6 research outputs found
The HOX Gene Family’s Role as Prognostic and Diagnostic Biomarkers in Hematological and Solid Tumors
No full textThe HOX gene family encodes for regulatory transcription factors that play a crucial role in embryogenesis and differentiation of adult cells. This highly conserved family of genes consists of thirty-nine genes in humans that are located in four clusters, A–D, on different chromosomes. While early studies on the HOX gene family have been focused on embryonic development and its related disorders, research has shifted to examine aberrant expression of HOX genes and the subsequent implication in cancer prediction and progression. Due to their role of encoding master regulatory transcription factors, the abnormal expression of HOX genes has been shown to affect all stages of tumorigenesis and metastasis. This review highlights the novel role of the HOX family’s clinical relevance as both prognostic and diagnostic biomarkers in hematological and solid tumors
Hyperthermic Enhancement of Immunotherapy: Findings of In Vitro Modeling
No full textPurpose/Objective(s) Despite advancement in understanding and manipulation of immune checkpoint molecules in immunotherapeutic design, limitations in treatment efficacy persist. Strategies to enhance effectiveness include use of multiple immunotherapeutic agents or combination with radiation therapy. Prior studies have also shown potential for hyperthermia to augment response to both of these therapeutic modalities. We hypothesized that in vitro assessment of moderate hyperthermia effects on the anti-tumor immune response will aid in development of targeted strategies that best combine hyperthermia with other immune manipulating therapies. Materials/Methods To understand the consequences of temperature on carcinogenic phenotypes in vitro, B16-F10 melanoma cells were grown at 37°C or 41°C and biochemical profiles including protein expression were evaluated. Impact of hyperthermia on cell migration and proliferation were also assessed as were changes in the immune milieu including cytokine expression in response to heat. Data obtained was used to define ongoing in vivo experiments in which B16-F10 cells are implanted into C57BL/6 mice, grown to palpable tumors than treated with infrared radiation in combination with either anti-PDL1, anti-PD-1, or IL-15. Future studies based on these initial in vivo studies will explore integration of radiotherapy with hyperthermia and immunotherapy. Results B16-F10 cells grown at 41°C decreased cell migration by 70% in 24 hours, and decreased proliferation by 62% at 48 hours and 94% at 72 hours. To assess biochemical orchestrations exemplified by these data, protein expression profiles were evaluated. Expression of pERK and ERK decreased by 86% and 50% and caspase-3 increased by 31% at 41°C. Activation of sphingomyelinase and caspase-3 both rely on caspase-8. Sphingomyelinase activation results in CD95 receptor translocation, leading to cell death initiation in melanoma cells. Cell stress can induce death pathways and the heat shock protein response simultaneously. Of note, Hsp70 has an established role in fostering a tumor specific immune response. Thus, we investigated inducible hsp70 expression. Hsp70 expression increased by 188% at 41°C vs. 37°C. To evaluate the immune milieu, cytokine array data from conditioned media showed that at 41°C, TNFa expression was increased and IL-4 expression was decreased, suggesting a proinflammatory shift in cytokine profiles at hyperthermic temperatures. In support of our data, hyperthermia-induced TNFa apoptotic responses have been reported. In direct relation to clinical practice, we observed that hyperthermic potentiation decreased PDL1 expression in B16-F10 by 35%. Conclusion Our work to date supports the hypothesis that hyperthermia can enhance immunotherapy via several mechanisms. In vivo study of the ability of hyperthermia to augment immune modulating therapies such as checkpoint blockade and radiation therapy is warranted
Tubulin-binding cofactor E-like (TBCEL), the protein product of the mulet gene, is required in the germline for the regulation of inter-flagellar microtubule dynamics during spermatid individualization
No full textIndividual sperm cells are resolved from a syncytium during late step of spermiogenesis known as individualization, which is accomplished by an Individualization Complex (IC) composed of 64 investment cones. mulet encodes Tubulin-binding cofactor E-like (TBCEL), suggesting a role for microtubule dynamics in individualization. Indeed, a population of ∼100 cytoplasmic microtubules fails to disappear in mulet mutant testes during spermatogenesis. This persistence, detected using epi-fluorescence and electron microscopy, suggests that removal of these microtubules by TBCEL is a prerequisite for individualization. Immunofluorescence reveals TBCEL expression in elongated spermatid cysts. In addition, testes from mulet mutant males were rescued to wild type using tubulin-Gal4 to drive TBCEL expression, indicating that the mutant phenotype is caused by the lack of TBCEL. Finally, RNAi driven by bam-GAL4 successfully phenocopied mulet, confirming that mulet is required in the germline for individualization. We propose a model in which the cytoplasmic microtubules serve as alternate tracks for investment cones in mulet mutant testes. This article has an associated First Person interview with the first author of the paper
