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1
Worth, Leon J. „Vancomycin-resistant enterococci in patients with hematological malignancy: curbing an endemic pathogen“. Leukemia & Lymphoma 55, Nr. 6 (06.11.2013): 1225–26. http://dx.doi.org/10.3109/10428194.2013.845887.
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Rajeswari, K. S. Raja, und V. Nandhana. „Disseminated peritoneal leiomyomatosis-diagnostic dilemma in an acute presentation-a case report“. International Journal of Reproduction, Contraception, Obstetrics and Gynecology 12, Nr. 8 (28.07.2023): 2575–77. http://dx.doi.org/10.18203/2320-1770.ijrcog20232315.
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Diffuse peritoneal leiomyomatosis is a rare benign condition which has a multifactorial origin with genetic or hormonal component leading to metaplasia of peritoneal mesenchymal cells. Thus, a combination of radiology with clinical correlation is an ideal approach for diagnosis. Though benign, radiologically it could give a picture of malignancy. In our case, patient came with an acute presentation resembling torsion ovary which usually needs emergency detorsion. In this scenario, multiple radiology component directed the case towards malignancy while ultimately a history, clinical correlation and biopsy revealed its benign nature. Reviewing the reported cases of disseminated peritoneal leiomyomatosis (DPL) incidence has slightly increased in recent years and is more common in patients with a past history of unconfined laparoscopic myomectomy wherein spillage of the myoma content into the abdominal cavity can trigger DPL as these are hormone sensitive tissues. The indolent course of the disease usually suggests a borderline disease, but only histological and immunohistochemical studies can confirm DPL, showing smooth muscle cells without nuclear atypia, strongly expressing estrogen and progesterone receptors. Mainstay of treatment targets in curbing the hormone influence on DPL and surgical management.
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Tilakaratne, Aruni, und Mena Soory. „Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities“. Open Dentistry Journal 8, Nr. 1 (30.05.2014): 109–24. http://dx.doi.org/10.2174/1874210601408010109.
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The non-antimicrobial properties of tetracyclines such as anti-inflammatory, proanabolic and anti-catabolic actions make them effective pharmaceuticals for the adjunctive management of chronic inflammatory diseases. An over-exuberant inflammatory response to an antigenic trigger in periodontitis and other chronic inflammatory diseases could contribute to an autoimmune element in disease progression. Their adjunctive use in managing periodontitis could have beneficial effects in curbing excessive inflammatory loading from commonly associated comorbidities such as CHD, DM and arthritis. Actions of tetracyclines and their derivatives include interactions with MMPs, tissue inhibitors of MMPs, growth factors and cytokines. They affect the sequence of inflammation with implications on immunomodulation, cell proliferation and angiogenesis; these actions enhance their scope, in treating a range of disease entities. Non-antimicrobial chemically modified tetracyclines (CMTs) sustain their diverse actions in organ systems which include anti-inflammatory, anti-apoptotic, anti-proteolytic actions, inhibition of angiogenesis and tumor metastasis. A spectrum of biological actions in dermatitis, periodontitis, atherosclerosis, diabetes, arthritis, inflammatory bowel disease, malignancy and prevention of bone resorption is particularly relevant to minocycline. Experimental models of ischemia indicate their specific beneficial effects. Parallel molecules with similar functions, improved Zn binding and solubility have been developed for reducing excessive MMP activity. Curbing excessive MMP activity is particularly relevant to periodontitis, and comorbidities addressed here, where specificity is paramount. Unique actions of tetracyclines in a milieu of excessive inflammatory stimuli make them effective therapeutic adjuncts in the management of chronic inflammatory disorders. These beneficial actions of tetracyclines are relevant to the adjunctive management of periodontitis subjects presenting with commonly prevalent comorbidities addressed here.
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Khromova, Natalia, Maria Vasileva, Vera Dugina, Dmitry Kudlay, Peter Chumakov, Sergei Boichuk und Pavel Kopnin. „Actin-Dependent Mechanism of Tumor Progression Induced by a Dysfunction of p53 Tumor Suppressor“. Cancers 16, Nr. 6 (11.03.2024): 1123. http://dx.doi.org/10.3390/cancers16061123.
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Cancer cell aggressiveness, marked by actin cytoskeleton reconfiguration critical for metastasis, may result from an imbalanced ratio favoring γ-actin. Dysfunctional p53 emerges as a key regulator of invasiveness and migration in various cancer cells, both in vitro and in vivo. P53 inactivation (via mutants R175H, R248W, R273H, or TP53 repression) significantly enhanced the migration, invasion, and proliferation of human lung adenocarcinoma A549 cells in vitro and in vivo, facilitating intrapulmonary xenograft metastasis in athymic mice. Conversely, wild-type TP53 (TP53 WT) overexpression in p53-deficient non-small- cell lung cancer (NSCLC) H1299 cells substantially reduced proliferation and migration in vitro, effectively curbing orthotopic tumorigenicity and impeding in vivo metastasis. These alterations in cell motility were closely associated with actin cytoskeleton restructuring, favoring γ-actin, and coincided with ERK1/2-mediated signaling activation, unveiling an innovative regulatory mechanism in malignancy progression. Cancer cell aggressiveness, driven by actin cytoskeleton reorganization and a shift towards γ-actin predominance, may be regulated by p53 dysfunction, thereby providing novel insight into tumor progression mechanisms.
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Woogeng, Ivo N., Lu Han, Samaneh Saberi, Cameron Bumbleburg, Joseph Beaudet, Sudarshana Sharma und Michael Ostrowski. „Abstract C041: Oncostatin-M and transforming growth factor-beta promote loss of PTEN in PDAC cancer associated fibroblasts“. Cancer Research 84, Nr. 2_Supplement (16.01.2024): C041. http://dx.doi.org/10.1158/1538-7445.panca2023-c041.
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Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly malignancy with poor prognosis and treatment options. Cancer associated fibroblasts (CAFs) play a complex role in the PDAC tumor microenvironment (TME), contributing significantly to the progression of the tumor and the dense desmoplastic stroma. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and its loss in both the tumor and in CAFs is associated with increased tumor aggressiveness and resistance to therapy. Our group previously demonstrated PTEN loss occurs in CAFs in ~25% of PDAC patient samples, which correlated with worsened outcomes. In addition, PTEN expression was lost in 80% of SMA+ CAFs in mouse PDAC models. Genetic or pharmacologic inhibition of the hedegehog pathway leads to ubiquitin-dependent destruction of PTEN by the proteosome. However, little is known of the signals produced by tumor cells that trigger PTEN degradation in CAFs. In order to address this problem, we developed an in vitro assay system based on wild type murine PDAC-CAFs that expresses a PTEN-GFP fusion protein. Initially, we focused on IL6 and IL6 family members Leukemia Inhibitory Factor (LIF) and Oncostatin-M (OSM) and Transforming Growth Factor beta 1 (TGFb1). The SMO inhibitor GDC-0449 was used as a positive control. PTEN stability was evaluated using the LSM 880 confocal microscope and GFP+ cells were quantified with QuPath-0.4.3 and analyzed with GraphPad Prism. Among the repertoire of secreted factors, we found that only OSM and TGFb1 could destabilize PTEN after 48H of treatment. When queried against the single cell RNA sequence dataset produced by our lab, we observed that CD45+ leukocytes were the likely source of OSM whereas TGFb1 was produced by tumor cells, fibroblasts, and immune cells. In conclusion, OSM and TGFb1 can downregulate PTEN in CAFs in vitro. Current efforts are aimed at testing whether inhibition of these pathways can restore PTEN expression in mouse PDAC models, and in identifying signaling pathways and E3-ligases that mediate PTEN destruction. These pathways and interactions could be further exploited for selective inhibition aimed at therapeutic benefits in curbing PDAC progression. Citation Format: Ivo N. Woogeng, Lu Han, Samaneh Saberi, Cameron Bumbleburg, Joseph Beaudet, Sudarshana Sharma, Michael Ostrowski. Oncostatin-M and transforming growth factor-beta promote loss of PTEN in PDAC cancer associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C041.
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Dovizio, Melania, Angela Sacco und Paola Patrignani. „Curbing tumorigenesis and malignant progression through the pharmacological control of the wound healing process“. Vascular Pharmacology 89 (Februar 2017): 1–11. http://dx.doi.org/10.1016/j.vph.2017.01.003.
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Kazawa, Kana, Md Moshiur Rahman und Michiko Moriyama. „An Investigation of Factors Influencing High Usage of Medical and Long-Term Care Services in an Aging Society in Japan“. Asia Pacific Journal of Public Health 30, Nr. 2 (05.01.2018): 95–106. http://dx.doi.org/10.1177/1010539517751444.
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Medical and long-term care costs are increasing all over the world. In this study, we investigated the characteristics of groups with high cost of medical and long-term care to define targets for curbing social security costs. As a result, for the population covered by the National Health Insurance, a large portion of medical costs were incurred for mental disorders, malignant neoplasms, and lifestyle-related diseases. For those covered by the Late Elderly Health Insurance System, most medical costs were incurred for lifestyle-related diseases, femoral fractures, neurological diseases, mental disorders, pneumonia, malignant neoplasms, and Alzheimer’s disease. From multiple regression analysis, the hospitalization days, use of advanced medical treatment, outpatient days, and high long-term care level influenced the increased costs. On the other hand, disease characteristics had only a very low effect. These findings suggest that the target population has complex medical and long-term care needs because they have multiple diseases.
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Cai, Jing, Bodou Zhang, Yuqi Li, Wanfang Zhu, Toshihiro Akihisa, Wei Li, Takashi Kikuchi, Wenyuan Liu, Feng Feng und Jie Zhang. „Prophylactic and Therapeutic EBV Vaccines: Major Scientific Obstacles, Historical Progress, and Future Direction“. Vaccines 9, Nr. 11 (07.11.2021): 1290. http://dx.doi.org/10.3390/vaccines9111290.
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The Epstein-Barr virus (EBV) infects more than 95% of adults worldwide and is associated with various malignant tumors and immune diseases, imparting a huge disease burden on the human population. Available EBV vaccines are imminent. Prophylactic vaccines can effectively prevent the spread of infection, whereas therapeutic vaccines mainly stimulate cell-mediated immunity and kill infected cells, thus curbing the development of malignant tumors. Nevertheless, there are still no approved EBV vaccines after decades of effort. The complexity of the EBV life cycle, the lack of appropriate animal models, and the limited reports on adjuvant selection and immune responses are gravely impeding progress in EBV vaccines. The soluble gp350 vaccine could reduce the incidence of infectious mononucleosis (IM), which seemed to offer hope, but could not prevent EBV infection. Continuous research and vaccine trials provide deep insights into the structural biology of viruses, the designs for immunogenicity, and the evolving vaccine platforms. Moreover, the new vaccine candidates are expected to achieve further success via combined immunization to elicit both a dual protection of B cells and epithelial cells, and sustainable immunization against infected cells at several phases of infection.
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Bosch, Mark, Manveer Dhadda, Mette Hoegh-Petersen, Yiping Liu, Laura M. Hagel, Peter Podgorny, Alejandra Ugarte-Torres et al. „Immune Reconstitution After Antithymocyte Globulin (ATG)-Conditioned Hematopoietic Cell Transplantation (HCT)“. Blood 118, Nr. 21 (18.11.2011): 1981. http://dx.doi.org/10.1182/blood.v118.21.1981.1981.
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Abstract Abstract 1981 Introduction: Immune reconstitution after HCT is important for curbing infections and malignancy. ATG has been increasingly used to prevent graft-vs-host disease (GVHD), however, its impact on immune reconstitution has not been well studied. Here we studied (1) immune reconstitution after ATG-conditioned HCT, (2) compared it to non-ATG-conditioned HCT, and (3) determined factors influencing the immune reconstitution. Patients and Methods: Immune subset cell counts were determined on day 28, 56, 84, 180, 365 and 730 post transplant in 125 recipients of allogeneic filgrastim-mobilized blood stem cells who received ATG (Thymoglobulin, 4.5 mg/kg) during conditioning. The subset counts were also determined in 47 non-ATG-conditioned patients (otherwise similarly treated). Subset counts (in blood) and ATG levels (in serum) were quantified by flow cytometry. Mann-Whitney rank sum test was used to compare subset counts (1) in ATG-conditioned patients vs donors, (2) in ATG-conditioned patients vs non-ATG-conditioned patients, and (3) between subgroups of ATG-conditioned patients; Spearman rank correlation test was used to determine associations between subset counts and ordinal variables like ATG levels. Results: (1) After ATG-conditioned HCT, the counts of the following subsets normalized (became not significantly lower than in donors) by day 28: NK cells, monocytes, myeloid dendritic cells (MDCs), and plasmacytoid dendritic cells (PDCs). The counts of the following subsets normalized by day 84: memory/effector CD8 T cells, and CD4−CD8− T cells. The counts of naïve B cells normalized by day 180. The counts of the following subsets have not normalized by day 365 or 730: memory B cells (both isotype switched and unswitched), both naïve and memory/effector CD4 T cells, naïve CD8 T cells, CD4+CD8+ T cells, and invariant NKT (iNKT) cells. (2) Compared to non-ATG-conditioned HCT, counts of B cells, CD4 T cells and CD8 T cells were significantly lower after ATG-conditioned HCT on day 28. Thereafter, recovery of both naïve and memory B cells and memory/effector CD8 T cells was significantly faster in ATG-conditioned patients, leading to higher total B and higher total CD8 T cell counts on day 84 (Figure). On the contrary, recovery of naïve CD8 T cells and both naïve and memory/effector CD4 T cells was significantly slower, the latter leading to low total CD4 T cell counts throughout the first year (Figure). (3) Reconstitution after ATG-conditioned HCT was influenced by (a) the number of cells of the same subset transferred with the graft in case of increased memory B cells, naïve CD4 T cells, naïve CD8 T cells, iNKT cells and MDCs, (b) age of recipient in case of decreased naïve CD4 T cells and naïve CD8 T cells, (c) cytomegalovirus (CMV) serostatus of recipient in case of increased memory/effector T cells, (d) GVHD in case of increased naïve B cells, and (e) day 7 or 28 ATG levels in case of decreased T cell subsets. Conclusion: (1) Reconstitution after ATG conditioned HCT is very fast for NK cells, monocytes, MDCs and PDCs, fast for memory/effector CD8 T cells and CD4−CD8− T cells, slow for naïve B cells, and very slow for memory B cells, both naïve and memory/effector CD4 T cells, naïve CD8 T cells, CD4+CD8+ T cells and iNKT cells. (2) Compared to no ATG, the patients conditioned with ATG have lower counts of B and T cells on day 28. Thereafter, the ATG-conditioned patients have faster recovery of both naïve and memory B cells and memory/effector CD8 T cells, and slower recovery of both naïve and memory/effector CD4 T cells and naïve CD8 T cells. (3) Similar to what has been described for non-ATG-conditioned HCT, reconstitution after ATG-conditioned HCT is influenced by the number of the immune cells transferred with the graft, recipient age, recipient CMV serostatus and GVHD. Moreover, the reconstitution after ATG-conditioned HCT is influenced by ATG clearance. Disclosures: No relevant conflicts of interest to declare.
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Schuster, Philipp, Georg Lindner, Sabrina Thomann, Sebastian Haferkamp und Barbara Schmidt. „Prospect of Plasmacytoid Dendritic Cells in Enhancing Anti-Tumor Immunity of Oncolytic Herpes Viruses“. Cancers 11, Nr. 5 (11.05.2019): 651. http://dx.doi.org/10.3390/cancers11050651.
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The major type I interferon-producing plasmacytoid dendritic cells (pDC) surround and infiltrate certain tumors like malignant melanoma, head and neck cancer, and ovarian and breast cancer. The presence of pDC in these tumors is associated with an unfavorable prognosis for the patients as long as these cells are unstimulated. Upon activation by synthetic Toll-like receptor agonists or viruses, however, pDC develop cytotoxic activities. Viruses have the additional advantage to augment cytotoxic activities of pDC via lytic replication in malignant lesions. These effects turn cold tumors into hotspots, recruiting further immune cells to the site of inflammation. Activated pDC contribute to cross-presentation of tumor-associated antigens by classical dendritic cells, which induce cytotoxic T-cells in particular in the presence of checkpoint inhibitors. The modification of oncolytic herpes viruses via genetic engineering favorably affects this process through the enhanced production of pro-inflammatory cytokines, curbing of tumor blood supply, and removal of extracellular barriers for efficient viral spread. Importantly, viral vectors may contribute to stimulation of memory-type adaptive immune responses through presentation of tumor-related neo- and/or self-antigens. Eventually, both replication-competent and replication-deficient herpes simplex virus 1 (HSV-1) may serve as vaccine vectors, which contribute to tumor regression by the stimulation of pDC and other dendritic cells in adjuvant and neo-adjuvant situations.
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Kang, Sangjo, Anirudh Sattiraju, Yuhuan Li, Shalaka Wahane, Theo Hanna, Roland Friedel und Hongyan Zou. „TAMI-21. TUMOR-ASSOCIATED MICROGLIA GUIDE GBM INFILTRATION VIA PLEXIN-B2“. Neuro-Oncology 23, Supplement_6 (02.11.2021): vi202. http://dx.doi.org/10.1093/neuonc/noab196.805.
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Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor. The nature of invasiveness of GBM makes complete surgical resection difficult. However, how GBM cells achieve wide infiltration in the brain is poorly understood. Microglia, the resident immune cells in the brain can support GBM growth and invasion, but the underlying mechanisms remain elusive. Here, we show that microglia are activated in a wide field away from tumor boundaries, ahead of tumor cell infiltration. Invading GBM cells are in close contact with microglia, progressively aligned with one another in the direction of tumor invasion. Moreover, ECM is also aligned with the infiltrating tumor and microglia, which may serve as invasion tracks in the brain. Mechanistically, we demonstrate that microglia direct cellular alignment and ECM remodeling in the invasion tracks through an axon guidance receptor Plexin-B2. Myeloid-specific ablation of Plexin-B2 perturbs microglia and tumor cell alignment, microglia migration, ECM organization, and GBM invasiveness. Together, our data reveal a hitherto under-appreciated role of microglia in providing directional cues for GBM invasion through physical interaction and alignment of ECM and tumor cells, thus providing new insights and novel molecular targets in curbing GBM invasion.
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Ali, Robert, Julio Perez-Downes, Firas Baidoun, Bashar Al Turk, Carmen Isache, Girish Mohan und Charles Perniciaro. „Challenges in Treating Secondary Syphilis Osteitis in an Immunocompromised Patient with a Penicillin Allergy: Case Report and Review of the Literature“. Case Reports in Infectious Diseases 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/4983504.
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Syphilis is a sexually transmitted infection that remains fairly commonplace. The introduction of penicillin aided in curbing the incidence of disease; however, with the advent of the human immunodeficiency virus (HIV), syphilis is now on a resurgence with sometimes curious presentations. We present a case of a 36-year-old Caucasian gentleman with untreated HIV who complained of a skin eruption and joint pains for 6 weeks, prompting the diagnosis of secondary syphilis osteitis. Skin lesions were reminiscent of “malignant” syphilis. CD4 count was 57 cells/μL. RPR was elevated with 1 : 64 titer and positive confirmatory TP-PA. Radiography of the limbs revealed polyostotic cortical irregularities corroborated on bone scintigraphy. The patient had an unknown penicillin allergy and was unwilling to conduct a trial of penicillin-based therapy. He was subsequently treated with doxycycline 100 mg twice daily for 6 weeks and commenced antiretroviral therapy, noting dramatic improvement in both the skin lesions and joint pains. Unfortunately, he defaulted on follow-up, precluding serial RPR and bone imaging. Penicillin allergies have proven to be quite a conundrum in such patients, without much recourse for alternative therapy. Doxycycline with/without azithromycin is other options worth considering.
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Guo, Yichen, Yinan Jiang, J. Bart Rose, Ganji Purnachandra Nagaraju, Renata Jaskula-Sztul, Anita B. Hjelmeland, Adam W. Beck, Herbert Chen und Bin Ren. „Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity“. Cells 11, Nr. 23 (01.12.2022): 3885. http://dx.doi.org/10.3390/cells11233885.
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Pancreatic neuroendocrine tumors (pNETs) are extremely diverse and highly vascularized neoplasms that arise from endocrine cells in the pancreas. The pNETs harbor a subpopulation of stem cell-like malignant cells, known as cancer stem cells (CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study, we demonstrate that CSCs in human pNETs co-express protein kinase PKD1 and CD44. We further identify PKD1 signaling as a critical pathway in the control of CSC maintenance in pNET cells. PKD1 signaling regulates the expression of a CSC- and EMT-related gene signature and promotes CSC self-renewal, likely leading to the preservation of a subpopulation of CSCs at an intermediate EMT state. This suggests that the PKD1 signaling pathway may be required for the development of a unique CSC phenotype with plasticity and partial EMT. Given that the signaling networks connected with CSC maintenance and EMT are complex, and extend through multiple levels of regulation, this study provides insight into signaling regulation of CSC plasticity and partial EMT in determining the fate of CSCs. Inhibition of the PKD1 pathway may facilitate the elimination of specific CSC subsets, thereby curbing tumor progression and metastasis.
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Mathsyaraja, Haritha, Benjamin Wolf, Chari Cortez, Adam Kashishian, Alison Karst, Madelyn Cueva, Min Wang, Kathleen S. Keegan und Jennifer Cain. „Abstract 2079: Tumor cell intrinsic inactivation of TREX1 increases type I IFN signaling and immune cell recruitment“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 2079. http://dx.doi.org/10.1158/1538-7445.am2022-2079.
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Abstract Tumor cells employ mechanisms to evade anti-tumor immune responses that can include the downregulation or silencing of cytosolic nucleic acid sensing pathway components to dampen Type I IFN signaling. It has been documented that genomic instability and mitotic stress in malignant cells can lead to aberrant cytosolic DNA accumulation and activation of the cGAS-STING pathway. A key negative regulator of cytosolic DNA is the DNA exonuclease TREX1. TREX1 assists in removing DNA from the cytosol, in turn reducing cGAS-STING mediated type I IFN induction. Not surprisingly, TREX1 is overexpressed in several tumor types when compared to normal tissue. The functional importance of TREX1 in cytoplasmic nucleic acid surveillance is evidenced by inactivating TREX1 mutations having an association with Type I inteferonopathies such as Aicardi-Goutières syndrome and SLE. Specifically, most of these mutations impact the enzymatic function of TREX1, underscoring the importance of its exonuclease function. To directly assess TREX1 function in cancer, we inactivated TREX1 in a panel of tumor cell lines. Loss of TREX1 resulted in reduced proliferation and increased expression of the Type I IFN-stimulated gene CXCL10. This finding was validated with CRISPR knockout of TREX1, which also led to the activation of IRF3 and a Type I IFN associated gene signature. To characterize the role of TREX1 function in curbing anti-tumor immunity in vivo, we inactivated Trex1 in the murine syngeneic B16F10 melanoma model. TREX1 knockout together with PD1 blockade resulted in slower tumor growth when compared to PD1 blockade alone. This was accompanied by an increase in CD8+ T and NK cell infiltration in tumors. In addition, gene expression profiling of whole tumors revealed that TREX1 loss resulted in increased type I IFN signaling within the tumor microenvironment. In summary, our data strongly suggest a critical role for TREX1 in suppressing anti-tumor immunity and indicate it would be an attractive target for therapeutic intervention. Citation Format: Haritha Mathsyaraja, Benjamin Wolf, Chari Cortez, Adam Kashishian, Alison Karst, Madelyn Cueva, Min Wang, Kathleen S. Keegan, Jennifer Cain. Tumor cell intrinsic inactivation of TREX1 increases type I IFN signaling and immune cell recruitment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2079.
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Cosgun, Kadriye Nehir, Gauri Deb, Xin Yang, Gang Xiao, Teresa Sadras, Franziska Auer, Jaewoong Lee et al. „Lgr5 Enables Positive B-Cell Selection and Tumor-Initiation in B-Cell Malignancies“. Blood 132, Supplement 1 (29.11.2018): 547. http://dx.doi.org/10.1182/blood-2018-99-116956.
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Abstract Background and rationale. Leukemia-initiating cells (LIC) were extensively studied in AML (Bonnet 1997) and CML (Graham 2002), while LIC populations in B-ALL remained elusive. In the absence of a functional definition, targeted approaches for LIC-eradication are not feasible in B-ALL. Some studies suggested immunophenotypes for B-ALL LIC-populations (Cox 2004, Castor 2005, Wang 2007). However, other groups demonstrated that tumor-initiation in B-ALL is not limited to rare populations or developmental hierarchy (Kelly 2007; Le Viseur 2008; Rehe 2013; Aoki 2015). Concept: We hypothesize that self-renewal in the B-cell lineage is induced by positive selection and antigen-receptor (BCR) signaling, i.e. encounter of cognate antigen. Self-renewal at this stage leads to clonal expansion and survival. Unlike stemness in AML and CML, which is determined by a developmental hierarchy, we propose that self-renewal in the B-cell lineage is transient and driven by environmental antigen and the ability of BCRs to bind with high affinity. In B-cell malignancies, positive B-cell selection events, resulting in Lgr5 surface expression, are mimicked by transforming oncogenes (e.g. BCR-ABL1, NRASG12D, MYD88L265P). Results: Combining flow cytometry and genetic approaches, we identified surface expression of the leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) as new biomarker of positively selected pre-B cells in the bone marrow. Conversely, conditional ablation of Lgr5 during earliest stages of B-cell development resulted in near-complete failure to develop a mature B cell pool (reduced by 2-3 log orders). Lgr5 is a Wnt target gene and an established cancer stem cell marker for epithelial cancers (e.g. colorectal cancer and mammary tumors), however, a role for Lgr5 in normal and malignant hematopoiesis is not known. Importantly, Lgr5 represents a previously unrecognized predictor of poor clinical outcome in children and adults with pre-B ALL, including worse overall survival and higher risks of drug-resistance and relapse. Limiting dilution transplant experiments showed that Lgr5-overexpression increased LIC-frequencies in NSG recipient mice. Inducible activation of Cre in Lgr5fl/fl mouse models for BCR-ABL1- or NRASG12D-driven B-ALL resulted in cell cycle arrest, abolished colony forming capacity and compromised the ability of leukemia cells to initiate fatal disease in NSG transplant recipients. Deletion of Lgr5 in pre-B ALL cells caused massive accumulation of nuclear β-catenin and increased expression of β-catenin target genes. Phosphoproteomic analyses revealed increased levels of β-catenin S675-phosphorylation, which increases β-catenin transcriptional activity (Taurin 2006; Hino 2015). Inducible activation of a gain-of-function mutant of β-catenin revealed that pre-B ALL cells are extremely sensitive to β-catenin activation. Thus, Lgr5 enables positive selection and self-renewal of B-ALL cells by curbing β-catenin activity. Therapeutic implication: To assess Lgr5 surface expression on B-ALL as a target for antibody-drug conjugate (ADC), we treated refractory B-ALL PDX with the Lgr5-MMAE ADC. Single-agent treatment with Lgr5-MMAE significantly reduced B-ALL leukemia burden. Treatment with dexamethasone not only enforced persistent surface expression of Lgr5, but also potentiated efficacy of by Lgr5-MMAE. Conclusion: Unlike self-renewal in myeloid leukemia that is determined by a developmental hierarchy, our results here show that self-renewal in the B-cell lineage is transient and driven by the ability of BCRs to bind antigen with high affinity. Lgr5 is a biomarker of this selection event, critical for the initiation of B-ALL and other B-cell malignancies in transplant recipients. Given that positive B-cell selection events, resulting in Lgr5 surface expression are mimicked by transforming oncogenes, Lgr5 also represents a promising target for ADC therapy for instance Lgr5-MMAE (Genentech). Disclosures No relevant conflicts of interest to declare.
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Chakravarti, Sayak, Ujjal Kumar Mukherjee, Suman Mazumder, Timothy Moore und Amit Kumar Mitra. „In silico Prediction Followed By I n Vitro validation Identifies a Survivin Inhibitor and an MCL-1 Inhibitor As a Potent Secondary Drug Against Refractory or Relapsed Mantle Cell Lymphoma“. Blood 138, Supplement 1 (05.11.2021): 1191. http://dx.doi.org/10.1182/blood-2021-154479.
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Abstract Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm that develops from malignant B-lymphocytes in the outer edge or mantle zone of a lymph node. This is a sub-type of B-cell non-Hodgkin lymphoma characterized by rapid clinical progression and poor response rate to conventional chemotherapeutic drugs with recurrent relapse resulting in a short estimated 5-year overall survival (OS) of 2-5 years depending on the clinical risk. Combination therapies such as R-CHOP, R-DHAP, Hyper-CVAD, VcR-CAP constitute the front-line chemotherapeutic treatment landscape for MCL. Despite good initial response to the combination regimens, all patients develop resistance over time. The Bruton's tyrosine kinase inhibitor (BTKi) Ibrutinib and the proteasome inhibitor (PI) Bortezomib are FDA-approved therapies for refractory or relapsed (R/R) MCL with demonstrated high initial response rate in clinical trials. However, highly variable treatment response along with dose-limiting toxicities has limited the efficacy in real-world settings with the median progression-free survival (PFS) of <15 months and Over-al of 1-2 years. Thus, the identification of novel drugs that function either alone or as combination to curb the oncogenic progression as well as to reduce drug-associated toxicities is of high clinical significance. We have designed a novel optimization-regularization-based computational prediction algorithm called "secDrug" that uses large-scale pharmacogenomics databases like the GDSC1000 to identify novel secondary drugs for the management of treatment-resistant B-cell malignancies. We hypothesize that combination of our predicted secDrugs with BTKi/ PI will be useful in curbing oncogenic progressions of R/R MCL and abrogate drug resistance through simultaneous inhibition of multiple oncogenic factors/pathways. When applied to BTKi/PI-resistant R/R MCL, the top predicted secondary drugs (secDrugs) were YM155 (Survivin inhibitor) and S63845 (selective MCL-1 inhibitor). Interestingly, both Survivin and MCL-1 are reported to be over-expressed in MCL, and their expression is strongly correlated with the oncogenic progression and survivability of the patients. To validate our in-silico predictions, we performed in vitro cytotoxicity assays with the top predicted secDrugs (YM155 and S63845) as single agents (IC50 for YM155 4.87±0.66 nM, for S63845 0.9±1.1 uM) as well as in combination with BTKi/PI against a panel of MCL cell lines representing PI/BTKi sensitive, innate resistant (representing refractory MCL) and clonally-derived acquired resistant (representing relapsed MCL). Our results showed that the YM155 and S63845 exhibited significant synergistic cell killing activities (Combination index/ CI value of 0.31±0.49 as calculated using Chou-Talalay's CI theorem, C.I>1 depicts synergism) alone and in combination with Bortezomib (PI) and Ibrutinib (BTKi), especially in R/R MCL cell lines. Further, our results also showed that both YM155 and S63845 in combination with BTKi/PI were able to significantly lower the effective dose of both BTKi/PI required to achieve desired therapeutic response by >12 times (Dose Reduction Index or DRI for YM155 in combination is 15.87±4.93; DRI for S63845 in combination is 12.34±2.67), thereby making the cell lines relatively more BTKi/PI sensitive. Next, we performed next-generation RNA sequencing analysis to identify mechanisms of secDrug action and synergy. Our Gene expression profiling and Ingenuity pathway analysis of the RNAseq data among YM155-treated MCL cell lines revealed eIF4-p70S6K signaling and mTOR signaling as the top canonical pathways. Our study thus identified YM155 and S63845 as potential novel candidates for repurposing as secondary drugs in combination with BTKi/PI for the treatment of R/R MCL. Currently, we are exploring the probable subclonal molecular mechanisms governing the synergistic drug action by using single-cell transcriptomics analysis. As both YM155 and S63845 have reported activity against cancer stem-ness, we will further investigate the effect of our novel drugs on the cancer stem-like cells in MCL, which have a potential role in treatment resistance. The secDrug algorithm promises to serve as a universal prototype for the discovery of novel drug combination regimens for treatment outcomes in any cancer type by enhancing sensitivity or overcoming resistance to standard of care drugs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Yao, Hui, Siyu Zhang, Haijing Xie, Yue Fan, Mengyu Miao, Rui Zhu, Ling Yuan, Miao Gu, Yiwen You und Bo You. „RCN2 promotes Nasopharyngeal carcinoma progression by curbing Calcium flow and Mitochondrial apoptosis“. Cellular Oncology, 23.03.2023. http://dx.doi.org/10.1007/s13402-023-00796-8.
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Abstract Objective Evidence suggests that calcium release from the endoplasmic reticulum (ER) can be induced to cause calcium overload, which in turn can trigger mitochondrial-dependent apoptosis. Dysregulation of systemic calcium homeostasis and changing levels of calcium-binding proteins have been shown to be associated with the malignant behavior of tumors. However, the precise molecular mechanism underlying Nasopharyngeal carcinoma (NPC) remains uncertain. Methods Reticulocalbin (RCN2) expression in NPC was assessed using GEO database, western blot analysis and qRT-PCR. Apoptosis was assessed using flow cytometric analysis and the expression levels of apoptosis-related proteins were determined using western blot analysis. Intracellular calcium ion concentrations were measured using fluorescence imaging. The findings from these analyses were validated in vitro using nude mice models. Luciferase and ChIP assays were used to measure transcriptional regulation. Clinical significance was evaluated using tissue microarray analysis (n=150). Results Our results showed that RCN2 promotes malignancy by causing Ca2+ flow imbalance, which leads to the initiation of the stress-mediated mitochondrial apoptosis pathway. We demonstrate that calreticulin (CALR) resides primarily in the endoplasmic reticulum and interacts with RCN2. Moreover, the transcription factors YY1 and homeobox protein goosecoid (GSC) both contribute to the initiation of RCN2 transcription by directly binding to the predicted promoter region of RCN2. Finally, high expression of RCN2 combined with high expression of GSC and YY1 may serve as an important clinical biomarker of poor prognosis in patients with NPC. Conclusion YY1 and GSC are upstream regulators of RCN2, involved in mitochondrial calcium overload and stress-induced mitochondrial apoptosis. Thus, they can play significant role in the malignant development of NPCs.
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Ugege, M. O., und B. I. Garba. „A Two-year Retrospective Review of Paediatric Mortality in a Tertiary Facility in North-western Nigeria“. Journal of Advances in Medicine and Medical Research, 31.12.2020, 119–28. http://dx.doi.org/10.9734/jammr/2020/v32i2430759.
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Introduction: Mortality pattern is reflective of both the severity of illness and the quality of treatment given.
Objective: To identify the age, time and cause of death in the paediatric wards of Usmanu Danfodiyo University Teaching Hospital (UDUTH), Sokoto.
Methods: This was a retrospective review of mortalities in children 5weeks to 15 years at the paediatric wards of UDUTH from 1st January 2016 to 31st December 2017. The bio-data, duration of illness, diagnoses, complications and duration of hospital stay were extracted from the mortality case files and analysed.
Results: There were 121 mortalities, representing 2.3% of 5,355 total admissions during the study period. Sixty-seven (55.4%) were males (M: F ratio 1.2:1). Seventy-five (62.0%) were under-fives and mean age ± standard deviation was 54 months ± 46.3. Most deaths 76 (62.0%) occurred between July and December and majority 96 (79.3%) occurred ≥ 24 hours after admission. Severe acute malnutrition [SAM] 31 (41.3%), severe malaria 12(16.0%), and septicaemia 9 (12.0%), were the leading causes of death in the under-fives, whereas severe malaria 8 (17.4%), meningitis 7(15.2%) and malignancy 5 (10.9%) predominate in those > 5 years [P<0.001]. There was delayed presentation ≥ 7 days in 87 (71.9%) children and 90 (74.4%) had at least one or more complications.
Conclusion: Severe acute malnutrition and severe malaria were the leading causes of mortalities in our facility. It is needful to scale up preventive and curative services targeted at curbing these diseases in Sokoto and environs.
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Cao, Cong, Jun Li, Guangzhi Li, Gaoyu Hu, Zhihua Deng, Bing Huang, Jing Yang, Jiequn Li und Song Cao. „Long Non-coding RNA TMEM220-AS1 Suppressed Hepatocellular Carcinoma by Regulating the miR-484/MAGI1 Axis as a Competing Endogenous RNA“. Frontiers in Cell and Developmental Biology 9 (05.08.2021). http://dx.doi.org/10.3389/fcell.2021.681529.
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Long non-coding RNAs (lncRNAs) have a considerable regulatory influence on multiple biological processes. Nevertheless, the role of TMEM220-AS1 in hepatocellular carcinoma (HCC) remains unclear. We used The Cancer Genome Atlas (TCGA) database to analyze the differentially expressed lncRNAs. qRT-PCR was used to verify the results for a large population. The in vitro effects of TMEM220-AS1 on HCC cells were determined using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), flow cytometry, and Transwell assays in HCC cells. We used qRT-PCR and western blotting to identify the epithelial-mesenchymal transition (EMT). Moreover, we performed bioinformatics analysis, western blotting, dual luciferase reporter gene assay, RNA pull-down, and RNA binding protein immunoprecipitation (RIP) to investigate the underlying molecular mechanisms of TMEM220-AS1 function. Finally, the function of TMEM220-AS1 was verified in vivo. The results showed that TMEM220-AS1 was expressed at considerably low levels in HCC. It was demonstrated that malignant phenotypes and EMT of HCC cells were promoted by the knock down of TMEM220-AS1 both in vivo and in vitro. TMEM220-AS1, which was detected primarily in the cytoplasm, functioned as an miRNA sponge to bind miR-484 and promote the level of membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1), thereby curbing the malignant phenotypes of HCC cells. In conclusion, low levels of TMEM220-AS1 promote proliferation and metastasis through the miR-484/MAGI1 axis in HCC.
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Das, Shubhashree, Gurudutta Pattnaik, Sovan Pattanaik, Bikash Ranjan Jena, Bhabani Sankar Satapathy und Ayushi Pradhan. „Envisioning Clinical Management of Breast Cancer: a Comprehensive Review“. Current Drug Discovery Technologies 21 (29.04.2024). http://dx.doi.org/10.2174/0115701638300812240417055802.
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Abstract:: Coming to the edge of disease manufacturing in the twenty-first-century, breast cancer occupies a terrifying scenario in the globe, especially in adult women. Its curiosity endeavours remarkable advances made during the past decennaries for cancer treatment and diagnosis. It accounts for the fifth leading cause of transience, killing approximately 570,000 people per annum. To reduce the prognosis of clinical oncological development with the application of a new chemical entity, some of the critical challenges, like active pharmaceutical ingredients with high chemical resistance, extreme side effects, and high treatment costs are some of the limitations in the curbing aspects of breast melanoma. In cancer research, hence, the development of drugs that are safe, efficient, and cost-effective remains a 'Holy Grail' that may be considered as a boon to target the malignant tissues with novel therapeutics devices. Through the findings on overcoming the drawbacks of traditional methods, researchers have given special attention to cancer-preventive and theranostic approaches based on some novel drug delivery systems. The present study forecasts the wide-ranging modern applications, and on developing some novel liposomal drug delivery therapy against breast cancer.
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Zhang, Defa, Tong Su, Bei Lyu, Yanchao Yang und Xiangzhi Zhuo. „The effects of adolescent physical activity participation on cell phone dependence: the mediating role of self-control“. Work, 19.06.2022, 1–10. http://dx.doi.org/10.3233/wor-210702.
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BACKGROUND: The rapid development of science and technology and the swift improvement of people’s material living standards enabled smartphones to be indispensable of people’s daily lives. OBJECTIVE: The purpose of this paper was to examine the influence of self-control in adolescents’ participation in physical activity on cell phone dependence. METHODS: The Physical Activity Rating Scale (PARS-3), the Self-Control Scale, and the Cell Phone Dependence Scale were used to measure the influence of self-control in adolescents’ participation in physical activity on cell phone dependence among 649 adolescents. RESULTS: The results show: (1) There were significant differences (p < 0.01) in the physical activity levels of adolescents under different gender, birthplace, and education background. (2) Each dimensional variable of physical activity was negatively correlated with the cell phone dependence variable, and positively correlated with each variable of self-control, and the self-control variables were negatively correlated with cell phone dependence. (3) Self-control was partially mediating the effects of physical activity on cell phone dependence, with the mediating effect accounting for 39.68% . CONCLUSIONS: Adolescents’ participation in physical exercise activities will improve self-control and ultimately reduce cell phone dependence. Curbing the negative and malignant events of cell phone addiction among adolescents, timely investigation of mobile phone and Internet addiction, pathological formation mechanisms and intervention measures are important measures to reshape the healthy lifestyle of adolescents and have great practical significance for the prosperity and development of families, society, nation and country.