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Giada Bianchi , Paul G. Richardson and Kenneth C. Anderson
Blood 2015 126:300-310; doi: https://doi.org/10.1182/blood-2015-03-575365
Giada Bianchi
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Paul G. Richardson
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Kenneth C. Anderson
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Introduction

Progress in medical research has enhanced our understanding of tumor biology, delineated genetic and molecular mechanisms of tumor growth and survival, and defined the impact of the microenvironment in cancer pathogenesis. As a consequence of these advances, cancers deemed rapidly fatal only a few decades ago can now be treated effectively, with prolonged survival in an increasing proportion of patients. This is particularly true for multiple myeloma (MM), in which the introduction of drugs targeting the tumor in its microenvironment, such as the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, into initial, consolidation, maintenance, and salvage therapies has markedly improved patient outcome. In this perspective, we discuss the most promising therapies to even further improve MM treatment, with a focus on drugs inhibiting the ubiquitin-proteasome pathway; histone deacetylase (HDAC) inhibitors (HDACIs); immune therapies including IMiDs, monoclonal antibodies (mAbs), immune checkpoint inhibitors, agents targeting accessory plasmacytoid dendritic cells (pDCs), vaccines, and chimeric antigen receptor–engineered T (CAR-T) cells; drugs targeting tumor cell homing to, and exploiting hypoxia in, the bone marrow (BM) microenvironment; molecularly targeted therapies against kinesin spindle protein (KSP), v-akt murine thymoma viral oncogene homolog 1 (AKT), exportin 1 (XPO1), cyclin-dependent kinases (CDKs), bromodomain and extraterminal (BET) bromodomain 4, and serine/threonine kinase 4 (STK4); as well as delineating the impact of genomics on MM therapy. These advances in understanding the biology of MM will allow for earlier treatment of patients using rationally informed combination therapies with curative potential.

Melphalan plus prednisone treatment of MM was introduced in the 1960s and achieved median survival of 2 to 3 years. 1 High-dose IV melphalan followed by autologous hematopoietic stem cell transplant (ASCT) was pioneered in the 1970s, with the first randomized trial of high-dose chemotherapy followed by ASCT vs conventional chemotherapy showing a 5-year overall survival (OS) rate of 52% vs 12%, respectively, in the 1990s. 2 Remarkably, over the last decade, the introduction of novel agents targeting MM in the context of the BM microenvironment has transformed the MM treatment paradigm and markedly improved patient outcome. 3 Landmark studies of the IMiDs thalidomide and lenalidomide and the proteasome inhibitor (PI) bortezomib provided the basis for rapid US Food and Drug Administration (FDA) approval of these treatments for patients with MM. 4 - 6 Incorporation of combination novel agents into the ASCT algorithm as induction, consolidation, and maintenance therapy has resulted in unprecedented overall response rates (ORRs) and a threefold increase in OS. 7 In this perspective, we focus on the targeted therapies that, in our view, hold the greatest potential to even further improve on this progress ( Table 1 outlines investigational agents in advanced clinical development).

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A network connects computers, mobile phones, peripherals, and even IoT devices. Switches, routers, and wireless access points are the essential networking basics. Through them, devices connected to your network can communicate with one another and with other networks, like the Internet.

Switches, routers, and wireless access points

Switches, routers, and wireless access points perform very different functions in a network.

Switches

Switches are the foundation of most business networks. A switch acts as a controller, connecting computers, printers, and servers to a network in a building or a campus.

Switches allow devices on your network to communicate with each other, as well as with other networks, creating a network of shared resources. Through information sharing and resource allocation, switches save money and increase productivity.

There are two basic types of switches to choose from as part of your networking basics: managed and unmanaged.

Routers

Routers connect multiple networks together. They also connect computers on those networks to the Internet. Routers enable all networked computers to share a single Internet connection, which saves money.

A router acts a dispatcher. It analyzes data being sent across a network, chooses the best route for data to travel, and sends it on its way.

Routers connect your business to the world, protect information from security threats, and can even decide which computers receive priority over others.

Beyond those basic networking functions, routers come with additional features to make networking easier or more secure. Depending on your needs, for example, you can choose a router with a firewall, a virtual private network (VPN), or an Internet Protocol (IP) communications system.

Access points

An access point* allows devices to connect to the wireless network without cables. A wireless network makes it easy to bring new devices online and provides flexible support to mobile workers.

An access point acts like an amplifier for your network. While a router provides the bandwidth, an access point extends that bandwidth so that the network can support many devices, and those devices can access the network from farther away.

But an access point does more than simply extend Wi-Fi. It can also give useful data about the devices on the network, provide proactive security, and serve many other practical purposes.

*Access points support different IEEE standards. Each standard is an amendment that was ratified over time. The standards operate on varying frequencies, deliver different bandwidth, and support different numbers of channels.

Wireless networking

To create your wireless network, you can choose between four types of deployment. Each deployment has attributes that will work better for different solutions.

Cisco Mobility Express

Mobility Express is a simple, high-performance wireless solution for small or medium-sized organizations. It has the full complement of advanced Cisco features, which are preconfigured with Cisco best practices. The defaults allow for a quick and effortless Wi-Fi deployment that can be operational in minutes. It's perfect for small businesses' basic networking.

Centralized deployment

The most common type of wireless network system, centralized deployments are traditionally used in campuses where buildings and networks are in close proximity. This deployment consolidates the wireless network, which makes upgrades easier and facilitates advanced wireless functionality. Controllers are based on-premises and are installed in a centralized location.

Converged deployment

For small campuses or branch offices, converged deployments offer consistency in wireless and wired connections. This deployment converges wired and wireless on one network device--an access switch--and performs the dual role of both switch and wireless controller.

Cloud-based deployment

This system uses the cloud to manage network devices deployed on-premises at different locations. The solution requires Cisco Meraki cloud-managed devices, which provide full visibility of the network through their dashboards.

Learn more about Cisco products and solutions related to wireless networking.

More recently, the government of Nepal cut the HIV prevalence among people who inject drugs from 68% in 2002 to 6.3% in 2011 by scaling up its harm reduction programme. Likewise, the implementation of harm reduction programmes in Xichang City in China cut the number of new HIV cases among people who inject drugs by 75%. 9

Since 2008, HIV prevalence among people who inject drugs in Ukraine has more than halved with the roll-out of harm reduction programmes. In contrast, the same period saw a surge in HIV prevalence among people who inject drugs, from 1% to 41.6%, in the Philippines where there has been little implementation of harm reduction programmes. 10

Case study: Harm reduction in Ukraine In Ukraine, the first harm reduction programmes were introduced in 2004. Since then there has been a significant expansion of harm reduction services, with more than 212,800 people who inject drugs reached in 2015 and more than 19 million syringes distributed. During this period national HIV prevalence rates have reduced dramatically – falling from 41.8% in 2008 to 19.7% in 2014. 11 Despite this success, harm reduction services in Ukraine are at risk. Support from the Global Fund, on which these services rely, is scheduled to end in 2017. The Ukrainian government recently committed to coverage of some methadone but at present, this modest contribution will not be sufficient to plug the gap left by the Global Fund or reach the necessary coverage levels. 12

Research has shown that harm reduction programming is cost-effective. For example, in Australia every dollar invested in needle and syringe programmes (NSPs) returned four dollars in healthcare savings. A study carried out across eight countries in Eastern Europe and Central Asia found that investments in NSPs returned savings of between 1.6 and 2.7 times the original investment by preventing HIV and hepatitis C infections. 13

Needle and syringe programmes (NSPs) allow people who inject drugs to obtain new, sterile needles and other drug paraphernalia at little or no cost to reduce the risk of HIV infection. NSPs have the added bonus of preventing the transmission of other blood-borne viruses such as hepatitis B and C. 14

NSPs can also serve as a crucial gateway to other HIV services. People who inject drugs engage with NSPs on a consistent basis creating a number of opportunities to provide access to other forms of relevant healthcare such as opioid substitution therapy (OST), HIV testing and counselling (HTC), and treatment for HIV, tuberculosis (TB) and hepatitis. 15

NSPs can be delivered through a range of means including pharmacies, vending machines and outreach services. 16 With high incarceration levels among people who inject drugs, access to sterile injecting equipment and NSP services are a vital component of healthcare in prisons. 17 In 2016, NSPs were available in 90 countries worldwide. 18

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