP in EtOH even with no autoionization of TMPD.

The steady-state fluorescence spectra of TMPD excited at 266nm in pure H2O and EtOH with and without the presence of CDDP are shown in E and F. It is seen that for TMPD in pure H2O (E), there were two emission peaks at 370 and approximately 425430nm. With the addition of CDDP, the peak at 370nm became dominant, while the peak at 425nm was significantly depleted. These peaks can be reasonably attributed to the fluorescence peaks of TMPD+ and neutral TMPD, respectively (43). This attribution is further confirmed by the results shown in F: The fluorescence spectrum of TMPD in pure EtOH exhibited only a peak at approximately 420nm, while a new peak around 370nm appeared as CDDP was introduced. Again, the fluorescence spectra in E and F confirm the autoionization of TMPD in water but not in pure EtOH and the DET reaction of TMPD with CDDP in both H2O and EtOH solvents.

Moreover, under the condition that the CDDP concentration (e.g., 2mM) is far larger than the TMPD concentration (100M) (Fig.S1), the DET reaction between TMPD and CDDP, leading to the formation of the ion pair and the radical:

can be described by pseudo-first order reaction kinetics. Here, the reaction rate constant k can be determined by the absorption intensity I variation of TMPD at 261nm with reaction time t. As detailed in SI Text and Fig.S2, the obtained reaction rate constant is k=1.70.210-2M-1s-1. This indicates that without extra excitation, the DET reaction between ground-state TMPD and CDDP (Eq.1) can effectively occur on the time scale of hours.

To examine the above hypothesis, we measured plasmid DNA damage induced by cisplatin only and its combination with TMPD by agarose gel electrophoresis (7). The gel image and double-strand break (DSB) yields for plasmid DNA incubated with CDDP alone at various concentrations and in combination with 100M TMPD for 24h are shown in . The DSB yields were determined from the DSB peak areas in the gel densitograms, which are shown in Fig.S3. The intrastrand cross-link is the well-known form of the CDDP-DNA adduct, but the platinated DNA is invisible in the gel image because the fluorescence emission of the DNA-binding dye (EtBr) is quenched. This resulted in a much weaker band of the supercoiled DNA for CDDP-treated DNA than the untreated DNA (control). Of particular interest, however, is our result shown in and Fig. S3: Cisplatin directly induces DSBs of the DNA. In fact, CDDP-induced DSBs in replicating yeast, Escherichia coli, and mammalian cells had been reported previously (44, 45), but they were thought to arise from the repair process of DNA cross-links in which DSBs act as an intermediate step. Because no repair could be involved in the extracted and purified plasmid DNA in the present experiments, our observation of DNA DSBs gives direct evidence that DSB is an intrinsically damaging form of cisplatin interacting with DNA. More remarkably, the combination of CDDP with TMPD increased the DNA DSB yield by a factor of approximately 3.5 (). This result provides strong evidence of the expected enhancement in DNA DSBs induced by reactive radicals due to the DET reaction.

Gel electrophoresis measurements of strand breaks in plasmid DNA treated by cisplatin alone and in combination with TMPD: (A) gel image, where the bands for supercoiled (SC) DNA, open circular DNA with single-strand breaks (SSBs), and linear DNA with …

We further investigated whether TMPD in combination with CDDP modulates the sensitivity of human cancer cells to CDDP. Based on spectroscopic results (), the concentrated stock solution (40mM) of TMPD must be prepared in pure EtOH to prevent the loss of electrons from TMPD. We compared the effects of CDDP and TMPD alone and in combination on the viability of CDDP-sensitive cervical cancer (HeLa) cells and highly CDDP-resistant ovarian cancer (NIH:OVCAR-3) and lung cancer (A549) cells. As shown in A and B, 100M of TMPD alone caused only a small cell-killing effect (approximately 10%) of the treated cells. For HeLa cells (A), a 24-h treatment with CDDP alone decreased the cell survival rate in a dose-dependent manner: A CDDP concentration as high as 60M was required to kill the cells completely. Interestingly, the addition of 100M TMPD to CDDP greatly enhanced the killing of cancer cells in a synergistic manner: At CDDP concentrations of 30M, nearly all of the HeLa cells were killed. Even more interesting were the results for highly CDDP-resistant ovarian cancer cells (B): About 40% of the treated NIH:OVCAR-3 cells survived from the treatment of CDDP alone, even at very high concentrations of 200300M. This result confirms the strong resistance of NIH:OVCAR-3 cells to CDDP (3639). Strikingly, we found that the combination of CDDP with 100M TMPD dramatically enhanced the killing of NIH:OVCAR-3 cells: The killing rate increased from approximately 50% to 95% at 100M CDDP and from 60% to 100% at 200M CDDP. Similar enhancements in killing A549 cells by combination of CDDP with TMPD are shown in Fig.S4. Also shown in and Fig. S4 are the results of fractional effect analysis (28), which is one of the most straightforward methods to evaluate the synergetic effect; the effects of CDDP and TMPD alone were simply multiplied and compared with the observed effect of the combination at the same concentration of the single agents. The results clearly show that the observed effect was significantly greater than the product of the effects of individual agents. As also shown in TableS1, moreover, the values of CDDP IC50 (the concentration required to kill 50% of untreated cells) for these treated cancer cells are reduced by factors of 24 by combination with TMPD, which are about 50% the values expected for the additive effect of the two agents. From these results, we conclude that the combination treatment showed strong synergistic effects in killing cervical, ovarian, and lung cancer cells and removed the resistance of CDDP-resistant ovarian and lung cancer cells to CDDP.

MTT cell viability assays of cancer cells with treatments of cisplatin alone and in combination with TMPD:(A) HeLa cells; (B) NIH:OVCAR-3 cells. The cells were treated by vehicle alone (0.2% EtOH),various concentrations of CDDP alone,and their combinations …

To show that the DET reaction between TMPD and CDDP indeed led to observed synergetic killing of cancer cells, we additionally tested the combination by using a stock solution of TMPD prepared in pure H2O for 24h as a negative control. According to spectroscopic results in , the autoionization (i.e., electron knockout from TMPD to form the TMPD+) had mainly occurred prior to adding to the cell culture medium and therefore no or few DET reactions were expected to occur between CDDP and the so-prepared (ionized) TMPD. The results for cell viability measurements on cells so treated are shown in Fig.S5, which indeed shows that the enhancements in cell killing of CDDP by the presence of ionized TMPD (mainly TMPD+) were negligibly small compared with those with fresh TMPD prepared in EtOH. These electron-knockout results therefore confirm that the DET killing mechanism was responsible for strong synergetic effects in killing cancer cells in the combination of CDDP with unoxidized TMPD.

To study whether the TMPD-enhanced cytotoxicity of CDDP was due to the induction of apoptosis, we detected caspase activation and nuclear morphology of cancer cells treated with CDDP alone and in combination with TMPD. As shown in , the combination treatment resulted in a significant activation of caspase-3 and -7 in the NIH:OVCAR-3 cells, which was evident from the significant enhancement in green fluorescence. Also, the results from the Hoechest 33342 staining showed that the combination significantly enhanced the nuclear fragmentation/condensation of treated cells. From these images, we estimated that the combination of CDDP with TMPD led to an enhancement in apoptosis by a factor of 35 compared to treatment with CDDP alone.

Fluorescence microscopy observation of NIH:OVCAR-3 cells undergoing apoptosis induced by treatments indicated for 10h. Hoechest 33342 staining (blue fluorescence) detects the nuclear fragmentation/condensation, while green fluorescence of FLICA …

To further confirm the above results, we used flow cytometry to quantify apoptotic cells and analyze cell cycle profiles. A landmark of cellular self-destruction by apoptosis is the activation of nucleases that eventually degrade the nuclear DNA into fragments. Detection of these fragments is relatively straightforward to quantify apoptotic cells and can be conducted using the APO-BrdU TUNEL Assay Kit. As shown in for the NIH:OVCAR-3 cells, the 24-h treatment of 100M TMPD alone resulted in a small percentage of DNA fragmentation (approximately 0.3%), while the treatments with CDDP alone increased DNA fragmentation to 2.6% at 30M and 3.2% at 50M. In contrast, the DNA fragmentation contents were significantly increased to 5.0% and 16.9% for 30 and 50M CDDP in combination with 100M TMPD, respectively, 25 times those expected for the additive effect of the two agents. Similar enhancements for HeLa cells treated with various concentrations of CDDP plus 100M TMPD are shown in Fig.S6. These data clearly show that the combination of CDDP with TMPD resulted in large synergetic enhancements in apoptosis of both cisplatin-sensitive and -resistant cancer cells.

APO-BrdU DNA fragmentation assay of NIH:OVCAR-3 cells with treatments indicated for 24h. Cells in the region above the line in each histogram are BrdU-positive cells (cells exhibiting DNA fragmentation); the line was drawn based on the samples …

We also performed cell cycle analysis of cancer cells treated by the combination of cisplatin with TMPD. The results for NIH:OVCAR-3 cells are shown in Fig.S7 and SI Text. Overall, the observed results in and , and Figs. S6 and S7 have clearly demonstrated a synergetic increase in apoptosis of the cells treated by the combination of cisplatin with TMPD.

One of the practical ways to improve the therapeutic efficacy of cisplatin is to combine it with a molecular promoter in a synergetic manner. According to the DET mechanism (13, 14), CDDP is an extremely reactive compound with electrons. As it enters a cell, CDDP may react with e–donating components such as amino acids in proteins other than G bases in DNA, leading to the loss of its target to DNA and, hence, the cytotoxic activity. This loss in capacity to damage DNA is likely to result in insensitivity of cancer cells to CDDP (17). Indeed, intracellular CDDP inactivation by glutathione has been proposed as a mechanism of CDDP resistance (16, 46, 47). Glutathione is a cellular antioxidant, preventing damage to important cellular components caused by reactive radicals (48). It reduces disulfide bonds formed within cytoplasmic proteins to cysteines by serving as an electron donor. Thus, glutathione may direct cisplatin to target protein sites relatively distant from DNA in the cell. Reversely, the resistance may be circumvented by activating CDDP with an e–donating compound like TMPD to produce reactive radicals that then lead to DNA damage and cell death.

In the present model study, our results from spectroscopic measurements confirm that the exemplary e–donating compound, TMPD, indeed has a strong DET reaction with CDDP, consistent with the expectation from the DET mechanism of CDDP (13, 14, 34). Furthermore, our gel electrophoresis results on plasmid DNA show that the DET reaction indeed leads to DNA double-strand breaks. Correspondingly, the results from cell viability and apoptosis measurements show that the combination of CDDP with TMPD significantly reduced the doses of CDDP required to kill both CDDP-sensitive cervical cancer cells and highly CDDP-resistant ovarian cancer cells in a synergetic manner. And most strikingly, we found that adding TMPD led to a complete killing of highly CDDP-resistant ovarian cancer cells. It might be considered that the effect of TMPD may involve not the reversal of CDDP resistance but a simple enhancement of toxicity of CDDP. As confirmed in B, however, even for NIH:OVCAR-3 cells treated with CDDP alone in extremely high concentrations of 200300M (at which CDDP is supposed to have an extremely high toxicity), a large fraction (40%) of the cancer cells still survived. Only with TMPD did we observe that NIH:OVCAR-3 cells became sensitive to CDDP. It is more likely that the DET reaction of CDDP with TMPD competed with or suppressed the reaction causing CDDP resistance (e.g., the reaction of CDDP with glutathione or cysteines in proteins in the cell). As a result, the highly CDDP-resistant cancer cells became sensitive to CDDP and the drug resistance was circumvented. It should also be noted that TMPD also enhanced the killing of CDDP-sensitive HeLa cells. However, this is not surprising because the DET reaction between CDDP and TMPD in CDDP-sensitive cells will also increase the yield of reactive radicals that lead to DNA damage and apoptosis.

Moreover, the tumor microenvironment is well known to be associated with hypoxia in cancer biology. This has multiple consequences for tumor progression and treatment outcome (17, 31). However, hypoxia could be an advantage if a therapy activated only in hypoxic cells were designed; this would provide a method of killing cancer cells while having no or little harm to healthy cells in normal tissue. Thus, the unique presence of hypoxia in human tumors could provide an important target for selective cancer therapy (49). In our unique design, the combination of TMPD and cisplatin should predominantly target hypoxic cancer cells, while the remaining oxic cells will only be killed with the low dose of cisplatin. This is due to the consideration that DET will be mainly effective in a hypoxic environment, while in an oxic environment the electron-donating agent will easily become oxidized and lose its reaction capability with cisplatin. In fact, this has partially been demonstrated by our results of negative control experiments on cancer cells treated by the combination of ionized (oxidized) TMPD with cisplatin. Thus, a preferential targeting of tumor cells is expected to be achieved; further studies will be needed.

Finally, due to the wide application of CDDP in treating various human cancers, the strategy developed from this study may have potential for improving the treatment of multiple types of cancer beyond ovarian, cervical, and lung cancers. Furthermore, a similar structural feature exists in all clinically active platinum-based chemotherapy agents, and the DET reaction mechanism is expected to operate for all such Pt-based agents, such as oxaliplatin and carboplatin (13, 14). Thus, this combination strategy is expected to be applicable to all Pt-based chemotherapy. Through an increasing number of successful case studies, our results have demonstrated the potential of femtomedicine as an exciting new frontier to yield breakthroughs in understanding fundamental biological processes and improving the therapeutic efficacy of human diseases such as cancer.

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Posted: September 9, 2015 at 3:43 am

January 8th, 2015

Mayo Clinic in the News Weekly Highlights

By Karl W Oestreich

Mayo Clinic in the Newsis a weekly highlights summary of major media coverage. If you would like to be added to the weekly distribution list, send a note toLaura Wuotilawith this subject line: SUBSCRIBE toMayo Clinic in the News.

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Wall Street JournalWhat CEOs Expect for Business in 2015by John Bussey

We asked the 153 members of the Wall Street Journals CEO Council to tell uswhether theyre positive or negativeabout business prospects in 2015, and why. Heres what several had to say:John Noseworthy, Mayo Clinic, Disruptive technologies ranging from regenerative and genomic medicine to remote monitoring devices have already begun to alter health care delivery. Were excited to work with diverse business partners to quickly commercialize these and other novel scientific discoveries so they benefit patients everywhere.

Reach:The Wall Street Journal, a US-based newspaper published by Dow Jones & Company, is second in newspaper circulation in America with an average circulation of 223 million copies on week days. Its website has more than 4.3 million unique visitors each month.

Previous Coverage in December 12, 2014 Mayo Clinic in the News Weekly HighlightsContext:John Noseworthy, M.D. is Mayo Clinic President and CEO. Dr. Noseworthy participated in the Wall Street Journal CEO Council.In early December, top global CEOs gathered once again in Washington, D.C., for the annual meeting of The Wall Street Journal CEO Council.

Public Affairs Contact: Traci Klein

Wall Street JournalThe Day You Look Up to Your Childby Sue Shellenberger

It is a parenting milestone that seems to take place overnight: Your child is suddenly taller than you Children are reaching their adult height at younger ages, however, says Siobhan Pittock, a pediatric endocrinologist at the Mayo Clinic Childrens Center in Rochester, Minn. She cites a gradual trend toward puberty starting a few months earlier, causing children to start their growth spurt earlier Eric Sorensons son Tom rocketed past him in a matter of weeks, says Toms mother, Kristin, of Rochester, Minn. They noticed the shift when looking at a couple of family photos taken two months apart, when Tom was 14. In the first, Tom appears about 2 inches shorter than his 5-foot-9 dad.

Reach:The Wall Street Journal, a US-based newspaper published by Dow Jones & Company, is second in newspaper circulation in America with an average circulation of 223 million copies on week days. Its website has more than 4.3 million unique visitors each month.

Related Coverage:Wall Street Journal, The 10-Point. A personal, guided tour to the best scoops and stories every day in The Wall Street Journal, from Editor in ChiefGerard Baker. A Tall Tale. Its a strange thing to look up to your child. Our Work & Family columnist Sue Shellenbarger writes about a milestone that in many households seems to take place overnight: when achild grows tallerthan mom and dad. Adults height hasnt changed much in recent years, but a pediatric endocrinologist at the Mayo Clinic Childrens Center says children are reaching their grown-up height at younger ages.

Star Tribune2014 Twelve in Review. Looking back at the newsmakers

Dr. John Noseworthy, CEO, Mayo Clinic. In 2014, the Mayo Clinic set in motion a 20-year, $6 billion economic development project in its hometown of Rochester. The goal is to enhance Mayos status as a global destination for health care, while growing the local economy.

Reach:TheStar TribuneSunday circulation is 518,745 copies and weekday circulation is 300,277. TheStar Tribuneis the states largest newspaper and ranks 16thnationally in circulation.

Previous Coverage on the future of Mayo Clinicin December 12, 2014 Mayo Clinic in the News Weekly Highlights

Context:John Noseworthy, M.D. is Mayo Clinic President and CEO.

Public Affairs Contact: Karl Oestreich

Star TribuneA visionary blueprint arrives for Rochester, Mayo Clinicby Tina Smith and Ardell Brede

The 20-year plan for the Destination Medical Center lays out the steps toward a global center for health and wellnessA global destination for health care and wellness. This is the vision of the Destination Medical Center (DMC) initiative a vision that is now one step closer to becoming reality with the completion of the comprehensive draft development plan on Dec. 17.

Reach:TheStar TribuneSunday circulation is 518,745 copies and weekday circulation is 300,277. TheStar Tribuneis the states largest newspaper and ranks 16thnationally in circulation.

Additional Coverage: Chicago Chronicle, Florida Statesman, Atlanta Leader,Winona Daily News

Related Coverage:KARE11 (AP), Rochester businesses closing amid Mayo plan. The face of downtown Rochester is changing as the city remakes itself amid Mayo Clinic’s development of its massive Destination Medical Center. Minnesota Public Radio News reports several longstanding businesses will soon close due to the rising cost of commercial downtown space. The effects of the 20-year plan to cement Mayo as a global health care destination have prompted concerns from residents who want to ensure Rochester doesn’t simply become a city for nonlocals.

Additional coverage: Pioneer Press, Mankato Free Press

Previous Coverage in December 18, 2014 Mayo Clinic in the News Weekly Highlights

Context:The development plan proposed at the DMCC Board meeting Dec. 17 is a BIG PLAN (694 pages) in support of a bold vision. And what everyone wants to know is: Whats going to happen and how much will it cost? More information can be found on the DMC blog.

Public Affairs Contact: Jamie Rothe

KMSP FOX92-time transplant survivor’s new heart ready for a weddingby Rob Olson

In a 100-year-old home in Rochester, originally built for one of Mayo Clinic’s first surgeons, is where Alyssa Sandeen spent 5 months of her life. We first told you about Sandeen in the summer of 2013, not long after she got her second heart transplant. Shegot her first at age 8 in 1998, a heart that lasted 15 years but barely.

Reach: FOX 9 News broadcasts in Minneapolis-St.Paul, the16thlargest television marketin the United States with 1.7 million TV homes.

Context:Mayo Clinic Transplant Center, with transplant services in Arizona, Florida and Minnesota, performs more transplants than any other medical center in the world.

Public Affairs Contact: Ginger Plumbo

Red Wing Republican Eagle2014 top stories: #4 – Cannon Falls has healthy developmentby Michael Brunt

It was a big summer for Mayo Clinic Health System and the city of Cannon Falls, which celebrated the opening of a new 92,000-square-foot medical center off Goodhue County Road 24. The new facility has allowed us to serve our patients better in many ways, said Bill Priest, operations administrator.

Reach:The Red Wing Republican Eagle, which is published twice each week and has a circulation of more than 5,400, has served residents of Red Wing, Minn., since 1857.

Previous Coverage in July 31, 2014 Mayo Clinic in the News Weekly HighlightsContext:The new clinic openedon Aug. 4, 2014 and the hospital and emergency department opened on Aug. 7, 2014. More information on the new clinic and hospital can be found here.

Public Affairs Contact: Asia Christensen

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Femto Medicine | Mayo Clinic In The News

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Scientists discover new molecules that kill … – EurekAlert!

Posted: July 10, 2015 at 7:44 pm

Research in mice suggests molecules could treat cervical, breast, ovarian, and lung cancers

Amsterdam, May 13, 2015 – A new family of molecules that kill cancer cells and protect healthy cells could be used to treat a number of different cancers, including cervical, breast, ovarian and lung cancers. Research published in EBioMedicine shows that as well as targeting and killing cancer cells, the molecules generate a protective effect against toxic chemicals in healthy cells.

Cells can become cancerous when their DNA is damaged. Many different things can cause DNA damage, including smoking, chemicals and radiation; understanding exactly what happens at the point of DNA damage can help scientists develop new cancer treatments. By studying this mechanism, researchers from the University of Waterloo in Canada could identify new molecules that selectively target cancer cells.

The researchers studied the process of DNA damage using a sort of molecular filming technique called femtosecond time-resolved laser spectroscopy. The technique is like a high-speed camera, which uses two pulses of light: one to start a reaction, and the other to monitor the way the molecules react. This technique let researchers watch how molecules interact in real-time, revealing how cells become cancerous.

Researchers have been using femtosecond laser spectroscopy to study biological molecules for decades, in fields called femtochemistry and femtobiology. More recently, this technique was fused with molecular biology and cell biology techniques to advance our understanding of human diseases, notably cancer, and how their treatments work. This potential new field is being dubbed femtomedicine (FMD).

“We know DNA damage is the initial and crucial step in the development of cancer,” said Professor Qing-Bin Lu, lead author of the study from the University of Waterloo, Canada. “With the FMD approach we can go back to the very beginning to find out what causes DNA damage in the first place, then mutation, then cancer. FMD is promising as an efficient, economical and rational approach for discovering new drugs, as it can save resources required to synthesize and screen a large library of compounds.”

Taking advantage of the FMD approach, Professor Lu and his colleagues discovered a new family of molecules called nonplatinum-based halogenated molecules, or FMD compounds. These are similar to cisplatin – a drug used to treat ovarian, testicular, lung, brain and other cancers. However, while cisplatin is highly toxic, the new FMD compounds are not harmful to normal cells.

When the FMD compounds enter a cancer cell, they react strongly and form reactive radicals, which cause the cell to kill itself. When the FMD compounds enter a healthy cell, the cell starts to increase the amount of a protective molecule called glutathione (GSH) in the cell. This protects the cell against chemical toxins, so it is not damaged.

The researchers tested the molecules on human cells and in mice, and found very consistent results. They treated human cells – various normal and cancer cells – with the FMD compounds and tested them to see whether the cells were killed. They also tested the levels of GSH in the cells, revealing that the amount of protective molecule increased in the normal cells, while it decreased in cancer cells.

They then tested the FMD compounds on a range of tumors in mice, representing cervical, ovarian, breast and lung cancers. They measured the extent to which the FMD compounds slowed down tumor growth, and found it was effective at slowing or halting the growth of all tumors.

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Scientists discover new molecules that kill … – EurekAlert!

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