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Crucial roles of XCR1-expressing dendritic cells and the XCR1-XCL1 chemokine axis in intestinal immune homeostasis.

Intestinal immune homeostasis requires dynamic crosstalk between innate and adaptive immune cells. Dendritic cells (DCs) exist as multiple phenotypically and functionally distinct sub-populations within tissues, where they initiate immune responses and promote homeostasis. In the gut, there exists a minor DC subset defined as CD103(+)CD11b(-) that also expresses the chemokine receptor XCR1. In other tissues, XCR1(+) DCs cross-present antigen and contribute to immunity against viruses and cancer, however the roles of XCR1(+) DCs and XCR1 in the intestine are unknown. We showed that mice lacking XCR1(+) DCs are specifically deficient in intraepithelial and lamina propria (LP) T cell populations, with remaining T cells exhibiting an atypical phenotype and being prone to death, and are also more susceptible to chemically-induced colitis. Mice deficient in either XCR1 or its ligand, XCL1, similarly possess diminished intestinal T cell populations, and an accumulation of XCR1(+) DCs in the gut. Combined with transcriptome and surface marker expression analysis, these observations lead us to hypothesise that T cell-derived XCL1 facilitates intestinal XCR1(+) DC activation and migration, and that XCR1(+) DCs in turn provide support for T cell survival and function. Thus XCR1(+) DCs and the XCR1/XCL1 chemokine axis have previously-unappreciated roles in intestinal immune homeostasis.

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HepaRG culture in tethered spheroids as an in vitro three-dimensional model for drug safety screening.

Conventional two-dimensional (2D) monolayer cultures of HepaRG cells allow in vitro maintenance of many liver-specific functions. However, cellular dedifferentiation and functional deterioration over an extended culture period in the conventional 2D HepaRG culture have hampered its applications in drug testing. To address this issue, we developed tethered spheroids of HepaRG cells on Arg-Gly-Asp (RGD) and galactose-conjugated substratum with an optimized hybrid ratio as an in vitro three-dimensional (3D) human hepatocyte model. The liver-specific gene expression level and drug metabolizing enzyme activities in HepaRG-tethered spheorids were markedly higher than those in 2D cultures throughout the culture period of 7 days. The inducibility of three major cytochrome P450 (CYP) enzymes, namely CYP1A2, CYP2B6 and CYP3A4, was improved in both mRNA and activity level in tethered spheroids. Drug-induced cytotoxic responses to model hepatotoxins (acetaminophen, chlorpromazine and ketoconazole) in tethered spheroids were comparable to 2D cultures as well as other studies in the literature. Our results suggested that the HepaRG-tethered spheroid would be an alternative in vitro model suitable for drug safety screening.
Copyright © 2014 John Wiley &amp; Sons, Ltd.

Merck Foundation Awards Grant to American Cancer Society for Program to Improve Access to High-Quality Cancer Care in Underserved Communities

On March 24, 2016 The Merck Foundation (the Foundation) and the American Cancer Society (ACS) reported that the Foundation provided a grant of $1.58 million over four years to the ACS to implement a comprehensive Patient Navigation Program in three U.S. communities where substantial cancer care disparities exist (Press release, Merck & Co, MAR 24, 2016, View Source [SID:1234509919]). This funding will allow the ACS to enhance its already substantial Patient Navigation Program and expand its focus on access to high-quality care, patient empowerment and care coordination.

Sites selected to participate in the community-based program include the Queens Hospital Center in Queens, N.Y.; the Phoenix Cancer Center/Maricopa Integrated Health System in Phoenix; and the University of New Mexico Cancer Center in Albuquerque, N.M. The organizations were selected because they provide services to diverse, low-income and often underserved patient populations.

"For 125 years, Merck has focused on finding solutions to improve care for patients facing devastating diseases like cancer," said Brenda D. Colatrella, president, Merck Foundation and executive director, Corporate Responsibility, Merck. "Receiving a cancer diagnosis can be an overwhelming experience, and we are proud to work with the American Cancer Society to help empower those touched by cancer to navigate the often complicated path to finding the best care available."

"Many people don’t know how to access the health care system. They don’t have insurance, they’re afraid or they have personal beliefs that lead them to ignore their health and avoid the health care system altogether," said Katherine Sharpe, senior vice president, Patient and Caregiver Support, American Cancer Society. "The Patient Navigation Program addresses these issues and helps people get the care they need even under very difficult cultural, economic, educational and financial circumstances. At the heart of patient navigation is the lesson that offering an ear to listen and a hand to help can have remarkable impact on the health of those most in need. We are grateful to the Merck Foundation for providing this grant to bring much-needed support to cancer patients in vulnerable communities in Arizona, New Mexico and New York."

The Patient Navigation Program is a proactive approach to providing guidance and support for cancer patients, their families and caregivers. Currently, more than 100 Patient Navigators are working in hospitals and cancer treatment centers nationwide. They help with identifying and reducing barriers to treatment, such as challenges with language, transportation and health insurance. In 2015, the Patient Navigation Program provided services to more than 44,000 patients across the nation, more than one-third of whom were covered by Medicaid or were uninsured.

About the American Cancer Society

The American Cancer Society is a global grassroots force of 2.5 million volunteers saving lives and fighting for every birthday threatened by every cancer in every community. As the largest voluntary health organization, the Society’s efforts have contributed to a 22 percent decline in cancer death rates in the U.S. since 1991, and a 50 percent drop in smoking rates. Thanks in part to our progress,14.5 million Americans who have had cancer and countless more who have avoided it will celebrate more birthdays this year. We’re determined to finish the fight against cancer. We’re finding cures as the nation’s largest private, not-for-profit investor in cancer research, ensuring people facing cancer have the help they need and continuing the fight for access to quality health care, lifesaving screenings, clean air and more. For more information, to get help, or to join the fight, call us anytime, day or night, at (800) 227-2345 or visit cancer.org.

New Data with FoundationOne® Supports Clinical Utility and Improved Outcomes from Molecularly Matching Non-Small Cell Lung Cancer Patients to Targeted Therapy

On March 24, 2016 Foundation Medicine, Inc. (NASDAQ:FMI) reported the publication of two manuscripts that underscore the importance of integrating comprehensive genomic profiling with FoundationOne into the management of patients with advanced lung cancer (Press release, Foundation Medicine, MAR 24, 2016, View Source [SID:1234509914]). Data from these studies demonstrate that comprehensive genomic profiling enabled identification of cancer-driving alterations that were or would have been missed by narrow, more limited hotspot testing. In both studies, researchers concluded that the discordant findings of the testing approaches underscore the fact that comprehensive genomic profiling consistently provides non-small cell lung cancer patients with more accurate and a broader range of treatment options, including clinical trials, versus narrow hotspot tests.

Findings from the two studies were published in Oncotarget and Clinical Cancer Research.

"Targeted therapies have revolutionized the treatment of lung cancer; however, for such therapies to be optimally matched to the right patients, there is an inherent mandate for comprehensive, highly accurate and sensitive clinical testing that can detect all actionable genomic alterations," said Mohamed Mohamed, M.D., Ph.D., co-director of the Thoracic Oncology Program, Cone Health Cancer Center in Greensboro, NC and co-author of the study published in Clinical Cancer Research. "Taken together, these studies reveal the inherent limitations of single-gene or hotspot testing, which fail to characterize the entire coding regions of cancer genes and detect all four classes of genomic alterations, thereby missing targeted therapy options that are often clinically relevant for treatment of advanced cancer."

Lung cancer is the leading cancer killer in both men and women in the United States1. An estimated 159,260 Americans died from lung cancer in 2014, accounting for approximately 27 percent of all cancer deaths2. There are two major types of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC is the most common and accounts for approximately 85 percent of all lung cancer cases3. Adenocarcinoma is the most common subtype of NSCLC.

"These studies demonstrate the clinical utility and the opportunity for improved clinical outcomes achieved by integrating comprehensive genomic profiling into clinical care for advanced non-small cell lung cancer," stated Byoung Chul Cho, M.D., Ph.D., associate professor, division of medical oncology, Yonsei Cancer Center and Department of Internal Medicine, Yonsei University College of Medicine in Korea and senior author of the study published in Oncotarget.

Key Findings Published in Oncotarget

The article, entitled "Genomic Profiling of Lung Adenocarcinoma Patients Reveals Therapeutic Targets and Confers Clinical Benefit When Standard Molecular Testing is Negative," was published online in the journal Oncotarget and demonstrates that maximally identifying actionable genomic alterations in advanced lung cancer patients is an important factor in improving clinical outcomes. Comprehensive genomic profiling using FoundationOne was performed on tumor specimens from 51 patients with advanced lung adenocarcinomas, which previously tested negative for the known driver oncogenes EGFR, KRAS and ALK. Key study findings include:

31 percent of patients harbored clinically relevant genomic alterations that were not previously discovered by the prior clinical testing.

A genomic alteration with a corresponding targeted therapeutic based on the National Comprehensive Cancer Network (NCCN) guidelines was identified in 39 percent of patients. This data supports a previous finding by Drilon et al4 showing 26 percent of previously negative NSCLC patients harbored a genomic alteration with a corresponding targeted therapy in NCCN guidelines.

Genomic alterations for which clinical trials of targeted therapies could be considered were discovered in an additional 27 percent of patients. Similarly, in the study referenced above, Drilon et al demonstrated that 39 percent of NSCLC patients enrolled in that study harbored genomic alterations that could be linked to a clinical trial at the principal investigator’s cancer center.

Seven patients with ROS1 rearrangements were enrolled in an ongoing trial assessing ceritinib, an inhibitor of activated ROS1. All but one of the patients who received ceritinib experienced objective responses.
Key Findings Published in Clinical Cancer Research

The article, entitled "Comprehensive Genomic Profiling Identifies Frequent Drug Sensitive EGFR Exon 19 Deletions in NSCLC Not Identified by Prior Molecular Testing," was published online in Clinical Cancer Research and highlights the importance of using comprehensive genomic profiling in advanced NSCLC to allow for sensitive detection of clinically relevant mutations. From a larger series of NSCLC cases assayed with FoundationOne in the course of clinical care, 400 consecutive cases harboring EGFR ∆ex19 deletions were reviewed. Key study findings include:

Pathology reports for 250 NSCLC cases harboring classic EGFR ∆ex19 deletions identified by comprehensive genomic profiling were systematically reviewed. Of these, previous EGFR test results were available for 71 cases, and 17 percent had previously tested negative for EGFR mutation.

In a subset of these patients with available clinical outcome information, treatment benefit with EGFR inhibitors was observed with EGFR TKI therapy.

Of 14 NSCLC cases with an EGFR ∆ex19 C-helical deletion, previous non-hybrid capture based EGFR sequencing results were available for six cases, and of these cases, five (83 percent) had negative prior testing.

"These studies show the discordant results between narrow sequencing and comprehensive genomic profiling with FoundationOne, implying that potentially clinically actionable targets may only be reliably detected when comprehensive genomic profiling is incorporated into clinical care," said Vincent Miller, M.D., chief medical officer, Foundation Medicine and co-author of the study. "As a result, advanced stage lung cancer patients are losing precious time with multiple rounds of hot spot and limited sequencing tests and ultimately, potentially missing critical opportunities to benefit from approved targeted therapies and clinical studies. We continue to provide evidence validating care efficiencies and clinical value that can be realized through use of our comprehensive genomic profiling approach at initial diagnosis of advanced lung cancer."

Potent neutralizing anti-CD1d antibody reduces lung cytokine release in primate asthma model.

CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically &lt;100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical.