bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming
Authors: Pateras Ioannis S. , Williams Chloe , Gianniou Despoina D. , Margetis Aggelos T. , Avgeris Margaritis , Rousakis Pantelis , Legaki Aigli-Ioanna , Mirtschink Peter , Zhang Wei , Panoutsopoulou Konstantina , Delis Anastasios D. , Pagakis Stamatis N. , Tang Wei , Ambs Stefan , Warpman Berglund Ulrika , Helleday Thomas , Varvarigou Anastasia , Chatzigeorgiou Antonios , Nordström Anders , Tsitsilonis Ourania E. , Trougakos Ioannis P. , Gilthorpe Jonathan D. , Frisan Teresa 
Published: March 2023

Abstract
Background
Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.

Methods
The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.

Results
We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.

Conclusions
Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.
Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies
Authors: Vargas-Soria María , García-Alloza Mónica , Corraliza-Gómez Miriam 
Published: March 2023

AbstractDiabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia–metabolism interface.
Scorpionfish rapidly change colour in response to their background
Authors: John Leonie , Santon Matteo , Michiels Nico K. 
Published: March 2023

Abstract
Background
To facilitate background matching in heterogenous environments, some animals rapidly change body colouration. Marine predatory fishes might use this ability to hide from predators and prey. Here, we focus on scorpionfishes (Scorpaenidae), well-camouflaged, bottom-dwelling sit-and-wait predators. We tested whether Scorpaena maderensis and Scorpaena porcus adjust body luminance and hue in response to three artificial backgrounds and thereby achieve background matching. Both scorpionfish species are also red fluorescent, which could contribute to background matching at depth. Therefore, we tested whether red fluorescence is also regulated in response to different backgrounds. The darkest and the lightest backgrounds were grey, while the third background was orange of intermediate luminance. Scorpionfish were placed on all three backgrounds in a randomised repeated measures design. We documented changes in scorpionfish luminance and hue with image analysis and calculated contrast to the backgrounds. Changes were quantified from the visual perspective of two potential prey fishes, the triplefin Tripterygion delaisi and the goby Pomatoschistus flavescens. Additionally, we measured changes in the area of scorpionfish red fluorescence. Because scorpionfish changed quicker than initially expected, we measured luminance change at a higher temporal resolution in a second experiment.

Results
Both scorpionfish species rapidly adjusted luminance and hue in response to a change of background. From prey visual perspective, scorpionfishes’ body achromatic and chromatic contrasts against the background were high, indicating imperfect background matching. Chromatic contrasts differed considerably between the two observer species, highlighting the importance of choosing natural observers with care when studying camouflage. Scorpionfish displayed larger areas of red fluorescence with increasing luminance of the background. With the second experiment, we showed that about 50% of the total luminance change observed after one minute is achieved very rapidly, in five to ten seconds.

Conclusion
Both scorpionfish species change body luminance and hue in response to different backgrounds within seconds. While the achieved background matching was suboptimal for the artificial backgrounds, we propose that the observed changes were intended to reduce detectability, and are an essential strategy to camouflage in the natural environment.
International comparison of pharmaceutical industry payment disclosures in the UK and Japan: implications for self-regulation, public regulation, and transparency
Authors: Ozieranski Piotr , Saito Hiroaki , Rickard Emily , Mulinari Shai , Ozaki Akihiko 
Published: March 2023

Abstract
Background
Self-regulation of payment disclosure by pharmaceutical industry trade groups is a major global approach to increasing transparency of financial relationships between drug companies and healthcare professionals and organisations. Nevertheless, little is known about the relative strengths and weaknesses of self-regulation across countries, especially beyond Europe. To address this gap in research and stimulate international policy learning, we compare the UK and Japan, the likely strongest cases of self-regulation of payment disclosure in Europe and Asia, across three dimensions of transparency: disclosure rules, practices, and data.

Results
The UK and Japanese self-regulation of payment disclosure had shared as well unique strengths and weaknesses. The UK and Japanese pharmaceutical industry trade groups declared transparency as the primary goal of payment disclosure, without, however, explaining the link between the two. The rules of payment disclosure in each country provided more insight into some payments but not others. Both trade groups did not reveal the recipients of certain payments by default, and the UK trade group also made the disclosure of some payments conditional on recipient consent. Drug company disclosure practices were more transparent in the UK, allowing for greater availability and accessibility of payment data and insight into underreporting or misreporting of payments by companies. Nevertheless, the share of payments made to named recipients was three times higher in Japan than in the UK, indicating higher transparency of disclosure data.

Conclusions
The UK and Japan performed differently across the three dimensions of transparency, suggesting that any comprehensive analysis of self-regulation of payment disclosure must triangulate analysis of disclosure rules, practices, and data. We found limited evidence to support key claims regarding the strengths of self-regulation, while often finding it inferior to public regulation of payment disclosure. We suggest how the self-regulation of payment disclosure in each country can be enhanced and, in the long run, replaced by public regulation to strengthen the industry’s accountability to the public.
Access to tablet injectable opioid agonist therapy in rural and smaller urban settings in British Columbia, Canada: a qualitative study
Authors: Bardwell Geoff , Bowles Jeanette M. , Mansoor Manal , Werb Dan , Kerr Thomas 
Published: March 2023

Abstract
Background
Rural and smaller urban settings in Canada are disproportionately impacted by the overdose crisis, highlighting the need for novel public health interventions within these jurisdictions. Tablet injectable opioid agonist therapy (TiOAT) programs have been implemented in select rural communities as a means to address drug-related harms. However, little is known about the accessibility of these novel programs. Therefore, we conducted this study to understand the rural context and factors that affected access of TiOAT programs.

Methods
Between October 2021 to April 2022, individual qualitative semi-structured interviews were conducted with 32 individuals enrolled in a TiOAT program at participating rural and smaller urban sites in British Columbia, Canada. Interview transcripts were coded using NVivo 12 and data were analyzed thematically.

Results
TiOAT access varied considerably. TiOAT delivery in rural settings is complicated due to geographic challenges. Participants who were homeless and staying at a nearby shelter or those in centrally-located supportive housing had minimal issues compared to those living in more affordable housing on the outskirts of town with limited transportation options. Dispensing policies that required daily-witnessed ingestion multiple times daily were challenging for most. Only one site provided evening take-home doses whereas participants at the other site could only resort to the illicit opioid supply to address withdrawal outside of program hours. Participants described the clinics as providing a positive and familial social environment compared to experiences of stigma elsewhere. Medication interruptions did occur when participants were in hospital and custodial settings, leading to withdrawal, program discontinuation, and overdose risk.

Conclusions
This study highlights the beneficial ways in which health services tailored for people who use drugs can create a stigma-free environment with an emphasis on social bonds. Other factors such as transportation access, dispensing policies, and access in rural hospitals and custodial settings produced unique challenges for rural people who use drugs. Public health authorities in rural and smaller settings should consider these factors when designing, implementing, and scaling up future substance use services, including TiOAT programs.
Outcome of patients with soft tissue sarcomas of the extremities and trunk treated by (neo)adjuvant intensity modulated radiation therapy with curative intent
Authors: Dapper Hendrik , Diehl Christian , Knebel Carolin , Mogler Carolin , Borm Kai , Dobiasch Sophie , Combs Stephanie E. , Peeken Jan C. 
Published: March 2023

Abstract
Background
Soft tissue sarcomas (STS) are a relatively rare group of malignant tumors. Currently, there is very little published clinical data, especially in the context of curative multimodal therapy with image-guided, conformal, intensity-modulated radiotherapy.

Methods
Patients who received preoperative or postoperative intensity-modulated radiotherapy for STS of the extremities or trunk with curative intent were included in this single centre retrospective analysis. A Kaplan–Meier analysis was performed to evaluate survival endpoints. Multivariable proportional hazard models were used to investigate the association between survival endpoints and tumour-, patient-, and treatment-specific characteristics.

Results
86 patients were included in the analysis. The most common histological subtypes were undifferentiated pleomorphic high-grade sarcoma (UPS) (27) and liposarcoma (22). More than two third of the patients received preoperative radiation therapy (72%). During the follow-up period, 39 patients (45%) suffered from some type of relapse, mainly remote (31%). The two-years overall survival rate was 88%. The median DFS was 48 months and the median DMFS was 51 months. Female gender (HR 0.460 (0.217; 0.973)) and histology of liposarcomas compared to UPS proved to be significantly more favorable in terms of DFS (HR 0.327 (0.126; 0.852)).

Conclusion
Conformal, intensity-modulated radiotherapy is an effective treatment modality in the preoperative or postoperative management of STS. Especially for the prevention of distant metastases, the establishment of modern systemic therapies or multimodal therapy approaches is necessary.
Calibration procedure and biomechanical validation of an universal six degree-of-freedom robotic system for hip joint testing
Authors: Rychlik Michal , Wendland Georg , Jackowski Michal , Rennert Roland , Schaser Klaus-Dieter , Nowotny Joerg 
Published: March 2023

Abstract
Purpose
Among various test methods for different human joints, the use of robot systems has attracted major interest and inherits the potential to become a gold standard in biomechanical testing in the future. A key issue associated with those robot-based platforms is the accurate definition of parameters, e.g., tool center point (TCP), length of tool or anatomical trajectories of movements. These must be precisely correlated to the physiological parameters of the examined joint and its corresponding bones. Exemplified for the human hip joint, we are creating an accurate calibration procedure for a universal testing platform by using a six degree-of-freedom (6 DOF) robot and optical tracking system for recognition of anatomical movements of the bone samples.

Methods
A six degree-of-freedom robot (TX 200, Stäubli) has been installed and configured. The physiological range of motion of the hip joint composed of a femur and a hemipelvis was recorded with an optical 3D movement and deformation analysis system (ARAMIS, GOM GmbH). The recorded measurements were processed by automatic transformation procedure (created in Delphi software) and evaluated in 3D CAD system.

Results
The physiological ranges of motion were reproduced for all degrees of freedom with the six degree-of-freedom robot in adequate accuracy. With the establishment of a special calibration procedure by using a combination of different coordinate systems, we were able to achieve a standard deviation of the TCP depending of the axis between 0.3 and 0.9 mm and for the length of tool between + 0.67 and − 0.40 mm (3D CAD processing) resp. + 0.72 mm to − 0.13 mm (Delphi transformation). The accuracy between the manual and robotic movement of the hip shows an average deviation between − 0.36 and + 3.44 mm for the points on the movement trajectories.

Conclusion
A six degree-of-freedom robot is appropriate to reproduce the physiological range of motion of the hip joint. The described calibration procedure is universal and can be used for hip joint biomechanical tests allowing to apply clinically relevant forces and investigate testing stability of reconstructive osteosynthesis implant/endoprosthetic fixations, regardless of the length of the femur, size of the femoral head and acetabulum or whether the entire pelvis or only the hemipelvis will be used.
Subtype-specific kinase dependency regulates growth and metastasis of poor-prognosis mesenchymal colorectal cancer
Authors: Buikhuisen Joyce Y. , Gomez Barila Patricia M. , Cameron Kate , Suijkerbuijk Saskia J. E. , Lieftink Cor , di Franco Simone , Krotenberg Garcia Ana , Uceda Castro Rebeca , Lenos Kristiaan J. , Nijman Lisanne E. , Torang Arezo , Longobardi Ciro , de Jong Joan H. , Dekker Daniëlle , Stassi Giorgio , Vermeulen Louis , Beijersbergen Roderick L. , van Rheenen Jacco , Huveneers Stephan , Medema Jan Paul 
Published: March 2023

AbstractBackgroundColorectal cancer (CRC) can be divided into four consensus molecular subtypes (CMS), each with distinct biological features. CMS4 is associated with epithelial-mesenchymal transition and stromal infiltration (Guinney et al., Nat Med 21:1350–6, 2015; Linnekamp et al., Cell Death Differ 25:616–33, 2018), whereas clinically it is characterized by lower responses to adjuvant therapy, higher incidence of metastatic spreading and hence dismal prognosis (Buikhuisen et al., Oncogenesis 9:66, 2020).MethodsTo understand the biology of the mesenchymal subtype and unveil specific vulnerabilities, a large CRISPR-Cas9 drop-out screen was performed on 14 subtyped CRC cell lines to uncover essential kinases in all CMSs. Dependency of CMS4 cells on p21-activated kinase 2 (PAK2) was validated in independent 2D and 3D in vitro cultures and in vivo models assessing primary and metastatic outgrowth in liver and peritoneum. TIRF microscopy was used to uncover actin cytoskeleton dynamics and focal adhesion localization upon PAK2 loss. Subsequent functional assays were performed to determine altered growth and invasion patterns.ResultsPAK2 was identified as a key kinase uniquely required for growth of the mesenchymal subtype CMS4, both in vitro and in vivo. PAK2 plays an important role in cellular attachment and cytoskeletal rearrangements (Coniglio et al., Mol Cell Biol 28:4162–72, 2008; Grebenova et al., Sci Rep 9:17171, 2019). In agreement, deletion or inhibition of PAK2 impaired actin cytoskeleton dynamics in CMS4 cells and, as a consequence, significantly reduced invasive capacity, while it was dispensable for CMS2 cells. Clinical relevance of these findings was supported by the observation that deletion of PAK2 from CMS4 cells prevented metastatic spreading in vivo. Moreover, growth in a model for peritoneal metastasis was hampered when CMS4 tumor cells were deficient for PAK2.ConclusionOur data reveal a unique dependency of mesenchymal CRC and provide a rationale for PAK2 inhibition to target this aggressive subgroup of colorectal cancer.
Target attainment and population pharmacokinetics of flucloxacillin in critically ill patients: a multicenter study
Authors: Meenks Sjoerd D. , Punt Nieko , le Noble Jos L. M. L. , Foudraine Norbert A. , Neef Kees , Janssen Paddy K. C. 
Published: March 2023

Abstract
Purpose
Insufficient antimicrobial exposure has been associated with worse clinical outcomes. Reportedly, flucloxacillin target attainment in critically ill patients was heterogeneous considering the study population selection and reported target attainment percentages. Therefore, we assessed flucloxacillin population pharmacokinetics (PK) and target attainment in critically ill patients.

Methods
This prospective, multicenter, observational study was conducted from May 2017 to October 2019 and included adult, critically ill patients administered flucloxacillin intravenously. Patients with renal replacement therapy or liver cirrhosis were excluded. We developed and qualified an integrated PK model for total and unbound serum flucloxacillin concentrations. Monte Carlo dosing simulations were performed to assess target attainment. The unbound target serum concentration was four times the minimum inhibitory concentration (MIC) for ≥ 50% of the dosing interval (ƒT>4xMIC ≥ 50%).

Results
We analyzed 163 blood samples from 31 patients. A one-compartment model with linear plasma protein binding was selected as most appropriate. Dosing simulations revealed 26% ƒT>2 mg/L ≥ 50% following continuous infusion of 12 g flucloxacillin and 51% ƒT>2 mg/L ≥ 50% for 24 g.

Conclusion
Based on our dosing simulations, standard flucloxacillin daily doses of up to 12 g may substantially enhance the risk of underdosing in critically ill patients. Prospective validation of these model predictions is needed.