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    Skeletal muscle mass, strength, and physical performance gains are similar between healthy postmenopausal women and postmenopausal breast cancer survivors after 12 weeks of resistance exercise training.
    (Springer Nature, 2024-11-23) Artigas-Arias M; Alegría-Molina A; Vidal-Seguel N; Muñoz-Cofre R; Carranza-Leiva J; Sepúlveda-Lara A; Vitzel KF; Huard N; Sapunar J; Salazar LA; Curi R; Marzuca-Nassr GN
    Purpose Resistance exercise training (RET) effectively increases skeletal muscle mass and strength in healthy postmenopausal women. However, its effects on these parameters in postmenopausal breast cancer survivors are controversial or limited. Therefore, the aim of this study was to compare the effects of a 12-week progressive whole-body RET program on skeletal muscle mass, strength, and physical performance in healthy postmenopausal women versus postmenopausal women who survived breast cancer. Methods Thirteen healthy postmenopausal women (HEA, 54 ± 3 years, BMI 26.6 ± 2.7 kg·m2, n = 13) and eleven postmenopausal breast cancer survivors (BCS, 52 ± 5 years, BMI 26.8 ± 2.1 kg·m2, n = 11) participated in the study. Before and after the RET program, evaluations were performed on quadriceps muscle thickness, one-repetition maximum strength (1RM) for various exercises, grip strength, and physical performance. Results Both groups showed significant improvements in quadriceps muscle thickness (time effect, P < 0.001); 1RM strength for leg extension, leg press, chest press, horizontal row, and elbow extension (time effect, all P < 0.001); as well as handgrip strength (time effect, P = 0.035) and physical performance (time effect, all P < 0.001) after the 12-week RET program. There were no significant differences between the groups in response to RET for any of the outcomes measured. Conclusion Twelve weeks of RET significantly increases skeletal muscle mass, strength, and physical performance in postmenopausal women. No differences were observed between healthy postmenopausal women and postmenopausal breast cancer survivors. These findings point out that this study’s RET promotes skeletal muscle mass, strength, and performance gains regardless of breast cancer. Pre-Print Platform Research Square: https://doi.org/10.21203/rs.3.rs-4145715/v1; https://www.researchsquare.com/article/rs-4145715/v1 Clinical trial registration: NCT05690295.
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    EP400NL is involved in PD-L1 gene activation by forming a transcriptional coactivator complex
    (Elsevier B V, 2023-03) Li Z; Kim H; Kim J; Park JH
    EP400 is an ATP-dependent chromatin remodelling enzyme that regulates DNA double-strand break repair and transcription, including cMyc-dependent gene expression. We previously showed that the N-terminal domain of EP400 increases the efficacy of chemotherapeutic drugs against cancer cells. As the EP400 N-terminal-Like (EP400NL) gene resides next to the EP400 gene locus, this prompted us to investigate whether EP400NL plays a similar role in transcriptional regulation to the full-length EP400 protein. We found that EP400NL forms a human NuA4-like chromatin remodelling complex that lacks both the TIP60 histone acetyltransferase and EP400 ATPase. However, this EP400NL complex displays H2A.Z deposition activity on a chromatin template comparable to the human NuA4 complex, suggesting another associated ATPase such as BRG1 or RuvBL1/RuvBL2 catalyses the reaction. We demonstrated that the transcriptional coactivator function of EP400NL is required for serum and IFNγ-induced PD-L1 gene activation. Furthermore, transcriptome analysis indicates that EP400NL contributes to cMyc-responsive mitochondrial biogenesis. Taken together, our studies show that EP400NL plays a role as a transcription coactivator of PD-L1 gene regulation and provides a potential target to modulate cMyc functions in cancer therapy.
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    Nanoengineered polymers and other organic materials in lung cancer treatment: Bridging the gap between research and clinical applications
    (Elsevier Ltd, 2024-03-25) Jin X; Heidari G; Hua Z; Lei Y; Huang J; Wu Z; Paiva-Santos AC; Guo Z; Karimi Male H; Neisiany RE; Sillanpää M; Prakash C; Wang X; Tan Y; Makvandi P; Xu Y
    Cancer remains a major global health challenge, with increasing incidence and mortality rates projected for the coming years. Lung cancer, in particular, poses significant obstacles due to late-stage diagnosis and limited treatment options. While advancements in molecular diagnostics have been made, there is a critical need to connect the dots between laboratory and hospital for better lung cancer treatment. Systemic therapy plays a crucial role in treating advanced-stage lung cancer, and recent efforts have focused on developing innovative drug delivery techniques. Nanoparticles (NPs) have emerged as a promising approach to lung cancer treatment, offering enhanced drug delivery, active targeting, and reduced toxicity. Organic-based nanomaterials, like polymeric nanoparticles, solid lipid nanoparticles, and liposomes hold great potential in this field. This review examines the application of NPs in lung cancer treatment, highlights current therapies, explores organic nanoparticle-based approaches, and discusses limitations and future perspectives in clinical translation.
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    Single cases from multiple perspectives: a qualitative study comparing the experiences of patients, patients’ caregivers, surgeons, and nurses when bad news is delivered about cancer
    (Wolters Kluwer Health Inc, 2020-10) Matthews T; Baken D; Ross K
    Background: Qualitative literature on the experiences of those delivering and receiving bad news about cancer has revealed what these parties consider important during the process across many different patient cases. The current study aims to add to this understanding by employing a “linked case" study design to directly compare the perspectives of patients, their caregivers, and health care professionals (HCPs) involved in a series of single-patient cases of breaking bad news. Method: Semistructured interviews were conducted with 13 participants (5 patients, 4 caregivers, 2 surgeons, and 2 nurses) who formed 5 linked cases. Interviews were analyzed using interpretative phenomenological analysis and directly compared within each linked case. Results: Analyses identified 2 main superordinate themes. The first labeled “accurately perceiving and responding to needs," included HCPs recognizing and responding to patients’ and caregivers’ individual emotional and informational needs. The second labeled “carers fulfilling necessary roles," identified the various roles HCPs and patients’ caregivers took to satisfactorily meet patients’ needs. Conclusions: The findings suggest the importance of HCPs accurately perceiving and responding to patients’ and caregivers’ various needs and caregivers ability and willingness to fulfilling support roles in a way that aligns with their own resources and patients’ needs. This highlights the value of HCPs developing and applying interpersonal skills within bad news encounters, working as a team, and exploring caregivers’ resources for patient support.
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    Microbiome and host immune responses in colorectal cancer development and radiotherapy response : a thesis presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Genetics at Massey University, Auckland, New Zealand
    (Massey University, 2022) Sulit, Arielle Kae
    Colorectal cancer (CRC) is a highly heterogeneous disease that manifests differently from patient to patient, making prognosis, management, and therapy more complex as no universal solution is available. With the advent of high throughput sequencing, descriptions of CRC tumors have moved from histopathological features and descriptions to molecular characterization, allowing for the subtyping of CRC into groups with similar characteristics. This inter-tumoral heterogeneity affects CRC development and patient response to treatments. Understanding the different mechanisms of CRC development and response to therapy is therefore crucial to personalized healthcare. The majority of CRC tumors do not have a familial background, suggesting the environment plays a large role in their development. Environmental factors include the microbiome, which has been shown previously to affect CRC development. However, the role of the microbiome has largely been overlooked in studies of the CRC subtyping and radiotherapy response in rectal cancer treatment. In this thesis, I show that bacteria in CRC may affect immune responses that drive CRC development in different subtypes, and radiotherapy response. I used RNA sequencing to revisit the consensus molecular subtypes (CMS) of CRCs and identified microbes that have possible contributions to their different characteristics. As microbes have been associated with differing responses to therapy, I also looked at their putative roles in radiotherapy response in a rectal cancer cohort. I first developed a computational pipeline that takes raw sequencing reads as input and yields host gene expression data, microbiome abundances and functional information. I then focused on two subtypes of CRC, CMS1 and CMS4. Analysis of host gene expression in these subtypes confirmed that their expression profiles are enriched in gene sets associated with immune responses. Analysis of the microbiome content found that lipopolysaccharides (LPS) from Fusobacterium periodonticum and Bacteroides fragilis in CMS1, and Porphyromonas asaccharolytica in CMS4 potentially affect the production of the immune infiltrates of their respective subtypes. F. periodonticum LPS enhanced cytokine production while LPS from the latter two bacteria suppressed cytokine production in peripheral blood mononuclear cells (PBMCs) in vitro. These data indicate possible roles of LPS from these microbes in CRC development via immune response. These also indicate possible roles of these molecules in CRC therapy. I also found that in complete responders of radiotherapy, there was an enrichment in host gene functions that are associated with complement activation, response to viruses, and B-cell activation, all of which indicated a link to immunotherapy responses triggered by radiotherapy. Furthermore, bacteria that had previous associations with immunotherapy responses were enriched in complete responders indicating a role in enhancement of these cytotoxic immune responses in radiosensitivity. Immune infiltrates have always been a crucial element in cancers, and the type of infiltrates can have conflicting effects on cancer development and therapeutic responses. In this work, I show that the types of bacterial molecules and how they interact between species can affect specific immune responses in CRC development, that dampening of immune responses in CRC is as crucial as inducing immunogenicity, and that specific bacteria also affect immune responses in a manner that may be similar to immunotherapy that will increase radiosensitivity. This work provides an initial look into mechanisms of how microbes interact with host immune responses affecting CRC development into two different subtypes, and radiosensitivity. It also provides initial experimental evidence for effects of LPS in CRC development and a possible mechanism of radiotherapy sensitivity to test in the laboratory.
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    Loss of HP1α alters nuclear integrity to promote cellular invasion : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry at Massey University, Manawatū, New Zealand
    (Massey University, 2019) Solomon, Raoul
    The onset of invasion is a key step towards the development of metastatic cancer. For a cell to invade through interstitial spaces in the tissue requires a reduction in nuclear rigidity as the cell needs to deform to squeeze through small spaces. Heterochromatin Protein 1α (HP1α) is a protein that defines domains of heterochromatin, the highly compact regions of the genome, and is essential for maintaining the appropriate patterns of gene expression and genome stability. Loss or reduction of HP1α has been correlated with an increase in invasive potential in human tumours. Using an established model of Drosophila melanogaster epithelial cell invasion, the causative role HP1α plays in suppressing cellular invasive is confirmed within an epithelial tissue microenvironment. This model also demonstrates that loss of the Drosophila melanogaster HP1 homologue synergistically promotes cellular invasion in conjunction with an activated malignant signalling pathway. Importantly, human HP1α is shown to rescue this highly invasive Drosophila phenotype and demonstrates the relevance of this model to human disease, and its use for exploring protein interactions in a cellular microenvironment. As loss of nuclear integrity has been linked to a reduction in peripheral heterochromatin, the biophysical mechanisms by which HP1α acts as a suppressor of invasive potential were explored in the poorly invasive MCF7 breast cancer cell line with constitutive HP1α knock-down. These cells with reduced HP1α expression had a significant loss of nuclear membrane integrity and stiffness. The underlying nuclear lamina meshwork and associated peripheral heterochromatin was disrupted. This was associated with an increased solubility of lamina proteins, particularly lamin A, as well as the altered localisation of a number of peripheral nuclear proteins. In summary, this work established the important contribution of HP1α to the mechanical integrity of the nucleoskeleton and the role HP1α plays in suppressing malignant signalling pathways that promote cell invasion.
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    Biophysical and biochemical characterisation of DNA-based inhibitors of the cytosine-mutating APOBEC3 enzymes : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Palmerston North, New Zealand
    (Massey University, 2020) Barzak, Fareeda Maged Yahya Mohammad
    With the rise of antiviral and anticancer drug resistance, a new approach must be taken to overcome this burden. The APOBEC3 (A3) family of cytosine deaminases hypermutate cytosines to uracils in single-stranded DNA (ssDNA). These enzymes act as double-edged swords: on one side they protect humans against a range of retroviruses and other pathogens, but several A3s are exploited by viruses and cancer cells to increase their rate of evolution using the enzyme’s mutagenic actions. This latter mode permits escape of cancer cells from the adaptive immune response and leads to the development of drug resistance. In particular, APOBEC3B (A3B) is considered to be a main driving source of genomic mutations in cancer cells. Inhibition of A3B, while retaining the beneficial actions of the other A3 in the immune system, may be used to augment existing anticancer therapies. In this study, we showed for the first time that short ssDNAs containing cytosine analogue nucleosides, 2'-deoxyzebularine (dZ) or 5-fluoro-2'-deoxyzebularine (5FdZ) in place of the substrate 2'-deoxycytidine (dC) in the preferred 5'-TC motif, inhibit the catalytic activity of A3B. However, as most A3 enzymes (except A3G) prefer to deaminate ssDNA with a 5'-TC motif, selective A3B inhibition was uncertain. We noted that nucleotides adjacent to the 5'-CCC motif influence the dC deamination preference of A3A, A3B, and A3G’s. Replacement of the A3B’s preferred dC in the 5'-CCC motif with dZ (5'-dZCC) led to the first selective inhibitor of A3B, in preference to A3A and A3G. Furthermore, using small-angle X-ray scattering (SAXS) we obtained the first model of a full-length two-domain A3 in complex with a dZ-ssDNA inhibitor. Our model showed that the ssDNA was largely bound to the C-terminal domain (CTD) with limited contact to the N-terminal domain in solution, due to the high affinity of the dZ for the CTD active-site. Our work provides a new platform for use of ssDNA-based inhibitors in targeting the mutagenic action of the A3B. Further developments using more potent inhibitors will help to achieve inhibition in cellular studies, with the ultimate goal to complement anti-cancer and antiviral treatments.
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    The psychosocial interactions of adolescent and young adult (AYA) cancer survivors and the possible relationship with their development : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Clinical Psychology at Massey University, Palmerston North, New Zealand
    (Massey University, 2019) Cameron, Nicole
    Adolescents and Young Adults (AYAs) with cancer may be particularly affected by social interactions, as they can be grappling with both a serious illness and normal developmental challenges. The present research aims to increase the understanding of the psychosocial interactions of AYAs with cancer and how these interactions can be grouped and organised in relation to each other. Furthermore, this research hopes to examine the relationship that cancer has with the developmental trajectory of this population, and how social interactions influence this relationship. As development is an important aspect of this age group, it is appropriate to consider both psychosocial interactions and the development of AYA survivors. Qualitative interviews asked ten participants (aged 16-25 years) to describe their psychosocial interactions and examined how these might affect their development. Thematic analysis identified a range of themes including: the importance of personal privacy and controlled sharing of information, independence, identity formation, positivity, acknowledgement of cancer vs. being treated normally, and receiving support instead of supporting others. In the one year follow-up interviews with five participants, half of these themes remained constant; however the personal privacy, independence and supporting others themes changed. Development appeared to be impacted by cancer for both adolescents and young adults, but this impact lessened over a one-year period. A quantitative study followed, which involved asking thirty AYAs to sort psychosocial interactions using a GOPA card-sort process, resulting in a multidimensional model of interactions. Interactions were derived from a combination of the aforementioned interviews, and a similar model completed for an Honours thesis. This model showed that AYAs conceptualise interactions in two main ways: through their perception of emotional response (avoidance/discomfort interactions opposed support interactions) and empathy (empathic actions/encouragement interactions opposed thoughtlessness interactions). Unfortunately the sample size was too small to complete two separate models comparing age differences, and therefore an understanding of developmental disparities in conceptualising interactions was unable to occur. Overall, social interactions and developmental stage appear to influence AYAs’ experience of cancer. Together, these two studies provide an understanding of how AYAs in New Zealand experience and perceive psychosocial interactions. Furthermore, there is an enhanced understanding of the developmental impact that cancer has on AYAs’ interactions. This research proudly contributes to the body of knowledge on AYAs in New Zealand, their psychosocial needs and the way cancer impacts on their development.
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    Breaking bad news about cancer : the experiences of patients, patients' family/whānau members and healthcare professionals : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Clinical Psychology at Massey University, Wellington, New Zealand
    (Massey University, 2020) Matthews, Tamyra
    Breaking bad news is a reality of medical practice in oncology, and can be a challenging task for those receiving and delivering the news. For patients and their family members, ‘bad news’ is understandably accompanied by strong emotions and ongoing implications for their lives as they adjust to the news. For healthcare professionals (HCPs), there are numerous variables to consider and balance when having these difficult conversations, as well as managing the personal impact. The current study aims to explore the subjective experiences of patients, patients’ family/whānau members, and HCPs when bad news was delivered to patients about their cancer within the surgical departments of MidCentral District Health Board. The study is designed to allow multiple perspectives to be gathered and compared, and recommendations for practice to be made that align with the goals of those involved in the project’s inception, as well as attend to the underrepresentation of family members’ perspectives and New Zealand-based data in the literature. To achieve this, the current study utilised a qualitative approach with the epistemological and methodological basis informed by interpretative phenomenological analysis. The study also included a consumer perspective with the involvement of the Otaki advisory group to guide how the study was conducted and provide feedback on the study outcomes. Data was collected through semi-structured interviews with 10 patients, 6 family/whānau members, 5 surgeons, and 6 nurses. Interviews were analysed in two ways: by participant group (i.e., patients, family members, and HCPs) and by ‘linked case’ (i.e., direct comparisons of the perspectives of all those involved in the same patient’s case of breaking bad news). The findings are presented as a series of superordinate and subordinate themes. The group-based analysis highlighted that patients understood their bad news experiences through the lens of their health beliefs and expectations of care, the relational and support needs they, and others, had during and following the encounter, and the ongoing shifts in perspective and priorities they experienced. Family members identified the patient as the focus of care, but also acknowledged their need for support in order to cope. HCPs recognised that breaking bad news was challenging based on the variation between instances of breaking bad news and patients’ needs, organisational constraints they had to work under, and the personal toll this task could take. The linked case-based analysis demonstrated that the receivers of bad news have a range of emotional and informational needs and that HCPs and family members fulfil important roles in accurately meeting patients’ needs. Four conclusions can be drawn from the study as a whole about the process of breaking bad news. Firstly, there is variability in the situations, delivery approaches and needs of those involved in breaking bad news, requiring a flexible and tailored approach. Secondly, establishing an interpersonal connection between the deliverer and receiver of bad news is a central part of the process. Thirdly, breaking bad news is a challenge for all and receiving support in order to cope, is paramount. Lastly, there is a shared responsibility across healthcare organisations, training providers, HCP teams, and individual HCPs to make this process go as well as possible for all those involved. The current research makes an important contribution to understanding that, without doubt, breaking bad news is a complex process for those delivering and receiving the news, and improvements in this area require careful consideration, prioritising and resourcing as part of delivering effective cancer care.
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    Molecular dynamics simulation of inter-molecular interactions : a thesis submitted to Massey University in Albany, Auckland in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Computational Biochemistry
    (Massey University, 2019) Shadfar, Shamim Zahra
    Many aspects of the operation of chemical and biological systems are based on intermolecular interactions. In this work, binding modes and interactions between molecules at a range of scales have been studied, using molecular dynamics (MD) simulations. The first chapter provides an introduction of each of the different chemical and biological systems that are studied in this work. It also introduces MD and its role in the context of this research. The second chapter corresponds to the study of host-guest interactions for cyclodextrin- bullvalene complexes. Bullvalene is a shapeshifter molecule, which interconverts between different isomers at room temperature. The goal of this chapter is to capture one favourable isomer of bullvalene (guest molecule) by binding it to cyclodextrin as a host molecule. This chapter consists of two smaller chapters (2i and 2ii). The former details the development and validation of a “host-guest binding potential energy profiling” (HGBPEP) method, which is a rotational interaction energy screening method designed for prediction of the most favourable orientation and position of bullvalene isomers with respect to cyclodextrin. The latter investigates the interaction of bullvalene isomers and cyclodextrin molecules, and finally binding free energy values of the complexes are calculated. The third chapter describes KstR, a transcriptional repressor in Mycobacteria. KstR is required for Mycobacterium tuberculosis (Mtb) pathogenesis as well as regulating the initial steps in cholesterol degradation by controlling the expression of the enzymes that carry out the early stages of cholesterol catabolism. Therefore, this protein is of great interest for development of new tuberculosis treatments. In this chapter, the stability and conformational changes of KstR in its different states – apo, DNA-bound and ligand-bound –have been studied. The main goal is to investigate the binding mechanism of KstR to DNA, as well as the effect of DNA and ligand binding on the structure and dynamics of KstR more generally, using MD simulations. In the fourth chapter, KstR2, another Mtb transcriptional repressor, is studied. KstR2 represses a 14-gene regulon involved in the later steps of cholesterol degradation. It is structurally similar to KstR, but has been proposed to act through a novel scissor-like mechanism. This chapter investigates two key questions regarding the mechanism of action of KstR2: first, the effect of mutating the key switch residue ARG170 to ALA, and second, the effect of ligand binding on its structure and motion. The focus of the fifth and final chapter is phosphatidylinositide 3-kinases (PI3Ks), which are proteins that take part in signalling pathways regulating factors like cell growth, survival and proliferation, which in turn are involved in cancer. The interaction between PI3Kα and another protein, RAS, is very important in the formation, growth and maintenance of RAS- driven tumours. A model of PI3Kα (class IA PI3K) has therefore been built, as well as of RAS associated with a model cell membrane, and MD simulations used to investigate the process by which the two proteins interact with one another and with the lipid bilayer. Altogether, this thesis uses MD simulations to provide insight into intermolecular interactions at a range of scales, with a particular focus on proteins involved in tuberculosis and in cancer.