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Sierra Pellizzari,1 Harjot Athwal,1 Anne Claudine Bonvissuto,1,2 Armen Parsyan1– 4 1Department of Anatomy and Cell Biology, Western University, London, ON, Canada; 2Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON, Canada; 3Department of Oncology, Western University, London, ON, Canada; 4Department of Surgery, St Joseph’s Health Care and London Health Sciences Centre, Western University, London, ON, CanadaCorrespondence: Armen Parsyan, Department of Surgery, St Joseph’s Health Care London, Room D1-104, 268 Grosvenor Street, London, ON, N6A 4V2, Canada, Tel +1-519-646-4831, Email aparsyan@uwo.caAbstract: Breast cancer is a leading cause of cancer-related deaths in females. Triple-negative breast cancer (TNBC) subtype is the most aggressive form of breast cancer that lacks biomarkers and effective targeted therapies. Its high degree of heterogeneity as well as innate and acquired resistance to treatment creates further barriers in achieving positive clinical outcomes in TNBC. Thus, development of novel treatment approaches in TNBC is of high clinical significance. Multimodality approaches with targeted agents and radiotherapy (RT) are promising for increasing efficacy of treatment and circumventing resistance. Here we examined anticancer effects of the Aurora Kinase B (AURKB) inhibitor AZD1152 as a single agent and in combination with RT using various TNBC cell lines, MDA-MB-468, MDA-MB-231 and SUM-159. We observed that AZD1152 alone effectively inhibited colony formation in TNBC cell lines. The combination of AZD1152 at IC50 concentrations together with ionizing radiation further reduced colony formation as compared to the single agent treatment. Our data support the notion that inhibition of the AURKB pathway is a promising strategy for treatment and radiosensitization of TNBC and warrants further translational studies.Plain Language Summary: Breast cancer is a leading cause of cancer death in women globally. The triple negative breast cancer subtype confers the poorest oncologic outcomes and requires novel treatment approaches. Development of new therapeutics as well as combination treatments with radiation are crucial. Aurora Kinase B (AURKB) protein regulates cell division that is often altered in breast cancer, contributing to tumor pathogenesis. This study examined the combination of an AURKB inhibitor, AZD1152, with radiation therapy, compared to single-agent treatments, in treating triple negative breast cancer cells. Our results show that AZD1152 and ionizing radiation alone were able to delay cancer cell proliferation effectively. However, their combination further significantly inhibited cell proliferation compared to single-agent treatments. This suggests that further studies on this combination would be valuable in developing novel treatment strategies for breast cancer.Keywords: breast cancer, Aurora Kinase B, AZD1152, radiation, combination treatment, multimodality treatment, AURKB

Background. By 2020, breast cancer (BC) has become the most frequent malignancy in the world. The most common type of BC is HR+/HER2-negative cancer,2540% of which harbors PIK3CA mutations that affect the catalytic subunit of the PI3K protein. PIK3CA alterations are actionable, as such neoplasms can be treated with a combination of fulvestrant and the PI3K inhibitor alpelisib. As PIK3CA mutations have an extremely versatile effect on the characteristics of a tumor cell, numerous associations of PIK3CA mutations and various clinico-pathological characteristics of BC can be traced. Aim. Our aim was to clarify the information on the frequency and spectrum of PIK3CA mutations in Russian patients with HR+/HER2- advanced BC, and to study the association of PIK3CA mutations with clinical and pathological parameters of BC. Materials and methods. Tissue samples from 694 patients with HR+/HER2- advanced BC (mixed population of primary metastatic and relapsed tumors) who received any line of anti-cancer treatment in Dec 2020 to June 2021 in Russian Federation were analyzed by high-resolution melting, allele-specific PCR, digital droplet PCR and Sanger sequencing (exons 7,9, and 20 of the PIK3CA gene). Mutation rates in different BC subgroups were compared using the Fishers exact test. The age at diagnosis in patients with different PIK3CA status was compared using the MannWhitney U-test. The relationship between the PIK3CA status and the degree of tumor differentiation was compared using the CochraneArmitage test for trends. Luminal A and B BC expression subtypes were distinguished with surrogate IHC markers according to St.-Gallen recommendations (2013). Results. Mutations were identified in 220/694 (32%) BC patients. The three most frequent missense substitutions in the PIK3CA gene (p.E542K, p.E545K, and p.H1047R) accounted for 190/220 (86%) mutations. Associations of PIK3CA mutations with luminal A subtype of BC, low proliferation index, small size of the primary tumor, and absence of signs of hereditary cancer were revealed. Associations of mutations in the kinase domain of PIK3CA (p.H1047R) with late recurrence of locally advanced BC and with non-Slavic ethnic origin of patients were found. Conclusion. PIK3CA mutation rate of 32% confirms high prevalence of mutation in Russian population, with some differences reflecting the ethnic origin of patients.

Development of novel multimodality radiotherapy treatments in metastatic breast cancer, especially in the most aggressive triple negative (TNBC) subtype, is of significant clinical interest. Here we show that a novel inhibitor of Polo-Like Kinase 4 (PLK4), CFI-400945, in combination with radiation, exhibits a synergistic anti-cancer effect in TNBC cell lines and patient-derived organoids in vitro and leads to a significant increase in survival to tumor endpoint in xenograft models in vivo, compared to control or single-agent treatment. Further preclinical and proof-of-concept clinical studies are warranted to characterize molecular mechanisms of action of this combination and its potential applications in clinical practice.

This study investigates the shift in private banking from conventional creditworthiness assessment to advanced machine learning (ML) models. Employing a synthesis technique, this study conducts a review of literature and case studies and highlights how ML models, through the integration of alternative big data and advanced algorithms, can enhance accuracy in forecasting customer defaults and contribute to financial inclusion. The research underscores legal and ethical concerns regarding alternative data processing, necessitating thorough compliance checks by banks and regulatory authorities. Furthermore, it underlines the necessity for banks and regulators to develop technical skills to ensure ML models remain transparent and understandable, avoiding the pitfalls of becoming "black boxes". Future research is suggested to explore risk mitigation strategies based on its ML deployment approach, technical aspects of ML algorithms, and the impact of ML-based credit scoring on broader macro-financial linkages. [ABSTRACT FROM AUTHOR]

Breast cancer remains a leading cause of mortality among women worldwide. Brain metastases confer extremely poor prognosis due to a lack of understanding of their specific biology, unique physiologic and anatomic features of the brain, and limited treatment strategies. A major roadblock in advancing the treatment of breast cancer brain metastases (BCBM) is the scarcity of representative experimental preclinical models. Current models are predominantly based on the use of animal xenograft models with immortalized breast cancer cell lines that poorly capture the disease’s heterogeneity. Recent years have witnessed the development of patient-derived in vitro and in vivo breast cancer culturing systems that more closely recapitulate the biology from individual patients. These advances led to the development of modern patient-tissue-based experimental models for BCBM. The success of preclinical models is also based on the imaging technologies used to detect metastases. Advances in animal brain imaging, including cellular MRI and multimodality imaging, allow sensitive and specific detection of brain metastases and monitoring treatment responses. These imaging technologies, together with novel translational breast cancer models based on patient-derived cancer tissues, represent a unique opportunity to advance our understanding of brain metastases biology and develop novel treatment approaches. This review discusses the state-of-the-art knowledge in preclinical models of this disease.

Background: Parathyroid dysfunction leading to symptomatic hypocalcemia is not uncommon following a total or completion thyroidectomy and is often associated with significant patient morbidity and a prolonged hospital stay. A simple, reliable indicator to identify patients at risk would permit earlier pharmacologic prophylaxis to avoid these adverse outcomes. We examined the role of intact parathormone (PTH) levels 1 hour after surgery as a predictor of post-thyroidectomy hypocalcemia. Methods: We prospectively reviewed the cases of consecutive patients undergoing total or completion thyroidectomy. Ionized calcium ([Ca.sup.2+]) and intact PTH levels were measured preoperatively and at 1-, 6- and 24-hour intervals postoperatively. The specificity, sensitivity, negative and positive predictive values of the 1-hour PTH serum levels (PTH-1) in predicting 24-hour post-thyroidectomy hypocalcemia and eucalcemia were determined. Results: We reviewed the cases of 149 patients. Biochemical hypocalcaemia ([Ca.sup.2+] < 1.1 mmol/L) developed in 38 of 149 (25.7%) patients 24 hours after thyroidectomy. The sensitivity, speciicity, positive and negative predictive values of a low PTH-1 were 89%, 100%, 97% and 100%, respectively. Conclusion: We found that PTH-1 levels were predictive of symptomatic hypocalcemia 24 hours after thyroidectomy. Routine use of this assay should be considered, as it could prompt the early administration of calcitriol in patients at risk of hypocalcemia and allow for the safe and timely discharge of patients expected to remain eucalcemic. Contexte: Il n'est pas rare qu'un dysfonctionnement des glandes parathyroides entrainant une hypocalcemie symptomatique s'observe apres une thyroidectomie totale ou de completion et il est souvent associe a une importante morbidite chez les patients et a un sejour hospitalier prolonge. Un indicateur simple et iable permettant de reconnaitre les patients a risque pourrait favoriser une prophylaxie pharmacologique precoce ain d'eviter ces complications. Nous avons examine le role des taux de parathormone (PTH) intacte une heure apres la chirurgie comme predicteurs de l'hypocalcemie post-thyroidectomie. Methodes: Nous avons passe en revue de maniere prospective des cas consecutifs de patients soumis a une thyroidectomie totale ou de completion. Les taux de calcium ionise ([Ca.sup.2+]) et de PTH intacte ont ete mesures avant l'intervention, puis 1 heure, 6 heures et 24 heures apres. Il a ainsi ete possible de determiner la speciicite, la sensibilite, la valeur predictive negative et positive des taux seriques de PTH 1 heure apres l'intervention (PTH-1) pour ce qui est de predire l'hypocalcemie et l'eucalcemie 24 heures apres la thyroidectomie. Resultats: Nous avons analyse 149 cas. L'hypocalcemie biochimique ([Ca.sup.2+] < 1,1 mmol/L) a ete observee chez 38 patients sur 149 (25,7 %) 24 heures apres la thyroidectomie. La sensibilite, la speciicite, la valeur predictive positive et negative d'un taux de PTH-1 faible ont ete respectivement de 89 %, 100 %, 97 % et 100 %. Conclusion: Nous avons note que les taux de PTH-1 etaient predictifs d'une hypocalcemie symptomatique 24 heures apres la thyroidectomie. L'utilisation d'emblee de ce test est a envisager puisqu'elle permettrait l'administration precoce de calcitriol chez les patients exposes a un risque d'hypocalcemie et un conge securitaire et rapide chez les patients dont on s'attend a ce qu'ils demeurent eucalcemiques., Parathyroid dysfunction leading to hypocalcemia is not uncommon after total or completion thyroidectomy and, if symptomatic, is often associated with significant patient morbidity and a prolonged hospital stay. (1) Often, [...]