bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of a fasting mimicking diet on the metabolic health of a prospective cohort of patients with prostate cancer: a pilot implementation study
Authors: Fay-Watt V. , O’Connor S. , Roshan D. , Romeo A. C. , Longo V. D. , Sullivan F. J. 
Published: March 2022

Abstract
Background
This pilot prospective study investigated the effect of a periodic fasting mimicking diet (FMD) on metabolic health factors in patients with Prostate Cancer (PC). There is a well-documented association between PC and metabolic health. Impaired metabolic health is a significant risk factor for the development of PC, and a metabolic syndrome can be induced by hormonal therapies commonly required for its management. (ClinicalTrials.gov Identifier: NCT04292041).

Methods
We introduced a periodic 4-day FMD -low in calories, sugars, and proteins but high in unsaturated fats -to a cohort of PC patients and features of metabolic syndrome. 29/35 patients completed 3-monthly cycles of the 4-consecutive day packaged FMD. We compared the subjects’ baseline weight, abdominal circumference (AC), blood pressure (BP) and selected laboratory results to the same measurements 3-months after completing the FMD cycles.

Results
Several important metabolic factors showed improvements post-intervention. On average patients’ weights dropped by 3.79 kg (95% CI: −5.61, −1.97, p = 0.0002). AC was reduced on average by 4.57 cm, (95% CI: −2.27, −6.87, p = 0.0003). There was also a decrease in systolic and diastolic BP by 9.52 mmHg (95% CI: −16.16, −2.88, p = 0.0066) and 4.48 mmHg (95% CI: −8.85, −0.43, p = 0.0316) respectively. A sub-analysis indicates that FMD had more relevant effects in ‘at-risk’ patients than those with normal values of risk factors for metabolic syndrome. For example, subjects with baseline levels of systolic BP > 130 mmHg experienced a greater reduction in BP(−16.04 mmHg, p = 0.0001) than those with baseline systolic BP < 130 mmHg (−0.78 mmHg, p = 0.89).

Conclusions
The FMD cycles were safely introduced to this small cohort of PC patients with little or no observed toxicity, and a high overall compliance of 83%. Analysis of the metabolic variables showed an overall decrease in weight, AC, and BP. Larger clinical trials focused on metabolic risk factors, PC quality of life and progression free survival are needed to assess the effect of the FMD on prostate cancer patients.
Structural diversity of p63 and p73 isoforms
Authors: Osterburg Christian , Dötsch Volker 
Published: March 2022

Abstract
The p53 protein family is the most studied protein family of all. Sequence analysis and structure determination have revealed a high similarity of crucial domains between p53, p63 and p73. Functional studies, however, have shown a wide variety of different tasks in tumor suppression, quality control and development. Here we review the structure and organization of the individual domains of p63 and p73, the interaction of these domains in the context of full-length proteins and discuss the evolutionary origin of this protein family.

Facts

Distinct physiological roles/functions are performed by specific isoforms.

The non-divided transactivation domain of p63 has a constitutively high activity while the transactivation domains of p53/p73 are divided into two subdomains that are regulated by phosphorylation.

Mdm2 binds to all three family members but ubiquitinates only p53.

TAp63α forms an autoinhibited dimeric state while all other vertebrate p53 family isoforms are constitutively tetrameric.

The oligomerization domain of p63 and p73 contain an additional helix that is necessary for stabilizing the tetrameric states. During evolution this helix got lost independently in different phylogenetic branches, while the DNA binding domain became destabilized and the transactivation domain split into two subdomains.

Open questions

Is the autoinhibitory mechanism of mammalian TAp63α conserved in p53 proteins of invertebrates that have the same function of genomic quality control in germ cells?

What is the physiological function of the p63/p73 SAM domains?

Do the short isoforms of p63 and p73 have physiological functions?

What are the roles of the N-terminal elongated TAp63 isoforms, TA* and GTA?
The role of dietary sugars, overweight, and obesity in type 2 diabetes mellitus: a narrative review
Authors: Veit Meike , van Asten Renske , Olie Andries , Prinz Philip 
Published: March 2022

AbstractNowadays, there is still a popular belief that dietary sugars, in particular sucrose, are directly linked to the development of type 2 diabetes mellitus (T2DM). Furthermore, since insulin action is impaired in T2DM, it is still believed that excluding dietary sugars from the diet can adequately treat T2DM. This might be based on the assumption that dietary sugars have a stronger impact on blood glucose levels than other carbohydrates. Therefore, the aim of this review is to discuss the effects of dietary sugars intake, including sugar-sweetened beverages (SSBs) against the background of overall energy intake and weight gain in the development of T2DM. Furthermore, the effect of dietary sugars, including SSBs on glycemic control will be discussed. Results from various systematic reviews and meta-analyses do not support the idea that the intake of sucrose and other dietary sugars is linked to T2DM. Long-chain or complex carbohydrates can have a greater impact on postprandial glycemic response than sucrose. SSBs do not affect glycemic control if substituted for other calorie sources. Current scientific evidence clearly points toward excess energy intake followed by excess body fat gain being most relevant in the development of T2DM.
Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures
Authors: Dhanwani Rekha , Lima-Junior João Rodrigues , Sethi Ashu , Pham John , Williams Gregory , Frazier April , Xu Yaqian , Amara Amy W. , Standaert David G. , Goldman Jennifer G. , Litvan Irene , Alcalay Roy N. , Peters Bjoern , Sulzer David , Arlehamn Cecilia S. Lindestam , Sette Alessandro 
Published: March 2022

AbstractParkinson’s disease (PD) is a multi-stage neurodegenerative disorder with largely unknown etiology. Recent findings have identified PD-associated autoimmune features including roles for T cells. To further characterize the role of T cells in PD, we performed RNA sequencing on PBMC and peripheral CD4 and CD8 memory T cell subsets derived from PD patients and age-matched healthy controls. When the groups were stratified by their T cell responsiveness to alpha-synuclein (α-syn) as a proxy for an ongoing inflammatory autoimmune response, the study revealed a broad differential gene expression profile in memory T cell subsets and a specific PD associated gene signature. We identified significant enrichment of transcriptomic signatures previously associated with PD, including for oxidative stress, phosphorylation, autophagy of mitochondria, cholesterol metabolism and inflammation, and the chemokine signaling proteins CX3CR1, CCR5, and CCR1. In addition, we identified genes in these peripheral cells that have previously been shown to be involved in PD pathogenesis and expressed in neurons, such as LRRK2, LAMP3, and aquaporin. Together, these findings suggest that features of circulating T cells with α-syn-specific responses in PD patients provide insights into the interactive processes that occur during PD pathogenesis and suggest potential intervention targets.
Dysregulated affective arousal regulates reward-based decision making in patients with schizophrenia: an integrated study
Authors: Liu Hong-Hsiang , Liu Chih-Min , Hsieh Ming H. , Chien Yi-Ling , Hsu Yung-Fong , Lai Wen-Sung 
Published: March 2022

AbstractSchizophrenia is a chronic and severe mental disorder. Dysregulated decision-making and affective processing have been implicated in patients with schizophrenia (SZ) and have significant impacts on their cognitive and social functions. However, little is known about how affective arousal influences reward-based decision-making in SZ. Taking advantage of a two-choice probabilistic gambling task and utilizing three facial expressions as affective primes (i.e., neutral, angry, and happy conditions) in each trial, we investigated how affective arousal influences reward-related choice based on behavioral, model fitting, and feedback-related negativity (FRN) data in 38 SZ and 26 healthy controls (CTRL). We also correlated our measurements with patients’ symptom severity. Compared with the CTRL group, SZ expressed blunted responses to angry facial primes. They had lower total game scores and displayed more maladaptive choice strategies (i.e., less win-stay and more lose-shift) and errors in monitoring rewards. Model fitting results revealed that the SZ group had a higher learning rate and lower choice consistency, especially in the happy condition. Brain activity data further indicated that SZ had smaller amplitudes of FRN than their controls in the angry and happy conditions. Importantly, the SZ group exhibited attenuated affective influence on decision-making, and their impairments in decision-making were only correlated with their clinical symptoms in the angry condition. Our findings imply the affective processing is dysregulated in SZ and it is selectively involved in the regulation of choice strategies, choice behaviors, and FRN in SZ, which lead to impairments in reward-related decision-making, especially in the angry condition.
KRAS is vulnerable to reversible switch-II pocket engagement in cells
Authors: Vasta James D. , Peacock D. Matthew , Zheng Qinheng , Walker Joel A. , Zhang Ziyang , Zimprich Chad A. , Thomas Morgan R. , Beck Michael T. , Binkowski Brock F. , Corona Cesear R. , Robers Matthew B. , Shokat Kevan M. 
Published: March 2022

AbstractCurrent small-molecule inhibitors of KRAS(G12C) bind irreversibly in the switch-II pocket (SII-P), exploiting the strong nucleophilicity of the acquired cysteine as well as the preponderance of the GDP-bound form of this mutant. Nevertheless, many oncogenic KRAS mutants lack these two features, and it remains unknown whether targeting the SII-P is a practical therapeutic approach for KRAS mutants beyond G12C. Here we use NMR spectroscopy and a cellular KRAS engagement assay to address this question by examining a collection of SII-P ligands from the literature and from our own laboratory. We show that the SII-Ps of many KRAS hotspot (G12, G13, Q61) mutants are accessible using noncovalent ligands, and that this accessibility is not necessarily coupled to the GDP state of KRAS. The results we describe here emphasize the SII-P as a privileged drug-binding site on KRAS and unveil new therapeutic opportunities in RAS-driven cancer.
Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial
Authors: Neelapu Sattva S. , Dickinson Michael , Munoz Javier , Ulrickson Matthew L. , Thieblemont Catherine , Oluwole Olalekan O. , Herrera Alex F. , Ujjani Chaitra S. , Lin Yi , Riedell Peter A. , Kekre Natasha , de Vos Sven , Lui Christine , Milletti Francesca , Dong Jinghui , Xu Hairong , Chavez Julio C. 
Published: March 2022

AbstractHigh-risk large B-cell lymphoma (LBCL) has poor outcomes with standard first-line chemoimmunotherapy. In the phase 2, multicenter, single-arm ZUMA-12 study (ClinicalTrials.gov NCT03761056) we evaluated axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as part of first-line treatment in 40 patients with high-risk LBCL. This trial has completed accrual. The primary outcome was complete response rate (CRR). Secondary outcomes were objective response rate (ORR), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), assessment of safety, central nervous system (CNS) relapse and blood levels of CAR T cells and cytokines. The primary endpoint in efficacy-evaluable patients (n = 37) was met, with 78% CRR (95% confidence interval (CI), 62–90) and 89% ORR (95% CI, 75–97). As of 17 May 2021 (median follow-up, 15.9 months), 73% of patients remained in objective response; median DOR, EFS and PFS were not reached. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in three patients (8%) and nine patients (23%), respectively. There were no treatment-related grade 5 events. Robust CAR T-cell expansion occurred in all patients with a median time to peak of 8 days. We conclude that axi-cel is highly effective as part of first-line therapy for high-risk LBCL, with a manageable safety profile.
Increase in b-wave amplitude after light stimulation of the blind spot is positively correlated with the axial length of myopic individuals
Authors: Schilling Tim , Amorim-de-Sousa Ana , A Wong Nikita , Bahmani Hamed , González-Méijome José Manuel , Fernandes Paulo 
Published: March 2022

AbstractAltered retinal dopamine and ON-pathway activity may underlie myopia development. It has been shown that the stimulation of the blind spot with short-wavelength light increases the electroretinogram (ERG) b-wave amplitude of myopic eyes and may engage the retinal dopaminergic system. This study evaluated the impact of various durations of blind spot stimulation on the electrophysiological response of the myopic retina and their relationship to axial length. Six myopic individuals underwent three short-wavelength blue light blind spot stimulation protocols (10 s, 1 min, 10 min) using a virtual reality headset. As a control condition, no stimulation was shown for 1 min. The b-wave amplitude of the photopic full-field ERG was measured at baseline and 10, 20, 30, 40, 50, and 60 min after each condition. A significant increase in b-wave amplitude was observed for all stimulation protocols compared to the control. The peak b-wave amplitude was observed 20 min after the 1-min stimulation protocol and 60 min after the 10-min stimulation protocol. A significant positive correlation was found between axial length of the eye and percent change in b-wave amplitude for the 10-min stimulation protocol. A rapid and a delayed b-wave time course responses were observed following 1 min and 10 min of blind spot stimulation, respectively. Overall, these results indicate that light stimulation of the blind spot for various durations elevates ON-bipolar cell activity in the retina and as such is assumed to reduce the myopic response. These findings could have implications for future myopia treatment.
Novel functional insights into a modified sugar-binding protein from Synechococcus MITS9220
Authors: Ford Benjamin A. , Michie Katharine A. , Paulsen Ian T. , Mabbutt Bridget C. , Shah Bhumika S. 
Published: March 2022

AbstractParadigms of metabolic strategies employed by photoautotrophic marine picocyanobacteria have been challenged in recent years. Based on genomic annotations, picocyanobacteria are predicted to assimilate organic nutrients via ATP-binding cassette importers, a process mediated by substrate-binding proteins. We report the functional characterisation of a modified sugar-binding protein, MsBP, from a marine Synechococcus strain, MITS9220. Ligand screening of MsBP shows a specific affinity for zinc (KD ~ 1.3 μM) and a preference for phosphate-modified sugars, such as fructose-1,6-biphosphate, in the presence of zinc (KD ~ 5.8 μM). Our crystal structures of apo MsBP (no zinc or substrate-bound) and Zn-MsBP (with zinc-bound) show that the presence of zinc induces structural differences, leading to a partially-closed substrate-binding cavity. The Zn-MsBP structure also sequesters several sulphate ions from the crystallisation condition, including two in the binding cleft, appropriately placed to mimic the orientation of adducts of a biphosphate hexose. Combined with a previously unseen positively charged binding cleft in our two structures and our binding affinity data, these observations highlight novel molecular variations on the sugar-binding SBP scaffold. Our findings lend further evidence to a proposed sugar acquisition mechanism in picocyanobacteria alluding to a mixotrophic strategy within these ubiquitous photosynthetic bacteria.
Validation of a CE-IVD, urine exosomal RNA expression assay for risk assessment of prostate cancer prior to biopsy
Authors: Kretschmer Alexander , Kajau Holger , Margolis Eric , Tutrone Ronald , Grimm Tobias , Trottmann Matthias , Stief Christian , Stoll Georg , Fischer Christian A. , Flinspach Claudia , Albrecht Anja , Meyer Lisa , Priewasser Tina , Enderle Daniel , Müller Romy , Torkler Phillipp , Alter Jason , Skog Johan , Noerholm Mikkel 
Published: March 2022

AbstractImproved risk stratification of patients suspected of prostate cancer prior to biopsy continues to be an unmet clinical need. ExoDx Prostate (IntelliScore) “EPI” is a non-invasive urine test utilizing RNA from exosomes to provide a risk score that correlates with the likelihood of finding high grade prostate cancer at biopsy. Here, we present the results from a prospective clinical validation study of EPI-CE, a CE-marked in-vitro diagnostic (IVD) assay, specifically developed for use in European clinical laboratories. The study (NCT04720599) enrolled patients with ≥ 50 years, PSA 2–10 ng/mL, prior to MRI, who were scheduled for initial biopsy. First catch urine samples were collected from participants without prior digital rectal examination or prostate massage. Exosomal RNA was isolated and expression levels of three biomarkers ERG, PCA3 and SPDEF were analyzed according to the EPI-CE Instructions For Use. In the study cohort of N = 109 patients, EPI-CE was validated to have a Negative Predictive Value of 89%, a Sensitivity of 92% and a superior performance to two commonly used multiparametric risk calculators (PCPT and ERSPC) in both Receiver Operating Characteristics with a higher Area Under the Curve for EPI-CE 0.67 (95% CI 0.56–0.77) versus PCPT 0.59 (95% CI 0.47–0.71) and ERSPC 0.60 (95% CI 0.49–0.72) and higher Net Benefits analysis across a wide range of risk acceptance levels. This is the first clinical study reporting on the performance of EPI-CE. We demonstrate that EPI-CE provides information beyond standard clinical parameters and provides a better risk assessment prior to MRI, of patients suspected of prostate cancer, than the commonly used multiparametric risk calculators.
C9orf72 dipeptides disrupt the nucleocytoplasmic transport machinery and cause TDP-43 mislocalisation to the cytoplasm
Authors: Ryan Sarah , Rollinson Sara , Hobbs Eleanor , Pickering-Brown Stuart 
Published: March 2022

AbstractA repeat expansion in C9orf72 is the major cause of both frontotemporal dementia and amyotrophic lateral sclerosis, accounting for approximately 1 in 12 cases of either disease. The expansion is translated to produce five dipeptide repeat proteins (DPRs) which aggregate in patient brain and are toxic in numerous models, though the mechanisms underlying this toxicity are poorly understood. Recent studies highlight nucleocytoplasmic transport impairments as a potential mechanism underlying neurodegeneration in C9orf72-linked disease, although the contribution of DPRs to this remains unclear. We expressed DPRs in HeLa cells, in the absence of repeat RNA. Crucially, we expressed DPRs at repeat-lengths found in patients (> 1000 units), ensuring our findings were relevant to disease. Immunofluorescence imaging was used to investigate the impact of each DPR on the nucleus, nucleocytoplasmic transport machinery and TDP-43 localisation. DPRs impaired the structural integrity of the nucleus, causing nuclear membrane disruption and misshapen nuclei. Ran and RanGAP, two proteins required for nucleocytoplasmic transport, were also mislocalised in DPR-expressing cells. Furthermore, DPRs triggered mislocalisation of TDP-43 to the cytoplasm, and this occurred in the same cells as Ran and RanGAP mislocalisation, suggesting a potential link between DPRs, nucleocytoplasmic transport impairments and TDP-43 pathology.
Spinal cord microstructural changes are connected with the aberrant sensorimotor cortical oscillatory activity in adults with cerebral palsy
Authors: Trevarrow Michael P. , Reelfs Anna , Baker Sarah E. , Hoffman Rashelle M. , Wilson Tony W. , Kurz Max J. 
Published: March 2022

AbstractPrevious animal models have illustrated that reduced cortical activity in the developing brain has cascading activity-dependent effects on the microstructural organization of the spinal cord. A limited number of studies have attempted to translate these findings to humans with cerebral palsy (CP). Essentially, the aberrations in sensorimotor cortical activity in those with CP could have an adverse effect on the spinal cord microstructure. To investigate this knowledge gap, we utilized magnetoencephalographic (MEG) brain imaging to quantify motor-related oscillatory activity in fourteen adults with CP and sixteen neurotypical (NT) controls. A subset of these participants also underwent cervical-thoracic spinal cord MRI. Our results showed that the strength of the peri-movement beta desynchronization and the post-movement beta rebound were each weaker in the adults with CP relative to the controls, and these weakened responses were associated with poorer task performance. Additionally, our results showed that the strength of the peri-movement beta response was associated with the total cross-sectional area of the spinal cord and the white matter cross-sectional area. Altogether these results suggest that the altered sensorimotor cortical activity seen in CP may result in activity-dependent plastic changes within the spinal cord microstructure, which could ultimately contribute to the sensorimotor deficits seen in this population.
A method for forecasting the number of hospitalized and deceased based on the number of newly infected during a pandemic
Authors: Scitovski Rudolf , Sabo Kristian , Ungar Šime 
Published: March 2022

AbstractIn this paper we propose a phenomenological model for forecasting the numbers of deaths and of hospitalized persons in a pandemic wave, assuming that these numbers linearly depend, with certain delays $$\tau >0$$

τ
>
0

for deaths and $$\delta >0$$

δ
>
0

for hospitalized, on the number of new cases. We illustrate the application of our method using data from the third wave of the COVID-19 pandemic in Croatia, but the method can be applied to any new wave of the COVID-19 pandemic, as well as to any other possible pandemic. We also supply freely available Mathematica modules to implement the method.
The hallucal interphalangeal ossicle: anatomy and basis for ultrasound-guided surgical shaving
Authors: Moroni Simone , Márquez Javier , Fernández-Gibello Alejandro , Nieves Gabriel Camunas , Montes Ruben , Vázquez Teresa , Sanudo José Ramon , Moriggl Bernhard , Stecco Carla , Tubbs R. Shane , Konschake Marko 
Published: March 2022

AbstractPainful lesions on the plantar aspect of the first interphalangeal joint (IPJ) of the hallux can be attributed to structures called ossicles, nodules, or sesamoids. The aims of the present study were first to verify that ultrasonography (US) is a high-sensitivity tool for diagnosing an interphalangeal ossicle (IO), and second to prove that US-guided-shaving surgery (“milling”) is a safe and feasible technique for remodeling the IO. The study is divided into three parts. In the first part, the prevalence of IOs was estimated in 12 cadaver feet using US, anatomical dissection, and fluoroscopy. In the second, a detailed US and morphological description of the IO was obtained. In the third, six cadaver feet were subjected to surgical milling. IO prevalence was 41.6% in gross anatomy, 41.6% in US examination and just 16.6% in fluoroscopy. The ossicles had a mean length of 4 mm (± 2 mm) and a width of 7 mm (± 2 mm). The ossicles could be completely shaved in all specimens without injuring important anatomical structures. Our results indicate that US is a more precise tool for diagnosing an IO than X-ray. Moreover, our US-guided mini-invasive surgical technique appears feasible and safe.