bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PD2-07: Tumor CD73 regulates zoledronate induced TIL accumulation into triple negative breast cancer
Authors: Petruk Nataliia , Siddiqui Arafat , Tadayon Sina , Jukkola Arja , Määttä Jorma , Mattila Pieta , Sandholm Jouko , Selander Katri S. 
Published: March 2023

Abstract
Background: CD73 is a membrane-bound protein that by extracellular adenosine production, regulates immune cell function. Low CD73 expression is associated with better prognosis among triple-negative breast cancer (TNBC) patients. Adjuvant bisphosphonates (BPs, such as zoledronate) improve survival among post-menopausal breast cancer patients, but the mechanism for this is unknown. Since BPs also affect immune cells, we studied 1) whether zoledronate-treatment has an effect on tumor infiltrating lymphocytes (TILs) and 2) whether tumor CD73 expression affects these responses in TNBC tumors. Methods: 4T1 mouse mammary cells, stably expressing non-targeting shRNA (sh-NT, control cells) or sh-CD73 were inoculated into the mammary fat pads of Balb/c mice. The mice were treated with i.p. vehicle or zoledronate (ZOL) each 4th day for total of six times. Additionally, to deplete B-cells, the mice were treated with an anti-CD20 or control IgG antibody. Tumor sizes were assessed with a caliper, TILs were studied with immunostainings. Blood lymphocytes were analyzed with Flow cytometry. Results: Sh-CD73 cells formed significantly smaller tumors, than sh-NT cells. ZOL significantly inhibited the growth of both sh-CD73 and sh-NT tumors, but at sacrifice, this effect of ZOL was more significant against sh-CD73 tumors. ZOL increased the % of CD19+/CD21+ and CD19+/23+ in blood of both mice groups, and this effect was inhibited by anti-CD20 antibody. Although neither treatment alone had an effect, the % of CD3+/CD8+ cells in blood were increased in both mice groups by the combination of ZOL and anti-CD20-antibody. ZOL induced accumulation of B220+, CD4+ and CD8+ TILs into both tumor groups. These TIL effects were reduced with anti-CD20 antibody treatment. Anti-CD20 antibody alone inhibited significantly sh-CD73 tumor growth. Anti-CD20 antibody did not interfere with ZOL inhibition of tumor growth in either group. Conclusions: ZOL has inflammatory effects on blood lymphocytes and TILs, which may be affected by tumor expression of immune system regulating proteins, such as CD73. B cell depletion may further prevent tumor growth, in the context of CD73 inhibition. Further studies are needed to investigate whether B-cell inhibition affects ZOL-induced tumor growth inhibition.
Citation Format: Nataliia Petruk, Arafat Siddiqui, Sina Tadayon, Arja Jukkola, Jorma Määttä, Pieta Mattila, Jouko Sandholm, Katri S. Selander. Tumor CD73 regulates zoledronate induced TIL accumulation into triple negative breast cancer. [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 PD2-07.
Abstract PD5-07: PD5-07 Hepatic Leukemia Factor (HLF), a potential therapeutic target in triple negative breast cancer
Authors: BOUAKKA Ibrahim , TRAN-DIEN Alicia , SIREROL Marine , Silvin Aymeric , Andre Fabrice , ROCCA Anna 
Published: March 2023

Abstract
The importance of the antitumor immune response in triple negative breast cancer (TNBC) is well established. We showed previously that the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after neoadjuvant chemotherapy is associated with a better prognosis. By analyzing 99 pretreatment samples we discovered that the expression of the transcription factor Hepatic Leukemia Factor (HLF) in tumor cells is associated with lower infiltration of immune cells, leading to bad prognosis. Thereby, the aim of our project is to investigate the cellular and molecular mechanism regulated by HLF to better understand the tumor immune microenvironment, so we can develop better treatment options for patients with TNBC. Analysis of publicly available datasets of TNBC (METABRIC and TCGA) showed that tumors with low levels of HLF correlate with the upregulation of genes involved in biological processes associated with the regulation of immune response and in particular with neutrophils activation. Analysis of HLF expression patterns in these patients indicate that tumors presenting a mesenchymal profile exhibited higher HLF levels than the other TNBC subtypes. To elucidate the mechanism of this phenomenon regulated by HLF and his implication in anti-tumoral immune response, we developed several human TNBC cell lines knock-out or knock-down for our target gene using CRISPR/Cas9 editing technology. Comparison of the transcriptomes showed that the silencing of HLF in some mesenchymal TNBC cell lines lead to the upregulation of components involved in the attraction and activation of neutrophils, including CXCL8 (Neutrophil-activating peptide 1), a major cytokine directly responsible for the attraction of neutrophils in the tumor site. In vitro migration experiments supported these observations since purified blood circulating neutrophils have defective migration capacity that depends on the presence or absence of HLF. Finally, the co-culture of neutrophils with tumor cells silenced for HLF showed us, using a large panel of antibodies by spectral flow cytometry, an activated state of mature neutrophils. In conclusion, our study suggest that HLF plays a fundamental role in the regulation of genes involved in the control of tumoral immune microenvironment through the attraction and the activation of mature neutrophils. These findings have the potential for important implications since they suggest that HLF can be a potential target in treating TNBC.
Citation Format: Ibrahim BOUAKKA, Alicia TRAN-DIEN, Marine SIREROL, Aymeric Silvin, Fabrice Andre, Anna ROCCA. PD5-07 Hepatic Leukemia Factor (HLF), a potential therapeutic target in triple negative breast cancer [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 PD5-07.
Abstract PD5-10: PD5-10 Dual therapeutic targeting of CDK8/19 and mTOR in triple negative breast cancer
Authors: Ding Xiaokai , Ji Hao , Sharko Amanda C. , Loskutov Juergen , Mack Zachary , Myers Jadyn , Chen Mengqian , Pugacheva Elena , Roninson Igor , Broude Eugenia 
Published: March 2023

Abstract
Triple negative breast cancer (TNBC) is the most aggressive subtype of all breast cancers. However, unlike other breast cancer subtypes, current treatments for TNBC are restricted and this scarcity of viable options is the key contributor to the poorer prognosis. Despite early response, almost all the targeted drugs tested in TNBC eventually fail due to the development of resistance. Patients’ data have shown that the expression level of Mediator kinases CDK8 and CDK19 are elevated in TNBC, and that higher expression of CDK8/19 is correlated with more advanced diseases and worse prognosis. Selective CDK8/19 inhibitor SNX631, when used as a single agent, inhibited the growth of several TNBC cell lines in vitro, cell-derived xenografts (CDXs) as well as patient derived xenografts (PDXs) in vivo, suggesting the potential of targeting CDK8/19 in treating TNBC. We also analyzed the effect of CDK8/19 inhibition on the outcome of treatment with mTORC1 inhibitor everolimus (RAD001), an approved drug for several cancers with mutations of PTEN or PI3KCA. SNX631 exhibited a synergistic effect in combination with everolimus on suppressing TNBC cell growth in vitro. In vivo treatment with everolimus alone achieved a strong tumor growth inhibition in TNBC xenograft models but all the tumors eventually resumed growth, indicated the development of resistance. Significantly, the addition of a CDK8/19 inhibitor prevented the emergence of in vivo everolimus resistance both in CDX and PDX tumors upon treatment for up to 150 days, suggesting a potential for extending remission or even achieving cures in TNBC. Transcriptomic analysis demonstrated that this effect was due to the prevention of transcriptional reprogramming associated with everolimus resistance in tumor cells.
Citation Format: Xiaokai Ding, Hao Ji, Amanda C. Sharko, Juergen Loskutov, Zachary Mack, Jadyn Myers, Mengqian Chen, Elena Pugacheva, Igor Roninson, Eugenia Broude. PD5-10 Dual therapeutic targeting of CDK8/19 and mTOR in triple negative breast cancer [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 PD5-10.
Sensitivity of Intrinsic Error Growth to Large-Scale Uncertainty Structure in a Record-Breaking Summertime Rainfall Event
Authors: Zhang Yunji 
Published: March 2023

Abstract
It is recognized that the atmosphere’s predictability is intrinsically limited by unobservably small uncertainties that are beyond our capability to eliminate. However, there have been discussions in recent years on whether forecast error grows upscale (small-scale error grows faster and transfers to progressively larger scales) or up-amplitude (grows at all scales at the same time) when unobservably small-amplitude initial uncertainties are imposed at the large scales and limit the intrinsic predictability. This study uses large-scale small-amplitude initial uncertainties of two different structures—one idealized, univariate, and isotropic, the other realistic, multivariate, and flow dependent—to examine the error growth characteristics in the intrinsic predictability regime associated with a record-breaking rainfall event that happened on 19–20 July 2021 in China. Results indicate upscale error growth characteristics regardless of the structure of the initial uncertainties: the errors at smaller scales grow fastest first; as the forecasts continue, the wavelengths of the fastest error growth gradually shift toward larger scales with reduced error growth rates. Therefore, error growth from smaller to larger scales was more important than the growth directly at the large scales of the initial errors. These upscale error growth characteristics also depend on the perturbed and examined quantities: if the examined quantity is perturbed, then its errors grow upscale; if there is no initial uncertainty in the examined quantity, then its errors grow at all scales at the same time, although its smaller-scale errors still grow faster for the first several hours, suggesting the existence of the upscale error growth.

Significance Statement
This study compared the error growth characteristics associated with the atmosphere’s intrinsic predictability under two different structures of unobservably small-amplitude, large-scale initial uncertainties: one idealized, univariate, and isotropic, the other realistic, multivariate, and flow dependent. The characteristics of the errors growing upscale rather than up-amplitude regardless of the initial uncertainties’ structure are apparent. The large-scale errors do not grow if their initial amplitudes are much bigger than the small-scale errors. This study also examined how the error growth characteristics will change when the quantity that is used to describe the error growth is inconsistent with the quantity that contains uncertainty, suggesting the importance of including multivariate, covariant uncertainties of state variables in atmospheric predictability studies.
Barotropic and Nonlinear Decay of the Wintertime Baroclinic Wave Packets over the North Pacific: Energetics Analysis
Authors: Zhuge Anran , Tan Benkui , Bueh Cholaw , Xie Zuowei 
Published: March 2023

Abstract
Based on daily data from the Japanese 55-year Reanalysis (JRA-55) covering the winters (NDJFM) from 1958 to 2018, this study examines the growth and decay mechanisms of the baroclinic wave packet (BWP) inferred from regression analysis over the North Pacific. Day-to-day kinetic energy (KE) and available potential energy (APE) budget analysis suggest that BWP is driven mainly by baroclinic energy conversion (CPB), barotropic energy conversion (CKB), and the nonlinear term (CKE). CPB acts as a predominant APE source for BWP. Part of CPB acts to overcome the APE loss caused by transient eddy flux and most of it acts as a dominant KE source to drive BWP throughout its lifespan. CKB acts as a KE source before day −1, and as a major KE sink to damp BWP afterward, in which the north–south gradient of the climatological meridional flow plays a key role. Similarly, CKE acts as a KE source before day 0 and as a major KE sink afterward. The damping effect of CKE comes mainly from the scale interaction through the advection of high-frequency meridional momentum by the low-frequency zonal flow. It turns out that the vertical geopotential flux divergence also plays an active role in the dynamical coupling of different vertical BWP parts. There is persistent geopotential flux transfer from the middle-tropospheric layer into the lower- and upper-tropospheric layers, which serves as a major KE source to drive the BWP anomalies for the two layers and a major KE sink for the middle-tropospheric layer where the baroclinic energy conversion is the strongest.

Significance Statement
Previous studies indicate that baroclinic waves tend to organize into wave packets and are driven by the baroclinic instability. This study finds that the baroclinic waves decay mainly through the barotropic energy conversion and nonlinear processes. The results also indicate that the vertical geopotential flux divergence plays an active role in the dynamical coupling of the BWP anomalies in different layers of the troposphere. It is therefore very important to improve the representations of the climatological-mean flow, wave–mean flow interaction, and wave–wave interaction between high- and low-frequency waves in the midlatitudes, as well as the process of vertical transfer of the geopotential flux in numerical models for a better prediction of weather and climate variability in the extratropic regions.
A comparative study of four thoracic mortality scores
Authors: Schlachtenberger Georg , Doerr Fabian , Menghesha Hruy , Amorin Andres , Gaisendrees Christopher , Miesen Sebastian , Seibel Christian , Wahlers Thorsten , Hekmat Khosro , Heldwein Matthias B. 
Published: March 2023

Background The percentage of patients in resectable stages at initial diagnosis of non-small cell lung cancer (NSCLC) raises due to better screening programs. Therefore, risk prediction models are becoming more critical. Here, we validated and compared four established scoring models, the Thoracoscore, Epithor, Eurloung 2, and the simplified Eurolung 2 (2b), in their ability to predict 30-day mortality. Methods All consecutive patients undergoing anatomical pulmonary resection were included. The performance of the four scoring systems was assessed with Hosmer–Lemeshow goodness-of-fit test (calibration) and receiver operating characteristic (ROC) curves (discrimination). We compared the area under the curve (AUC) of the ROC curves by DeLong's method. Results A total of 624 patients underwent surgery for NSCLC at our institution between 2012 and 2018 30-day mortality was 2.2% (14 patients). The AUC for Eurolung 2 and the simplified Eurolung 2 (0.82) were greater than those of the other scoring systems, Epithor (0.71) and Thoracoscore (0.65). In addition, the DeLong analysis showed a significant superiority of Eurolung 2 and Eurolung 2b over the Thoracoscore ( p = 0.04); there were no significant differences compared to Epithor. Conclusion Eurolung 2 and the simplified Eurolung 2 were the favorable scoring systems for predicting 30-day mortality compared to Thoracoscore and Epithor. Therefore, we recommend using Eurolung 2 or the simplified Eurolung 2 for preoperative risk stratification.
Phlebological insole: Can it help in the lymphoedema treatment? A scoping review
Authors: De Michele Manuela , Mastrullo Monica , Melotto Gianluca , Tedeschi Roberto 
Published: March 2023

Background The treatment of lymphoedema requires a multi-professional and interdisciplinary approach. Despite being prescribed in the management of lymphatic disorders, the effectiveness of the phlebological insoles is still under investigation. Aim This scoping review aims to identify and analyse evidence regarding the efficacy of phlebological insoles as a conservative intervention for lower limb lymphoedema. Method The following databases were searched up to November 2022: PubMed, Cochrane Library, CINAHL Complete, PEDro and Scopus. Preventive and conservative interventions were considered. Studies considering people with lower limb oedema, of any age and type of oedema, were eligible for inclusion. No restrictions in terms of language, year of publication, study design and type of publication were applied. Additional studies were sought through grey literature. Results From 117 initial records, 3 studies met the inclusion criteria. Two quasi-experimental studies and one randomised cross-over study were included. The results of the examined studies confirmed the positive effects of insoles usage and foot and ankle mobility on the venous return. Conclusion This scoping review provided an overview of the topic. The studies analysed in this scoping review have shown that insoles seem to be beneficial in reducing the lower limb oedema in healthy individuals. However, there are still no comprehensive trials confirming this evidence on people with lymphoedema. The small number of identified articles, the selection of participants not affected by lymphoedema, the use of heterogeneous devices in terms of modifications and materials highlight the need of further investigations. Future trails should include people affected by lymphoedema, address the choice of materials in manufacturing the insoles and take in consideration the patients’ adherence to the device and concordance to the treatment.
Bridging gaps across levels of care in rehabilitation of patients with rheumatic and musculoskeletal diseases: Results from a stepped-wedge cluster randomized controlled trial
Authors: Berdal Gunnhild , Sand-Svartrud Anne-Lene , Linge Anita Dyb , Aasvold Ann Margret , Tennebø Kjetil , Eppeland Siv G , Hagland Anne Sirnes , Ohldieck-Fredheim Guro , Valaas Helene Lindtvedt , Bø Ingvild , Klokkeide Åse , Sexton Joseph , Azimi Maryam , Dager Turid N , Kjeken Ingvild 
Published: March 2023

Objective To compare the effectiveness of a structured goal-setting and tailored follow-up rehabilitation intervention with existing rehabilitation in patients with rheumatic and musculoskeletal diseases. Design A pragmatic stepped-wedge cluster randomized trial. Setting Eight rehabilitation centers in secondary healthcare, Norway. Participants A total of 374 adults with rheumatic and musculoskeletal diseases were included in either the experimental (168) or the control group (206). Interventions A new rehabilitation intervention which comprised structured goal setting, action planning, motivational interviewing, digital self-monitoring of goal progress, and individual follow-up support after discharge according to patients’ needs and available resources in primary healthcare (the BRIDGE-intervention), was compared to usual care. Main measures Patient-reported outcomes were collected electronically on admission and discharge from rehabilitation, and after 2, 7, and 12 months. The primary outcome was patients’ goal attainment measured by the Patient Specific Functional Scale (0–10, 10 best) at 7 months. Secondary outcome measures included physical function (30-s Sit-To-Stand test), health-related quality of life (EQ-5D-5L-index), and self-assessed health (EQ-VAS). The main statistical analyses were performed on an intention-to-treat basis using linear mixed models. Results No significant treatment effects of the BRIDGE-intervention were found for either primary (Patient Specific Functional Scale mean difference 0.1 [95% CI: −0.5, 0.8], p = 0.70), or secondary outcomes 7 months after rehabilitation. Conclusion The BRIDGE-intervention was not shown to be more effective than existing rehabilitation for patients with rheumatic and musculoskeletal diseases. There is still a need for more knowledge about factors that can improve the quality, continuity, and long-term health effects of rehabilitation for this patient group.
Minimum effective volume of ropivacaine for ultrasound-guided adductor canal + IPACK block in total knee arthroplasty: A double-blind, randomized dose-finding trial
Authors: Wang Qiuru , Ma Ting , Hu Jian , Yang Jing , Kang Pengde 
Published: March 2023

Background Our previous study reported that when a respective 20 mL of ropivacaine was used for adductor canal block (ACB) combined with infiltration between the popliteal artery and capsule of the posterior knee (IPACK) block for patients undergoing total knee arthroplasty (TKA), the minimum concentration of 0.275% could provide successful block in almost all patients. Based on the results, the primary objective of this study was to investigate the minimum effective volume (MEV90, defined as the volume which can provide successful block in 90% of patients) of ACB + IPACK block. Methods This double-blind, randomized dose-finding trial was based on a biased coin up-and-down sequential design, where the volume of ropivacaine administered to a given patient depended on the previous patient’s response. The first patient received 15 mL of 0.275% ropivacaine for ACB and again for IPACK. If the block failed, the next subject received a 1 mL higher volume for ACB and IPACK, respectively; otherwise, the next subject received either a 1 mL lower volume (probability of 0.11) or the same volume (probability of 0.89). The primary outcome was whether the block was successful. Block success was defined as the patient did not suffer significant pain and did not receive rescue analgesia within 6 h after surgery. Then the MEV90 was estimated by isotonic regression. Results Based on analysis of 53 patients, the MEV90 was 17.99 mL (95% CI 17.47–18.61 mL), MEV95 was 18.48 mL (95% CI 17.45–18.98 mL) and MEV99 was 18.90 mL (95% CI 17.38–19.07 mL). Patients whose blocks succeeded had significantly lower NRS pain scores, lower morphine consumption, and shorter hospitalization. Conclusion 0.275% ropivacaine in 17.99 mL respectively can provide successful ACB + IPACK block in 90% of patients undergoing TKA. The minimum effective volume (MEV90) of ACB + IPACK block was 17.99 mL.
Beyond burnout I: Doctors health services and unmet need
Authors: Lele Kiran , Mclean Loyola M , Peisah Carmelle 
Published: March 2023

Objectives Doctors’ mental health has received renewed attention given the epidemic of burnout, high suicide rates and the recent pressures of the COVID-19 pandemic. Internationally, various service designs and primary prevention initiatives have been trialled to address these needs. Systemic barriers such as stigma as well as individual characteristics of doctors have historically prevented access to mental health services. This paper outlines the Australian service context from which a new publicly funded doctors’ mental health programme emerged. Methods A narrative review of current services and a description of the challenges is outlined. Results A picture of urgency and unmet needs emerged with particular challenges, such as the need for privacy. Conclusions Doctors’ mental health is an urgent priority with direct impacts on patient safety and care. The complex context and the unmet need suggest the focus must go far beyond burnout and has prompted the establishment of a new service model designed to complement existing services in the Australian context, to be described in a sister paper.