Publications by authors named "Craig Harris"

Article Synopsis
  • Patients undergoing elective pelvic exenteration surgery are at risk of getting inadequate concentrations of the antibiotics piperacillin and tazobactam during surgery.
  • This study aimed to analyze how these antibiotics are processed in the body (pharmacokinetics) and to find better dosing recommendations to ensure effective levels during surgery.
  • Results showed that a lower continuous infusion dosage of piperacillin/tazobactam is effective in maintaining proper antibiotic levels, but patients with higher weights and kidney function might need higher doses to avoid suboptimal exposure.
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Article Synopsis
  • Pelvic exenteration for rectal cancer is a complex surgical procedure aimed at achieving complete cancer removal, but access to this service is limited in Queensland.
  • A study reviewed data from 176 patients referred to the Royal Brisbane and Women's Hospital between 2009 and 2023, revealing that more patients from major cities underwent surgery compared to those from regional areas.
  • Findings suggest that many patients in remote areas chose not to proceed with surgery, highlighting the need for better awareness of the pelvic exenteration service to improve patient access and care.
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Background & Aims: Pelvic exenteration (PE) surgery is now a widely accepted procedure that is increasingly being performed worldwide but has significant morbidity. Although nutrition status, body mass index (BMI) and postoperative nutrition support practices are modifiable risk factors, few studies have examined the relationship of these with clinical outcomes following PE. The aim of this study was therefore to investigate the impact of these factors on postoperative complications and length of hospital stay (LOHS) following PE.

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A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed.

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Introduction: Historically, surgical resection for patients with locally recurrent rectal cancer (LRRC) had been reserved for those without metastatic disease. 'Selective' patients with limited oligometastatic disease (OMD) (involving the liver and/or lung) are now increasingly being considered for resection, with favourable five-year survival rates.

Methods: A retrospective analysis of consecutive patients undergoing multi-visceral pelvic resection of LRRC with their oligometastatic disease between 1 January 2015 and 31 August 2021 across four centres worldwide was performed.

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Tetralysal® is a Galderma oral drug product (DP) marketed for the treatment of acne. Tetralysal® is sold in capsules containing either 150 mg or 300 mg of the drug substance. In the British Pharmacopoeia monograph for Lymecycline Capsules, the impurities already specified in the drug substance (A-G), visible in the European Pharmacopoeia 〈1654〉, are also specified together with an unidentified impurity at RRT 1.

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Valproic acid (VPA) is an anti-epileptic medication that increases the risk of neural tube defect (NTD) outcomes in infants exposed during gestation. Previous studies into VPA's mechanism of action have focused on alterations in gene expression and metabolism but have failed to consider how exposure changes the abundance of critical developmental proteins over time. This study evaluates the effects of VPA on protein abundance in the developmentally distinct tissues of the mouse visceral yolk sac (VYS) and embryo proper (EMB) using mouse whole embryo culture.

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Lymecycline is the drug substance (DS) used in the Galderma drug product Tetralysal® capsules with 7 impurities currently described in the pharmacopeia labelled as A-G. In the current monograph, the structural identity of all impurities except E and F have been formally identified. In this manuscript, through both formal synthesis and preparative chromatography, we are the first group to confirm the structural identity, response factor of Impurity F and conditions which exacerbate the formation of both impurities.

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Background: Anastomotic leak (AL) is the anathema of colorectal surgery. Early diagnosis is an essential segue to early intervention. A temporary diverting ileostomy (TDI) does not prevent an AL and presents inherent complications of its own.

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Valproic acid (VPA) is a widely prescribed medication that has traditionally been used to treat epilepsy, yet embryonic exposure to VPA increases the risk of the fetus developing neural tube defects (NTDs). While the mechanism by which VPA causes NTDs is unknown, we hypothesize that VPA causes dysmorphogenesis through the disruption of redox-sensitive signaling pathways that are critical for proper embryonic development, and that protection from the redox disruption may decrease the prevalence of NTDs. Time-bred CD-1 mice were treated with 3H-1,2-dithiole-3-thione (D3T), an inducer of nuclear factor erythroid 2-related factor 2 (NRF2)-a transcription factor that activates the intracellular antioxidant response to prevent redox disruptions.

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Redox regulation during metazoan development ensures that coordinated metabolic reprogramming and developmental signaling are orchestrated with high fidelity in the hypoxic embryonic environment. Valproic acid (VPA), an anti-seizure medication, is known to increase markers of oxidation and also increase the risk of neural tube defects (NTDs) when taken during pregnancy. It is unknown, however, whether oxidation plays a direct role in failed neural tube closure (NTC).

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In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library.

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Purpose: Anastomotic leakage (AL) is the anathema of colorectal surgery. Its occurrence leads to increased morbidity and mortality and a prolonged hospital stay. Much work has gone into studying various biomarkers in drain fluid to facilitate early detection of AL.

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Article Synopsis
  • The SUDEP and Seizure Safety Checklist helps understand the risks for people with epilepsy by looking at their different problems and lifestyles.
  • The study looked at people with epilepsy in two different types of healthcare: primary care (like regular doctor visits) and secondary care (more specialized treatment).
  • Results showed that while people in secondary care had higher overall risks, those in primary care had more things they could change, like mental health concerns, indicating that there are differences in how risks are managed in each setting.
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Significant gaps exist in our knowledge of how cellular redox status, sometimes referred to as oxidative stress, impacts placental trophoblasts. The present study used tert-butyl hydroperoxide (TBHP) as a known generator of reactive oxygen species (ROS) in the extravillous trophoblast cell line HTR-8/SVneo to examine the role of cellular redox disruption of prostaglandin E (PGE) and the cytokine IL-6 in cell death. Cells were exposed to 0, 12.

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Dynamic covalent hydrogels crosslinked by boronate ester bonds are promising materials for biomedical applications. However, little is known about the impact of the crosslink structure on the mechanical behaviour of the resulting network. Herein, we provide a mechanistic study on boronate ester crosslinking upon mixing hyaluronic acid (HA) backbones modified, on the one hand, with two different arylboronic acids, and on the other hand, with three different saccharide units.

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The hypothesis that in utero exposures to low levels of trichloroethylene (TCE) may increase the risk of congenital heart defects (CHDs) in offspring remains a subject of substantial controversy within the scientific community due primarily to the reliance on an inconsistent and unreproducible experimental study in rats. To build on previous assessments that have primarily focused on epidemiological and experimental animal studies in developing conclusions, the objective of the current study is to conduct a systematic evaluation of mechanistic data related to in utero exposures to TCE and the development of CHDs. The evidence base was heterogeneous; 79 mechanistic datasets were identified, characterizing endpoints which ranged from molecular to organismal responses in seven species, involving both in vivo and in vitro study designs in mammalian and non-mammalian models.

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The geological record shows that as atmospheric O levels increased, it concomitantly coincided with the evolution of metazoans. More complex, higher organisms contain a more cysteine-rich proteome, potentially as a means to regulate homeostatic responses in a more O-rich environment. Regulation of redox-sensitive processes to control development is likely to be evolutionarily conserved.

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Minor structural modifications-sometimes single atom changes-can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.

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We demonstrate here, for the first time, formation of injectable dynamic covalent hydrogels at physiological pH using benzoxaborin-saccharide complexation as a reversible cross-linking method. The gels were prepared by simply mixing hyaluronic acid modified with an original boronic acid derivative, 3,4-dihydro-2-benzo[][1,2]oxaborinin-2-ol (1,2-ABORIN), and HA functionalized with 1-amino-1-deoxy-d-fructose. Dynamic rheological experiments confirmed the gel-like behavior (storage modulus (') > loss modulus (″) in the frequency window explored) for the designed HA-1,2-ABORIN/HA-fructose network.

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Histiotrophic nutrition is a process whereby the rodent visceral yolk sac (VYS) internalizes exogenous macromolecules, degrades them, and sends the degradation products to the embryo. Quantification and visualization of histiotrophic nutrition can be accomplished using fluorescent tracer molecules such as fluorescein isothiocyanate-conjugated albumin (FITC-albumin). The methods are simple and can provide complimentary functional and structural information in studies of the effects of embryotoxicants on visceral yolk sac function.

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Rat Whole Embryo Culture.

Methods Mol Biol

November 2019

The direct effects of chemical exposures, environmental extremes, and nutrient quality/quantity have been very difficult to study in mammalian embryos due to their anatomical inaccessibility, paucity of tissue, and other factors that make human studies unethical. Many acute and chronic developmental anomalies can trace their origins to postimplantation phases of gestation, where the organs are first being established and growth and differentiation are in highly active states of flux. Most chemical insults and conditions that produce birth defects are believed to act during this period of organogenesis.

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Article Synopsis
  • White adipose tissue (WAT) is crucial in understanding obesity, and its redox signaling hasn't been fully explored, particularly regarding the thiol redox environment.
  • Research measured thiol redox parameters in various WAT depots, finding more oxidizing redox states in gonadal and subinguinal WAT compared to mesenteric WAT, with variations based on sex, age, and body weight.
  • A follow-up mouse study revealed that early exposure to bisphenol A and different high-fat diets significantly affected the thiol redox environment in mesenteric WAT, especially in females, suggesting developmental exposures could influence long-term obesity risk.
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