Publications by authors named "Nikola A Bowden"

Drug repurposing has potential to improve outcomes for high-grade serous ovarian cancer (HGSOC). Repurposing drugs with PARP family binding activity may produce cytotoxic effects through the multiple mechanisms of PARP including DNA repair, cell-cycle regulation, and apoptosis. The aim of this study was to determine existing drugs that have PARP family binding activity and can be repurposed for treatment of HGSOC.

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  • Low grade serous carcinoma (LGSOC) is a rare type of ovarian cancer that behaves differently than the more common high-grade serous ovarian carcinoma, making treatment challenging and clinical trial data less applicable to it.
  • Current treatment options for relapsed LGSOC are limited and there's a pressing need for new therapies tailored to this subtype.
  • A study involving extensive drug screening tested 3436 compounds on LGSOC cell lines, identifying 60 promising and 19 moderately effective drugs that target specific pathways, including some well-known and new potential drug classes.
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SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in , encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42-67% of ovarian clear cell carcinomas (OCCC).

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  • Excision repair cross-complementation group 2 (ERCC2) is key for DNA repair, and mutations in this gene are found in about 10% of bladder cancer cases, potentially indicating how well patients respond to cisplatin therapy.
  • * In a study, mutations in ERCC2 were found to independently predict prognosis for bladder cancer and significantly change the mutation patterns in the genome, leading to specific mutation hotspots.
  • * Researchers used these findings to create a machine learning model that may help predict harmful ERCC2 mutations, aiming to improve treatment strategies for bladder cancer patients.
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Gynecological and obstetric infectious diseases are crucial to women's health. There is growing evidence that links the presence of (), an anaerobic oral commensal and potential periodontal pathogen, to the development and progression of various human diseases, including cancers. While the role of this opportunistic oral pathogen has been extensively studied in colorectal cancer in recent years, research on its epidemiological evidence and mechanistic link to gynecological diseases (GDs) is still ongoing.

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Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin-angiotensin system (RAS), well-known for its function in the cardiovascular system, to the progression of cancers. We studied the expression of RAS-related genes (, , , , , and ) in The Cancer Genome Atlas (TCGA) glioblastoma cohort, their relationship to patient survival, and association with tumour microenvironment pathways.

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Glioblastoma cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation causing downstream DDR activation. Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines.

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Vasculogenic mimicry (VM), the ability of tumour cells to form functional microvasculature without an endothelial lining, may contribute to anti-angiogenic treatment resistance in glioblastoma. We aimed to assess the extent of VM formation in primary and recurrent glioblastomas and to determine whether VM vessels also express prostate-specific membrane antigen (PSMA), a pathological vessel marker. Formalin-fixed paraffin-embedded tissue from 35 matched pairs of primary and recurrent glioblastoma was immunohistochemically labelled for PSMA and CD34 and stained with periodic acid-Schiff (PAS).

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Purpose: Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma.

Experimental Design: A total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab.

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Background: Glioblastoma, the most common primary malignant brain tumour in adults, is a highly vascular tumour characterised by abnormal angiogenesis. Additional mechanisms of tumour vascularisation have also been reported in glioblastoma, including the formation of tumour cell-derived vessels by vasculogenic mimicry (VM) or the transdifferentiation of tumour cells to endothelial cells. VM and endothelial transdifferentiation have frequently been reported as distinct processes, however, the use of both terms to describe a single process of vascularisation also occurs.

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Background: A lack of clarity exists regarding contraceptive uptake and counselling among women with cancer, despite these women having unique family planning needs. This study aimed to systematically review the available literature and produce an overall summary estimate of contraceptive use and counselling among women with cancer across the cancer care continuum.

Methods: A systematic search of articles reporting on contraceptive counselling and/or contraceptive use among women of reproductive age (15-49 years) with cancer across the cancer care continuum (e.

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The advent of molecular targeted therapies has made a significant impact on survival of women with ovarian cancer who have defects in homologous recombination repair (HRR). High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, with over 50% displaying defective HRR. Poly ADP ribose polymerases (PARPs) are a family of enzymes that catalyse the transfer of ADP-ribose to target proteins, functioning in fundamental cellular processes including transcription, chromatin remodelling and DNA repair.

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Melanoma gave science a window into the role immune evasion plays in the development of malignancy. The entire spectrum of immune focused anti-cancer therapies has been subjected to clinical trials in this disease, with limited success until the immune checkpoint blockade era. That revolution launched first in melanoma, heralded a landscape change throughout cancer that continues to reverberate today.

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Article Synopsis
  • Glioblastoma is an aggressive and treatment-resistant tumor, with a focus on the DNA damage response (DDR) that helps these cells manage damage from therapies.
  • Researchers examined DDR expression in both patient samples and cell lines, studying its link to treatment outcomes and patient survival following standard treatments like temozolomide (TMZ) and radiation (RT).
  • While distinct DDR gene clusters were identified, no significant differences in overall survival or treatment response emerged; however, high expression of certain DDR genes correlated with poor prognosis, highlighting the need for future research on targeting DDR pathways for better treatment strategies.
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Background: Platinum chemoresistance results in high-grade serous ovarian cancer (HGSOC) disease recurrence. Recent treatment advances using checkpoint inhibitor immunotherapy has not benefited platinum-resistant HGSOC. In ovarian cancer, DNA methyltransferase inhibitors (DNMTi) block methylation and allow expression of silenced genes, primarily affecting immune reactivation pathways.

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  • High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer, with poor survival rates and high recurrence within 3 years.
  • Current research highlights the challenge of treating HGSOC due to the development of resistance to platinum-based chemotherapy, potentially linked to unknown epigenetic modifications.
  • Promising epigenetic therapies, such as demethylating agents and histone deacetylase inhibitors, are being explored in clinical trials, aiming to improve treatment outcomes despite some leading to off-target side effects.
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  • Immunotherapies targeting PD-1-expressing tumor-infiltrating lymphocytes (TILs) have shown potential in glioblastoma but limited success in clinical settings.
  • A study analyzed TIL density in matched primary and recurrent glioblastoma samples, finding mostly low TIL densities, with CD8+ TILs being more prevalent than CD4+ TILs.
  • The research indicated that PD-1+ TILs were rare, appearing in only 25% of primary and 50% of recurrent tumors, which may explain the poor outcomes of anti-PD-1 therapies in glioblastoma.
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Trial data support an absence of an exposure-survival relationship for pembrolizumab. As these relationships remain unexamined in a real-world setting, we determined them in metastatic melanoma prospectively in an observational study. Translational objectives included identifying biomarkers of progressive disease (PD).

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Background: The aggressive, invasive and treatment resistant nature of glioblastoma makes it one of the most lethal cancers in humans. Total surgical resection is difficult, and a combination of radiation and chemotherapy is used to treat the remaining invasive cells beyond the tumour border by inducing DNA damage and activating cell death pathways in glioblastoma cells. Unfortunately, recurrence is common and a major hurdle in treatment, often met with a more aggressive and treatment resistant tumour.

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Introduction: Resistance to targeted and immune checkpoint blockade treatment remains a major problem in patients with advanced metastatic melanoma. To overcome this problem, there needs to be a decrease in burden of disease as well as re-establishing of immune sensitivity. The aim of this early phase 2 clinical trial is to investigate a novel way of sequencing and combining decitabine and carboplatin to decrease methylation and increase DNA repair resulting in a decrease in the disease burden and to re-establish sensitivity to the immune response.

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Immune checkpoint blockade has transformed outcomes across solid organ tumours. Monoclonal antibodies targeting the negative inhibitory cytotoxic T lymphocyte-associated protein 4 and programmed-death 1/programmed death-ligand 1 axis can lead to deep and durable responses across several tumour streams in the advanced setting. This immunotherapy approach is increasingly used earlier in the treatment paradigm.

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Exhausted T cells are effector T cells that are silenced due to continuous T cell receptor (TCR) stimulation from persistent antigens. Characteristics of exhaustion include the increased expression of multiple inhibitory receptors such as programme death-1[PD-1], lymphocyte activation gene 3 [LAG-3], T cell Ig and mucin domain [TIM-3], the loss of effector cytokine secretion and altered transcriptional profile. The PD-1/PD-L1 interaction induces functional exhaustion of tumor-reactive cytotoxic T cells and interferes with anti-tumor T cell immunity.

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