Discovery Category Highlights

Therapeutic Applications of Human Adipose-Derived Stromal Cells for Soft Tissue Reconstruction

Abstract: Adipose derived stromal cells (ASCs) are a multipotent cell population derived from the stromal vascular fraction of lipoaspirate. Given their relatively broad differentiation potential and paracrine capabilities, ASCs represent a readily accessible, endogenous resource for novel reconstructive strategies. In particular, augmentation of autologous fat grafts with ASCs has already been employed clinically for restoration of soft tissue defects. While fat grafting alone remains highly unpredictable, enrichment of fat with supplemental ASCs, also known as cell-assisted lipotransfer (CAL), has been shown to significantly enhance volume retention. How addition of these cells to fat grafts results in improved outcomes, however, remains poorly understood. Furthermore, the safety of CAL in the setting of prior malignancy and post-radiation wound beds has yet to be fully determined, an important consideration for its use in cancer reconstruction. Thus, further studies to determine the "how" and "why" behind the efficacy of CAL are necessary before it can be widely adopted as a safe and reliable surgical technique. ... Read more

The CRISPR/Cas9 Genome Editing Methodology as a Weapon Against Human Viruses

Abstract: Viruses are a therapeutic challenge since their life cycles occur within the host cells and often utilize cellular proteins and hence it is harder to identify therapeutic targets compared to bacteria, which have their own cellular metabolism that is quite different from the host and often present unique targets such as enzymes, etc. Nevertheless, viral proteins may present useful targets for therapy, e.g., small molecule inhibitors of viral polymerases, or prevention, e.g., viral coat proteins for vaccination. However, some viruses may enter an inactive state of persistence or latency where no or very few viral proteins are produced. Thus, methodologies that are specifically able to target nucleotide sequences within viral genomes would be a useful addition to the antiviral armamentarium. Such a methodology is the clustered regulatory interspaced short palindromic repeat (CRISPR)-associated 9 (Cas9) system, which is effective, specific, and versatile and provides unprecedented control over genome editing. Here, we will discuss how CRISPR/Cas9 has been used against human viruses and future prospects for novel therapeutic approaches. ... Read more

Liquid Biopsy in Liver Cancer

Abstract: Liver cancer has become the second cause of cancer-related death worldwide. Most patients are still diagnosed at intermediate or advanced stage, where potentially curative treatment options are not recommended. Unlike other solid tumors, there are no validated oncogenic addiction loops and the only systemic agent to improve survival in advanced disease is sorafenib. All phase 3 clinical trials testing molecular therapies after sorafenib have been negative, none of which selected patients based on predictive biomarkers of response. Theoretically, analysis of circulating cancer byproducts (e.g., circulating tumor cells, cell-free nucleic acids), namely "liquid biopsy," could provide easy access to molecular tumor information, improve patients' stratification and allow to assess tumor dynamics over time. Recent technical developments and preliminary data from other malignancies indicate that liquid biopsy might have a role in the future management of cancer patients. ... Read more

New Approaches for the Immunotherapy of Acute Myeloid Leukemia

Abstract: Acute myeloid leukemia (AML) is a set of related diseases characterized by the immortalization and uncontrolled expansion of myeloid precursor cells. Core therapy for AML has remained unchanged for nearly 30 years, and survival rates remain unsatisfactory. However, advances in the immunotherapy of AML have created opportunities for improved outcomes. Enforcing a tumor-specific immune response through the re-direction of the adaptive immune system, which links remarkable specificity with potent cytotoxic effector functions, has proven particularly compelling. This may be coupled with immune checkpoint blockade and conventional therapies for optimal effect. Engineered antibodies are currently in use in AML and the repertoire of available therapeutics will expand. NK cells have shown effectiveness in this disease. New methods to optimize their activation and the targeting of AML show potential. Most significantly, adoptive immunotherapy with tumor-specific T cells, and particularly T cells re-directed using genetically introduced TCR or chimeric antigen receptors, have demonstrated promise. Each of these approaches has unique benefits and challenges that we explore in this review. ... Read more

Advances in Gene Therapy for Heart Failure

Abstract: Chronic heart failure is expected to increase its social and economic burden as a consequence of improved survival in patients with acute cardiac events. Cardiac gene therapy holds significant promise in heart failure treatment for patients with currently very limited or no treatment options. The introduction of adeno-associated virus (AAV) gene vector changed the paradigm of cardiac gene therapy, and now it is the primary vector of choice for chronic heart failure gene therapy in clinical and preclinical studies. Recently, there has been significant progress towards clinical translation in this field spearheaded by AAV-1 mediated sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) gene therapy targeting chronic advanced heart failure patients. Meanwhile, several independent laboratories are reporting successful gene therapy approaches in clinically relevant large animal models of heart failure and some of these approaches are expected to enter clinical trials in the near future. This review will focus on gene therapy approaches targeting heart failure that is in clinical trials and those close to its initial clinical trial application. ... Read more

Advances in Strategies and Methodologies in Cancer Immunotherapy

Abstract: Since the invention of Coley's toxin by William Coley in early 1900s, the path for cancer immunotherapy has been a convoluted one. Although still not considered standard of care, with the FDA approval of trastuzumab, Provenge and ipilimumab, the medical and scientific community has started to embrace the possibility that immunotherapy could be a new hope for cancer patients with otherwise untreatable metastatic diseases. This review aims to summarize the development of some major strategies in cancer immunotherapy, from the earliest peptide vaccine and transfer of tumor specific antibodies/T cells to the more recent dendritic cell (DC) vaccines, whole cell tumor vaccines, and checkpoint blockade therapy. Discussion of some major milestones and obstacles in the shaping of the field and the future perspectives is included. Photoimmunotherapy is also reviewed as an example of emerging new therapies combining phototherapy and immunotherapy. ... Read more

Wnt Signaling in Dendritic Cells: Its Role in Regulation of Immunity and Tolerance

Abstract: A fundamental puzzle in immunology is how the immune system launches robust immunity against pathogens while maintaining a state of tolerance to the body's own tissues and the trillions of commensal microorganisms and food antigens that confront them every day. Innate immune cells, such as dendritic cells (DCs) and macrophages, play a fundamental role in this process. Emerging studies have highlighted that the Wnt signaling pathway, particularly in DCs, plays a major role in regulating tolerance versus immunity. Here, we review our current understanding of how Wnt-signaling shapes the immune response and, in addition, highlight unanswered questions, the solution of which will be imperative in the rational exploitation of this pathway in vaccine design and immune therapy. ... Read more

BMP4 Promotes Human Sertoli Cell Proliferation Via Smad1/5 and ID2/3 Pathway and Its Abnormality Is Associated with Azoospermia

Abstract: Sertoli cell plays critical roles in regulating testis development and spermatogenesis. Any change in the number or biological functions of Sertoli cells can affect the normal formation of spermatozoa. However, the roles and molecular mechanisms of factors in controlling the fate determinations of human Sertoli cells and underlying male infertility remain unknown. Here we have for the first time explored the function and signaling pathway of BMP4 in regulating adult human Sertoli cells and their association with non-obstructive azoospermia (NOA) patients. Immunocytochemistry and immunohistochemistry revealed that BMP4 and its multiple receptors were present in human Sertoli cells. Cell proliferation and BrdU incorporation assays showed that BMP4 promoted DNA synthesis and proliferation of Sertoli cells. In contrast, BMP4 antagonist noggin and BMP4 knockdown reduced the division of Sertoli cells. Moreover, BMP4 knockdown inhibited the synthesis of FGF2, SCF, zonula occludens 1, and claudin 11 but enhanced p27kip1 transcription. BMP4 activated Smad1/5 phosphorylation and upregulated ID2 and ID3 transcription, whereas noggin counteracted these increases. Significantly, tissue arrays disclosed that overexpression of BMP4 may be associated with Sertoli cell-only syndrome and maturation arrest in spermatogonia or spermatocytes. Collectively, BMP4 was identified as the first autocrine factor that regulates the proliferation and protein synthesis of human Sertoli cells via Smad1/5 and ID2/3 pathway and its abnormality is associated with human non-obstructive azoospermia patients. This study thus provides novel insights into molecular mechanism underlying adult human Sertoli cell growth and offers new targets for gene therapy of male infertility. ... Read more

An Unexpected Journey: How Cancer Immunotherapy Has Paved the Way for an HIV-1 Cure

Abstract: Over 30 million people worldwide are currently infected with human immunodeficiency virus type-1 (HIV-1). While HIV-1 infection was initially thought to be a death sentence, the advent of combination antiretroviral therapy (cART) in the mid-1990's resulted in decreases in viremia and an extended lifespan for infected persons. Despite this, long-term control of the virus in the absence of drug therapy has yet to be achieved, owing to the rebound in viral load and resumption of disease progression that follows removal of the patient from cART. Currently, the most promising candidates for an HIV-1 cure are immunotherapies that harness the patient's own immune system and induce cytotoxic T lymphocyte (CTL)-mediated clearance of infected cells. Most of these approaches were developed and optimized in the cancer setting and have had varying degrees of success, the findings from which have wide applications to various disease models. In this review, we evaluate the past successes and failures of cancer immunotherapy and how the findings have shaped our journey toward an HIV-1 cure. ... Read more

Immune Effects of Targeted Radiation Therapy for Cancer

Abstract: Radiation therapy plays an important role in the treatment of the majority of cancers, and is commonly used to treat both localized and metastatic disease. Immunotherapy has recently been firmly integrated into the treatment of metastatic melanoma, and holds significant promise in treating a variety of other cancers. Although large field radiation has historically been appreciated for its immunosuppressive ability, targeted radiation can induce substantial changes in the tumor microenvironment beyond cellular cytotoxicity that evoke innate and adaptive immune responses. Previous studies have highlighted radiation-induced changes in proinflammatory cytokines, chemokines, effector, and immunosuppressive T cell subsets, as well as in immune receptors on tumor cells. Some of these changes in localized and systemic immune mediators have been linked to expansion of tumor-reactive T cells, improved clinical responses, and increased overall survival in preclinical and clinical models. Taken together, this evidence suggests that targeted radiation therapy can impact anti-tumor immune responses, and may potentially be combined with immunotherapy for synergistic effect. ... Read more

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