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A stunning and authoritative collection of 300 of jewelry's greatest names spanning more than 200 years. The Jewelry Book is a deep dive into the designers, creative houses, artists, collectors, and style icons from around the world who have produced and inspired the most memorable designs in jewelry. Edited by Melanie Grant, author of Coveted: Art and Innovation in High Jewelry, in collaboration with an international panel of experts, this stunning book spans more than two centuries of rich history, showcasing 300 of the industry's greatest contributors in one lavish, collectible volume. The Jewelry Book is arranged in A to Z order, placing early stars and iconic brands alongside today's most innovative designers and creatives. Entries ranging from Boucheron, Buccellati, Cartier, René Lalique, Elsa Peretti, Hemmerle, Tiffany & Co and Van Cleef & Arpels to Iris Apfel, Wallace Chan, Loulou de la Falaise, Olivier Rousteing, James de Givenchy, and Elizabeth Taylor reveal the jewelry world's inextricable connection to fashion, art, and culture. Filled with inspirational images, the book is designed as a gorgeous object in its own right, with a cover featuring a luxe, faceted deboss on a metallic material to evoke a dazzling gemstone.

Environmental triggers is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the environmental triggers section is focused on the main research gaps in elucidating causality of environmental factors in IBD. Research gaps were identified in: 1) epidemiology of exposures; 2) identification of signatures of biological response to exposures; and 3) mechanisms of how environmental exposures drive IBD. To address these gaps, the implementation of longitudinal prospective studies to determine disease evolution and identify sub-clinical changes in response to exposures is proposed. This can help define critical windows of vulnerability and risk prediction. In addition, systems biology analysis and in silico modeling were proposed as approaches to integrate the IBD exposome for the identification of biological signatures of response to exposures, and to develop prediction models of the effects of environmental factors in driving disease activity and response to therapy. This research could lead to identification of biomarkers of exposures and new modalities for therapeutic intervention. Finally, hypothesis-driven mechanistic studies to understand gene-environment interactions and to validate causality of priority factors should be performed to determine how environment influences clinical outcomes.

Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. Here we develop a proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that aberrant splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminate tumor cells in vitro. Targeting tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors. Targeting tumor-associated antigens in paediatric medulloblastomas (MB) is challenging due to their low mutational burden. Here, the authors develop a sensitive proteogenomic approach to identify tumour specific neoantigens, which may enable personalised T cell immunotherapy in paediatric MB.

Cell therapy product (CTP) developers face the significant challenge of developing appropriate potency tests for their CTPs. A review of the known potency tests used for the 31 United States Food and Drug Administration-approved CTPs (US FDA) can guide developers in designing effective potency tests for future CTPs. Data on these tests were primarily collected from publicly available regulatory documentation on the US FDA website (90%) as well as other sources (literature, company communications, etc.). Based on these data, an estimated 104 total potency tests have been used for the 31 CTPs. Of these, 33 are redacted (32%), leaving 71 non-redacted potency tests. On average, each CTP has 3.4 potency tests (standard deviation 2.0). The 71 non-redacted potency tests were categorized into 5 bins: “Viability and count” (37 tests, 52%), “Expression” (19 tests, 27%), “Bioassays” (7 tests, 7%), “Genetic modification” (6 tests, 9%) and “Histology” (2 tests, 3%). Measurements of gene or protein expression were used by 20 of the 31 CTPs (65%), and 19 CTPs (61%) used measurements of cell viability or cell count as a potency test. “Viability and count” and “Expression” are the two tests that have most often been used together for the same product, occurring for 16 CTPs (52%). It is unclear if bioassays are commonly used as potency tests since only 7 of 31 CTPs (23%) reported bioassays as potency tests. However, due to redactions, as many 24 (77%) CTPs could potentially have a bioassay as a potency test. Additionally, 26 of the 31 CTPs (84%) cite physicochemical assays (non-bioassays) as a potency test. This analysis of potency tests for approved CTPs provides valuable insights for developing potency tests for new CTPs.

One of the most challenging aspects of developing advanced cell therapy products (CTPs) is defining the mechanism of action (MOA), potency and efficacy of the product. This perspective examines these concepts and presents helpful ways to think about them through the lens of metrology. A logical framework for thinking about MOA, potency and efficacy is presented that is consistent with the existing regulatory guidelines, but also accommodates what has been learned from the 27 US FDA-approved CTPs. Available information regarding MOA, potency and efficacy for the 27 FDA-approved CTPs is reviewed to provide background and perspective. Potency process and efficacy process charts are introduced to clarify and illustrate the relationships between six key concepts: MOA, potency, potency test, efficacy, efficacy endpoint and efficacy endpoint test. Careful consideration of the meaning of these terms makes it easier to discuss the challenges of correlating potency test results with clinical outcomes and to understand how the relationships between the concepts can be misunderstood during development and clinical trials. Examples of how a product can be “potent but not efficacious” or “not potent but efficacious” are presented. Two example applications of the framework compare how MOA is assessed in cell cultures, animal models and human clinical trials and reveals the challenge of establishing MOA in humans. Lastly, important considerations for the development of potency tests for a CTP are discussed. These perspectives can help product developers set appropriate expectations for understanding a product’s MOA and potency, avoid unrealistic assumptions and improve communication among team members during the development of CTPs.

Human Parainfluenza Virus-3 (HPIV3) causes severe respiratory illness in immunocompromised patients and lacks approved anti-viral therapies. A phase I study of adoptively transferred virus-specific T-cells (VSTs) targeting HPIV3 following bone marrow transplantation is underway (NCT03180216). We sought to identify immunodominant epitopes within HPIV3 Matrix protein and their cross-reactivity against related viral proteins. VSTs were generated from peripheral blood of healthy donors by ex-vivo expansion after stimulation with a 15-mer peptide library encompassing HPIV3 matrix protein. Epitope mapping was performed using IFN-γ ELIspot with combinatorial peptide pools. Flow cytometry was used to characterize products with intracellular cytokine staining. In 10 VST products tested, we discovered 12 novel immunodominant epitopes. All products recognized an epitope at the C-terminus. On IFN-γ ELISpot, individual peptides eliciting activity demonstrated mean IFN-γ spot forming units per well (SFU)/1x10 cells of 115.5 (range 24.5-247.5). VST products were polyfunctional, releasing IFN-γ and TNF-α in response to identified epitopes, which were primarily HLA Class II restricted. Peptides from Human Parainfluenza Virus-1 corresponding to the HPIV3 epitopes showed cross-reactivity for HPIV1 in 11 of 12 tested epitopes (mean cross reactivity index: 1.19). Characterization of HPIV3 epitopes may enable development of third-party VSTs to treat immune suppressed patients with HPIV infection.

Mycobacterial Infections can be severe in patients with T-cell deficiency or phagocyte disorders, and treatment is frequently complicated by antimicrobial resistance. Restoration of T-cell immunity via stem cell transplantation facilitates control of mycobacterial infections, but presence of active infections during transplantation is associated with a higher risk of mortality. Adoptive T cell immunotherapy has been successful in targeting viruses, but has not been attempted to treat mycobacterial infections. We sought to expand and characterize mycobacterial-specific T-cells derived from healthy donors in order to determine suitability for adoptive immunotherapy. Mycobacteria-specific T-cells (MSTs) were generated from 10 healthy donors using a rapid expansion protocol targeting five known mycobacterial target proteins (AG85B, PPE68, ESXA, ESXB, and ADK). MSTs were compared to T-cells expanded from the same donors using lysate from or purified protein derivative from (sensitin). MST expansion from seven patients with primary immunodeficiency disorders (PID) and two patients with IFN-γ autoantibodies and invasive infections. MSTs expanded from healthy donors recognized a median of 3 of 5 antigens, with production of IFN-γ, TNF, and GM-CSF in CD4 T cells. Comparison of donors who received BCG vaccine ( = 6) to those who did not ( = 4) showed differential responses to PPE68 ( = 0.028) and ADK ( = 0.015) by IFN-γ ELISpot. MSTs expanded from lysate or sensitin also recognized multiple mycobacterial antigens, with a statistically significant differences noted only in the response to PPE68 ( = 0.016). MSTs expanded from patients with primary immunodeficiency (PID) and invasive mycobacterial infections showed activity against mycobacterial antigens in only two of seven subjects, whereas both patients with IFN-γ autoantibodies recognized mycobacterial antigens. Thus, MSTs can be generated from donors using a rapid expansion protocol regardless of history of BCG immunization. Most tested PID patients had no detectable T-cell immunity to mycobacteria despite history of infection. MSTs may have clinical utility for adoptive immunotherapy in T-cell deficient patients with invasive mycobacterial infections.

The dendritic cell (DC) is the foremost antigen‐presenting cell (APC) for ex vivo expansion of tumour‐specific patient T cells. Despite marked responses in some patients following reinfusion of DC‐activated autologous or HLA‐matched donor T cells, overall response rates remain modest in solid tumours. Furthermore, most studies aim to generate immune responses against defined tumour‐associated antigens (TAA), however, meta‐analysis reveals that those approaches have less clinical success than those using whole tumour cells or their components. Tumour lysate (TL) is used as a source of tumour antigen in clinical trials and potentially represents the full range of TAAs in an undefined state. Little is known about how different APCs cooperate to present TL antigens. We examined the effect of oxidised whole‐cell lysate (ox‐L) versus soluble fraction freeze–thaw lysate (s‐L) on bone marrow‐derived DCs and macrophages, and magnetic bead‐isolated splenic B cells. The APCs were used individually, or in combination, to prime T cells. CD8+ T cells produced interferon (IFN)‐γ in response to both s‐L and ox‐L, but only proliferated in response to ox‐L. IFN‐γ production and proliferation was enhanced by priming with the DC+B cell combination. Compared to DC alone, a trend toward greater interleukin (IL)‐12 production was observed when DC+B cell were loaded with s‐L and ox‐L antigens. CD8+ T‐cell specific lysis in vivo was greatest in ox‐L‐primed groups and DC+B cell priming significantly increased in vivo cytotoxicity compared to DC alone. These improved T‐cell responses with two APCs and stressed cell lysate has implications for APC‐based adoptive cell therapies. Cancer therapy: Turning T‐cells against tumors An improved approach to cell‐based immunotherapy may help patients mount a more potent counterattack against cancer. Clinical researchers have attempted to train patients' T‐cells to destroy tumors by combining them with other immune cells that present tumor‐specific antigens. Until now results have been disappointing, but researchers led by Sarah Young at New Zealand's University of Otago have potentially found a way to improve the effectiveness of this approach. Antigen‐presenting cells are targeted against cancer by exposing them to broken‐up tumor cells. Young's team found this targeting was more effective when the tumor cells were first exposed to chemical stress. The researchers also identified a combination of antigen‐presenting cells that promoted a more aggressive T‐cell response in a mouse melanoma model. Young and colleagues are now exploring whether their improved immunotherapy approach might benefit glioma patients.

Throughout the past decade, states have been enacting renewables portfolio standards (RPS) policies aimed at developing and incorporating renewable energy into the state energy scheme in order to improve and diversify energy sources across the country. Although there is no nationwide requirement or policy enacted, thus far twenty-nine states and the District of Columbia have independently adopted some form of RPS policy. Additionally, seven other states have developed nonmandatory renewable portfolio goals. The projected improvement in energy security and diversity, economic development, and environmental protection has induced many states to incorporate such policies. Furthermore, RPS policies have been spurred on by many factors, including federal tax incentives, state renewable energy funds, voluntary green power markets, the specter of future greenhouse gas regulations, and the economic fundamentals of certain forms of renewable energy relative to conventional generation. This Comment will focus on what is actually being accomplished by states having RPS policies.

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