Lessons learned during the journey of data: from experiment to model for predicting kinase affinity, selectivity, polypharmacology, and resistance.

Recent advances in machine learning (ML) are reshaping drug discovery. Structure-based ML methods use physically-inspired models to predict binding affinities from protein:ligand complexes. These methods promise to enable the integration of data for many related targets, which addresses issues related to data scarcity for single targets and could enable generalizable predictions for a broad range of targets, including mutants.

Pose, duplicate, then elaborate: Steps towards increased affinity for inhibitors targeting the specificity surface of the Pim-1 kinase.

In this study, fragment-sized hits binding to Pim-1 kinase with initially modest affinity were further optimized by combining computational, synthetic and crystallographic expertise, eventually resulting in potent ligands with affinities in the nanomolar range that address rarely-targeted regions of Pim-1 kinase. Starting from a set of crystallographically validated, chemically distinct fragments that bind to Pim-1 kinase but lack typical nucleotide mimetic structures, a library of extended fragments was built by exhaustive in silico reactions. After docking, minimization, clustering, visual inspection of the top-ranked compounds, and evaluation of ease of synthetic accessibility, either the original compound or a close derivative was synthesized and tested against Pim-1.

TeachOpenCADD 2022: open source and FAIR Python pipelines to assist in structural bioinformatics and cheminformatics research.

Computational pipelines have become a crucial part of modern drug discovery campaigns. Setting up and maintaining such pipelines, however, can be challenging and time-consuming-especially for novice scientists in this domain. TeachOpenCADD is a platform that aims to teach domain-specific skills and to provide pipeline templates as starting points for research projects.

Structure and Thermodynamics of Eu(III) and Cm(III) Complexes with Glucuronic Acid.

Complexation by small organic ligands controls the bioavailability of contaminants and influences their mobility in the geosphere. We have studied the interactions of Cm, as a representative of the trivalent actinides, and Eu, as an inactive homologue, with glucuronic acid (GlcA) a simple sugar acid. Time-resolved laser-induced luminescence spectroscopy (TRLFS) shows that complexation at pH 5.

Investigation of the structure and dynamics of gallium binding to high-affinity peptides elucidated by multi-scale simulation, quantum chemistry, NMR and ITC.

Gallium (as Ga) is a Group IIIa metal and its recovery from wastewaters has become increasingly important for its reuse. The use of peptides for recycling offers a low-cost and environmentally-friendly option but the structural characteristics of peptides likely to bind Ga are largely unknown. Multiple computational methods, coupled with experimental verification via NMR and Isothermal Calorimetry (ITC), were used to establish that Ga binds with high affinity to peptide sequences and to elucidate the structural characteristics that contributed.

Gallium-binding peptides as a tool for the sustainable treatment of industrial waste streams.

Here we provide a proof of principle for an application-oriented concept for the peptide-based recovery of gallium in industrial wastewater, which was supported by biosorption studies with a real wastewater sample. We investigated the interaction of the gallium-binding peptides TMHHAAIAHPPH, NYLPHQSSSPSR, SQALSTSRQDLR, HTQHIQSDDHLA, and NDLQRHRLTAGP with gallium and arsenic through different experimental and computational approaches. Data obtained from isothermal titration microcalorimetry indicated a competitive influence by the presence of acetate ions with an exothermic contribution to the otherwise endothermic peptide gallium interactions.

Two eARCHT3.0 Lines for Optogenetic Silencing of Dopaminergic and Serotonergic Neurons.

Dopaminergic and serotonergic neurons modulate and control processes ranging from reward signaling to regulation of motor outputs. Further, dysfunction of these neurons is involved in both degenerative and psychiatric disorders. Elucidating the roles of these neurons has been greatly facilitated by bacterial artificial chromosome (BAC) transgenic mouse lines expressing channelrhodopsin to readily enable cell-type specific activation.

Postural Preference and Musculoskeletal Complaints in Oral and Maxillofacial Surgeons.

Purpose: Oral and maxillofacial surgeons traditionally have musculoskeletal pain. The aim of this study was to determine the postural preferences of oral and maxillofacial surgeons and their effect on musculoskeletal pain.

Materials And Methods: The authors designed and implemented a cross-sectional study.

Breast cancer characteristics and survival differences between Maori, Pacific and other New Zealand women included in the Quality Audit program of Breast Surgeons of Australia and New Zealand.

Background: The Quality Audit (BQA) program of the Breast Surgeons of Australia and New Zealand (NZ) collects data on early female breast cancer and its treatment. BQA data covered approximately half all early breast cancers diagnosed in NZ during roll-out of the BQA program in 1998-2010. Coverage increased progressively to about 80% by 2008.

Breast cancer survival in New Zealand women.

Background: The Quality Audit (BQA) of Breast Surgeons of Australia and New Zealand includes a broad range of data and is the largest New Zealand (NZ) breast cancer (BC) database outside the NZ Cancer Registry. We used BQA data to compare BC survival by ethnicity, deprivation, remoteness, clinical characteristic and case load.

Methods: BQA and death data were linked using the National Health Index.

Analysing risk factors for poorer breast cancer outcomes in residents of lower socioeconomic areas of Australia.

Objective: To investigate patient, cancer and treatment factors associated with the residence of female breast cancer patients in lower socioeconomic areas of Australia to better understand factors that may contribute to their poorer cancer outcomes.

Methods: Bivariable and multivariable analyses were performed using the Breast Quality Audit database of Breast Surgeons of Australia and New Zealand. RESULTS Multivariable regression indicated that patients from lower socioeconomic areas are more likely to live in more remote areas and to be treated at regional than major city centres.

Impact of geographic location on surgical outcomes of women with breast cancer.

Background: The aim of this study is to use the Breast Surgeons of Australia and New Zealand Quality Audit to evaluate the diagnostic work up and surgical treatment path for Australian women with early breast cancer in relation to geographic location.

Methods: We accessed data on patient geographic demographics, diagnostic and surgical procedures and cancer characteristics in 115,872 episodes of early breast cancer reported to the Quality Audit between 1998 and 2012. Tumour size, grade and number, lymph node positivity and lymphovascular invasion are the major prognostic factors adjusted for.

Initial axillary surgery: results from the BreastSurgANZ Quality Audit.

Background: The aim of this study was to establish the preference and reasons for initial axillary surgery performed on women with invasive breast cancer in Australia and New Zealand using data from the Breast Surgeon's Society of Australia and New Zealand Quality Audit (BQA) according to whether sentinel lymph node (SLN) biopsy, axillary lymph node dissection (ALND) or no axillary surgery was used.

Methods: Patient data from 1999 to 2011 were categorized according to primary tumour size (≤3 cm or >3 cm) and analysed by year of diagnosis, type of initial axillary surgery and frequency of second axillary surgery following SLN biopsy. Patient age at diagnosis, health insurance status, surgeon caseload and hospital location were also examined as factors affecting the likelihood of performing different types of axillary surgery.

Surgical treatment for women with breast cancer in relation to socioeconomic and insurance status.

Based on the National Breast Cancer Audit of the Royal Australasian College of Surgeons an association between patient age and type of breast cancer surgery received has already been demonstrated. The aim of this study is to assess the patterns of surgical treatment for women with early breast cancer in relation to socioeconomic and insurance status. Data on patient demographics, diagnostic, and surgical procedures and cancer characteristics in 115,872 episodes of early breast cancer reported to the National Breast Cancer Audit between 1998 and 2012 is used for this study.

Subsequent axillary surgery after sentinel lymph node biopsy: results from the BreastSurgANZ Quality Audit 2006-2010.

Objectives: To use data from the BreastSurgANZ Quality Audit (BQA) to examine the patterns of completion axillary lymph node dissection (cALND) after sentinel lymph node (SLN) biopsy in women treated for early breast cancer in Australia and New Zealand and to compare it to the Australian and New Zealand guidelines in cases of both positive and negative SLN results.

Materials And Methods: Patients were sub grouped as having primary tumours ≤3 cm and >3 cm and further analysed according to year of surgery, SLN status and final nodal status where cALND was recorded. Multivariate analysis was performed examining tumour size, grade, presence of lymphovascular invasion (LVI), HER2 and oestrogen receptor status, patient age and number of positive sentinel nodes as predictors for subsequent axillary surgery.

Risk factors for poorer breast cancer outcomes in residents of remote areas of Australia.

To investigate patient, cancer and treatment characteristics in females with breast cancer from more remote areas of Australia, to better understand reasons for their poorer outcomes, bi-variable and multivariable analyses were undertaken using the National Breast Cancer Audit database of the Society of Breast Surgeons of Australia and New Zealand. Results indicated that patients from more remote areas were more likely to be of lower socio- economic status and be treated in earlier diagnostic epochs and at inner regional and remote rather than major city centres. They were also more likely to be treated by low case load surgeons, although this finding was only of marginal statistical significance in multivariable analysis (p=0.

Factors predictive of treatment by Australian breast surgeons of invasive female breast cancer by mastectomy rather than breast conserving surgery.

Background: The National Breast Cancer Audit Database of the Society of Breast Surgeons of Australia and New Zealand is used by surgeons to monitor treatment quality and for research. About 60% of early invasive female breast cancers in Australia are recorded. The objectives of this study are: (1) to investigate associations of socio-demographic, health-system and clinical characteristics with treatment of invasive female breast cancer by mastectomy compared with breast conserving surgery; and (2) to consider service delivery implications.