SA-4-1BBL as a modulator of innate, adaptive, and regulatory immunity : implications for cancer prevention and treatment.

SA-4-1BBL is a recombinant costimulatory molecule that is active in its soluble form and has pleiotropic effects on the functions of innate, adaptive, and regulatory immune cells. We have previously shown that SA-4-1BBL makes CD4+ T conventional cells (Tconvs) resistant to suppression by CD4+CD25+Foxp3+ T regulatory cells (Tregs). The mechanistic basis of this observation is the subject of this study. We demonstrate that Tconvs, but not Tregs, are the direct targets of SA-4-1BBL-mediated evasion of Treg suppression without contribution from antigen presenting cells (APCs). SA-4-1BBL engagement with its receptor, 4-1BB, on Tconvs resulted in the production of high levels of IL-2 cytokine that was necessary and sufficient in overcoming Treg suppression. Removal of IL-2 from culture supernatant restored Treg suppression and repletion of Tconv:Treg cocultures with exogenous recombinant IL-2 overcame suppression. In a series of studies our laboratory demonstrated the therapeutic efficacy of SA- 4-1BBL as an adjuvant component of subunit cancer vaccines in various preclinical rodent cancer models. Inasmuch as SA-4-1BBL contains streptavidin (SA) as a foreign bacterial protein, repeated vaccinations may generate anti-SA antibodies. Such antibodies may have positive or negative effect on the efficacy of the vaccines. Therefore, a series of studies were conducted to assess the potential impact of SA’s immunogenicity on the immuno-stimulatory function of SA-4-1BBL molecule. We demonstrated that repeated treatments with SA-4-1BBL generate both cellular and humoral immune responses against the SA portion of the molecule. Antibodies against SA neither blocked nor improved the costimulatory function of SA-4-1BBL on T cells. Importantly, preimmunization with SA-4-1BBL protein alone did not interfere with the therapeutic efficacy of a subunit vaccine consisting of the human papillomavirs (HPV) E7 tumor associated antigen (TAA) + SA-4-1BBL in the TC-1 cervical cancer tumor model. Surprisingly, pretreatment with SA-4-1BBL alone conferred protection regardless of the type of tumor tested. The robust anti-tumor function of SA-4-1BBL involved a communication bridge between CD4 and NK cells without significant contribution from CD8 cells or B cells. NK cells were found to be critical to the observed tumor suppression and required CD4+ T cell help for protective efficacy at both priming and effector stages. Depletion of either NK or CD4 cells negated SA-4-1BBL’s anti-tumor protection. Moreover, the tumor suppressive effect of SA-4-1BBL was shown to be a bona fide property of this molecule, as immunizing mice with an agonistic antibody to 4-1BB receptor did not confer any protection against TC-1 tumors. The significance of understating the mechanisms underlying SA-4-1BBL’s mode of action provides new tools in the evolving field of cancer immunotherapy and prevention. The implications also extend to transplantation settings as well as infectious diseases where tipping the balance between Tregs and T effector cells (Teffs) plays a critical role in achieving desired outcomes

Survive and thrive: an exploration of methods implemented by small businesses in the construction industry to sustain their business beyond 5 years

Small businesses represent an influential portion of the American economy yet retain a high rate of closure especially in their early years, therefore; this study sought to address a lack of available research regarding small businesses in the construction industry, by investigating the methods and strategies existing small business owners use to support business survivability, in the regionally specific area of Southern California. The purpose of this study was to investigate strategies used by existing construction industry small businesses, identify the challenges experienced as a construction industry small business organization in Southern California, and determine how the small business owners define and measure success. The guiding theoretical framework for this study followed the Resource Based View, which perceives the organization as a collection of unique resources and capabilities. This qualitative case study included 8 participants who worked in the Southern California area and took part in a short recorded interview. Qualitative interview data was transcribed, coded and analyzed by the researcher. Three research questions helped guide this study: RQ1: What strategies do small businesses in the construction industry located in Southern California apply to sustain their business beyond 5 years? RQ2: What challenges do small businesses in the construction industry, located in Southern California, face? What strategies and resources are used to assist these small businesses to overcome challenges?; and RQ3: How do small businesses in the construction industry, located in Southern California define, measure, and track their organizational success? Results found for RQ1 indicated participant utilization of specific strategies and resources such as learning orientation, human capital, and market orientation. Results for RQ2 showed participants perceived employee turnover, capital management, and internal fears/doubts as major challenges to sustaining a construction industry small business. Results for RQ3 found participants defined and measured success through achievement, employee retention, and internal feelings. Recommendations for future practice and research include the research addressing knowledge gaps for technology usage, research into women-owned construction industry small business owners, in addition to continued qualitative research performed in this subject area

India’s Use it or Lose it: Time to Revisit TRIPS?, 11 J. Marshall Rev. Intell. Prop. L. 797 (2012)

India is one of a number of countries which impose a “local working” requirement on patented inventions. This finds its source in sections 83, 84, and 89 of India’s Patent Act. A recent decision by the Controller of Patents granting a compulsory license to Natco for a Bayer-patented anti-cancer drug confirms that importation will not satisfy this requirement. Corporations seeking to produce and market products for international sale will receive varying degrees of patent protection from different nations. This comment proposes an amendment to the Agreement on Trade-Related Aspects of Intellectual Property Rights (“TRIPS”) defining what local working requirements are permitted, and requiring that nations meet and confer when making decisions on compulsory licenses against foreign patent-holders

Communicating CSR Between Businesses - Where do reports fit in?

The successful implementation of CSR depends on the ability to ensure that the communication efforts associated with the programme are effective. As more and more companies practice CSR reporting, it is interesting to look at how CSR reports can have a potential to become useful in the b-t-b communication realm. With implications that relate to the core motivations of CSR implementation; enhanced risk management, enhanced reputation, competitiveness and market positioning, the potential impact that reports can have in the communication efforts between businesses is great. This thesis looks at how reports are read in the b-t-b communication context; if there is a demand and a willingness to supply reports to fellow businesses as a means of corporate communication, as well as explore the challenges and opportunities for the potential increase in use of reports in communication efforts within this context. Findings show that reports are mainly read between companies for benchmarking reasons, that they lack strong demand and a willingness to supply in other cases. This is attributed to the existence of other preferred channels of communication between businesses, and to having their information needs satisfied through other means

Hereditary diffuse gastric cancer therapeutic roadmap: current and novel approaches in a nutshell

Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 gene encoding E-cadherin, which is involved in cell–cell adhesion, maintenance of epithelial architecture, tumor suppression, and regulation of intracellular signaling pathways. Late-stage recognition of HDGC is typically associated with a poor clinical outcome due to its metastatic potential and risk of lobular breast cancer (LBC) development. The American College of Gastroenterology issued guidelines to evaluate HDGC, test for CDH1 genetic variants, and recommend prophylactic gastrectomy for carriers of CDH1 mutations. If surgery is not pursued, endoscopy is a surveillance alternative, although it carries a limited ability to detect malignant foci. As part of clinical research efforts, novel endoscopy advances are currently studied, and a center of excellence for HDGC was created for a comprehensive multidisciplinary team approach. Within this review, we cover current conventional treatment modalities such as gastrectomy and chemotherapy, as the mainstay treatments, in addition to Pembrolizumab, an immune checkpoint inhibitor, as the last therapeutic resort. We also shed light on novel and promising approaches with emphasis on immunotherapy to treat HDGC. We further break down the therapeutic paradigms to utilize molecular tools, antibodies against checkpoint inhibitors, TGF-β and tyrosine kinase inhibitors, cell-based adoptive therapies, and oncolytic viral therapies. We aim to expand the understanding on how to modulate the tumor microenvironment to tip the balance towards an anti-tumor phenotype, prevent metastasis of the primary disease, and potentially alter the therapeutic landscape for HDGC

Lipid metabolism in tumor immunology and immunotherapy

Lipids are a diverse class of biomolecules that have been implicated in cancer pathophysiology and in an array of immune responses, making them potential targets for improving immune responsiveness. Lipid and lipid oxidation also can affect tumor progression and response to treatment. Although their importance in cellular functions and their potential as cancer biomarkers have been explored, lipids have yet to be extensively investigated as a possible form of cancer therapy. This review explores the role of lipids in cancer pathophysiology and describes how further understanding of these macromolecules could prompt novel treatments for cancer

Antimicrobial Stewardship Training for Infectious Diseases Fellows: Program Directors Identify a Curriculum Need

A needs assessment survey of infectious diseases (ID) training program directors identified gaps in educational resources for training and evaluating ID fellows in antimicrobial stewardship. An Infectious Diseases Society of America-sponsored core curriculum was developed to address that need

Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities

Evaluation of the Infectious Diseases Society of America’s Core Antimicrobial Stewardship Curriculum for Infectious Diseases Fellows

Background Antimicrobial stewardship (AS) programs are required by Centers for Medicare and Medicaid Services and should ideally have infectious diseases (ID) physician involvement; however, only 50% of ID fellowship programs have formal AS curricula. The Infectious Diseases Society of America (IDSA) formed a workgroup to develop a core AS curriculum for ID fellows. Here we study its impact. Methods ID program directors and fellows in 56 fellowship programs were surveyed regarding the content and effectiveness of their AS training before and after implementation of the IDSA curriculum. Fellows’ knowledge was assessed using multiple-choice questions. Fellows completing their first year of fellowship were surveyed before curriculum implementation (“pre-curriculum”) and compared to first-year fellows who complete the curriculum the following year (“post-curriculum”). Results Forty-nine (88%) program directors and 105 (67%) fellows completed the pre-curriculum surveys; 35 (64%) program directors and 79 (50%) fellows completed the post-curriculum surveys. Prior to IDSA curriculum implementation, only 51% of programs had a “formal” curriculum. After implementation, satisfaction with AS training increased among program directors (16% to 68%) and fellows (51% to 68%). Fellows’ confidence increased in 7/10 AS content areas. Knowledge scores improved from a mean of 4.6 to 5.1 correct answers of 9 questions (P = .028). The major hurdle to curriculum implementation was time, both for formal teaching and for e-learning. Conclusions Effective AS training is a critical component of ID fellowship training. The IDSA Core AS Curriculum can enhance AS training, increase fellow confidence, and improve overall satisfaction of fellows and program directors