bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nocturnal pulse oximetry for the detection and prediction of acute mountain sickness: An observational study
Authors: Joyce Kelsey E. , Ashdown Kimberly , Delamere John P. , Bradley Chris , Lewis Christopher T. , Letchford Abigail , Lucas Rebekah A. I. , Malein Will , Thomas Owen , Bradwell Arthur R. , Lucas Samuel J. E. 
Published: September 2024

AbstractAcute mountain sickness (AMS) is a well‐studied illness defined by clinical features (e.g., headache and nausea), as assessed by the Lake Louise score (LLS). Although obvious in its severe form, early stages of AMS are poorly defined and easily confused with common travel‐related conditions. Measurement of hypoxaemia, the cause of AMS, should be helpful, yet to date its utility for identifying AMS susceptibility remains unclear. This study quantified altitude‐induced hypoxaemia in individuals during an ascent to 4800 m to determine the utility of nocturnal pulse oximetry measurements for prediction of AMS. Eighteen individuals (36 ± 16 years of age) ascended to 4800 m over 12 days. Symptomology of AMS was assessed each morning via LLS criteria, with participants categorized as either AMS‐positive (LLS ≥ 3 with headache) or AMS‐negative. Overnight peripheral oxygen saturations (ov‐) were recorded continuously (1 Hz) using portable oximeters. Derivatives of these recordings were compared between AMS‐positive and ‐negative subjects (Mann–Whitney U‐test). Exploratory analyses (Pearson's) were conducted to investigate relationships between overnight parameters and AMS severity. Overnight derivatives, including ov‐, heart rate/ov‐, variance, oxygen desaturation index, hypoxic burden and total sleep time at <80% , all differed significantly between AMS‐positive and ‐negative subjects (all P < 0.01), with cumulative/relative frequency plots highlighting these differences visually. Exploratory analysis revealed that ov‐ from 3850 m was correlated with peak LLS at 4800 m (r = 0.58–0.61). The findings highlight the potential for overnight oximetry to predict AMS susceptibility during ascent to high altitude. Further investigation is required to develop, evaluate and optimize predictive models to improve AMS management and prevention.
Hypothyroidism alters the rhythmicity of the central clock, body temperature and metabolism: evidence of Bmal1 transcriptional regulation by T3
Authors: Emrich Felipe , Gomes Bruno Henrique , Selvatici‐Tolentino Letícia , Lopes Roberta Araújo , Secio‐Silva Ayla , Carvalho‐Moreira João Pedro , Bittencourt‐Silva Paloma Graziele , Guarnieri Leonardo de Oliveira , Silva Ana Bárbara de Paula , Drummond Lucas Rios , da Silva Glauber Santos Ferreira , Szawka Raphael Escorsim , Moraes Márcio Flávio Dutra , Coimbra Cândido Celso , Peliciari‐Garcia Rodrigo Antonio , Bargi‐Souza Paula 
Published: September 2024

AbstractIn mammals, the central circadian oscillator is located in the suprachiasmatic nucleus (SCN). Hypothalamus–pituitary–thyroid axis components exhibit circadian oscillation, regulated by both central clock innervation and intrinsic circadian clocks in the anterior pituitary and thyroid glands. Thyroid disorders alter the rhythmicity of peripheral clocks in a tissue‐dependent response; however, whether these effects are influenced by alterations in the master clock remains unknown. This study aimed to characterize the effects of hypothyroidism on the rhythmicity of SCN, body temperature (BT) and metabolism, and the possible mechanisms involved in this signalling. C57BL/6J adult male mice were divided into Control and Hypothyroid groups. Profiles of spontaneous locomotor activity (SLA), BT, oxygen consumption () and respiratory quotient (RQ) were determined under free‐running conditions. Clock gene expression, and neuronal activity of the SCN and medial preoptic nucleus (MPOM) area were investigated in light–dark (LD) conditions. Triiodothyronine (T3) transcriptional regulation of Bmal1 promoter activity was evaluated in GH3‐transfected cells. Hypothyroidism delayed the rhythmicity of SLA and BT, and altered the expression of core clock components in the SCN. The activity of SCN neurons and their outputs were also affected, as evidenced by the loss of circadian rhythmicity in and RQ and alterations in the neuronal activity pattern of MPOM. In GH3 cells, T3 increased Bmal1 promoter activity in a time‐dependent manner. Thyroid hormone may act as a temporal cue for the central circadian clock, and the uncoupling of central and peripheral clocks might contribute to a wide range of metabolic and thermoregulatory impairments observed in hypothyroidism.
imageKey points
Hypothyroidism alters clock gene expression in the suprachiasmatic nucleus (SCN).
Thyroid hypofunction alters the phase of spontaneous locomotor activity and body temperature rhythms.
Thyroid hormone deficiency alters the daily pattern of SCN and medial preoptic nucleus neuronal activities.
Hypothyroidism alterations are extended to daily oscillations of oxygen consumption and metabolism, which might contribute to the development of metabolic syndrome.
Triiodothyronine increases Bmal1 promoter activity acting as temporal cue for the central circadian clock.
A hierarchy of WZW models related to super Poisson–Lie T-duality
Authors: Eghbali Ali , Rezaei-Aghdam Adel 
Published: September 2024

AbstractMotivated by super Poisson–Lie (PL) symmetry of the Wess–Zumino–Witten (WZW) model based on the $$(C^3+A)$$

(

C
3

+
A
)

Lie supergroup of our previous work (Eghbali et al., in J High Energy Phys 07:134, 2013. arXiv:1303.4069 [hep-th]), we first obtain and classify all Drinfeld superdoubles (DSDs) generated by the Lie superbialgebra structures on the $$({\mathscr {C}}^3+ {\mathscr {A}})$$

(

C

3

+
A
)

Lie superalgebra as a theorem. Then, introducing a general formulation we find the conditions under which a two-dimensional $$\sigma $$
σ
-model may be equivalent to a WZW model. With the help of this formulation and starting the super PL symmetric $$(C^3+A)$$

(

C
3

+
A
)

WZW model, we get a hierarchy of WZW models related to super PL T-duality, in such a way that it is different from the super PL T-plurality, because the DSDs are, in this process, non-isomorphic. The most interesting indication of this work is that the $$(C^3+A)$$

(

C
3

+
A
)

WZW model does remain invariant under the super PL T-duality transformation, that is, the model is super PL self-dual.
Surface conversion of the dynamics of bacteria escaping chemorepellents
Authors: Braham Asma , Lemelle Laurence , Ducasse Romain , Toukabri Houyem , Mottin Eleonore , Fabrèges Benoit , Calvez Vincent , Place Christophe 
Published: September 2024

Abstract
Flagellar swimming hydrodynamics confers a recognized advantage for attachment on solid surfaces. Whether this motility further enables the following environmental cues was experimentally explored. Motile E. coli (OD ~ 0.1) in a 100 µm-thick channel were exposed to off-equilibrium gradients set by a chemorepellent Ni(NO3)2-source (250 mM). Single bacterial dynamics at the solid surface was analyzed by dark-field videomicroscopy at a fixed position. The number of bacteria indicated their congregation into a wave escaping from the repellent source. Besides the high velocity drift in the propagation direction within the wave, an unexpectedly high perpendicular component drift was also observed. Swimming hydrodynamics CW-bends the bacteria trajectories during their primo approach to the surface (< 2 µm), and a high enough tumbling frequency likely preserves a notable lateral drift. This comprehension substantiates a survival strategy tailored to toxic environments, which involves drifting along surfaces, promoting the inception of colonization at the most advantageous sites.

Graphical abstract
Constitutional BRCA1 Epimutations: A Key for Understanding Basal‐Like Breast and High‐Grade Serous Ovarian Cancer
Authors: Lønning Per E. , Nikolaienko Oleksii , Knappskog Stian 
Published: September 2024

Germline pathogenic genetic variants in the BRCA1 and BRCA2 genes are the most frequent causes of familial breast and ovarian cancer. Contrasting BRCA2, epimutations in the BRCA1 gene are frequently detected in tissue from triple‐negative breast (TNBC) and high‐grade serous ovarian cancers (HGSOC). While studies over the last decade have reported BRCA1 epimutations in white blood cells (WBC) from breast and ovarian cancer patients, the potential hazard ratio for incident TNBC and HGSOC was not formally assessed until recently.Conducting a prospective nested case‐control study on women participating in the American Women’s Health Initiative Study, we provided firm evidence that mosaic WBC BRCA1 epimutations, even at allele frequencies < 0.1%, are associated with a significantly increased risk of both incident HGSOC and TNBC > 5 years after WBC collection. In a second study assessing BRCA1 epimutations in WBC and matched tumor samples from TNBC, our results indicated such epimutations to be the underlying cause of around 20% of TNBC, far exceeding the percentage of cases carrying BRCA1 germline pathogenic genetic variants.We detected primary constitutional BRCA1 epimutations in tissues derived from all three germ layers. They occur independently of BRCA1 promoter haplotypes but are present on the same allele in all WBC within affected individuals. Moreover, epimutations are consistently found on the same allele in normal and tumor breast tissue as well as in WBC. This finding, together with BRCA1 epimutations detected in WBC from newborns, strongly indicates an early embryonic event with clonal expansion affecting all germ layers.Future work in the field must lead to an understanding of exactly when and how the BRCA1 epimutations occur and, most importantly, whether primary constitutional epimutations in genes other than BRCA1 may cause an elevated risk of other cancer types.
Abstract A006: Generation of a flexible pancreatic cancer mouse model via somatic tissue engineering
Authors: Yang Ziyue (Zoey) , Cardenas Mara , Miyauchi Akihiko , Snider Caroline , Parchem Ronald 
Published: September 2024

Abstract
Pancreatic cancer, recognized as one of the most lethal cancer types, exhibits a dismal five-year survival rate below 12%. The genetic and epigenetic heterogeneity in human cancer poses a tremendous challenge in understanding disease mechanisms and developing targeted therapeutics. Current mouse models in the field can recapitulate some features of human pathophysiology but have limitations. While tumor formation in patients is focal, most genetically engineered mouse models (GEMMs) express oncogenes throughout the pancreas. GEMMs also have limited flexibility to manipulate gene expression and model the heterogeneity of human cancer. Additionally, GEMMs require significant time for crossing and tumor formation. Tumor transplantation models offer greater flexibility, however, they often require immunodeficient mice, which limits their applications in modeling the tumor microenvironment. To overcome the limits of current mouse models, we combined the piggyBac transposon system, CRISPR/Cas9, and in vivo electroporation to engineer somatic pancreatic tissue to induce focal tumor formation in immune-competent mice. With this approach, we engineered wildtype pancreata to express oncogenic KrasG12D while knocking out multiple tumor suppressors. We optimized this protocol by generating multiplexed gRNA constructs and cell type-specific promoters to improve reproducibility. Low-grade tumors formed within 10 days after electroporation, progressed to higher grade within a month, and metastasized to peritoneal organs during disease progression. Mouse tumors also recapitulated histopathological features in human patients. Lastly, we used our novel mouse model to study how mutant Kras disrupts post-transcriptional regulation by microRNA to drive pancreatic tumorigenesis. This model offers a powerful platform for manipulating gene expression and functionality to model cancer heterogeneity, ultimately advancing precision oncology's prospects for treating human patients.
Citation Format: Ziyue (Zoey) Yang, Mara Cardenas, Akihiko Miyauchi, Caroline Snider, Ronald Parchem. Generation of a flexible pancreatic cancer mouse model via somatic tissue engineering [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A006.
Abstract A010: A patient first approach using CRISPR-directed gene editing as an augmentative therapy for the treatment of pancreatic ductile adenocarcinoma
Authors: McGill London P , Banas Kelly H , Tiesi Gregory , Kmiec Eric B 
Published: September 2024

Abstract
At the Gene Editing Institute, we are advancing a novel strategy for the treatment of pancreatic ductile adenocarcinoma by employing CRISPR-directed gene editing to disable the functions of key genes that block effective drug application including chemotherapy, radiation and immunotherapy. No matter how careful one is at designing a specific drug against a specific protein, ultimately, the tumor cell develops a workaround. A paradigm shift is required to truly overcome this formidable barrier. We’ve accomplished this by leveraging the effectiveness of standard care and augmenting it, thereby reducing patient suffering, increasing treatment tolerance and, most importantly, improving outcomes. With an enthusiastic response for this concept from the FDA- INTERFACT meeting, we have demonstrated that a carefully selected CRISPR/Cas complex disables the NRF2 gene in the tumor cell and significantly reduces the dose of chemotherapy required to halt pancreatic tumor cell growth, and consequently promoting cell death. The efficiency of gene editing approaches 70 % routinely, which destroys the function of NRF2 and enables additional killing of residual tumor cells by chemotherapeutic agents. As a consequence of CRISPR/Cas activity, we effectively reduce the amount of chemotherapy needed to kill tumor cells by over 20-fold. This level of reduction should enable patients to complete their treatment regimens more successfully, at lower dosages and with far fewer adverse side effects. In addition to reduced suffering, this will invariably prolong survival as we are augmenting already proven treatments. This approach is agnostic to the haplotype of the tumor cell and does not rely on specific biomarker composition; radically expanding the patient population that would be suitable for this type of treatment. We will discuss the impact of CRISPR/Cas-gene editing to disable specific genes, including NRF2 and mutant KRAS, to enable current therapies to work at greater efficacy and at lower dosages.
Citation Format: London P McGill, Kelly H Banas, Gregory Tiesi, Eric B Kmiec. A patient first approach using CRISPR-directed gene editing as an augmentative therapy for the treatment of pancreatic ductile adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A010.
Abstract A011: Enhanced Radiosensitivity of Pancreatic Cancer Achieved through Inhibition of Cyclin-Dependent Kinase 1
Authors: Van Matre Stetson , Huq Saaimatul , Akana Lokesh , Zuniga Oscar , Rodrigues Henrique , Wolfe Adam 
Published: September 2024

Abstract
Introduction: One of the major challenges in treating Pancreatic Ductal Adenocarcinoma (PDAC) is overcoming radioresistance. This study investigates the targeting of Cyclin-dependent kinase-1 (CDK1) through both genetic and pharmaceutical inhibition as a strategy to increase the radiosensitivity of PDAC cells. Methods: We conducted mass spectrometry and phosphoproteomics analyses to compare engineered radiation-resistant PDAC cell lines (MIA PaCa-2 and PANC-1) with their parental controls. Additionally, we examined the TCGA PDAC database to correlate clinical outcomes, such as overall survival (OS), with CDK1 mRNA expression levels in PDAC patients. Furthermore, we developed a microRNA-based TET-on inducible shRNA to specifically inhibit CDK1 expression in PDAC cell lines. In an orthotopic PDAC model, we evaluated the radiation sensitivity of PDAC tumors with or without doxycycline treatment. We also employed a selective CDK1 inhibitor, RO-3306, to target CDK1 activation, followed by in vitro experiments using immunoblotting, immunocytochemistry, and clonogenic assays. Results: Our phosphoproteomics analysis revealed a significant increase in phospho-CDK1 (Tyr15) levels in the radiation-resistant cell lines. High CDK1 expression was associated with poorer OS in PDAC patients. Additionally, we observed heightened CDK1 phosphorylation at the threonine tyrosine 14 (Tyr14) residue following radiation exposure. Through our in vivo and in vitro experiments, we demonstrated that CDK1 inhibition, in conjunction with radiation therapy, delayed tumor growth and enhanced radiosensitivity in PDAC cells. Treatment with RO-3306 caused a substantial shift of cells into the G2/M phase and disrupted DNA repair post-radiation exposure, further enhancing radiosensitivity. Conclusion: Our findings underscore the critical role of CDK1 in PDAC radioresistance. Targeting CDK1 in combination with radiotherapy shows promise for future exploration as a potential treatment strategy in PDAC.
Citation Format: Stetson Van Matre, Saaimatul Huq, Lokesh Akana, Oscar Zuniga, Henrique Rodrigues, Adam Wolfe. Enhanced Radiosensitivity of Pancreatic Cancer Achieved through Inhibition of Cyclin-Dependent Kinase 1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A011.
Abstract A012: Meta-analysis comparing the incidence of serious adverse events, overall survival, and progression-free survival in Pancreatic Adenocarcinoma patients harboring unresectable tumors treated with modified FOLFIRINOX or FOLFIRINOX regimen
Authors: Trieu Vuong , Qazi Sanjive , Fein Seymour , Maida Anthony E , Joh Tenshang , Chang Wen-Han 
Published: September 2024

Abstract
Background. The evolution of first-line treatment for advanced pancreatic adenocarcinoma (PDAC) from Gemcitabine-based therapies to FOLFIRINOX-based regimens (fluorouracil, leucovorin, irinotecan, oxaliplatin) have demonstrated significant improvements in survival outcomes, however, this was associated with increased side effects such as neuropathy, fatigue, and diarrhea due to its heightened potency. Modified versions of FOLFIRINOX (mFOLFIRINOX) have since been developed with lower doses and longer breaks between cycles to manage side effects. Methods To systematically test the efficacy and side effects of mFOLIFINOX treatment, we conducted a meta-analysis relating FOLFIRINOX treatment with modified FOLFIROX on the frequency of Grade 3 or 4 adverse events reported in published literature (9 studies), and Serious Adverse Events (SAE) recorded from clinical trials (17 arms accessed from clinicaltrials.gov) in PDAC patients with unresectable tumors. Results For adverse events occurring in greater than 10% of patients, significant reductions in the frequency of patients experiencing the following events were observed in PDAC patients treated with mFOLFIRINOX: Neutropenia (29.31 % (226/771 patients across 8 arms) versus 18.8% (144/766 across 8 arms; Fisher Exact test, 2-tailed, P &lt; 0.001)), Anorexia (18.57 % (44/237 across 3 arms) versus 5.39% (18/334 across 3 arms); P &lt; 0.001), Peripheral sensory neuropathy (10.63 % (27/254 across 2 arms) versus 3.45% (4/116 across 2 arms); P = 0.025)), and Fatigue (10.57 % (83/785 across 9 arms) versus 6.77% (55/812 across 8 arms); P = 0.007)). Examination of 8 studies (N = 635) for PDAC patients treated with FOLFIRINOX exhibited a median OS time of 11.37 (Range = 10.07 - 13.9) months. Patients treated with mFOLFIRINOX (N = 475) exhibited a median OS time of 12.8 (10.2 - 14.4) months (Two-sample Wilcoxon test, P = 0.372). Conclusions In conclusion, modified FOLFIRINOX has maintained similar efficacy while reducing severe adverse events, making it more tolerable for adjuvant treatment after surgery.
Citation Format: Vuong Trieu, Sanjive Qazi, Seymour Fein, Anthony E Maida, Tenshang Joh, Wen-Han Chang. Meta-analysis comparing the incidence of serious adverse events, overall survival, and progression-free survival in Pancreatic Adenocarcinoma patients harboring unresectable tumors treated with modified FOLFIRINOX or FOLFIRINOX regimen [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A012.
Abstract A020: Exocytosed amino acids as a selective and side effect-free therapy for pancreatic cancer
Authors: Akinlalu Alfred , Flaten Zachariah , Rasuleva Komila , Guo Ang , Mathew Sijo , Sun Dali 
Published: September 2024

Abstract
Pancreatic adenocarcinoma (PDAC) remains one of the fatal cancers due to its poor prognosis and the lack of effective treatments, often diagnosed at advanced stages. There is an urgent need for innovative and selective therapies as current treatments show limited efficacy and significant side effects. Our proteomics analysis of extracellular vesicles from PDAC tumor cells revealed a distinctive imbalance in secreted amino acids. Specifically, we found that PDAC cells preferentially excrete proteins enriched with amino acids such as isoleucine and histidine, which are linked to disease progression. By targeting these exocytosed amino acids, we observed selective toxicity against PDAC cells in both in vitro and in vivo experiments. Additionally, we identified XRN1 as a potential target influenced by these amino acids. This approach demonstrated high selectivity, targeting tumor metabolism with minimal toxicity to normal tissues, and showed to be easy to administer with sustained tumor-killing effects. Our findings suggest that targeting exocytosed amino acids offers a promising therapeutic strategy for PDAC and potentially other cancers.
Citation Format: Alfred Akinlalu, Zachariah Flaten, Komila Rasuleva, Ang Guo, Sijo Mathew, Dali Sun. Exocytosed amino acids as a selective and side effect-free therapy for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A020.