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. For compounds showing the highest degree of Pim-1 inhibition the binding mode was determined crystallographically. Following a structure-guided approach, these were further optimized in a subsequent design cycle improving the compound's initial affinity by several orders of magnitude while synthesizing only a comparatively modest number of derivatives. The combination of computational and experimental approaches resulted in the development of a reasonably potent, novel molecular scaffold for inhibition of Pim-1 that targets specific surface regions, such as the interaction with R122 and P123 of the hinge region, which has been less frequently investigated in similar studies.

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. We offer Python-based solutions for common tasks in cheminformatics and structural bioinformatics in the form of Jupyter notebooks, based on open source resources only. Including the 12 newly released additions, TeachOpenCADD now contains 22 notebooks that cover both theoretical background as well as hands-on programming. To promote reproducible and reusable research, we apply software best practices to our notebooks such as testing with automated continuous integration and adhering to the idiomatic Python style. The new TeachOpenCADD website is available at https://projects.volkamerlab.org/teachopencadd and all code is deposited on GitHub.

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 Cm3+, as a representative of the trivalent actinides, and Eu3+, as an inactive homologue, with glucuronic acid (GlcA) a simple sugar acid. Time-resolved laser-induced luminescence spectroscopy (TRLFS) shows that complexation at pH 5.0 occurs only at high ligand to metal ratios in the form of 1:1 complexes with standard formation constants log ß0 = 1.84 ± 0.22 for Eu3+ and log ß0 = 2.39 ± 0.19 for Cm3+. A combination of NMR, QMMM, and TRLFS reveals the structure of the complex to be a half-sandwich structure wherein the ligand binds through its carboxylic group, the ring oxygen, and a hydroxyl group in addition to five to six water molecules. Surprisingly, Y3+, which was used as a diamagnetic reference in NMR, prefers a different coordination geometry with bonding through at least two hydroxyl groups on the opposite side of a distorted GlcA molecule. QMMM simulations indicate that the differences in stability among Cm, Eu, and Y are related to ring strain induced by smaller cations. At higher pH a stronger complex was detected, most likely due to deprotonation of a coordinating OH group.

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 Ga3+) 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 Ga3+ are largely unknown. Multiple computational methods, coupled with experimental verification via NMR and Isothermal Calorimetry (ITC), were used to establish that Ga3+ binds with high affinity to peptide sequences and to elucidate the structural characteristics that contributed. It was demonstrated that peptide pre-organisation is key to Ga3+ binding and that a favourable binding position is necessarily governed by the size and shape of the electrostatic environment as much as individual electrostatic interactions with peptide residues themselves. Given favourable conditions, Ga3+ retrieved plausible binding positions involving both charged and uncharged residues that greatly increases the range of bonding possibilities with other peptide sequences and offers insights for binding other metals. The addition of pH buffer substantially improved the affinity of Ga3+ and a structural role for a buffer component was demonstrated.

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. For peptide HTQHIQSDDHLA, a stabilizing influence of acetate ions on the metal peptide interaction was found. Peptide NYLPHQSSSPSR showed the highest affinity for gallium in ITC studies. Computational modeling of peptide NYLPHQSSSPSR was used to determine interaction parameters and to explain a possible binding mechanism. Furthermore, the peptides were immobilized on polystyrene beads. Thus, we created a novel and exceptionally robust peptide-based material for the biosorption of gallium from an aqueous solution. 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. For peptide HTQHIQSDDHLA, a stabilizing influence of acetate ions on the metal peptide interaction was found. Peptide NYLPHQSSSPSR showed the highest affinity for gallium in ITC studies. Computational modeling of peptide NYLPHQSSSPSR was used to determine interaction parameters and to explain a possible binding mechanism. Furthermore, the peptides were immobilized on polystyrene beads. Thus, we created a novel and exceptionally robust peptide-based material for the biosorption of gallium from an aqueous solution.

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. The association of demographic characteristics with postural preferences and use of loupes was explored. Then, the relation of demographic characteristics, postural preferences, and use of loupes to painful musculoskeletal complaints was analyzed. Contingency analysis was used to compare participants' responses and multiple logistic regression analysis was used to identify relevant predictor variables. RESULTS: The sample was composed of 153 oral and maxillofacial surgeons, of which 32% indicated that they had pain attributable to their practice that lasted longer than 2 weeks. Practitioners reported neck and back pain as being most common. Eighty-four percent of practitioners stood for extractions and placement of implants. Those who stood did so for visibility. Practitioners who sat indicated they did so for orthopedic reasons (P < .001). Thirty-one percent of practitioners indicated loupes use. Those who used loupes were more likely to report pain (P = .022). CONCLUSION: Most respondents stood and did not use loupes. Those who did use loupes were more likely to report pain. Those who stood did so for visibility; those who sat did so for orthopedic reasons. Almost one third of respondents reported pain lasting at least 2 weeks during practice.

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. This is the biggest NZ breast cancer database outside the NZ Cancer Registry and it includes cancer and clinical management data not collected by the Registry. We used these BQA data to compare socio-demographic and cancer characteristics and survivals by ethnicity. MATERIALS AND METHODS: BQA data for 1998-2010 diagnoses were linked to NZ death records using the National Health Index (NHI) for linking. Live cases were followed up to December 31st 2010. Socio-demographic and invasive cancer characteristics and disease-specific survivals were compared by ethnicity. RESULTS: Five-year survivals were 87% for Maori, 84% for Pacific, 91% for other NZ cases and 90% overall. This compared with the 86% survival reported for all female breast cases covered by the NZ Cancer Registry which also included more advanced stages. Patterns of survival by clinical risk factors accorded with patterns expected from the scientific literature. Compared with Other cases, Maori and Pacific women were younger, came from more deprived areas, and had larger cancers with more ductal and fewer lobular histology types. Their cancers were also less likely to have a triple negative phenotype. More of the Pacific women had vascular invasion. Maori women were more likely to reside in areas more remote from regional cancer centres, whereas Pacific women generally lived closer to these centres than Other NZ cases. CONCLUSIONS: NZ BQA data indicate previously unreported differences in breast cancer biology by ethnicity. Maori and Pacific women had reduced breast cancer survival compared with Other NZ women, after adjusting for socio-demographic and cancer characteristics. The potential contributions to survival differences of variations in service access, timeliness and quality of care, need to be examined, along with effects of co- morbidity and biological factors.

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. Disease-specific survival for invasive cases was benchmarked against Australian BQA data and NZ population-based survivals. Validity was explored by comparison with expected survival by risk factor. RESULTS: Compared with 93% for Australian audit cases, 5-year survival was 90% for NZ audit cases overall, 87% for Maori, 84% for Pacific and 91% for other. CONCLUSIONS: BC survival in NZ appears lower than in Australia, with inequities by ethnicity. Differences may be due to access, timeliness and quality of health services, patient risk profiles, BQA coverage and death-record methodology.

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. RESULTS: Seventy thousand six hundred and eighty-eight episodes of early breast cancer with axillary surgery data were reported to the BQA in the study period. The proportion of patients undergoing SLN biopsy as the first operation increased over this period in both tumour size groups with a concomitant decline in the use of ALND as the first operation over the same interval. Elderly women (>70 years old) were four times less likely to undergo axillary surgery for their initial management when compared with women aged 41-70 years old (P < 0.001). Factors favouring ALND as the initial surgery over SLN biopsy included larger tumour size, elderly age, uninsured status and having surgery in a regional centre. CONCLUSIONS: From 1999 to 2011, SLN biopsy as the initial axillary surgery has been widely adopted by surgeons reporting to the BQA. Future evaluation of the BQA data in the following 3-5 years will be performed to monitor this progression.

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. Although they appeared equally likely to be referred to surgeons from BreastScreen services as patients from higher socioeconomic areas, they were less likely to be referred as asymptomatic cases from other sources. In general, their cancer and treatment characteristics did not differ from those of women from higher socioeconomic areas, but ovarian ablation therapy was less common for these patients and bilateral synchronous lesions tended to be less frequent than for women from higher socioeconomic areas. CONCLUSIONS: The results indicate that patients from lower socioeconomic areas are more likely to live in more remote districts and have their treatment in regional rather than major treatment centres. Their cancer and treatment characteristics appear to be similar to those of women from higher socioeconomic areas, although they are less likely to have ovarian ablation or to be referred as asymptomatic patients from sources other than BreastScreen. What is known about this topic? It is already known from Australian data that breast cancer outcomes are not as favourable for women from areas of socioeconomic disadvantage. The reasons for the poorer outcomes have not been understood. Studies in other countries have also found poorer outcomes in women from lower socioeconomic areas, and in some instances, have attributed this finding to more advanced stages of cancers at diagnosis and more limited treatment. The reasons are likely to vary with the country and health system characteristics. What does this paper add? The present study found that in Australia, women from lower socioeconomic areas do not have more advanced cancers at diagnosis, nor, in general, other cancer features that would predispose them to poorer outcomes. The standout differences were that they tended more to live in areas that were more remote from specialist metropolitan centres and were more likely to be treated in regional settings where prior research has indicated poorer outcomes. The reasons for these poorer outcomes are not known but may include lower levels of surgical specialisation, less access to specialised adjunctive services, and less involvement with multidisciplinary teams. Women from lower socioeconomic areas also appeared more likely to attend lower case load surgeons. Little difference was evident in the type of clinical care received, although women from lower socioeconomic areas were less likely to be asymptomatic referrals from other clinical settings (excluding BreastScreen). What are the implications for practitioners? Results suggest that poorer outcomes in women from lower socioeconomic areas in Australia may have less to do with the characteristics of their breast cancers or treatment modalities and more to do with health system features, such as access to specialist centres. This study highlights the importance of demographic and health system features as potentially key factors in service outcomes. Health system research should be strengthened in Australia to augment biomedical and clinical research, with a view to best meeting service needs of all sectors of the population.

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. RESULTS: Core biopsy is the most frequently performed diagnostic method and open biopsy the least (P=0.001). Remote locations have the highest proportion of open biopsies and cities the lowest (13.8 versus 9.8%, P=0.001). The outer regional/remote patient group has a higher likelihood of an open biopsy than city patients (odds ratio 1.5; 95% confidence interval 1.1-2.2 P=0.02). Reconstruction rates are low throughout ranging from 3 to 4% (P=0.001). Cities have the highest proportion of no surgery (1.5%, P=0.001). Cities have the highest proportion of breast conserving surgery and the remote the lowest (64.5% versus 29.9%, P=0.001). Outer regional locations have the highest proportion of mastectomies and cities the lowest (38 versus 29.9%, P=0.001). The likelihood of receiving radiotherapy is associated with geographic location of residence and geographic distribution of the radiotherapy facility (P=0.002, P=0.001). CONCLUSION: Geographic location of residence is associated with the diagnostic work up and surgical treatment of Australian women with early breast cancer.

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. Tumor size, histologic grade, number of tumors, lymph node positivity, and lymphovascular invasion are the major prognostic factors adjusted for. Reconstruction following mastectomy is the most likely surgical procedure for the higher socioeconomic and privately insured patients. Mastectomy alone is the most likely surgical procedure for the lower socioeconomic and for public patients. No surgery is the most likely surgical outcome for the lower socioeconomic and the least likely for the higher socioeconomic population. Open biopsy is the most likely diagnostic procedure for the lower socioeconomic and fine needle aspiration for the higher socioeconomic population. Socioeconomic and insurance status, are both independently associated with the types of treatment and diagnostic procedure for women with breast cancer. Opportunities present to investigate an association of these factors with morbidity and survival outcomes.

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. RESULTS: 14879 patients were identified from 2006 to 2010. 79.8% of patients with a positive SLN result underwent cALND. Age >70 years and a greater number of involved SLN predicted no cALND among SLN positive patients. 10.3% of patients who had a negative SLN result underwent cALND. Younger age, higher grade, lymphovascular invasion and tumour size >3 cm predicted cALND among SLN negative patients. CONCLUSIONS: According to the BQA from 2006 to 2010 the Australian and New Zealand guideline recommendations for SLN positive patients to have cALND and SLN negative patients not to have cALND were adhered to in 79.8% and 89.7% of cases respectively.

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. MATERIALS AND METHODS: Bi-variable and multivariable analyses of associations of characteristics with surgery type for cancers diagnosed in 1998-2010. RESULTS: Of 30,299 invasive cases analysed, 11,729 (39%) were treated by mastectomy as opposed to breast conserving surgery. This proportion did not vary by diagnostic year (p>0.200). With major city residence as the reference category, the relative rate (95% confidence limits) of mastectomy was 1.03 (0.99, 1.07) for women from inner regional areas and 1.05 (1.01, 1.10) for those from more remote areas. Low annual surgeon case load (<10) was predictive of mastectomy, with a relative rate of 1.08 (1.03, 1.14) when compared with higher case loads. Tumour size was also predictive, with a relative rate of 1.05 (1.01, 1.10) for large cancers (40+ mm) compared with smaller cancers (<30 mm). These associations were confirmed in multiple logistic regression analysis. CONCLUSIONS: Results confirm previous studies showing higher mastectomy rates for residents of more remote areas, those treated by surgeons with low case loads, and those with large cancers. Reasons require further study, including possible effects of surgeon and woman's choice and access to radiotherapy services.

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=0.074). Patients from more remote areas were less likely than those from major cities to be treated by breast conserving surgery, as opposed to mastectomy, and less likely to have adjuvant radiotherapy when having breast conserving surgery. They had a higher rate of adjuvant chemotherapy. Further monitoring will be important to determine whether breast conserving surgery and adjuvant radiotherapy utilization increase in rural patients following the introduction of regional cancer centres recently funded to improve service access in these areas.