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Background Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are activating oncogenic events that occur in ~15% of breast cancers (BC). Early generation PI3Kα inhibitors target both wild-type (WT) and mutant PI3Kα and, as a result, their efficacy may be limited by on-target WT PI3Kα-mediated toxicities, including hyperglycemia, skin rash, and diarrhea. LOXO-783 is an oral, potent and highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor that is currently in phase 1 testing. Preclinically, LOXO-783 as a single agent is highly selective for PI3Kα H1047R over WT PI3Kα and other PI3K isoforms, and induces single-agent tumor regressions in ER+, HER2- PI3Kα H1047R-mutant breast cancer models without causing hyperglycemia or increases in plasma insulin/C-peptide. LOXO-783 also demonstrates brain penetration in vivo with dose-dependent tumor growth inhibition in brain metastasis models. Here we report the efficacy of LOXO-783 with SOC treatments in preclinical breast cancer models. Methods Cell proliferation assays and in vivo studies to evaluate combination effects were performed in various PI3Ka H1047R mutant HR+, HER2- and triple negative breast cancer models. For each combination in vitro, a combination index (CI) based on the Loewe Additivity Method was calculated (CI>2 antagonism, 0.5>CI< 2 additivity, CI< 0.5 synergy). For the in vivo studies, the Bliss Independence Method was used to evaluate the statistical significance of the combination effects. Results Combining LOXO-783 with either fulvestrant (FUL; CI at 50% inhibition = 0.28) or imlunestrant (CI at 50% inhibition = 0.43) showed increased efficacy in cell proliferation assays using the HR+, HER2-, PI3Kα H1047R-mutant T47D model. LOXO-783 also demonstrated an additive effect in combination with these endocrine therapies in vivo. Similar results were observed in a T47D model engineered to express ESR1 D538G, as well as in an HR+, HER2- PI3Kα double in-cis mutant model (H1047R/D350G) also harboring ESR1 D538G and derived from a patient who had progressed on prior letrozole plus taselisib. Moreover, LOXO-783 plus abemaciclib demonstrated an additive effect in vitro (CI at 50% inhibition = 0.61), and in T47D xenograft and PDX models in vivo. Combinations of LOXO-783 with abemaciclib plus imlunestrant resulted in a mean tumor regression of –48.1%; LOXO-783 with abemaciclib plus FUL showed mean tumor regression of –43.9% in T47D xenografts. Similar efficacy was not observed in the absence of LOXO-783 (mean tumor regression was –7.3% with abemaciclib plus imlunestrant, and 3.2% with abemaciclib plus FUL). We observed comparable results in PDX models. These data collectively demonstrate the additive effect of LOXO-783 with SOC treatments. Extending these studies to additional treatment settings, LOXO-783 was similarly efficacious as a single agent in abemaciclib-resistant and abemaciclib/FUL double-resistant models, and was additive in combination with paclitaxel in a triple negative breast cancer model in vitro and in vivo. Conclusions LOXO-783 shows additive effects when combined with SOC in breast cancers harboring the PI3Kα H1047R-mutation (as single or double in-cis mutations) in both HR+ and triple negative settings. LOXO-783 is also efficacious in ESR1 mutant as well as in abemaciclib and abemaciclib/FUL double-resistant models. A phase 1 trial of LOXO-783 alone or in combination with anticancer therapies is ongoing (PIKASSO-01; NCT05307705). Citation Format: Loredana Puca, Michele S. Dowless, Carmen M. Perez-Ferreiro, Maria Jesus Ortiz-Ruiz, Gregory P. Donoho, Andrew Capen, Lysiane Huber, Sarah M. Bogner, Dongling Fei, Jason R. Manro, Chun Ping Yu, Wei Guo Xu, Rui Wang, Shuang Chen, Mark A. Hicks, Parisa Zolfaghari, Andrew Faber, Raymond Gilmour, Monica D. Ramstetter, Matthew T. Chang, Maria Jose Lallena, Xuequian Gong, David M. Hyman, Lillian M. Smyth, Barbara J. Brandhuber, Barry S. Taylor, Anke Klippel. LOXO-783: A potent, highly mutant selective and brain-penetrant allosteric PI3Kα H1047R inhibitor in combination with standard of care (SOC) treatments in preclinical PI3Kα H1047R-mutant breast cancer models [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-02.

Indoor low-frequency noise levels due to road traffic has been modelled for facade examples consisting of a lightweight steel facade, a concrete facade and two types of windows. Possible audibility of heavy vehicles passing by has been investigated as well as the dependence of the exposure level on driving speed and distance to road. The results show that pass-by events may be audible at low frequencies for cases complying with building standards and noise guideline values exemplified by Swedish regulation. Moreover, the A-weighted levels may be dominated by low frequency noise, and the frequency of occurrence of pass-by traffic noise events may be sufficiently high to create disturbance for typical traffic situations. Furthermore, it is shown that the contribution of pass-by events to the equivalent level indoors may increase when the driving speed is lowered.

Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This study reports safety and efficacy among women treated with repeat BCS and reRT.Patients who underwent repeat BCS followed by RT from 2015 to 2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan-Meier estimates were used to evaluate overall survival (OS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LR-RFS).Sixty-six patients were reviewed with median follow-up of 16 months (range: 3-60 months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5 Gy BID; 27% with 1.8 Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2 Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%.In this series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens at a median follow up of 16 months. Longer follow up is required.

Drug resistance is one of the major factors associated with poor outcome of cancer patients. Treatment of Ewing sarcoma (EwS), an aggressive neoplasm mainly affecting children, adolescents and young adults, is associated with therapy failure and tumor relapse in 30-80% of the cases. Thus, it supports the need to explore the mechanisms modulating drug activity. Here, we describe a novel mechanism of drug sensitivity based on the role of EWS::FLI1 in R-loop metabolism. Our results demonstrate that EWS::FLI1 promotes R-loop formation favoring the interaction between DHX9 and elongating RNA polymerase II. In addition, we discovered that EWS::FLI1 kidnaps DHX9 preventing the resolution of TOP1 poisoning-associated R-loops. Our findings indicate that R-loops accumulation promotes replicative stress, genome instability and cell sensitivity to SN-38. Collectively, these results uncover a novel mechanism behind EwS sensitivity to genotoxic agents, with relevant implications for EwS treatment.

Measurements of acid volatile sulphide (AVS) and simultaneously extracted metals (SEM) in sediments are used to assess the toxicity of metals to native benthic organisms. The AVS is obtained from the sulphides contained in the sediments by addition of acid and the SEM are the metals extracted during the AVS treatment. The AVS/SEM method reflects a more precise estimation of sediment toxicity to benthic organisms than "total" metal values (cadmium, copper, lead, nickel and zinc) by measuring a "bioavailable" fraction of the metals present. Sediment toxicity is assessed by calculating the sum of the SEM (µmol/g dry weight) divided by the AVS concentration (in the same units): a ratio less than or equal to 1 indicates that the metals in the sediment are not bioavailable, while a ratio greater than 1 indicates that the metals are bioavailable.In this case, they are applied to soils containing mining waste and marine sediments that were buried under these inputs in Portman Bay (SE Spain) and compared with the values obtained from the ecotoxicity tests used: microtox, ostracodes and gambarus for sediments and phytotoxicity tests for topsoil samples.The results confirm the ecotoxic characteristics of some of the samples evaluated and also allow an approximation to be made of the impact that neighbouring materials may have if subjected to AMD, when there is intense precipitation and the waters of the wadis reach the bay with the runoff from the neighbouring mining areas.

In order to predict the future behaviour of technosols designed for the remediation of sites contaminated with mining waste, a pilot experiment was carried out in containers under an enclosed building.One-metre cubic polyvinyl chloride (PVC) containers were used and filled with soil of the different types that are abundant on the site. Four soil types were selected with different textures (sandy to silty-clay), different mineralogy and different PTE content. Soil mixtures were also prepared with limestone filler at different proportions (30, 40 and 50 %).These containers were subjected to a humidity and drying process, simulating the rainfall conditions that the site receives as an average annual value, in 10 successive cycles, maintaining the experience for 4 years. The drains obtained were analysed and their corresponding crystallised phases were obtained and characterised by XRD and electron microscopy. The metals determined were Fe, Cd, Cu, Pb, As and Zn.This experiment allows us to differentiate the behaviour of the selected soils with respect to humidity, since the untreated soils with a clayey loam texture are AMD producers, with very low pH and a high mobilisation of metals. In contrast, sandy textured soils and soils containing 30 % or more limestone filler have a pH close to 7 and small metal contents close to the limit of quantification.Efflorescences are more abundant in those leachates rich in Zn and Fe, being copiapite, hexahydrite, bianchite and gypsum the main soluble phases associated with these leachates. Finally, the percolates with a higher salt load correspond to the third percolation carried out approximately nine months after the start of the experiment.

Purpose:Endoglin (ENG; CD105) is a coreceptor of the TGFβ family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFβ, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease.Experimental Design:We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody–drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma.Results:Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro. Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line–derived xenografts and patient-derived xenografts in a dose-dependent manner.Conclusions:Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.

Supplementary Material & Methods, Figure Legends and Tables

Supplementary Figures

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) widely used as an immunosuppressant in transplant patients. In transplantation setting, several recommendations for therapeutic drug monitoring are available, due to potential drug-drug interactions with chronic medication, which can affect everolimus pharmacokinetic profile. Everolimus is also used in breast, neuroendocrine and renal cancer, at higher doses than in transplantation and without systematic drug monitoring requirement. We present a case-report of a 72years-old woman with epilepsy history to whom everolimus 10mg/daily was prescribed as third line of treatment for renal cell carcinoma. The patient´s chronic medication was checked by the outpatient hospital pharmacist before initiating treatment. As a result, two major interactions with inducers of CYP3A4 metabolism as carbamazepine and phenytoin were detected. Since trough plasma concentration of everolimus could be affected, by these pharmacokinetic interactions,a therapeutic drug monitoring of everolimus was proposed. Based on the literature, Cmin plasma concentration (Cminss) of everolimus over 10ng/ml is associated with better response to treatment and progression free survival. During the oncologist follow-up visit and according to pharmaceutical recommendations, everolimus dosage was increased to 10mg every 12 hours. In the following determinations of trough plasma everolimus concentration, Cmin grow up from 3.7ng/ml to 10.8ng/mL. Depending on the CYP3A4 induction capacity and potency of the drug/s administered concomitant to everolimus and how many of them can potentially interact with it, therapeutic everolimus monitoring would be advisable in order to adjust dosage if required to prevent underexposure.

In this paper, we review the social determinants of health in older adults and their complex interrelationship with medical diseases. Also, we provide recommendations to address these determinants in the integrated healthcare plan. The social determinants in older adults and its influence in health outcomes have been studied for decades. There is solid evidence for the interrelationship between social factors and the health of individuals and populations; however, these studies are unable to define their complex interrelatedness. Health is quite variable and depends on multiple biological and social factors such as genetics, country of origin, migrant status, etc. On the other hand, health status can affect social factors such as job or education. Addressing social determinants of health in the integrated healthcare plan is important for improving health outcomes and decreasing existing disparities in older adult health. We recommend a person-centered approach in which individualized interventions should be adopted by organizations to improve the health status of older adults at the national and global level. Some of our practical recommendations to better address the social determinants of health in clinical practice are EHR documentation strategies, screening tools, and the development of linkages to the world outside of the clinic and health system, including social services, community activities, collaborative work, and roles for insurance companies.

Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3,4,5, the underlying mechanisms are not well understood. Here we show that a peripheral myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum of subjects with MDD as well as in stress-susceptible (SUS) mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), thereby altering social behaviour. Using a combination of mass cytometry and single-cell RNA-sequencing, we performed high-dimensional phenotyping of immune cells in circulation and brain and demonstrate that peripheral monocytes are strongly affected by stress. Both peripheral and brain-infiltrating monocytes of SUS mice showed increased Mmp8 expression following CSDS. We further demonstrate that peripheral MMP8 directly infiltrates the NAc parenchyma to control the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a novel mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Objetivo. Establecer el efecto de las medidas morfométricas y productivas sobre los parámetros reproductivos: número de partos e intervalo entre partos en hembras Romosinuano (ROMO) y Costeño con Cuernos (CCC) bajo las condiciones agroclimáticas del Caribe húmedo colombiano. Materiales y métodos. Se utilizaron 408 vacas entre las razas ROMO (250) y CCC (158) se tomaron las medidas morfométricas de: amplitud del isquion (ADI), amplitud de cadera (ADC), altura del sacro (ADS), altura de la cruz (ADLC), así como el peso vivo, peso primer parto (PPP), peso último parto (PUP), condición corporal (CC), y los parámetros reproductivos como el número de partos e intervalos entre partos (IEP). Las diferencias entre los parámetros morfométricos y reproductivos por raza se establecieron por análisis de varianza. Las relaciones entre las variables morfométricas y reproductivas se analizaron a través correlaciones canónicas. Resultados. El análisis de varianza mostró diferencias estadísticamente significativas (p

Purpose: Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This multi-institutional study reports safety and efficacy among women treated with repeat BCS and reRT. Methods and Materials: Patients who underwent repeat BCS followed by RT from 2015–2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan Meier estimates were used to evaluate overall survival (OS), distant metastasis free survival (DMFS) and locoregional recurrence-free survival (LR-RFS). Results: Sixty-six patients were reviewed with median follow-up of 16 months (range: 3–60 months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5Gy BID; 27% with 1.8Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%. Conclusion: In this multi-institutional series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens.