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Lusebrink, Vija B. "A systems oriented approach to the expressive therapies: The expressive therapies continuum." Arts in Psychotherapy 18, no. 5 (January 1991): 395–403. http://dx.doi.org/10.1016/0197-4556(91)90051-b.
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Lusebrink, Vija Bergs, Kristīne Mārtinsone, and Ilze Dzilna-Šilova. "The Expressive Therapies Continuum (ETC): Interdisciplinary bases of the ETC." International Journal of Art Therapy 18, no. 2 (July 2013): 75–85. http://dx.doi.org/10.1080/17454832.2012.713370.
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Fernandez, Karina Therese G., Krista Camille M. Serrano, and Monica Camille C. Tongson. "An Intervention in Treating Selective Mutism Using the Expressive Therapies Continuum Framework." Journal of Creativity in Mental Health 9, no. 1 (January 2, 2014): 19–32. http://dx.doi.org/10.1080/15401383.2013.873706.
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Ziff, Katherine. "Expressive Therapies Continuum: A Framework for Using Art in Therapy by Lisa Hinz." Journal of Creativity in Mental Health 5, no. 2 (April 2010): 221–25. http://dx.doi.org/10.1080/15401383.2010.485121.
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Graves-Alcorn, Sandra. "A Review of “The Expressive Therapies Continuum: A Framework for Using Art in Therapy”." Art Therapy 28, no. 1 (April 19, 2011): 44–45. http://dx.doi.org/10.1080/07421656.2011.557353.
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Hintz, Lisa D. "Walking the Line Between Passion and Caution in Art Therapy: Using the Expressive Therapies Continuum to Avoid Therapist Errors." Art Therapy 25, no. 1 (January 2008): 38–40. http://dx.doi.org/10.1080/07421656.2008.10129352.
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Lusebrink, Vija B. "Assessment and Therapeutic Application of the Expressive Therapies Continuum: Implications for Brain Structures and Functions." Art Therapy 27, no. 4 (January 2010): 168–77. http://dx.doi.org/10.1080/07421656.2010.10129380.
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Hinz, Lisa D. "Expressive Therapies Continuum: Use and Value Demonstrated With Case Study (Le continuum des thérapies par l'expression : étude de cas démontrant leur utilité et valeur)." Canadian Art Therapy Association Journal 28, no. 1-2 (July 3, 2015): 43–50. http://dx.doi.org/10.1080/08322473.2015.1100581.
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Nolan, Emily. "A Review of "Beyond Self-Care for Helping Professionals: The Expressive Therapies Continuum and the Life Enrichment Model"." Art Therapy 36, no. 1 (January 2, 2019): 50–51. http://dx.doi.org/10.1080/07421656.2019.1579532.
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Duhovska, Jana, and Inga Millere. "EXPRESSIVE THERAPIES CONTINUUM-INFORMED EVALUATION OF THREE RESOURCE-ORIENTED RECEPTIVE AND ACTIVE MUSIC THERAPY TECHNIQUES IN CANCER PATIENTS IN PSYCHOSOCIAL REHABILITATION PROGRAMME." SOCIETY. INTEGRATION. EDUCATION. Proceedings of the International Scientific Conference 7 (May 20, 2020): 34. http://dx.doi.org/10.17770/sie2020vol7.5115.
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Expressive Therapies Continuum (ETC), a model posed by Lusebrink and widely used in arts therapies, stipulates that human being is perceiving the world and processing the information in three modes – motion (kinesthetic-sensory perception), emotion (perceptual-emotional perception) and thought (cognitive-symbolic perception), and that optimally functioning person can freely function in all the modes, can slide between the poles of each of the mode and can integrate the elements from various modes and poles. And vice versa - difficulty or inability to function or being stuck in certain modes, can indicate to malfunction and even psychopathology. If that is the case - purposeful integration of various functions by offering expressive activity promoting utilisation of various functions of the ETC, can promote the optimal functioning. In order to find out the capacity of the three resource-based music therapy activities – 1) receptive music therapy activity, 2) semi-structured musical improvisation, 3) song-writing activity - to stimulate the utilisation of specific levels and polarities of the ETC, participants (n=24 cancer patients participating in the psychosocial rehabilitation programme) were asked to assess the elements of the ETC they applied while executing each of the activities. Results of the study show that during the receptive music therapy activity participants mostly used the affective, symbolic and sensory function, during the song-writing activity the mostly used all ETC functions except for sensory, but musical improvisation provoked application of all the ETC functions, and therefore turned out as ultimate activity, capable of integrating all the modes of perception and information processing.
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Duhovska, Jana, and Inga Millere. "Music therapy for emotion regulation skills and better psychological well-being for cancer patients: Making of a therapeutic programme." SHS Web of Conferences 85 (2020): 03006. http://dx.doi.org/10.1051/shsconf/20208503006.
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Objective of this research is to explore the subjective experience and perceived benefits of 60 cancer patients participating in the music therapy based and Expressive Therapies Continuum and Dialectical Behaviour Therapy informed psychosocial support programme. The data was obtained by means of questionnaire and focus group discussions. All participants (n = 60) performed written evaluation of the programme: a) of their overall experience, b) its specific benefits for addressing pain, anxiety as well as social support, emotion regulation and overall quality of life issues, c) its most/least enjoyable/helpful elements. Participants (n = 20) of the four focus group discussions, on their turn, explored the specific elements (contents, organisation, instructions, timetable) of the programme to provide the grounds for future amendments. Results reveal that 70% of participants rated their overall experience as “very valuable” or “valuable”, 24% indicated as “neutral”, whereas 6% admitted that their participation has not led to “substantial gains”. The top five benefits included: improved mood, reduced stress, received support, improved communication, coping with negative emotions linked with disease or treatment. Among the most enjoyable and helpful elements, participants emphasized the ones that were linked with the acquired ability to face and survive difficult emotions (n = 43), discovering inner strength (n = 58), gaining more confidence by acquiring new skills or experience (n = 29), gaining connectedness with group and music (n = 32), musically beautiful moments and transcendence (n = 58) as well as normalization of their experience (n = 50). Focus group discussion provided with valuable recommendations regarding the inclusion of psycho-education elements, size of the group, format of task instructions, pace of the work and necessity for balance between the safety and novelty. It can be concluded that participation in the programme positively affected psychological and social well-being of the cancer patients. Results of this research provide valuable input for the further development of the programme – both organisation and content-wise.
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Schumann, Gerald, Monika Hermankova, Keith Cannon, Joseph L. Mankowski, and Jef D. Boeke. "Therapeutic Effect of a Gag-Nuclease Fusion Protein against Retroviral Infection In Vivo." Journal of Virology 75, no. 15 (August 1, 2001): 7030–41. http://dx.doi.org/10.1128/jvi.75.15.7030-7041.2001.
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ABSTRACT Recently, remarkable progress has been made in developing effective combination drug therapies that can control but not cure retroviral replication. Even when effective, these drug regimens are toxic, they require demanding administration schedules, and resistant viruses can emerge. Thus the need for new gene-based therapies continues. In one such approach, capsid-targeted viral inactivation (CTVI), nucleases fused to viral coat proteins are expressed in infected cells and become incorporated during virion assembly. CTVI can eliminate infectious murine retrovirus titer in tissue culture. Here we describe transgenic mice expressing fusions of the Moloney murine leukemia virus (Mo-MuLV) Gag protein to staphylococcal nuclease. This work tests the protective effect and demonstrates in vivo proof-of-principle of CTVI in transgenic mice expressing endogenous proviral copies of Mo-MuLV. The antiviral protein-expressing mice are phenotypically normal, attesting to the lack of toxicity of the fusion protein. The Mo-MuLV infection was much less virulent in transgenic littermates than in nontransgenic littermates. Gag-nuclease expression reduced infectious titers in blood up to 10-fold, decreased splenomegaly and leukemic infiltration, and increased life spans up to 2.5-fold in transgenic relative to nontransgenic infected animals. These results suggest that gene therapies based on similar fusion proteins, designed to attack human immunodeficiency virus or other retroviruses, could provide substantial therapeutic benefits.
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Nastoupil, Loretta J., Christopher R. Flowers, and John P. Leonard. "Sequencing of therapies in relapsed follicular lymphoma." Hematology 2018, no. 1 (November 30, 2018): 189–93. http://dx.doi.org/10.1182/asheducation-2018.1.189.
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Abstract Follicular lymphoma (FL) is an incurable but treatable disease with vast treatment options. Despite the abundance of efficacious treatment modalities, there is no universally agreed upon standard approach to treatment, particularly in the relapsed/refractory setting. There is an increasing need for more robust and clinically available tools to risk-stratify patients and identify those likely to experience early relapse, which is currently recognized as the unmet need in FL. Additionally, the use of gene-expression profiling and next-generation sequencing techniques in recent years has led to a wealth of knowledge regarding the molecular drivers of lymphomagenesis. However, much of this knowledge is not currently available in the clinic to inform treatment decisions. Future studies are needed to generate clinically relevant predictive models adept at incorporating patient-specific and molecular features to inform management strategies along the entire disease continuum as treatment decisions should not be made in a vacuum with a one-size-fits-all approach. Sequencing of therapy in the management of relapsed FL should involve personalized decision-making for care plans that balance patient characteristics, preferences, and comorbidities with treatment-related factors such as efficacy, toxicity profile, and mechanisms of action to achieve a durable, quality remission.
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Weiskirchen, Ralf, and Frank Tacke. "Liver Fibrosis: From Pathogenesis to Novel Therapies." Digestive Diseases 34, no. 4 (2016): 410–22. http://dx.doi.org/10.1159/000444556.
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Chronic liver injury is accompanied by a dysbalanced scarring process, termed fibrosis. This process is mainly driven by chronic inflammation and an altered activity of a multitude of different chemokines and cytokines, resulting in the infiltration by immune cells (especially macrophages) and increase of matrix-expressing cell types. These processes might lead to cirrhosis representing the end-stage of fibrosis. Recent clinical studies comprising patients successfully treated for viral hepatitis showed that liver fibrogenesis and even cirrhosis may be reverted. The hepatic capacity to remodel scar tissue and to revert into a normal liver follows specific mechanistic principles that include the termination of chronic tissue damage, shifting the cellular bias from inflammation to resolution, initiation of myofibroblast apoptosis or senescence and, finally, fibrinolysis of excess scar tissue. The plurality of molecular and cellular triggers involved in initiation, progression and resolution of hepatic fibrogenesis offers an infinite number of therapeutic possibilities. For instance, inflammatory macrophages can be targeted via inhibition of chemokine CCL2 or its receptor CCR2 (e.g., by cenicriviroc) as well as by transfer of restorative macrophage subsets. Another target is galectin-3 that acts at various stages along the continuum from acute to chronic inflammation. Profibrogenic cytokines (e.g., transforming growth factor-β), matricellular proteins (e.g., CCN1/CYR61) or signaling pathways involved in fibrogenesis offer further possible targets. Other options are the application of therapeutic antibodies directed against components involved in biogenesis or remodeling of connective tissue such as lysyl oxidase-like-2 or synthetic bile acids like obeticholic acid that activate the farnesoid X receptor and was antifibrotic in a phase 2 study (FLINT trial). Factors affecting the gut barrier function or the intestinal microbiome further expanded the repertoire of drug targets. In this review, we discuss novel concepts in resolution of hepatic fibrosis and focus on drug targets that might be suitable to trigger resolution of fibrosis.
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Banerjee, Diponkar. "Recent Advances in the Pathobiology of Hodgkin's Lymphoma: Potential Impact on Diagnostic, Predictive, and Therapeutic Strategies." Advances in Hematology 2011 (2011): 1–19. http://dx.doi.org/10.1155/2011/439456.
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From its first description by Thomas Hodgkin in 1832, Hodgkin's disease, now called Hodgkin's lymphoma, has continued to be a fascinating neoplasm even to this day. In this review, historical aspects, epidemiology, diagnosis, tumor biology, new observations related to host-microenvironment interactions, gene copy number variation, and gene expression profiling in this complex neoplasm are described, with an exploration of chemoresistance mechanisms and potential novel therapies for refractory disease.
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Fairchild, Carter K., Konstantinos V. Floros, Sheeba Jacob, Colin M. Coon, Madhavi Puchalapalli, Bin Hu, Hisashi Harada, et al. "Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA." Cancers 13, no. 10 (May 12, 2021): 2310. http://dx.doi.org/10.3390/cancers13102310.
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Synovial sarcoma (SS) is frequently diagnosed in teenagers and young adults and continues to be treated with polychemotherapy with variable success. The SS18-SSX gene fusion is pathognomonic for the disease, and high expression of the anti-apoptotic BCL-2 pathologically supports the diagnosis. As the oncogenic SS18-SSX fusion gene itself is not druggable, BCL-2 inhibitor-based therapies are an appealing therapeutic opportunity. Venetoclax, an FDA-approved BCL-2 inhibitor that is revolutionizing care in some BCL-2-expressing hematological cancers, affords an intriguing therapeutic possibility to treat SS. In addition, there are now dozens of venetoclax-based combination therapies in clinical trials in hematological cancers, attributing to the limited toxicity of venetoclax. However, preclinical studies of venetoclax in SS have demonstrated an unexpected ineffectiveness. In this study, we analyzed the response of SS to venetoclax and the underlying BCL-2 family biology in an effort to understand venetoclax treatment failure and find a therapeutic strategy to sensitize SS to venetoclax. We found remarkably depressed levels of the endogenous MCL-1 inhibitor, NOXA, in SS compared to other sarcomas. Expressing NOXA led to sensitization to venetoclax, as did the addition of the MCL-1 BH3 mimetic, S63845. Importantly, the venetoclax/S63845 combination induced tumor regressions in SS patient-derived xenograft (PDX) models. As a very close analog of S63845 (S64315) is now in clinical trials with venetoclax in AML (NCT03672695), the combination of MCL-1 BH3 mimetics and venetoclax should be considered for SS patients as a new therapy.
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Li, Lei, Eungyu Lee, and Neil Shaw. "Expression, purification and crystallization of phosphoribosyl transferase from a mycobacteriophage." Acta Crystallographica Section F Structural Biology Communications 74, no. 3 (February 26, 2018): 161–65. http://dx.doi.org/10.1107/s2053230x18002480.
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Tuberculosis (TB) continues to remain a leading cause of death globally. Of particular concern is the emergence and rise in incidence of multidrug-resistant and extremely drug-resistant cases of TB. To counter this threat, it is important to explore alternative therapies, including phage therapy. Phage BTCU-1 specifically infectsMycobacteriumspp. and kills the majority of them. Intriguingly, many proteins from the phage do not share high amino-acid sequence identity with proteins from species other than phages. Here, the expression, purification and crystallization of one such protein, a putative phosphoribosyl transferase from phage BTCU-1, is reported. The crystals belonged to space groupC2221, with unit-cell parametersa= 59.71,b= 64.42,c = 65.32 Å, α = β = γ = 90°. The crystals diffracted X-rays to 2.2 Å resolution.
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Kim, Yonghyo, Jeovanis Gil, Indira Pla, Aniel Sanchez, Lazaro Hiram Betancourt, Boram Lee, Roger Appelqvist, et al. "Protein Expression in Metastatic Melanoma and the Link to Disease Presentation in a Range of Tumor Phenotypes." Cancers 12, no. 3 (March 24, 2020): 767. http://dx.doi.org/10.3390/cancers12030767.
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Malignant melanoma is among the most aggressive skin cancers and it has among the highest metastatic potentials. Although surgery to remove the primary tumor is the gold standard treatment, once melanoma progresses and metastasizes to the lymph nodes and distal organs, i.e., metastatic melanoma (MM), the usual outcome is decreased survival. To improve survival rates and life span, advanced treatments have focused on the success of targeted therapies in the MAPK pathway that are based on BRAF (BRAF V600E) and MEK. The majority of patients with tumors that have higher expression of BRAF V600E show poorer prognosis than patients with a lower level of the mutated protein. Based on the molecular basis of melanoma, these findings are supported by distinct tumor phenotypes determined from differences in tumor heterogeneity and protein expression profiles. With these aspects in mind, continued challenges are to: (1) deconvolute the complexity and heterogeneity of MM; (2) identify the signaling pathways involved; and (3) determine protein expression to develop targeted therapies. Here, we provide an overview of the results from protein expression in MM and the link to disease presentation in a variety of tumor phenotypes and how these will overcome the challenges of clinical problems and suggest new promising approaches in metastatic melanoma and cancer therapy.
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Robinson, Kyle William, Yiyi Chen, Jennifer Podolak, Kerri Forquer, Megan Cook, George Thomas, and Christopher W. Ryan. "VHL protein (pVHL) and Src expression in metastatic RCC." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 457. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.457.
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457 Background: Rational therapeutic strategies are lacking for RCC with intact pVHL expression. We recently demonstrated that Src signaling output was elevated in RCC cells expressing pVHL (Suwaki Sci Transl Med 2011). We sought to prospectively identify and clinically characterize RCC patients according to tumor expression of pVHL and Src using an immunohistochemical (IHC) assay, including the association of pVHL and Src expression with response to targeted therapies. Methods: Metastatic RCC patients with available archival tumor tissue provided written informed consent. Primary and metastatic tumors were evaluated by IHC staining using the following scale: 0: absent; 1: weak; 2: moderate-strong. We scored the percent of tumor cells staining at these intensities, giving a total possible score of 200. Association of pVHL and Src score was determined using Spearman correlation coefficient. Time to treatment failure (TTF) > 300 days was used to stratify patients as treatment success versus failure. Logistic regression was used to analyze whether there was an association between pVHL and Src staining and clinical outcome, and ROC curve analysis was used to find the predictive ability of pVHL and Src positivity. Results: 27 patients were consented, from which the nephrectomy specimens of 23 patients and 17 metastatic tumor samples were available. 22 patients had received systemic therapy (21 with VEGF TKI, 1 with mTOR-I). Expression of pVHL and Src were positively correlated (p<0.001). Expression of pVHL in primary tumor, but not Src, was associated with fewer treatment failure events (p=0.0384). Those who had TTF > 300 days had a mean pVHL score of 127.3, and Src of 134, while those with TTF < 300 days had mean pVHL of 57.5, and Src 89.5. Performing ROC analysis, the combination of pVHL and Src score displayed a higher area under the curve (c=0.8) in predicting treatment failure or success than pVHL or Src score alone. Conclusions: We have shown a correlation between pVHL and Src expression in tumors from a prospective population of RCC patients. Accrual continues to this study of a novel quantitative IHC profile that could identify patients for whom currently available therapies may not be effective or for whom a clinical trial of a Src inhibitor may be appropriate.
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Kadia, Tapan M., Hagop Kantarjian, Srdan Verstovsek, Beth Newman, Guillermo Garcia-Manero, and Gautam Borthakur. "Treatment of Myelodysplastic Syndrome (MDS) with Cytokine Immunotherapy for Low-Risk MDS." Blood 110, no. 11 (November 16, 2007): 1463. http://dx.doi.org/10.1182/blood.v110.11.1463.1463.
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Abstract Patients with low- or intermediate 1- (Int-1) risk MDS, as defined by the International Prognostic Scoring System (IPSS) are generally asymptomatic at presentation, but nonetheless have an expected median survival of only 3.5 to 5.7 years. Highly effective and preferably non cytotoxic therapies are needed to prolong their survival and reduce their risk of transformation to acute myelogenous leukemia (AML). Cytokine modulating therapies including hematopoietic growth factors, steroids, and immune modulating agents have shown activity in low risk MDS. We have developed a phase II clinical trial of cytokine immune-therapy for patients who have not previously been treated with cytotoxic therapy, with low to intermediate risk MDS or ≤10% marrow blasts according to the following treatment plan: Erythropoietin (EPO) 40,000 units SQ weekly, (with escalation to 60,000 units weekly and then twice weekly if the hemoglobin response is inadequate); G-CSF 300 mcg SQ twice weekly, titrated to maintain an ANC between 1 and 10 x 109/dL; oral prednisone starting at 60mg PO daily tapered over 4 weeks; Cyclosporin A given at a dose of 300mg daily for at least 6 months. Treatment was continued until relapse, progressive disease, or lack of response after 6 months of therapy. Responses are evaluated according to the International Working Group (IWG) criteria. Being an efficacy study, the primary outcome is rate of complete remission (CR), although all responses are being considered and reported. We have 14 evaluable patients thus far, with a median age of 67 (46–79). Two-thirds of the patients are male and all had MDS with diploid cytogenetics. Twelve patients (86%) were classified as Int-1, 2 (14%) were low risk, and 1 (7%) was Int-2. The median number of prior therapies was 1 (0–3). So far 2 (14.3%) CRs, 2 (14.3%) PRs, and 4 (28.6%) hematologic improvements have been observed for an overall response rate of 57%. The median time to response was 3 (1–16) months, and the median duration of response was 2 (1–29) months. Of the 2 patients in CR, one required 6 months of therapy before achieving CR and continues to have normal counts with a followup of 33 months. The second patient was treated for 16 months with decreasing transfusion requirements until CR. She now continues on the study, in a CR with incomplete platelet recovery (CRp), with no transfusion requirements and no significant toxicities with a followup of 23 months. Overall, the regimen was well tolerated. Eleven (79%) of the patients required a cyclosporin A dose reduction, mostly due to renal insufficiency. The most common grade 3 toxicities are diarrhea and renal insufficiency, and 1 patient each with fatigue and confusion. No grade 4 toxicities have been seen. Correlation of response with EPO levels, HLA DR15 expression, and CD55/59 expression is ongoing. A cytokine immune-therapy program using a combination of growth factors, steroids, and immune suppression is well tolerated and effective with durable responses in a low to intermediate risk population of patients with MDS.
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Kaufman, Dan S. "Human Pluripotent Stem Cell-Derived Blood Cells for Therapies." Blood 132, Supplement 1 (November 29, 2018): SCI—14—SCI—14. http://dx.doi.org/10.1182/blood-2018-99-109424.
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Abstract It has now been twenty years since human embryonic stem cells (hESCs) were first isolated and described in 1998. In the next decade, induced pluripotent stem cells (iPSCs) were produced first from mouse somatic cells and then from human cells. Since these landmark advances, hESCs and iPSCs have been utilized to advance our understanding of basic human developmental biology and cellular plasticity. These lessons are crucial to fulfill the goal to use human pluripotent stem cells to derive new cellular therapies to better treat and repair organs and tissues damaged by disease, trauma or aging. Clinical trials are underway to utilize differentiated cells derived from hESCs or iPSCs for treatment of retinal disease, spinal cord injury, diabetes, cardiac failure, and other disorders. Production of therapeutic blood cells such as transplantable hematopoietic stem cells (HSCs) from hESCs and iPSCs remains a key goal. However, despite intensive research efforts by our group and many others, there remain challenging to achieve long-term multi-lineage engraftment in vivo with HSCs derived from unmodified hESCs/iPSCs. More successful approaches have used genetic modification or teratoma formation, though these strategies cannot be directly translated to clinical cell products. Reasons for this continued challenge and novel solutions such as use of a Runx1 genetic reporter system will be discussed. In contrast to production of transplantable HSCs, the ability use hESCs/iPSCs to produce functional lymphocytes with anti-tumor and anti-viral activity has been quite successful. Our group has defined methods to efficiently differentiate and expand clinical-scale quantities of natural killer (NK) cells. These hESC/iPSC-derived NK cells have phenotypic and genetic profiles similar to NK cells isolated from peripheral blood. Additionally, hESC/iPSC-derived NK cells are able to kill diverse tumor cells in vitro and in vivo. The hESCs/iPSCs also serve as a versatile platform to engineer genetic enhancements to produce NK cells with improved anti-tumor activity. For example, we have produced hESC/iPSC-derived NK cells that express novel chimeric antigen receptors (CARs) that are able to better target tumors that are more refractory to NK cell-mediated killing. This optimized NK-CAR construct utilizes the NKG2D transmembrane domain, 2B4 co-stimulatory domain, and the CD3ζ signaling domain to activate key NK cell-specific intracellular signaling pathways and increase NK cell survival and expansion in vivo. In one direct comparison between CAR-expressing-iPSC-derived NK cells and "conventional" CAR-expressing T cells, demonstrates the CAR-NK cells have similar ability to kill ovarian tumors in vivo, but with less toxicity, suggesting a safer approach. We have engineered other modifications into iPSC-NK cells to enhance NK cell targeting, proliferation, expansion and survival -- all key qualities to improve in vivo anti-tumor activity. These studies demonstrate that hESC/iPSC-provide an ideal platform to produce standardized, targeted, "off-the-shelf" cellular immunotherapies to treat refractory hematological malignancies and solid tumors. Finally, iPSC-derived NK cells are now being produced at clinical scale under current good manufacturing practices (cGMP) conditions with clinical trials scheduled to start by the end of 2018. Disclosures Kaufman: Fate Therapeutics: Consultancy, Research Funding.
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Coulton, G. R., B. Rogers, P. Strutt, M. J. Skynner, and D. J. Watt. "In situ localisation of single-stranded DNA breaks in nuclei of a subpopulation of cells within regenerating skeletal muscle of the dystrophic mdx mouse." Journal of Cell Science 102, no. 3 (July 1, 1992): 653–62. http://dx.doi.org/10.1242/jcs.102.3.653.
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Degeneration of muscle fibres during the early stages of Duchenne Muscular Dystrophy (DMD) is accompanied by muscle fibre regeneration where cell division and myoblast fusion to form multinucleate myotubes within the lesions appear to recapitulate the events of normal muscle development. The mechanisms that govern the expression of genes regulating differentiation of myoblasts in regenerating skeletal muscle are of great interest for the development of future therapies designed to stimulate muscle regeneration. We show here that single-stranded breaks in DNA are localised in nuclei, using an exogenously applied medium containing labelled deoxynucleotides and the Klenow fragment of DNA polymerase I. The nuclei of a sub-population of cells lying in the inflammatory infiltrate of lesions in the skeletal muscle of the muscular dystrophic mouse (mdx), a genetic homologue of DMD, were labelled in this fashion. By contrast, labelled cells were completely absent from the muscles of normal non-myopathic animals (C57BL/10) and non-lesioned areas of mdx muscles. Cells expressing the muscle-specific regulatory gene, myogenin, were also found within mononucleate cells and myotubes within similar mdx muscle lesions. While we cannot yet say that the cells labelled by the DNA polymerase reaction are in fact differentiating, they were found only in significant numbers within mdx muscle lesions where new muscle fibres appear, providing strong circumstantial evidence that they are intimately associated with the regenerative process. Using a range of nucleases and different DNA polymerases, we show that the DNA polymerase-labelling reaction observed was DNA-dependent and most probably due to infilling of naturally occurring single-stranded gaps in DNA. Since the regenerative process in human Duchenne Muscular Dystrophy is apparently less effective than that seen in mdx mice, continued study of single-stranded DNA breaks may help to elucidate further the mechanisms controlling the expression of genes that characterise the myogenic process during skeletal muscle regeneration. Such findings might be applied in the development of future therapies designed to stimulate muscle regeneration in human dystrophies.
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Alan, Ozkan, Okan Kuzhan, Sinan Koca, Tugba Akin Telli, Tugba Basoglu, Ozlem Ercelep, Deniz Filinte, et al. "How long should we continue crizotinib in ALK translocation-positive inflammatory myofibroblastic tumors? Long-term complete response with crizotinib and review of the literature." Journal of Oncology Pharmacy Practice 26, no. 4 (October 15, 2019): 1011–18. http://dx.doi.org/10.1177/1078155219879757.
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Introduction Inflammatory myofibroblastic tumor is a rare disease which is typically seen in children and young adults. Approximately half of the inflammatory myofibroblastic tumors contain translocations that result in over-expression of anaplastic lymphoma kinase gene. Herein, we present two anaplastic lymphoma kinase-positive cases with long-term remission with crizotinib. We do not know how long these therapies need to be continued. Case reports We present two cases of inflammatory myofibroblastic tumor treated with anaplastic lymphoma kinase inhibitor therapies: an 8-year-old Turkish boy and a 21-year-old Caucasian man. Management and outcome Two cases, both with good tumor control under crizotinib, but one who progressed on drug holiday, responded again to the same drug, and had a very short period of response after restarting crizotinib. Conclusion A molecular-targeted drug (anaplastic lymphoma kinase inhibitor) was found to be extremely effective as selective therapy for inflammatory myofibroblastic tumor with anaplastic lymphoma kinase translocation. Here, we want to emphasize the continuation of this treatment after achieving a good response until progression or a major side effect.
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Crombet Ramos, Ofelia, Claudia Hernandez, Kevin Morrow, John T. Cole, and Paulo Rodriguez. "L-arginine depletion by PEG-arginase I, a new potential therapy for acute lymphoblastic leukemia." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 6580. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.6580.
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6580 Background: Advances in therapies have resulted in an overall complete remission rate of approximately 85% for childhood acute lymphoblastic leukemia (ALL). In contrast, the overall remission rate of adults with leukemia continues to be poor, only about 40% in cases of T cell-ALL (T-ALL). Therefore, it is imperative to generate new therapies that alone or in combination with other treatments could potentially increase the percentages of complete responders or be used to treat the refractory ALL population. Our published results show that a pegylated form of human arginase I (peg-Arg I) prevented T-ALL cell proliferation in vitro and in vivo through the induction of tumor cell apoptosis. Interestingly, the anti-leukemic effects induced by peg-Arg I did not affect the anti-tumor activity of normal T cells, suggesting an anti-tumor specific effect. Our hypothesis states that peg-Arg I has an anti-tumoral effect on B-ALL and T-ALL cells in vitro and that the sensitivity of ALL cells to peg-Arg I depends on their expression of argininosuccinate synthase (ASS) and their ability to produce L-arginine de novo from citrulline. Methods: Malignant T cell proliferation was tested using nonradioactive cell proliferation yellow tretrazolium salt kit. Apoptosis studies were based on the expression of annexin V. Western blot assays were conducted to determine enzymatic expression in different cell lines. Results: The results of our in vitro experiments showed that peg-Arg I had a pro-apoptotic and anti-proliferattive effect on B-ALL cells similar to the one previously seen on T-ALL cells. These effects can be overcome in cell lines able that express ASS and therefore to produce L-arginine de novo. Conclusions: Our results suggest the role of ASS in the ALL-apoptosis induced by peg-Arg-I. Our next steps include: _Understand why ASS-expressing ALL cells do not undergo apoptosis when cultured with peg-Arg-I_Determine the role of ASS in the anti-leukemic effect induced by peg-Arg-I in vivo. Completion of this research is expected to lead to a better understanding of how peg-Arg-I kills ALL cells and could provide the foundation for a novel therapy for ALL patients.
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Chen, Dan-Qian, Gang Cao, Hui Zhao, Lin Chen, Tian Yang, Ming Wang, Nosratola D. Vaziri, Yan Guo, and Ying-Yong Zhao. "Combined melatonin and poricoic acid A inhibits renal fibrosis through modulating the interaction of Smad3 and β-catenin pathway in AKI-to-CKD continuum." Therapeutic Advances in Chronic Disease 10 (January 2019): 204062231986911. http://dx.doi.org/10.1177/2040622319869116.
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Background: Acute kidney injury (AKI) is one of the major risk factors for progression to chronic kidney disease (CKD) and renal fibrosis. However, effective therapies remain poorly understood. Here, we examined the renoprotective effects of melatonin and poricoic acid A (PAA) isolated from the surface layer of Poria cocos, and investigated the effects of combined therapy on the interaction of TGF-β/Smad and Wnt/β-catenin in a rat model of renal ischemia-reperfusion injury (IRI) and hypoxia/reoxygenation (H/R) or TGF-β1-induced HK-2 cells. Methods: Western blot and immunohistochemical staining were used to examine protein expression, while qRT-PCR was used to examine mRNA expression. Coimmunoprecipitation, chromatin immunoprecipitation, RNA interference, and luciferase reporter gene analysis were employed to explore the mechanisms of PAA and melatonin’s renoprotective effects. Results: PAA and combined therapy exhibited renoprotective and antifibrotic effects, but the underlying mechanisms were different during AKI-to-CKD continuum. Melatonin suppressed Smad-dependent and Smad-independent pathways, while PAA selectively inhibited Smad3 phosphorylation through distrupting the interactions of Smad3 with TGFβRI and SARA. Further studies demonstrated that the inhibitory effects of melatonin and PAA were partially depended on Smad3, especially PAA. Melatonin and PAA also inhibited the Wnt/β-catenin pathway and its profibrotic downstream targets, and PAA performed better. We further determined that IRI induced a nuclear Smad3/β-catenin complex, while melatonin and PAA disturbed the interaction of Smad3 and β-catenin, and supplementing with PAA could enhance the inhibitory effects of melatonin on the TGF-β/Smad and Wnt/β-catenin pathways. Conclusions: Combined melatonin and PAA provides a promising therapeutic strategy to treat renal fibrosis during the AKI-to-CKD continuum.
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Jensterle, Mojca, Manfredi Rizzo, and Andrej Janez. "Glucagon-Like Peptide 1 and Taste Perception: From Molecular Mechanisms to Potential Clinical Implications." International Journal of Molecular Sciences 22, no. 2 (January 18, 2021): 902. http://dx.doi.org/10.3390/ijms22020902.
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Preclinical studies provided some important insights into the action of glucagon-like peptide 1 (GLP-1) in taste perception. This review examines the literature to uncover some molecular mechanisms and connections between GLP-1 and the gustatory coding. Local GLP-1 production in the taste bud cells, the expression of GLP-1 receptor on the adjacent nerves, a functional continuum in the perception of sweet chemicals from the gut to the tongue and an identification of GLP-1 induced signaling pathways in peripheral and central gustatory coding all strongly suggest that GLP-1 is involved in the taste perception, especially sweet. However, the impact of GLP-1 based therapies on gustatory coding in humans remains largely unaddressed. Based on the molecular background we encourage further exploration of the tongue as a new treatment target for GLP-1 receptor agonists in clinical studies. Given that pharmacological manipulation of gustatory coding may represent a new potential strategy against obesity and diabetes, the topic is of utmost clinical relevance.
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Gupta, Shilpa, Jasreman Dhillon, Anthony Martin Magliocco, John Puskas, Gisela Caceres, Fadzai Masawi, Yulia Doronin, and Jingsong Zhang. "Results from a phase I/Ib trial of enzalutamide and gemcitabine and cisplatin in metastatic bladder cancer (mBC)." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 471. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.471.
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471 Background: Novel targeted therapies are an unmet need in mBC. Androgen receptor (AR) is a rational target in BC and we conducted a phase 1/1b trial assessing safety and tolerability of AR antonist, enzalutamide (ENZ) in combination with gemcitabine and cisplatin (GC) in mBC. Methods: The dose escalation phase allowed patients with mBC regardless of the AR status (assessed on routine IHC) and dose expansion cohort allowed only AR+ pts. The dose escalation phase had 2 cohorts testing ENZ at doses of 80 and 160 mg respectively with GC (G 1000 mg/m2 on days 1, 8 and C 70 mg/m2 on day 1 every 21 days). After 6 cycles of ENZ+GC, pts. continued maintenance ENZ until disease progression. Primary objective was safety and tolerability of ENZ and GC. Secondary objectives were PFS, OS and objective tumor response. Exploratory objectives included evaluation of AR expression in tumor tissues and correlation with outcomes and CTC evaluation at baseline and prior to cycle 3, including AR expression in CTCs and correlation with clinical outcomes. Key eligibility criteria included ECOG PS of 0-1, and no contraindications to ENZ and GC. Results: A total of 10 pts were enrolled between Nov. 2014 and Jan. 2017; 6 pts were enrolled on the dose escalation phase, there were no DLTs observed and ENZ dose of 160 mg was used for the dose expansion cohort, which enrolled 4 pts. The combination of ENZ and GC was well tolerated with expected toxicities, mainly from GC. Median age was 65.6 yrs, 9/10 pts were male; of the 8 evaluable pts, 1 had CR, 4 had PR, 2 had SD and 1 had PD; median OS was 10.59 mos and median PFS was 7.68 mos. CTCs were detectable in 9/10 pts and correlated with disease response. The pt with CR was a female pt with strongly AR + tumor (>90%) and continues to remain in CR 24 months from starting treatment. Exploratory analysis from CTCs and is ongoing. Conclusions: This is the 1st clinical trial to target AR signaling in mBC with ENZ and to evaluate safety of ENZ with GC. While there were limited number of pts enrolled, the results from this study provide early evidence that AR is a rational target in BC and anti-AR therapies can be safely combined with chemotherapy. Clinical trial information: NCT02300610.
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Sun, Weihong, Changqing Jiang, Ying Ji, Chao Xiao, and Haiping Song. "Long Noncoding RNAs: New Regulators of Resistance to Systemic Therapies for Gastric Cancer." BioMed Research International 2021 (January 6, 2021): 1–14. http://dx.doi.org/10.1155/2021/8853269.
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Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant disease, with approximately 951,000 new cases diagnosed and approximately 723,000 cases of mortality each year. The highest mortality rate of GC is in East Asia, and the lowest is in North America. A large number of studies have demonstrated that GC patients are characterized by higher morbidity, metastasis rates, and mortality and lower early diagnosis rates, radical resection rates, and 5-year survival rates. All cases of GC can be divided into two important stages, namely, early- and advanced-stage GC, and the stage mainly determines the treatment strategy for and the therapeutic effect in GC patients. Patients with early-stage GC undergo radical surgery followed by chemotherapy, and the 5-year survival rate can be as high as 90%. However, patients with advanced-stage GC cannot undergo radical surgery because they are at risk for metastasis; therefore, they can choose only radiotherapy or chemotherapy and have a poor prognosis. Based on the lack of specific clinical manifestations and detection methods, most GC patients (>70%) are diagnosed in the advanced stage; therefore, continued efforts toward developing treatments have been focused on advanced-stage GC patients and include molecular targeted therapy, immunotherapy, and small molecular therapy. Nevertheless, in recent years, accumulating evidence has indicated that small molecules, especially long noncoding RNAs (lncRNAs), are involved in the occurrence, development, and progression of GC, and their abundantly dysregulated expression has been identified in GC tissues and cell lines. Therefore, lncRNAs are considered easily detectable molecules and ideal biomarkers or target-specific agents for the future diagnosis or treatment of GC. In this review, we primarily discuss the status of GC, the role of lncRNAs in GC, and the emerging systemic treatments for GC.
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Onaolapo, O. J., A. Y. Onaolapo, O. A. Olowe, M. O. Udoh, D. O. Udoh, and I. T. Nathaniel. "Melatonin and Melatonergic Influence on Neuronal Transcription Factors: Implications for the Development of Novel Therapies for Neurodegenerative Disorders." Current Neuropharmacology 18, no. 7 (July 28, 2020): 563–77. http://dx.doi.org/10.2174/1570159x18666191230114339.
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Melatonin is a multifunctional signalling molecule that is secreted by the mammalian pineal gland, and also found in a number of organisms including plants and bacteria. Research has continued to uncover an ever-increasing number of processes in which melatonin is known to play crucial roles in mammals. Amongst these functions is its contribution to cell multiplication, differentiation and survival in the brain. Experimental studies show that melatonin can achieve these functions by influencing transcription factors which control neuronal and glial gene expression. Since neuronal survival and differentiation are processes that are important determinants of the pathogenesis, course and outcome of neurodegenerative disorders; the known and potential influences of melatonin on neuronal and glial transcription factors are worthy of constant examination. In this review, relevant scientific literature on the role of melatonin in preventing or altering the course and outcome of neurodegenerative disorders, by focusing on melatonin’s influence on transcription factors is examined. A number of transcription factors whose functions can be influenced by melatonin in neurodegenerative disease models have also been highlighted. Finally, the therapeutic implications of melatonin’s influences have also been discussed and the potential limitations to its applications have been highlighted.
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Eckfeldt, Craig E., Ernesto Diaz-Flores, Michaeleen D. Diers, Susan K. Rathe, Kevin M. Shannon, and David A. Largaespada. "Mechanisms of Relapse Following Targeted Therapy in An NRASG12V and Mll-AF9 Driven Mouse Model of AML." Blood 118, no. 21 (November 18, 2011): 2620. http://dx.doi.org/10.1182/blood.v118.21.2620.2620.
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Abstract Abstract 2620 Acute Myeloid Leukemia (AML) is driven by genetic mutations that promote proliferation and prevent maturation of myeloid progenitors. While the majority of adults with AML achieve a remission with aggressive cytotoxic chemotherapy, a large proportion will ultimately die of relapsed/refractory disease. Given the limited efficacy and significant toxicity associated with current AML treatment strategies, new therapies are needed. While many genetic mutations have been shown to contribute to the development AML, the genetic heterogeneity seen in AML presents a challenge for the development of targeted therapies. The NRAS proto-oncogene and other key mediators of RAS signaling are frequently mutated in AML, making RAS-targeted therapies an attractive strategy for the treatment of AML. We previously developed an in vivo genetically-engineered mouse (GEM) model of AML driven by a tetracycline-repressible, constitutively-active form of NRAS, NRASG12V, and the leukemogenic fusion gene Mll-AF9. The leukemia cells in this model are “addicted” to NRASG12V, and inhibiting its expression with doxycycline (dox) results in rapid, complete remission of the AML. However, we have found that some mice relapse with NRASG12V-independent “dox-resistant” disease after continued suppression of NRASG12V expression, a phenomenon we might expect to occur in human AML after Ras signal pathway inhibition. To investigate the mechanisms of relapse in this model we generated two NRASG12V-independent (NRI) AML clones from a single primary NRASG12V-dependent (NRD) AML. We performed Affymetrix-based global gene expression analysis to compare the expression profiles of the primary NRD AML with the relapsed NRI AMLs. We identified 79 genes that were expressed at ≥ 2-fold higher levels in the NRD AML compared to both NRI AMLs. Among these were the putative tumor suppressor Cav2, and a negative regulator of Ras/Raf/Mek/Erk signaling, Dusp6. Down regulation of Dusp6 could enhance Raf/Mek/Erk signaling in the absence of NRASG12V, and thereby circumvent “addiction” to NRASG12V. Expression analysis also identified 20 genes that were expressed at ≥ 2-fold higher levels in both relapsed NRI AMLs compared to the primary NRD AML. Interestingly a Myc oncogene family member, Mycn (N-Myc), was expressed at > 60-fold higher levels in relapsed NRI AMLs compared to the primary NRD AML. Enforced expression of Mycn is sufficient to give rise to AML in a mouse model, and MYCN is widely expressed in human AML (Kawagoe et al. Cancer Res. 2007;67:10677), suggesting a critical role for Mycn in the development of relapsed NRI AML in this model. We are in the process of investigating whether enforced expression of Mycn and/or loss of Dusp6 are sufficient for the development of resistant NRI AML, and conversely if loss of Mycn and/or enforced expression of Dusp6 restore NRASG12V dependence in this model. We are also performing multi-parameter phosho-flow cytometery to further elucidate the mechanisms of AML resistance and relapse and to identify potentially “druggable” targets for AML. This represents an important step toward understanding the genetic determinates of treatment response and disease relapse with Ras pathway targeted therapies for AML, and thus provides a foundation for developing more effective and less toxic therapies for AML. Disclosures: Largaespada: NeoClone Biotechnology, Inc.: Co-founder, Consultancy, Equity Ownership; Discovery Genomics Inc.: Co-founder, Consultancy, Equity Ownership.
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Jeyaretna, Deva S., Samuel D. Rabkin, and Robert L. Martuza. "Oncolytic herpes simplex virus therapy for peripheral nerve tumors." Neurosurgical Focus 22, no. 6 (June 2007): 1–6. http://dx.doi.org/10.3171/foc.2007.22.6.5.
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✓Oncolytic viruses are one of many emerging cancer therapies. The surgical management of peripheral nerve tumors carries an inherent risk of damaging the nerves involved and so the search for novel therapies with reduced risk of morbidity continues. In this review the authors discuss the use of oncolytic herpes simplex virus (HSV) in the treatment of peripheral nerve tumors. Herpes simplex virus has a number of characteristics that make it a useful oncolytic vector, including its large, sequenced genome that can accommodate multiple transgenes, its lack of insertional mutagenesis, its ability to infect a wide array of cell types in various species, and the availability of well-established antiviral therapies to treat it. The efficacy of oncolytic HSV therapy against schwannomas and malignant peripheral nerve sheath tumors has been studied in multiple experimental models both in vitro and in vivo. The virus utilizes cell pathways unique to tumors to enhance its oncolytic efficacy, preferentially and effectively targeting and destroying peripheral nerve tumor cells without harming normal cells. This effect is augmented by trans-genes expressing antiangiogenic factors, such as dominant-negative fibroblast growth factor receptor and platelet factor 4, and displays synergy with chemotherapy. Different oncolytic HSV vectors have been tested, including hrR3, G207, and G47Δ. In addition, new animal models have been developed to test the efficacy of oncolytic HSV therapy in peripheral nerve tumors. The safety of oncolytic HSV is well-established and has been tested in nonhuman primates and in human clinical trials.
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Adadey, Samuel Mawuli, Michael Bright Yakass, Seth Agyemang, and Samuel Duodu. "The Modulatory Effect of Lead Drug Candidates on Inflammatory Gene Expression in Sepsis: A Mini-Review." Current Drug Discovery Technologies 16, no. 1 (April 10, 2019): 48–56. http://dx.doi.org/10.2174/1570163815666180227162926.
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Sepsis is a debilitating clinical syndrome of systemic inflammation in response to microorganisms especially Gram-positive and Gram-negative bacteria. A minority of sepsis cases could be due to non-pathogenic insult such as trauma. Much of the tissue and organ injury observed among septic patients is a consequence of the inflammatory response. The search for effective treatments of sepsis has led to several studies by different research groups across the globe. Although many targets and molecules have been identified, there is still no effective treatment for sepsis. The aim of this report is to review the literature on drugs and drug candidates against sepsis and how they modulate the expression of inflammatory genes. Many compounds have been identified to regulate inflammatory gene expression by interacting with targets such as topoisomerase 1 and nuclear factor kappa B, which regulate the production of pro- and anti-inflammatory cytokines. Even though these compounds appear promising as potential drugs against sepsis, no effective therapies have been discovered to date and thus the fight against sepsis continues.
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Moon, Chang-In, William Tompkins, Yuxi Wang, Abigail Godec, Xiaochun Zhang, Patrik Pipkorn, Christopher A. Miller, Carina Dehner, Sonika Dahiya, and Angela C. Hirbe. "Unmasking Intra-Tumoral Heterogeneity and Clonal Evolution in NF1-MPNST." Genes 11, no. 5 (May 1, 2020): 499. http://dx.doi.org/10.3390/genes11050499.
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Sarcomas are highly aggressive cancers that have a high propensity for metastasis, fail to respond to conventional therapies, and carry a poor 5-year survival rate. This is particularly true for patients with neurofibromatosis type 1 (NF1), in which 8%–13% of affected individuals will develop a malignant peripheral nerve sheath tumor (MPNST). Despite continued research, no effective therapies have emerged from recent clinical trials based on preclinical work. One explanation for these failures could be the lack of attention to intra-tumoral heterogeneity. Prior studies have relied on a single sample from these tumors, which may not be representative of all subclones present within the tumor. In the current study, samples were taken from three distinct areas within a single tumor from a patient with an NF1-MPNST. Whole exome sequencing, RNA sequencing, and copy number analysis were performed on each sample. A blood sample was obtained as a germline DNA control. Distinct mutational signatures were identified in different areas of the tumor as well as significant differences in gene expression among the spatially distinct areas, leading to an understanding of the clonal evolution within this patient. These data suggest that multi-regional sampling may be important for driver gene identification and biomarker development in the future.
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Sonpavde, Guru, Andrea Necchi, Shilpa Gupta, Gary D. Steinberg, Juergen E. Gschwend, Michiel Simon Van Der Heijden, Nathalie Garzon, et al. "A phase 3 randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± BMS-986205 in cisplatin-eligible muscle invasive bladder cancer (MIBC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS4587. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps4587.
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TPS4587 Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible MIBC, the recommended tx regimen is cisplatin-based NAC prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, suggesting that the PD-1/PD-L1 axis is a valid therapeutic target. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. BMS-986205, a selective, potent, once-daily oral IDO1 inhibitor that works early in the IDO1 pathway to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + BMS-986205 in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± BMS-986205 followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + BMS-986205 (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320.
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Sonpavde, Guru, Andrea Necchi, Shilpa Gupta, Gary D. Steinberg, Juergen Gschwend, Michiel Simon Van Der Heijden, Audrey Richiero, et al. "A phase III randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± linrodostat mesylate, followed by adjuvant postsurgical NIVO ± linrodostat, in cisplatin-eligible muscle invasive bladder cancer (MIBC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS5091. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps5091.
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TPS5091 Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible, muscle invasive BC (MIBC), the recommended tx is cisplatin-based neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, supporting the therapeutic pursuit of the PD-1/PD-L1 axis. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. Linrodostat mesylate, a selective, potent, once-daily oral IDO1 inhibitor that works to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + linrodostat in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± linrodostat followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + linrodostat (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320 .
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Lee, Jinho, Marilyne Labrie, Gen Yong, Todd Camp, Hongli Ma, Megan Grout, Wei Xu, et al. "Multiomics profiling of longitudinal melanoma specimens unravels molecular mechanisms of resistance to sequential targeted and cancer immunotherapies." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e22015-e22015. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e22015.
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e22015 Background: We evaluated spatially-resolved protein profiling of longitudinal tumor specimens derived from two patients with metastatic melanoma who progressed on sequential therapies including targeted therapy (TT) and immune checkpoint blockade (ICB) therapy targeting T cell-surface antigens (CTLA-4 and PD-1). The purpose of this study was to identify molecular determinants of resistance to sequential TT and ICB therapies. Methods: We performed multiplexed and multidimensional spatial protein profiling using NanoString’s GeoMx Digital Spatial Profiling (DSP) platform and single-cell level imaging analysis with Cyclic Immunofluorescence (CycIF) to simultaneously determine dynamic changes in tumor intrinsic signaling pathways and immune response in the tumor microenvironment (TME). Results: The first patient presented with a BRAFV600E-positive brain metastasis. This patient was sequentially treated with ipilimumab (Ipi), the combination of dabrafenib and trametinib, and pembrolizumab (Pembro) and progressed despite of high expression of CD56 NK cell after all treatments. In addition, CycIF analysis revealed drug resistance in a subpopulation of cells that had continued activation of mTOR (pS6) and EGFR pathways. The second patient presented with dermal metastases on the flank with NRASQ61K mutation. This patient was sequentially treated with Pembo, Talimogene Laherparepvec, the combination of Ipi plus nivolumab, and two different investigational agents combined with Pembro. This patient displayed stable disease (SD) on Pembro but eventually progressed on the subsequent therapies. DSP analysis demonstrated CD68/CD40 myeloid cell infiltrates as well as HLA-DR and CD44 in the TME after the last treatment. CycIF analysis revealed dynamic changes in tumoral characteristics including DNA damage and proliferation during treatment. Furthermore, the analysis suggested that there might be a resistant subpopulation in the last tumor biopsy, which is in line with progression of the disease. Conclusions: In this study, we conducted detailed analyses on serial specimens from two patients to precisely define the spatial distribution of immune responses and cancer signaling pathways. The findings propose that concurrent proteomics analysis and immune monitoring of longitudinal tumor biopsies can be informative in clinical evaluation in order to identify salvage therapies to overcome drug resistance.
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Attili, Suresh VS, Dilip Pawar, and Chinnababu Sunkavalli. "Nimotuzumab as a single agent palliative therapy in performance score 3 and above in EGFR expressing tumors." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e21635-e21635. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e21635.
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e21635 Background: Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. However when used without radiation, its always used in adjunct to chemotherapy. With encouraging results of other EGFR monoclonal antibodies as single agent therapies, we explored the possibility of using Nimotuzumab as single agent by which we could avoid chemo related side effects. In view of the limited options availability for subjects with PS 3 and more we thought of choosing this population for analysis of Nimotuzumab as single agent palliative therapy in PS 3 and above EGFR expressing tumors for safety and efficacy Methods: Details of the 38 subjects with pre-treated advanced refractory or progressive solid tumors having PS of more than 2 were evaluated. Nimotuzumab was administered weekly at 200 mg/m2 as single agent for 4 weeks (induction phase) and patients were stratified into those with improved PS and those without. The subjects without PS improvement were continued on the single agent and those with improvement were offered additional chemotherapy . Nimotuzumab could be continued beyond disease progression. Results: Out of 38 patients, 18 had improvement in the PS and were offered chemotherapy later. 16 patients had stable PS and disease. 3 subjects were lost to follow up and 1 patient did not continued. The median number of nimotuzumab applications was 6 (2–11) in the induction phase and the median chemotherapy cycles were 3 (1-6). No toxicity occurred during induction phases (single agent nimotuzumab) and during chemotherapy the Grade II/IV toxicities were observed in 6 (33%) cases predominantly cytopeneas, neuropathy and diarrhea. The median PFS was 142 days (95% CI, 84 to 182), and the median improvement in QOL was 6 points on a scale of 30. Conclusions: Nimotuzumab is well tolerated and may have a role in the treatment of advanced cancers as a single agent in patients with poor performance status. 47% of the patients who are otherwise not eligible for chemo became eligible and had better QOL and longer PFS [compared to historical controls]
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Robilliard, L. D., C. MacDonald, C. E. Angel, G. J. Finlay, W. Joseph, and E. S. Graham. "P12.02 Glioblastoma Multiforme immunological blockades and the implications of glioma cancer stem cells." Neuro-Oncology 21, Supplement_3 (August 2019): iii59. http://dx.doi.org/10.1093/neuonc/noz126.213.
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Abstract BACKGROUND Glioblastoma Multiforme (GBM) is classified as a WHO grade IV astrocytoma that continues to circumvent classical and novel chemo-, radio- and immuno-therapies. The recent FDA approvals for the use of targeted immunotherapies against inhibitory checkpoint ligands (for melanoma; ipilimumab and nivolumab) have brought the use of monoclonal antibody therapies to the forefront of GBM research. However, poor immunological responses, exemplified by down-regulation of anti-tumour T-cell activity, and up-regulation of immunosuppressive cells and secreted factors within the tumour micro-environment, have limited the effectiveness of immunotherapy in GBM to date. Therefore, understanding how GBM modulates an extensive repertoire of immune checkpoint ligands and the functional consequence on immune evasion is necessary to develop more targeted immuno-therapeutics. MATERIAL AND METHODS Patient derived glioblastoma cell lines were cultured using established serum-based or glioma cancer stem cell (gCSC) conditions. The phenotypes of resultant GBM cells and gCSC’s were characterised using flow cytometry and immunocytochemistry, to assess expression of neural lineage and stem cell-associated markers. Thereafter, cells were screened for the expression of an extensive range of inhibitory checkpoint ligands by flow cytometry. Finally, the secretion of immune modulating factors by GBM cells and gCSC’s were evaluated by using XL cytokine proteome arrays. Cytokines that appeared to be differentially expressed were subsequently measured using Cytometric Bead Arrays. RESULTS Adherent gCSC’s and gCSC derived glioma-spheres express nestin, CD44, A2B5 and vimentin, consistent with a stem cell phenotype. Furthermore, the gCSC’s exhibited reduced expression of the neural lineage markers NeuN and OSP. Flow cytometry analyses revealed that glioblastoma cells expressed all 11 checkpoint ligands investigated. Interestingly, gCSC’s showed higher levels of PD-L1, B7-H3, CD155 and HVEM expression than GBM cells. CONCLUSION Glioblastoma Multiforme is highly immuno-suppressive, which is reinforced by this study. Glioblastoma cells express all the inhibitory checkpoint ligands investigated and glioma cancer stem cell cultures up-regulate expression levels further. This implies that GBM cells are heavily equipped to inhibit infiltrating T-cells, exemplifying the need to find suitable therapeutics that target multiple immuno-suppressive mechanisms simultaneously.
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Bastidas, Robert J., Cecelia A. Shertz, Soo Chan Lee, Joseph Heitman, and Maria E. Cardenas. "Rapamycin Exerts Antifungal ActivityIn VitroandIn Vivoagainst Mucor circinelloides via FKBP12-Dependent Inhibition of Tor." Eukaryotic Cell 11, no. 3 (December 30, 2011): 270–81. http://dx.doi.org/10.1128/ec.05284-11.
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ABSTRACTThe zygomyceteMucor circinelloidesis an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin inM. circinelloidesare mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12-encoding gene,fkbA, also conferred rapamycin and FK506 resistance. Expression ofM. circinelloidesFKBP12 (McFKBP12) complemented aSaccharomyces cerevisiaemutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of theMcTor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance inS. cerevisiae, andMcFKBP12 interacted in a rapamycin-dependent fashion with theMcTor FRB domain in a yeast two-hybrid assay, validatingMcFKBP12 andMcTor as conserved targets of rapamycin. We showed thatin vitro, rapamycin exhibited potent growth inhibitory activity againstM. circinelloides. In aGalleria mellonellamodel of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis.
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Abou-Alfa, Ghassan K., Tim Meyer, Jie Zhang, Scott Sherrin, Amin Yaqubie, Alison Clemens O’Neill, Feng Xu, et al. "Evaluation of neratinib (N), pembrolizumab (P), everolimus (E), and nivolumab (V) in patients (pts) with fibrolamellar carcinoma (FLC)." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 310. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.310.
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310 Background: FLC, a rare liver cancer of young adults, has no effective systemic therapies. Surgical resection is used extensively with non-curative intent. FLC is associated with a DNAJB1- PRKACA chimeric transcript that produces a fusion protein with retained kinase activity and increased expression of several oncogenic signaling pathways including, but not limited to, HER2 ( ERBB2). Methods: N (240 mg oral daily) was studied in FLC pts in the SUMMIT study (NCT01953926); and later under compassionate use for N-based combinations (combo): P (2 mg/kg q3w), E (7.5 mg daily), and V (240 mg q2w) in doublet or triplet regimens. Eligible pts: ≥12y; histologically confirmed FLC; adequate organ function; any number of prior therapies. Primary endpoint: objective response rate (ORR; RECIST v1.1). Secondary endpoints: duration of response; clinical benefit rate (CBR); safety (CTCAE v4.0); somatic and germline sequencing (MSK IMPACT). Results: As of 03-Sep-2020, 15 pretreated pts received N in SUMMIT (confirmed ORR 0%; CBR 13%). Efficacy data for 5 pts from SUMMIT and 2 more pts receiving combo under compassionate use (4 male, 3 female, median age 26 years, median 0 [range 0–4] prior systemic therapies) are in shown in the table. The most common adverse events (AE) with single-agent N (n = 5) were diarrhea (grade 1 80%; grade 2 20%) and nausea (grade 1 60%); other AEs were grade ≤1 in ≤20% of pts. Conclusions: N monotherapy had limited benefit as a single agent in FLC pts. Several case studies evaluating N-based combo with checkpoint inhibitors administered under compassionate use demonstrated that NP led to 1 PR, and the triplet of NPE to prolonged SD. These are case-limited observations but are critical and worth evaluating further in upcoming clinical trials given the continued lack of a standard of care therapy for pts with FLC. Clinical trial information: NCT01953926. [Table: see text]
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Stankov, Karmen. "Bioinformatic tools for cancer geneticists." Archive of Oncology 13, no. 2 (2005): 69–75. http://dx.doi.org/10.2298/aoo0502069s.
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Early detection is essential for the control and prevention of many diseases, particularly cancer, which is the reason why the need for new disease markers with improved sensitivity and specificity continues to grow. Utilization of sophisticated bioinformatic tools enables the increased specificity and a relatively large quantity of high quality assays for any gene of interest. Understanding the molecular characteristics of diseases, such as cancer and the detection of mutations or changes in gene expression patterns that occur as a result of the disease, will bring researchers one step closer to achieving the predictive power needed for the development of new therapies, the design of clinical trials, and specific patient treatment planning. Genetic screening is one of the fastest moving areas of medical science, particularly in oncology, and as more genes are cloned, and more disease-associated mutations discovered, the workload is set to increase considerably with the utilization of bioinformatics tools used in integration and analysis of genomic, proteomic and metabolomic profiles of cancer. .
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Spratt, Daniel E., Deaglan J. McHugh, Michael J. Morris, and Alicia K. Morgans. "Management of Biochemically Recurrent Prostate Cancer: Ensuring the Right Treatment of the Right Patient at the Right Time." American Society of Clinical Oncology Educational Book, no. 38 (May 2018): 355–62. http://dx.doi.org/10.1200/edbk_200319.
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Biochemically recurrent prostate cancer is an increasingly common disease state, with more than 25,000 cases occurring annually in the United States. Fortunately, progress continues to be made to more effectively identify metastatic disease, optimize existing therapies, and develop new technologies and therapeutic strategies for the timing and delivery of systemic treatments to improve outcomes. This review covers three topics related to the diagnosis and treatment of men with biochemical recurrence (BCR). First, we provide an update on the state of the rapidly evolving field of molecular imaging and its place in practice. Second, we describe validated clinicopathologic methods to risk stratify patients with biochemically recurrent disease, including new gene expression classifiers, to personalize postoperative radiotherapy (RT) timing. Last, we define our approach to optimal management with systemic therapy, including identifying the patients who may benefit most and balancing the duration and timing of treatment with consideration of the effect of therapy on quality of life (QOL) and medical complications associated with treatment.
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Jabandziev, Petr, Julia Bohosova, Tereza Pinkasova, Lumir Kunovsky, Ondrej Slaby, and Ajay Goel. "The Emerging Role of Noncoding RNAs in Pediatric Inflammatory Bowel Disease." Inflammatory Bowel Diseases 26, no. 7 (February 3, 2020): 985–93. http://dx.doi.org/10.1093/ibd/izaa009.
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Abstract Prevalence of inflammatory bowel disease (IBD), a chronic inflammatory disorder of the gut, has been on the rise in recent years—not only in the adult population but also especially in pediatric patients. Despite the absence of curative treatments, current therapeutic options are able to achieve long-term remission in a significant proportion of cases. To this end, however, there is a need for biomarkers enabling accurate diagnosis, prognosis, and prediction of response to therapies to facilitate a more individualized approach to pediatric IBD patients. In recent years, evidence has continued to evolve concerning noncoding RNAs (ncRNAs) and their roles as integral factors in key immune-related cellular pathways. Specific deregulation patterns of ncRNAs have been linked to pathogenesis of various diseases, including pediatric IBD. In this article, we provide an overview of current knowledge on ncRNAs, their altered expression profiles in pediatric IBD patients, and how these are emerging as potentially valuable clinical biomarkers as we enter an era of personalized medicine.
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Garris, Christopher S., Jeffrey L. Wong, Jeffrey V. Ravetch, and David A. Knorr. "Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer." Science Translational Medicine 13, no. 594 (May 19, 2021): eabd1346. http://dx.doi.org/10.1126/scitranslmed.abd1346.
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Intravesical immunotherapy using Bacille Calmette-Guérin (BCG) attenuated bacteria delivered transurethrally to the bladder has been the standard of care for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) for several decades. BCG therapy continues to be limited by high rates of disease recurrence and progression, and patients with BCG-unresponsive disease have few effective salvage therapy options besides radical cystectomy, highlighting a need for new therapies. We report that the immune-stimulatory receptor CD40 is highly expressed on dendritic cells (DCs) within the bladder tumor microenvironment of orthotopic bladder cancer mouse models, recapitulating CD40 expression by DCs found in human disease. We demonstrate that local CD40 agonism in mice with orthotopic bladder cancer through intravesical delivery of anti-CD40 agonist antibodies drives potent antitumor immunity and induces pharmacodynamic effects in the bladder tumor microenvironment, including a reduction in CD8+ T cells with an exhausted phenotype. We further show that type 1 conventional DCs (cDC1) and CD8+ T cells are required for both bladder cancer immune surveillance and anti-CD40 agonist antibody responses. Using orthotopic murine models humanized for CD40 and Fcγ receptors, we demonstrate that intravesical treatment with a fully human, Fc-enhanced anti-CD40 agonist antibody (2141-V11) induces robust antitumor activity in both treatment-naïve and treatment-refractory settings, driving long-term systemic antitumor immunity with no evidence of systemic toxicity. These findings support targeting CD40-expressing DCs in the bladder cancer microenvironment through an intravesical agonistic antibody approach for the treatment of NMIBC.
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Dzobo, Kevin, Dimakatso Alice Senthebane, Chelene Ganz, Nicholas Ekow Thomford, Ambroise Wonkam, and Collet Dandara. "Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review." Cells 9, no. 8 (August 13, 2020): 1896. http://dx.doi.org/10.3390/cells9081896.
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Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.
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Zhang, Zijun, Eva Asomugha, Lew Schon, Sharada Paudel, and Young Cho. "Accumulation of Advanced Glycation End-Products and Increased Expression of Estrogen Receptor in Tendinopathy." Foot & Ankle Orthopaedics 2, no. 3 (September 1, 2017): 2473011417S0004. http://dx.doi.org/10.1177/2473011417s000432.
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Category: Basic Sciences/Biologics Introduction/Purpose: Tendinopathy causes pain and dysfunction. Conservative treatments of tendinopathy include physical therapy, rest, training modification, splintage, taping, cryotherapy, electrotherapy, shock wave therapy, hyperthermia and local injections. These therapies, however, do not target specific pathology and are unable to modify the progression of the disease. The pathology of tendinopathy is considered as a continuum of tendon degeneration but the precise molecular pathology of tendinopathy is still lacking. Accumulation of advanced glycation end-products (AGEs) happens during connective tissue aging and affects tendon viscoelasticity. Estrogen, which functions via estrogen receptor (ER), is essential for metabolism and plays a role in tendon health and aging. This preliminary study investigated the expression of AGEs and ER in tendinopathy. Methods: This study included six patients with posterior tibial tendon (PTT) tendinopathy (age from 20 to 72 years, 5 male and 1 female). Normal flexor digitorum longus (FDL) tendon samples were collected from three donors (female, age from 42 to 51 years, approved by IRB). Tissue samples of tendinopathy and normal tendon were fixed with 4% paraformaldehyde and sectioned with a cryostat. Picrosirius Red stain was used for collagen structure. Immunohistochemistry of AGEs, AGEs receptor (RAGEs) and ER was performed on separate tissue sections. The primary antibody of AGEs, RAGEs and ER was separately applied onto the tissue sections for one hour. The proper secondary antibody that conjugated with peroxidase was applied and incubated for 30 min, followed by the application of 3,3’-diaminobenzidine for chromogenic detection of protein expression. Cell nuclei were conterstained with hematoxylin. Tissue sections omitted application of primary antibody were used as negative controls. Results: Tissue sections stained with Picosirius Red were examined under a circular polarizing microscope. Tendinopathy of PTT was confirmed by a disorderly organized collagen network and highly heterogeneous collagen contents. Cellularity was greatly increased in the pathological region. ER was uniformly expressed by tenocytes in the PTT pathologic tissues. The ER-positive cells were particularly located in areas featured disorganized collagen fibers and dense cellularity. After antigen retrieval with sodium citrate buffer, enhanced expression of AGEs was detected in the tendon tissue of PTT. RAGEs was expressed by a few tenocytes in the pathological region of PTT sections but not in normal FDL sections. Conclusion: The long-term goal of this study is to identify key molecules involved in tendinopathy, for developing disease- modifying therapies. This preliminary study revealed the expression of several molecules, which are associated with connective tissue aging process, in tendinopathy. The accumulation of AGEs and increased expression of ER in the pathological tendon add more molecular features to tendinopathy. Future study will focus on the pathological role of these molecules in regulation of tenocytes.
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Lilly, Michael B., Leslie Drapiza, Milan Sheth, Marina Zemskova, Svetlana Bashkirova, and Joan Morris. "Expression of Cyclooxygenase-2 (COX-2) in Human Leukemias and Hematopoietic Cells." Blood 104, no. 11 (November 16, 2004): 4336. http://dx.doi.org/10.1182/blood.v104.11.4336.4336.
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Abstract COX-2 has been implicated in the development of many epithelial cancers, as well as in tumor angiogenesis. COX-2 inhibitors have been shown to have anti-tumor activity in experimental cancer. Little information exists, however, on the expression or role of COX-2 in hematologic malignancies. We have use a variety of immunochemical assays to document expression of COX-2 in human and murine leukemias and hematopoietic cells. The factor-dependent murine cell lines FDCP1 and 32D expressed COX-2 when growing continuously in the presence of IL-3; expression declined markedly when growth factor was removed. FDCP1 cells constitutively expressing bcl-2, pim-1, or bcr-abl had markedly elevated levels of COX-2, and continued to express this enzyme even after removal of growth factor. To assess COX-2 expression in human hematopoietic cells we developed a flow cytometry assay using a FITC-labelled anti-COX-2 MoAb (Cayman). Cells were washed once in serum-free medium, fixed briefly in 1% paraformaldehyde, permeabilized with PBS/0.2% Triton X100, then stained with antibody. Negative control samples were processed similarly but stained with antibody that had been preincubated with immunizing peptide. Specific COX-2 staining was interpreted as the difference between the histograms from blocked versus unblocked anti-COX-2 antibody, as determined by Kolmogorov-Smirnoff analysis. In buffy coat preparations from normal donors, we found constitutive expression of COX-2 in lymphocytes (both B-cells and T-cells). In contrast little or no COX-2 was detected in unstimulated neutrophils or monocytes. In human acute myelogenous leukemia (AML) cell lines we found COX-2 expression to be universal and easily detected. In several cell lines we confirmed the results of our flow cytometry assay with immunoblotting. We further examined 25 cryopreserved samples of human acute leukemia blasts obtained from peripheral blood. COX-2 expression was variable, but universal. Levels generally were less than those seen in immortalized cell lines, and did not correlate with blasts morphology (AML, ALL, APL, AMoL, CML-BT). To determine if COX-2 inhibitors could play a role in the treatment of acute leukemias, we performed cytotoxicity assays using the COX-2 specific inhibitors, celecoxib and NS398. Survival and growth of human AML cell lines were inhibited by both agents. These data demonstrate that 1) a variety of oncogenes can induce expression of COX-2 in hematopoietic cells, 2) clinical human acute leukemias uniformly express COX-2 in circulating blasts, and 3) COX-2 inhibitors are cytotoxic for human leukemia cells. Combination therapies for acute leukemias may evaluate the incorporation of COX-2 inhibitors for added cytotoxic effects or angiogenesis inhibition.
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Kapoor, Arun, Hongyi Cai, Michael Forman, Ran He, Meir Shamay, and Ravit Arav-Boger. "Human Cytomegalovirus Inhibition by Cardiac Glycosides: Evidence for Involvement of the hERG Gene." Antimicrobial Agents and Chemotherapy 56, no. 9 (July 9, 2012): 4891–99. http://dx.doi.org/10.1128/aac.00898-12.
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ABSTRACTInfection with human cytomegalovirus (HCMV) continues to be a major threat for pregnant women and the immunocompromised population. Although several anti-HCMV therapies are available, the development of new anti-HCMV agents is highly desired. There is growing interest in identifying compounds that might inhibit HCMV by modulating the cellular milieu. Interest in cardiac glycosides (CG), used in patients with congestive heart failure, has increased because of their established anticancer and their suggested antiviral activities. We report that the several CG—digoxin, digitoxin, and ouabain—are potent inhibitors of HCMV at nM concentrations. HCMV inhibition occurred prior to DNA replication, but following binding to its cellular receptors. The levels of immediate early, early, and late viral proteins and cellular NF-κB were significantly reduced in CG-treated cells. The activity of CG in infected cells correlated with the expression of the potassium channel gene, hERG. CMV infection upregulated hERG, whereas CG significantly downregulated its expression. Infection with mouse CMV upregulated mouse ERG (mERG), but treatment with CG did not inhibit virus replication or mERG transcription. These findings suggest that CG may inhibit HCMV by modulating human cellular targets associated with hERG and that these compounds should be studied for their antiviral activities.
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Okerman, Travis, Taylor Jurgenson, Madelyn Moore, and Amanda H. Klein. "Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain." Molecular Pain 17 (January 2021): 174480692110033. http://dx.doi.org/10.1177/17448069211003375.
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Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.
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Lungmus, Jacqueline K., and Kenneth D. Angielczyk. "Antiquity of forelimb ecomorphological diversity in the mammalian stem lineage (Synapsida)." Proceedings of the National Academy of Sciences 116, no. 14 (March 18, 2019): 6903–7. http://dx.doi.org/10.1073/pnas.1802543116.
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Mammals and their closest fossil relatives are unique among tetrapods in expressing a high degree of pectoral girdle and forelimb functional diversity associated with fully pelagic, cursorial, subterranean, volant, and other lifestyles. However, the earliest members of the mammalian stem lineage, the “pelycosaur”-grade synapsids, present a far more limited range of morphologies and inferred functions. The more crownward nonmammaliaform therapsids display novel forelimb morphologies that have been linked to expanded functional diversity, suggesting that the roots of this quintessentially mammalian phenotype can be traced to the pelycosaur–therapsid transition in the Permian period. We quantified morphological disparity of the humerus in pelycosaur-grade synapsids and therapsids using geometric morphometrics. We found that disparity begins to increase concurrently with the emergence of Therapsida, and that it continues to rise until the Permo-Triassic mass extinction. Further, therapsid exploration of new regions of morphospace is correlated with the evolution of novel ecomorphologies, some of which are characterized by changes to overall limb morphology. This evolutionary pattern confirms that nonmammaliaform therapsid forelimbs underwent ecomorphological diversification throughout the Permian, with functional elaboration initially being more strongly expressed in the proximal end of the humerus than the distal end. The role of the forelimbs in the functional diversification of therapsids foreshadows the deployment of forelimb morphofunctional diversity in the evolutionary radiation of mammals.