New Frontiers in Cancer Chemotherapy — Targeting Cell Death Pathways

Cell death plays an important role in tumorigenesis, growth, and progression and affects the efficiency of chemotherapy to a great extent. Apoptosis is usually regarded as the principal mechanism of chemotherapy-induced cell death. However, the dysregulation of apoptosis occurs commonly in many cancers, which lowers the effectiveness of therapy and allows cells to survive. The mechanisms by which cells acquire this resistance to chemotherapy are not fully understood. Several studies uncovered alternative cell death pathways that are mechanistically distinct from apoptosis. These pathways, including autophagy and necrosis, represent potential targets for novel cancer treatment. By modulating the key regulatory molecules involved in the different types of cell death, more effective and less toxic chemotherapy might be developed. In this chapter, we describe the signaling pathways and the molecular events that are involved in these three major forms of programmed cell death. Additionally, we also discuss the emerging therapies targeting these cell death pathways as new strategies against cancer

Microenvironment Cell Contribution to Lymphoma Immunity

Lymphoma microenvironment is a complex system composed of stromal cells, blood vessels, immune cells as well as extracellular matrix, cytokines, exosomes, and chemokines. In this review, we describe the function, localization, and interactions between various cellular components. We also summarize their contribution to lymphoma immunity in the era of immunotherapy. Publications were identified from searching Pubmed. Primary literature was carefully evaluated for replicability before incorporating into the review. We describe the roles of mesenchymal stem/stromal cells (MSCs), lymphoma-associated macrophages (LAMs), dendritic cells, cytotoxic T cells, PD-1 expressing CD4+ tumor infiltrating lymphocytes (TILs), T-cells expressing markers of exhaustion such as TIM-3 and LAG-3, regulatory T cells, and natural killer cells. While it is not in itself a cell, we also include a brief overview of the lymphoma exosome and how it contributes to anti-tumor effect as well as immune dysfunction. Understanding the cellular players that comprise the lymphoma microenvironment is critical to developing novel therapeutics that can help block the signals for immune escape and promote tumor surveillance. It may also be the key to understanding mechanisms of resistance to immune checkpoint blockade and immune-related adverse events due to certain types of immunotherapy

Corrigendum: Microenvironment Cell Contribution to Lymphoma Immunity

Lymphoma microenvironment is a complex system composed of stromal cells, blood vessels, immune cells as well as extracellular matrix, cytokines, exosomes, and chemokines. In this review, we describe the function, localization, and interactions between various cellular components. We also summarize their contribution to lymphoma immunity in the era of immunotherapy. Publications were identified from searching Pubmed. Primary literature was carefully evaluated for replicability before incorporating into the review. We describe the roles of mesenchymal stem/stromal cells (MSCs), lymphoma-associated macrophages (LAMs), dendritic cells, cytotoxic T cells, PD-1 expressing CD4+ tumor infiltrating lymphocytes (TILs), T-cells expressing markers of exhaustion such as TIM-3 and LAG-3, regulatory T cells, and natural killer cells. While it is not in itself a cell, we also include a brief overview of the lymphoma exosome and how it contributes to anti-tumor effect as well as immune dysfunction. Understanding the cellular players that comprise the lymphoma microenvironment is critical to developing novel therapeutics that can help block the signals for immune escape and promote tumor surveillance. It may also be the key to understanding mechanisms of resistance to immune checkpoint blockade and immune-related adverse events due to certain types of immunotherapy

Approximation Algorithms for Min-Distance Problems

We study fundamental graph parameters such as the Diameter and Radius in directed graphs, when distances are measured using a somewhat unorthodox but natural measure: the distance between u and v is the minimum of the shortest path distances from u to v and from v to u. The center node in a graph under this measure can for instance represent the optimal location for a hospital to ensure the fastest medical care for everyone, as one can either go to the hospital, or a doctor can be sent to help. By computing All-Pairs Shortest Paths, all pairwise distances and thus the parameters we study can be computed exactly in O~(mn) time for directed graphs on n vertices, m edges and nonnegative edge weights. Furthermore, this time bound is tight under the Strong Exponential Time Hypothesis [Roditty-Vassilevska W. STOC 2013] so it is natural to study how well these parameters can be approximated in O(mn^{1-epsilon}) time for constant epsilon>0. Abboud, Vassilevska Williams, and Wang [SODA 2016] gave a polynomial factor approximation for Diameter and Radius, as well as a constant factor approximation for both problems in the special case where the graph is a DAG. We greatly improve upon these bounds by providing the first constant factor approximations for Diameter, Radius and the related Eccentricities problem in general graphs. Additionally, we provide a hierarchy of algorithms for Diameter that gives a time/accuracy trade-off

Acid Dissociation Equilibrium and Singlet Molecular Oxygen Quantum Yield of Acetylated 6,8–Dithioguanosine in Aqueous Buffer Solution

2’,3’,5’–Tri–O–acetyl–6,8–dithioguanosine (taDTGuo) is a modified nucleoside of drug 6–thioguanine and further developed as a potential photochemotherapeutic agent due to its desirable properties of photosensitivity to UVA light and singlet molecular oxygen generation. The photochemical characteristics of taDTGuo under biological conditions (namely in aqueous solution) were intensively investigated by the steady–state absorption and emission, time–resolved near–infrared emission measurements, and quantum chemical calculations. taDTGuo was found to be held in sequential acid dissociation equilibria within pH 3.79–11.93. With the global fitting analysis of the absorption spectra at various pHs, two pKa values of the equilibria were determined to be 7.02 ± 0.01 and 9.79 ± 0.01. Quantum chemical calculations suggested that its mono– and di–anionic species in the ground state should be 1–imide anionic form (N1–taDTGuo–) and 1,7–di–imide anionic form (taDTGuo2–) respectively. taDTGuo generates singlet molecular oxygen effectively and has pH–dependent quantum yields. In conclusion, taDTGuo would be most useful as a potent agent for photochemotherapy under certain carcinomatous pH conditions

Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific function

Epithelial cells, once dissociated and placed in two-dimensional (2D) cultures, rapidly lose tissue-specific functions. We showed previously that in addition to prolactin, signaling by laminin-111 was necessary to restore functional differentiation of mammary epithelia. Here, we elucidate two additional aspects of laminin-111 action. We show that in 2D cultures, the prolactin receptor is basolaterally localized and physically segregated from its apically placed ligand. Detachment of the cells exposes the receptor to ligation by prolactin leading to signal transducers and activators of transcription protein 5 (STAT5) activation, but only transiently and not sufficiently for induction of milk protein expression. We show that laminin-111 reorganizes mammary cells into polarized acini, allowing both the exposure of the prolactin receptor and sustained activation of STAT5. The use of constitutively active STAT5 constructs showed that the latter is necessary and sufficient for chromatin reorganization and β-casein transcription. These results underscore the crucial role of continuous laminin signaling and polarized tissue architecture in maintenance of transcription factor activation, chromatin organization, and tissue-specific gene expression

Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke

<p>Abstract</p> <p>Background</p> <p>Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, has been shown to promote therapeutic benefits in experimental stroke. However, equally compelling evidence demonstrates that the drug exerts variable and even detrimental effects in many neurological disease models. Assessment of the mechanism underlying minocycline neuroprotection should clarify the drug's clinical value in acute stroke setting.</p> <p>Results</p> <p>Here, we demonstrate that minocycline attenuates both <it>in vitro </it>(oxygen glucose deprivation) and <it>in vivo </it>(middle cerebral artery occlusion) experimentally induced ischemic deficits by direct inhibition of apoptotic-like neuronal cell death involving the anti-apoptotic Bcl-2/cytochrome c pathway. Such anti-apoptotic effect of minocycline is seen in neurons, but not apparent in astrocytes. Our data further indicate that the neuroprotection is dose-dependent, in that only low dose minocycline inhibits neuronal cell death cascades at the acute stroke phase, whereas the high dose exacerbates the ischemic injury.</p> <p>Conclusion</p> <p>The present study advises our community to proceed with caution to use the minimally invasive intravenous delivery of low dose minocycline in order to afford neuroprotection that is safe for stroke.</p

NFkB Disrupts Tissue Polarity in 3D by Preventing Integration of Microenvironmental Signals

The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres (\u27acini\u27), the malignant T4-2 cells that form large tumor-like clusters, and the \u27phenotypically reverted\u27 T4-2 cells that polarize as a result of correction of the microenvironmental signaling. We identified 180 genes that display an increased expression in disorganized compared to polarized structures. Network, GSEA and transcription factor binding site analyses suggested that NFkB is a common activator for the 180 genes. NFkB was found to be activated in disorganized breast cancer cells, and inhibition of microenvironmental signaling via EGFR, beta1 integrin, MMPs, or their downstream signals suppressed its activation. The postulated role of NFkB was experimentally verified: Blocking the NFkB pathway with a specific chemical inhibitor or shRNA induced polarization and inhibited invasion of breast cancer cells in 3D cultures. These results may explain why NFkB holds promise as a target for therapeutic intervention: Its inhibition can reverse the oncogenic signaling involved in breast cancer progression and integrate the essential microenvironmental control of tissue architecture