Thermo-responsive Block Copolymers Decorated with Guanosine for the Delivery of Gemcitabine

Pancreatic cancer is an aggressive and debilitating human cancer. Due to lack of symptoms and limited diagnostic methods, once diagnosed, the chance for survival is ominous. Gemcitabine has been studied extensively in a variety of tumours and has been found to be effective as a single agent in the treatment of pancreatic cancer. Gemcitabine is a nucleoside analogue of deoxycytidine. Nucleoside antimetabolites have long been the most successful class of anticancer drugs, due to their optimised structures. They are engineered and designed specifically to target DNA synthesis. Nucleosides are known to form complementary hydrogen bonds between base pairs, in this case guanosine. The interaction with guanosine was identified as a potential method of encapsulating gemcitabine. A biocompatible, thermo-responsive polymer was successfully synthesised by using a copolymer with NiPAAm. RAFT, a controlled living radical polymerisation technique pioneered in Australia, was used to produce moderately narrow polydispersed polymers. The polymer properties were subsequently investigated. Solution properties demonstrated self-assembly at near physiological temperature 33°C. Cytotoxicity testing revealed the polymer to be biocompatible and the gemcitabine loaded polymer had improved toxicity than the current administered form. The loading capacity for the micelle was low however, this has set an impetus to improve

Analytic Pontryagin Duality

Let X be a smooth compact manifold. We propose a geometric model for the group K⁰(X,R/Z): We study a well-defined and non-degenerate analytic duality pairing between K⁰(X,R/Z) and its Pontryagin dual group, the Baum-Douglas geometric K-homology K₀(X); whose pairing formula comprises of an analytic term involving the Dai-Zhang eta-invariant associated to a twisted Dirac-type operator and a topological term involving a differential form and some characteristic forms. This yields a robust R/Z-valued invariant. We also study two special cases of the analytic pairing of this form in the cohomology groups H¹(X,R/Z) and H²(X,R/Z):Thesis (Ph.D.) -- University of Adelaide, School of Mathematical Sciences, 201

Some Results On Spectrum And Energy Of Graphs With Loops

Let $G_S$ be a graph with loops obtained from a graph $G$ of order $n$ and loops at $S \subseteq V(G)$. In this paper, we establish a neccesary and sufficient condition on the bipartititeness of a connected graph $G$ and the spectrum Spec($G_S$) and Spec($G_{V(G)\backslash S}$). We also prove that for every $S \subseteq V(G)$, $E(G_S) \geq E(G)$ when $G$ is bipartite. Moreover, we provide an identification of the spectrum of complete graphs $K_n$ and complete bipartite graphs $K_{m,n}$ with loops. We characterize any graphs with loops of order n whose eigenvalues are all positive or non-negative, and also any graphs with a few distinct eigenvalues. Finally, we provide some bounds related to $G_S$.Comment: 16 pages, published versio

Testing the Concept of Mitigating Urban Flooding with Permeable Road: Case Study of Tong Wei Tah Street, Kuching City, Sarawak, Malaysia

This paper describes the investigation of permeable road as a mitigation measure for urban flooding. The study involves the reconstruction of a historical case of inundation, namely the 11 December 2019 flood event along the Tong Wei Tah Street in Greater Kuching City, Sarawak, Malaysia. The Storm Water Management Model version 5.0 was used as the platform to describe the flooding at the selected site and the functionality of permeable road to alleviate flooding. A permeable road with a dimension of 200 m long, 6 m wide and 1 m deep was used to simulate runoff after a structure was installed along the whole stretch of Tong Wei Tah Street. The model results show that flooding was caused by a backwater effect in the drainage system. Models predicted 0.1 to 0.5 m flood depths which matched the observed 0.3 m flood depth account of a local resident. The permeable road exhibited capability to absorb all the out-of-drain floodwaters, leaving no water due to the 11 December 2019 flood on the street. Modelling efforts demonstrated that the floodwater hydrographs in the drain rose and fell within 7 hours, while the underground storage, filled and drained within 13 hours. Moreover, the storage of permeable road was found to fill up to 75%, reserving the unfilled 25% for adverse weathers

Incidence and outcomes of delayed presentation and surgery in peritoneal surface malignancies

BackgroundPeritoneal surface malignancies (PSM) present insidiously and often pose diagnostic challenges. There is a paucity of literature quantifying the frequency and extent of therapeutic delays in PSM and its impact on oncological outcomes.MethodsA review of a prospectively maintained registry of PSM patients undergoing Cytoreductive Surgery and Hyperthermic Intra-peritoneal Chemotherapy (CRS-HIPEC) was conducted. Causes for treatment delays were identified. We evaluate the impact of delayed presentation and treatment delays on oncological outcomes using Cox proportional hazards models.Results319 patients underwent CRS-HIPEC over a 6-years duration. 58 patients were eventually included in this study. Mean duration between symptom onset and CRS-HIPEC was 186.0 ± 37.1 days (range 18-1494 days) and mean duration of between patient-reported symptom onset and initial presentation was 56.7 ± 16.8 days. Delayed presentation (> 60 days between symptom onset and presentation) was seen in 20.7% (n=12) of patients and 50.0% (n=29) experienced a significant treatment delay of > 90 days between 1st presentation and CRS-HIPEC. Common causes for treatment delays were healthcare provider-related i.e. delayed or inappropriate referrals (43.1%) and delayed presentation to care (31.0%). Delayed presentation was a significantly associated with poorer disease free survival (DFS) (HR 4.67, 95% CI 1.11-19.69, p=0.036).ConclusionDelayed presentation and treatment delays are common and may have an impact on oncological outcomes. There is an urgent need to improve patient education and streamline healthcare delivery processes in the management of PSM

Diagnostic tools for soil-transmitted helminths control and elimination programs: A pathway for diagnostic product development.

<p>Diagnostic tools for soil-transmitted helminths control and elimination programs: A pathway for diagnostic product development</p

A comprehensive framework for prioritizing variants in exome sequencing studies of Mendelian diseases

Exome sequencing strategy is promising for finding novel mutations of human monogenic disorders. However, pinpointing the casual mutation in a small number of samples is still a big challenge. Here, we propose a three-level filtration and prioritization framework to identify the casual mutation(s) in exome sequencing studies. This efficient and comprehensive framework successfully narrowed down whole exome variants to very small numbers of candidate variants in the proof-of-concept examples. The proposed framework, implemented in a user-friendly software package, named KGGSeq (http://statgenpro.psychiatry.hku.hk/kggseq), will play a very useful role in exome sequencing-based discovery of human Mendelian disease genes

Bridges of hope

This study explores the stories of students who had stopped formal schooling and experienced being in the Alternative Learning System (ALS), which is another form of education that is not commonly taken, for those who want to get back into the educational system. Using Narrative Inquiry, specifically Labov and Waletzky’s six-part narrative analysis for the construction (The Abstract, Orientation, Complicating Action, Evaluation, Resolution, and Coda), seven (7) informants were interviewed about their stories and experiences throughout the entirety of their academic pursuit with ALS. Five (5) main plots emerged from the interviews, namely: (a) “The Wanderer’s Quandary”; (b) “The Fork at the End of the Road”; (c) “The Path Less Traveled”; (d) “The Unceasing River”; and (e) “The Open Field.” Each main plot has corresponding subplots for each informant. The findings revealed that the experience of being an ALS student is not easy. Being in a different form of education, different from what society usually pursues, comes stigma. Strong will and perseverance had lead these people to go through with ALS. It became their bridge of hope to a second chance towards their pursuit through education

ICP curve morphology and intracranial flow-volume changes: a simultaneous ICP and cine phase contrast MRI study in humans

Background: The intracranial pressure (ICP) curve with its different peaks has been extensively studied, but the exact physiological mechanisms behind its morphology are still not fully understood. Both intracranial volume change (ΔICV) and transmission of the arterial blood pressure have been proposed to shape the ICP curve. This study tested the hypothesis that the ICP curve correlates to intracranial volume changes. Methods: Cine phase contrast magnetic resonance imaging (MRI) examinations were performed in neuro-intensive care patients with simultaneous ICP monitoring. The MRI was set to examine cerebral arterial inflow and venous cerebral outflow as well as flow of cerebrospinal fluid over the foramen magnum. The difference in total flow into and out from the cranial cavity (Flowtot) over time provides the ΔICV. The ICP curve was compared to the Flowtot and the ΔICV. Correlations were calculated through linear and logarithmic regression. Student’s t test was used to test the null hypothesis between paired samples. Results: Excluding the initial ICP wave, P1, the mean R2 for the correlation between the ΔICV and the ICP was 0.75 for the exponential expression, which had a higher correlation than the linear (p = 0.005). The first ICP peaks correlated to the initial peaks of Flowtot with a mean R2 = 0.88. Conclusion: The first part, or the P1, of the ICP curve seems to be created by the first rapid net inflow seen in Flowtot while the rest of the ICP curve seem to correlate to the ΔICV

Efficacious Intermittent Dosing of a Novel JAK2 Inhibitor in Mouse Models of Polycythemia Vera

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients