bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with health-related quality of life in patients with Crohn's disease in Iran: A prospective observational study
Authors: Karami Hassan , Shirvani Shiri Maryam , Ebadi Fard Azar Farbod , Bagheri Lankarani Kamran , Ghahramani Sulmaz , Rezapour Aziz , Tatari Maryam , Heidari Javargi Zahra
Published: January 2023

This was a 1-year prospective observational study of the health-related quality of life (HRQoL) of moderate to severe crohn's disease (CD) patients in Iran. Patients' HRQoL were measured using the EQ-5D 3L, EQ-VAS, and IBDQ-9 tools. HRQoL among CD patients were compared using the T-test, Mann–Whitney, Chi-square, and Fisher's exact tests. To discover factors influencing patients' HRQoL, multivariate linear regression and multivariate logistic regression tests were utilized. The study included 222 CD patients, with a mean age of 34.67 and mean disease duration of 7.32 years. The dimensions with the worst reported “relatively or extreme problems” were P/D: 77.5% and A/D: 63.1%. Employment, having “other chronic diseases,” and ADA consumption were the most important independent predictors of HRQoL in CD patients, [β = 0.21 (EQ-5D index), β = 19.61 (EQ-VAS), β = 12.26 (IBDQ-9), OR: 0.09 (MO), OR: 0.12 (UA), OR: 0.21 (P/D), OR: 0.22 (A/D)], [β = −0.15 (EQ-5D index), β = −5.84 (IBDQ-9), β = −11.06 (EQ-VAS), OR: 4.20 (MO), OR: 6.50 (UA)], and [OR: 2.29 (A/D)], respectively. Unemployment, presence of “other chronic conditions” had the greatest negative impact on HRQoL of CD patients. There were significant differences in the probability of reporting “relatively or extreme problems” in the SC and A/D dimensions between patients using adalimumab (ADA) and infliximab (IFX).
Ginkgolic acid promotes inflammation and macrophage apoptosis via SUMOylation and NF-κB pathways in sepsis
Authors: Liu Xinyong , Chen Longwang , Zhang Chen , Dong Wei , Liu Hongbing , Xiao Zhong , Wang Kang , Zhang Yaolu , Tang Yahui , Hong Guangliang , Lu Zhongqiu , Zhao Guangju
Published: January 2023

Background

Excessive inflammation and increased apoptosis of macrophages contribute to organ damage and poor prognosis of sepsis. Ginkgolic acid (GA) is a natural constituent extracted from the leaves of Ginkgo biloba, that can regulate inflammation and apoptosis. The present study aims to investigate the potential effect of GA in treating sepsis and its possible mechanisms.

Materials and methods

Here, a classic septic mice model and a lipopolysaccharide (LPS)-induced RAW 264.7 inflammation model were established. Cytokines in serum and culture supernatant were detected by ELISA, and the mRNA levels of them were examined by PCR. Hematoxylin and eosin (H&E) staining was performed to determine histopathological changes in liver, lung and kidney. Bacterial burden in the blood, peritoneal lavage fluids (PLFs) and organs were observed on Luria-Bertani agar medium. Flow cytometry and western blotting was used to detect apoptosis and the expression level of apoptosis related molecules, respectively. Moreover, the levels of SUMOylation were detected by western blotting. The activity of NF-κB p65 was assessed by immunofluorescence staining and western blotting.

Results

The result showed that GA promoted inflammatory responses, reduced bacterial clearance, aggravated organ damage, and increased mortality in septic mice. GA increased apoptosis in peritoneal macrophages (PMs) and RAW 264.7 cells. Meanwhile, GA inhibited SUMOylation and increased the nuclear translocation of NF-κB p65 as well as its phosphorylation level.

Conclusion

Collectively, GA promotes inflammation and macrophage apoptosis in sepsis, which may be mediated by inhibiting the SUMOylation process and increasing NF-κB p65 activity.
Torque Teno virus DNA is found in the intracranial aneurysm wall—Is there a causative role?
Authors: Rabelo Nícollas Nunes , Yoshikawa Marcia Harumy , Telles João Paulo Mota , Coelho Giselle , de Souza Caio Santos , de Oliveira Natan Ponzoni Galvani , Mendoza Tania Regina Tozetto , Braz-Silva Paulo Henrique , Boechat Antonio Luiz , Teixeira Manoel Jacobsen , Figueiredo Eberval Gadelha
Published: January 2023

Objective

Torque Teno virus (TTV) is a recently discovered virus with high prevalence worldwide, that has been associated with vascular diseases. The aim of this study is to investigate the prevalence of TTV molecular DNA in the intracranial aneurysm (IA) artery walls.

Method

Samples of IA walls were collected after microsurgical clipping from 35 patients with IA (22 ruptured/13 unruptured cases). The samples were submitted to molecular DNA extraction using the EasyMag automatized extractor and performed with Qiagen DNA extraction Minikit 250. The samples underwent PCR examination with primers for β-globin as internal control using the Nanodrop® 2000 spectrophotometer. A quantitative (real-time) PCR with TTV-specific primers was performed. Clinical and radiological data of patients included was collected.

Results

TTV was detected in 15 (42.85%) cases, being 10 (45.4%) ruptured and 5 (38.4%) unruptured (p = 0.732) lesions. Multiple IAs accounted for 14 (40%) cases. Five cases (17.2%) had TTV+ and multiple aneurysms (p = 0.73). Association between presence of virus and aneurysm rupture was not statistically significant (p = 0.96).

Conclusion

This study demonstrated a relatively high prevalence of viral DNA in the walls of IAs. This is the first study to identify the presence of TTV DNA in IA’s samples, which was found more often in ruptured lesions. This is an exploratory study, therefore, larger studies are required to clarify the relationships between inflammation, viral infection, IA formation and rupture.
Biomechanical changes in the gastrocnemius medius–Achilles tendon complex in people with hypermobility spectrum disorders: A cross-sectional compression sonoelastography study
Authors: Alsiri Najla , Palmer Shea
Published: January 2023

Objective

This study aimed to assess the biomechanical impact of Hypermobility Spectrum Disorders (HSD) on the elasticity of the gastrocnemius medius-Achilles tendon (GM-AT) complex.

Methods

Using a cross-sectional design, the GM-AT complex elasticity was compared using sonoelastography (SEG) in an HSD group and healthy controls during rest and maximal isometric plantar flexion contraction.

Results

The HSD group comprised 28 patients (26 women); mean ± SD age 28.7 ± 8.4 years, compared to 28 controls (26 women); 31.5 ± 8.7 years. During rest, greater elasticity was identified in HSD relative to controls at the GM-AT musculotendinous junction (strain ratio 2.05 ± 1.31 vs. 1.48 ± 0.49), mid-AT (3.60 ± 1.97 vs. 2.66 ± 1.00), and distal AT (4.57 ± 2.69 vs. 3.22 ± 1.94) (all p < 0.05). During contraction, no significant differences were found between groups at the GM-AT musculotendinous junction (3.40 ± 2.16 vs. 2.62 ± 1.07), mid AT (10.75 ± 5.29 vs. 8.49 ± 3.53), or distal AT (8.55 ± 5.39 vs. 8.83 ± 3.51) (all p > 0.05). No significant differences were found between groups in the GM strain ratio during rest (4.05 ± 1.43 vs. 3.62 ± 0.78), or contraction (4.23 ± 1.29 vs. 4.19 ± 1.31). Exploratory Receiver Operator Characteristics curve analysis suggested low sensitivity and specificity of the strain ratio for the diagnosis of HSD.

Conclusion

People with HSD have greater GM-AT complex elasticity. Although statistically significant group differences were identified, further research is required to establish the diagnostic, clinical, and research utility of strain ratio measurements.
Relationship between pyroptosis-mediated inflammation and the pathogenesis of prostate disease
Authors: Zhao Ming , Guo Jun , Gao Qing-He , Wang Hao , Wang Fu , Wang Zi-Rui , Liu Sheng-Jing , Deng Ying-Jun , Zhao Zi-Wei , Zhang Yue-Yang , Yu Wen-Xiao
Published: January 2023

The largest solid organ of the male genitalia, the prostate gland, is comprised of a variety of cells such as prostate epithelial cells, smooth muscle cells, fibroblasts, and endothelial cells. Prostate diseases, especially prostate cancer and prostatitis, are often accompanied by acute/chronic inflammatory responses or even cell death. Pyroptosis, a cell death distinct from necrosis and apoptosis, which mediate inflammation may be closely associated with the development of prostate disease. Pyroptosis is characterized by inflammasome activation via pattern recognition receptors (PRR) upon recognition of external stimuli, which is manifested downstream by translocation of gasdermin (GSDM) protein to the membrane to form pores and release of inflammatory factors interleukin (IL)-1β and IL-18, a process that is Caspase-dependent. Over the past number of years, many studies have investigated the role of inflammation in prostate disease and have suggested that pyroptosis may be an important driver. Understanding the precise mechanism is of major consequence for the development of targeted therapeutic strategies. This review summarizes the molecular mechanisms, regulation, and cellular effects of pyroptosis briefly and then discuss the current pyroptosis studies in prostate disease research and the inspiration for us.
Barriers to Treg therapy in Europe: From production to regulation
Authors: Hennessy Conor , Deptula Milena , Hester Joanna , Issa Fadi
Published: January 2023

There has been an increased interest in cell based therapies for a range of medical conditions in the last decade. This explosion in novel therapeutics research has led to the development of legislation specifically focused on cell and gene based therapies. In Europe, the European medicines agency (EMA) designates any medicines for human use which are based on genes, tissues, or cells as advanced therapy medicinal products or advanced therapy medicinal products (ATMPs). In this article we discuss the hurdles to widespread adoption of ATMPs in Europe, with a focus on regulatory T cells (Tregs). There are numerous barriers which must be overcome before mainstream adoption of Treg therapy becomes a reality. The source of the cells, whether to use autologous or allogenic cells, and the methods through which they are isolated and expanded, must all meet strict good manufacturing practice (GMP) standards to allow use of the products in humans. GMP compliance is costly, with the equipment and reagents providing a significant cost barrier and requiring specialized facilities and personnel. Conforming to the regulations set centrally by the EMA is difficult, and the different interpretations of the regulations across the various member states further complicates the regulatory approval process. The end products then require a complex and robust distribution network to ensure timely delivery of potentially life saving treatments to patients. In a European market whose logistics networks have been hammered by COVID and Brexit, ensuring rapid and reliable delivery systems is a more complex task than ever. In this article we will examine the impact of these barriers on the development and adoption of Tregs in Europe, and potential approaches which could facilitate more widespread use of Tregs, instead of its current concentration in a few very specialized centers.
LDP alleviates TKI-induced proteinuria through reversing the expression of RelA in renal tissues
Authors: Fu Zhou , Zhang Su , Gu Xiaoying , Guan Tao , Wang Chengmeng , Zhang Jiaqi , Wang Yun , Guo Hua , Wang Lu , Zhang Ti
Published: January 2023

Tyrosine kinase inhibitors (TKIs), as an important tumor therapy, can induce severe proteinuria that significantly affects anti-tumor therapy. Existing therapies against proteinuria induced by other etiologies are currently ineffective for TKI-induced proteinuria. It has been shown that various types of proteinuria are related to podocyte damage caused by changes in the RelA signaling pathway. Our experiments confirmed that TKIs activate the renal RelA signaling pathway, and induce death of podocytes and destruction of the glomerular filtration barrier. Here we found that Liuwei Dihuang Pill (LDP) attenuated the inflammatory injury of podocytes through inhibiting activation of RelA, and subsequently relieved TKI-related proteinuria and prevented the progression of TMA and FSGS. Our finding indicated that LDP may be effective for the treatment of TKI-induced proteinuria, which is clinically significant.
Assessment of the human placental microbiome in early pregnancy
Authors: Sharlandjieva Vassilena , Beristain Alexander G. , Terry Jefferson
Published: January 2023

Introduction

Bacteria derived from the maternal circulation have been suggested to seed the human placenta during development leading to an intrinsic placental microbiome. This concept has become controversial as numerous studies suggest that the apparent placental microbiome is mostly, if not completely, comprised of contaminants. If the maternal circulation seeds the placenta then there should be an increase in abundance and diversity of detectable bacteria with onset of maternal perfusion of the placenta around 10 weeks gestational age; however, if only contaminants are present then there should be no significant evolution of the placental microbiome with increasing gestational age. This pilot study addresses whether bacterial abundance and diversity increase in human placenta and whether there is an associated shift in the immunophenotype of the decidual immune cell complement before and after initiation of placental perfusion.

Methods

Human placental and decidual tissue from 5 to 19 weeks gestational age, handled aseptically to minimize contamination, is assessed by quantitative 16S polymerase chain reaction (PCR), 16S gene sequencing, and immunological flow cytometry studies.

Results

A weak positive correlation between placental bacterial abundance and gestational age is identified but is not statistically significant. No significant changes in bacterial diversity are found with increasing gestational age. The proportion of decidual activated memory T helper cells increases with gestational age but no change was observed in other lymphocyte subsets.

Discussion

This pilot study does not strongly support bacterial colonization of the placenta after initiation of maternal perfusion; however, the minor trends towards increases in bacterial abundance and activated memory T helper cells may represent an early stage of this process. Additional investigations in larger cohorts are warranted.
Dysregulated lipid metabolism in lymphangioleiomyomatosis pathogenesis as a paradigm of chronic lung diseases
Authors: Bernardelli Clara , Caretti Anna , Lesma Elena
Published: January 2023

A chronic inflammatory condition characterizes various lung diseases. Interestingly, a great contribution to inflammation is made by altered lipids metabolism, that can be caused by the deregulation of the mammalian target of rapamycin complex-1 (mTORC1) activity. There is evidence that one of mTOR downstream effectors, the sterol regulatory element-binding protein (SREBP), regulates the transcription of enzymes involved in the de novo fatty acid synthesis. Given its central role in cell metabolism, mTOR is involved in several biological processes. Among those, mTOR is a driver of senescence, a process that might contribute to the establishment of chronic lung disease because the characteristic irreversible inhibition of cell proliferation, associated to the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP) supports the loss of lung parenchyma. The deregulation of mTORC1 is a hallmark of lymphangioleiomyomatosis (LAM), a rare pulmonary disease predominantly affecting women which causes cystic remodeling of the lung and progressive loss of lung function. LAM cells have senescent features and secrete SASP components, such as growth factors and pro-inflammatory molecules, like cancer cells. Using LAM as a paradigm of chronic and metastatic lung disease, here we review the published data that point out the role of dysregulated lipid metabolism in LAM pathogenesis. We will discuss lipids’ role in the development and progression of the disease, to hypothesize novel LAM biomarkers and to propose the pharmacological regulation of lipids metabolism as an innovative approach for the treatment of the disease.
Identification of integrons and gene cassette-associated recombination sites in bacteriophage genomes
Authors: Qi Qin , Rajabal Vaheesan , Ghaly Timothy M. , Tetu Sasha G. , Gillings Michael R.
Published: January 2023

Bacteriophages are versatile mobile genetic elements that play key roles in driving the evolution of their bacterial hosts through horizontal gene transfer. Phages co-evolve with their bacterial hosts and have plastic genomes with extensive mosaicism. In this study, we present bioinformatic and experimental evidence that temperate and virulent (lytic) phages carry integrons, including integron-integrase genes, attC/attI recombination sites and gene cassettes. Integrons are normally found in Bacteria, where they capture, express and re-arrange mobile gene cassettes via integron-integrase activity. We demonstrate experimentally that a panel of attC sites carried in virulent phage can be recognized by the bacterial class 1 integron-integrase (IntI1) and then integrated into the paradigmatic attI1 recombination site using an attC x attI recombination assay. With an increasing number of phage genomes projected to become available, more phage-associated integrons and their components will likely be identified in the future. The discovery of integron components in bacteriophages establishes a new route for lateral transfer of these elements and their cargo genes between bacterial host cells.
A Boolean-based machine learning framework identifies predictive biomarkers of HSP90-targeted therapy response in prostate cancer
Authors: Shin Sung-Young , Centenera Margaret M. , Hodgson Joshua T. , Nguyen Elizabeth V. , Butler Lisa M. , Daly Roger J. , Nguyen Lan K.
Published: January 2023

Precision medicine has emerged as an important paradigm in oncology, driven by the significant heterogeneity of individual patients’ tumour. A key prerequisite for effective implementation of precision oncology is the development of companion biomarkers that can predict response to anti-cancer therapies and guide patient selection for clinical trials and/or treatment. However, reliable predictive biomarkers are currently lacking for many anti-cancer therapies, hampering their clinical application. Here, we developed a novel machine learning-based framework to derive predictive multi-gene biomarker panels and associated expression signatures that accurately predict cancer drug sensitivity. We demonstrated the power of the approach by applying it to identify response biomarker panels for an Hsp90-based therapy in prostate cancer, using proteomic data profiled from prostate cancer patient-derived explants. Our approach employs a rational feature section strategy to maximise model performance, and innovatively utilizes Boolean algebra methods to derive specific expression signatures of the marker proteins. Given suitable data for model training, the approach is also applicable to other cancer drug agents in different tumour settings.
New model of superior semicircular canal dehiscence with reversible diagnostic findings characteristic of patients with the disorder
Authors: Wackym P. Ashley , Balaban Carey D. , Van Osch Olivia J. , Morris Brian T. , Tamakloe Mark-Avery , Salvatore Victoria L. , Duwadi Sudan , Gay Jennifer D. , Mowery Todd M.
Published: January 2023

Background

Third window syndrome is a vestibular-cochlear disorder in humans in which a third mobile window of the otic capsule creates changes to the flow of sound pressure energy through the perilymph/endolymph. The nature and location of this third mobile window can occur at many different sites (or multiple sites); however, the most common third mobile window is superior semicircular canal dehiscence (SSCD). There are two essential objective diagnostic characteristics needed to validate a model of SSCD: the creation of a pseudoconductive hearing loss and cVEMP increased amplitude and decreased threshold.

Methods

Adult Mongolian gerbils (n = 36) received surgical fenestration of the superior semicircular canal of the left inner ear. ABR and c+VEMP testing were carried out prior to surgery and over acute (small 1 mm SSCD, 1–10 days) or prolonged (large 2 mm SSCD, 28 days) recovery. Because recovery of function occurred quickly, condenser brightfield stereomicroscopic examination of the dehiscence site was carried out for the small SSCD animals post-hoc and compared to both ABRs and c+VEMPs. Micro-CT analysis was also completed with representative samples of control, day 3 and 10 post-SSCD animals.

Results

The SSCD created a significant worsening of hearing thresholds of the left ear; especially in the lower frequency domain (1–4 kHz). Left (EXP)/right (CTL) ear comparisons via ABR show significant worsening thresholds at the same frequency representations, which is a proxy for the human pseudoconductive hearing loss seen in SSCD. For the c+VEMP measurements, increased amplitude of the sound-induced response (N1 2.5 ms and P1 3.2 ms) was observed in animals that received larger fenestrations. As the bone regrew, the c+VEMP and ABR responses returned toward preoperative values. For small SSCD animals, micro-CT data show that progressive osteoneogenesis results in resurfacing of the SSCD without bony obliteration.

Conclusion

The large (2 mm) SSCD used in our gerbil model results in similar electrophysiologic findings observed in patients with SSCD. The changes observed also reverse and return to baseline as the SSCD heals by bone resurfacing (with the lumen intact). Hence, this model does not require a second surgical procedure to plug the SSCD.
Rapid onset of functional tic-like behaviors among adolescent girls—Minnesota, September–November 2021
Authors: Firestone Melanie J. , Holzbauer Stacy , Conelea Christine , Danila Richard , Smith Kirk , Bitsko Rebecca H. , Klammer Susan M. , Gingerich Stefan , Lynfield Ruth
Published: January 2023

Background

On October 15, 2021, the Minnesota Department of Health began investigating a school cluster of students experiencing tic-like behaviors thought to be related to recent COVID-19. The objective of this report is to describe the investigation, key findings, and public health recommendations.

Methods

Affected students and proxies were interviewed with a standardized questionnaire including validated depression and anxiety screens.

Results

Eight students had tic-like behaviors lasting >24 h after initial report with onset during September 26–October 30, 2021. All eight students were females aged 15–17 years. All students either had a history of depression or anxiety or scored as having more than minimal anxiety or depression on validated screens. Four students previously had confirmed COVID-19: the interval between prior COVID-19 and tic symptom onset varied from more than a year prior to tic symptom onset to at the time of tic symptom onset.

Conclusion

The onset of tic-like behaviors at one school in Minnesota appeared to be related more to underlying mental health conditions than recent COVID-19. These findings highlight the need to better understand functional tic-like behaviors and adolescent mental health.
Explainable artificial intelligence model to predict brain states from fNIRS signals
Authors: Shibu Caleb Jones , Sreedharan Sujesh , Arun KM , Kesavadas Chandrasekharan , Sitaram Ranganatha
Published: January 2023

Objective: Most Deep Learning (DL) methods for the classification of functional Near-Infrared Spectroscopy (fNIRS) signals do so without explaining which features contribute to the classification of a task or imagery. An explainable artificial intelligence (xAI) system that can decompose the Deep Learning mode’s output onto the input variables for fNIRS signals is described here.

Approach: We propose an xAI-fNIRS system that consists of a classification module and an explanation module. The classification module consists of two separately trained sliding window-based classifiers, namely, (i) 1-D Convolutional Neural Network (CNN); and (ii) Long Short-Term Memory (LSTM). The explanation module uses SHAP (SHapley Additive exPlanations) to explain the CNN model’s output in terms of the model’s input.

Main results: We observed that the classification module was able to classify two types of datasets: (a) Motor task (MT), acquired from three subjects; and (b) Motor imagery (MI), acquired from 29 subjects, with an accuracy of over 96% for both CNN and LSTM models. The explanation module was able to identify the channels contributing the most to the classification of MI or MT and therefore identify the channel locations and whether they correspond to oxy- or deoxy-hemoglobin levels in those locations.

Significance: The xAI-fNIRS system can distinguish between the brain states related to overt and covert motor imagery from fNIRS signals with high classification accuracy and is able to explain the signal features that discriminate between the brain states of interest.
Acute beetroot juice consumption does not alter cerebral autoregulation or cardiovagal baroreflex sensitivity during lower-body negative pressure in healthy adults
Authors: Worley Morgan L. , Reed Emma L. , Chapman Christopher L. , Kueck Paul , Seymour Lauren , Fitts Triniti , Zazulak Hannah , Schlader Zachary J. , Johnson Blair D.
Published: January 2023

Introduction

Beetroot juice (BRJ) improves peripheral endothelial function and vascular compliance, likely due to increased nitric oxide bioavailability. It is unknown if BRJ alters cerebrovascular function and cardiovagal baroreflex control in healthy individuals.

Purpose

We tested the hypotheses that BRJ consumption improves cerebral autoregulation (CA) and cardiovagal baroreflex sensitivity (cBRS) during lower-body negative pressure (LBNP).

Methods

Thirteen healthy adults (age: 26 ± 4 years; 5 women) performed oscillatory (O-LBNP) and static LBNP (S-LBNP) before (PRE) and 3 h after consuming 500 mL of BRJ (POST). Participants inhaled 3% CO2 (21% O2, 76% N2) during a 5 min baseline and throughout LBNP to attenuate reductions in end-tidal CO2 tension (PETCO2). O-LBNP was conducted at ∼0.02 Hz for six cycles (−70 mmHg), followed by a 3-min recovery before S-LBNP (−40 mmHg) for 7 min. Beat-to-beat middle cerebral artery blood velocity (MCAv) (transcranial Doppler) and blood pressure were continuously recorded. CA was assessed using transfer function analysis to calculate coherence, gain, and phase in the very-low-frequency (VLF; 0.020–0.070 Hz) and low-frequency bands (LF; 0.07–0.20 Hz). cBRS was calculated using the sequence method. Comparisons between POST vs. PRE are reported as mean ± SD.

Results

During O-LBNP, coherenceVLF was greater at POST (0.55 ± 0.06 vs. 0.46 ± 0.08; P < 0.01), but phaseVLF (P = 0.17) and gainVLF (P = 0.69) were not different. CoherenceLF and phaseLF were not different, but gainLF was lower at POST (1.03 ± 0.20 vs. 1.12 ± 0.30 cm/s/mmHg; P = 0.05). During S-LBNP, CA was not different in the VLF or LF bands (all P > 0.10). Up-cBRS and Down-cBRS were not different during both LBNP protocols.

Conclusion

These preliminary data indicate that CA and cBRS during LBNP in healthy, young adults is largely unaffected by an acute bolus of BRJ.
Pain control based on oscillatory brain activity using transcranial alternating current stimulation: An integrative review
Authors: Takeuchi Naoyuki
Published: January 2023

Developing effective tools and strategies to relieve chronic pain is a high-priority scientific and clinical goal. In particular, the brain regions related to pain processing have been investigated as potential targets to relieve pain by non-invasive brain stimulation (NIBS). In addition to elucidating the relationship between pain and oscillatory brain activity, transcranial alternating current stimulation (tACS), which can non-invasively entrain oscillatory brain activity and modulate oscillatory brain communication, has attracted scientific attention as a possible technique to control pain. This review focuses on the use of tACS to relieve pain through the manipulation of oscillatory brain activity and its potential clinical applications. Several studies have reported that tACS on a single brain reduces pain by normalizing abnormal oscillatory brain activity in patients with chronic pain. Interpersonal tACS approaches based on inter-brain synchrony to manipulate inter-brain communication may result in pain relief via prosocial effects. Pain is encoded by the spatiotemporal neural communication that represents the integration of cognitive, emotional-affective, and sensorimotor aspects of pain. Therefore, future studies should seek to identify the pathological oscillatory brain communication in chronic pain as a therapeutic target for tACS. In conclusion, tACS could be effective for re-establishing oscillatory brain activity and assisting social interaction, and it might help develop novel approaches for pain control.
Surfeit folic acid, protein, and exercise modify oncogenic inflammatory biomarkers and fecal microbiota
Authors: Tuska Rebecca M. , Helm Sophia M. , Graf C. Foster , James Courtney , Kong Gabriel , Stiemsma Leah T. , Green David B. , Helm Susan Edgar
Published: January 2023

Intestinal microbiota, diet, and physical activity are inextricably linked to inflammation occurring in the presence of tumor progression and declining neurocognition. This study aimed to explore how fecal microbiota, inflammatory biomarkers, and neurocognitive behavior are influenced by voluntary exercise and surplus dietary protein and folic acid which are common health choices. Dietary treatments provided over 8 weeks to C57BL/CJ male mice (N = 76) were: Folic Acid (FA) Protein (P) Control (FPC, 17.9% P; 2 mgFA/kg); Folic Acid Deficient (FAD); Folic Acid Supplemented (FAS; 8 mgFA/kg); Low Protein Diet (LPD, 6% P); and High Protein Diet (HPD, 48% P). FAS mice had decreased plasma HCys (p < 0.05), therefore confirming consumption of FA. Objectives included examining influence of exercise using Voluntary Wheel Running (VWR) upon fecal microbiota, inflammatory biomarkers C - reactive protein (CRP), Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), nuclear factor kappa ß subunit (NF-κßp65), Caspase-3 (CASP3), Tumor Necrosis Factor-alpha (TNF-α), and neurocognitive behavior. CRP remained stable, while a significant exercise and dietary effect was notable with decreased VEGF (p < 0.05) and increased CASP3 (p < 0.05) for exercised HPD mice. Consumption of FAS did significantly increase (p < 0.05) muscle TNF-α and the ability to build a nest (p < 0.05) was significantly decreased for both FAD and LPD exercised mice. Rearing behavior was significantly increased (p < 0.05) in mice fed HPD. An emerging pattern with increased dietary protein intake revealed more distance explored in Open Field Testing. At week 1, both weighted and unweighted UniFrac principal coordinates analysis yielded significant clustering (permanova, p ≤ 0.05) associated with the specific diets. Consumption of a HPD diet resulted in the most distinct fecal microbiota composition. At the phylum level–comparing week 1 to week 8–we report a general increase in the Firmicutes/Bacteroidetes ratio, characterized by an outgrowth of Firmicutes by week 8 in all groups except the HPD. MaAsLin2 analysis corroborates this finding and emphasizes an apparent inversion of the microbiome composition at week 8 after HPD. Explicit modification of oncogenic inflammatory biomarkers and fecal microbiome post high FA and protein intake along with voluntary exercise contributed to current underlying evidence that this diet and exercise relationship has broader effects on human health and disease–perhaps importantly as a practical modulation of cancer progression and declining neurocognition.
A meta-analysis suggests the association of reduced serum level of vitamin D and T-allele of Fok1 (rs2228570) polymorphism in the vitamin D receptor gene with celiac disease
Authors: Shree Tanya , Banerjee Pratibha , Senapati Sabyasachi
Published: January 2023

Purpose

As an immune-modulator, vitamin D is known to regulate immune response and is implicated in disease pathogenesis. Celiac disease (CD) is a systemic autoimmune disease and susceptibility conferred by vitamin D metabolism is under investigation. Studies on the association of vitamin D metabolism and genetic polymorphisms are expected to explain CD pathogenesis. We performed a systematic review–based meta-analysis to investigate the 25(OH)D serum levels and susceptibility conferred by the genetic variants of VDR in CD.

Methods

Systematic review was conducted through a web-based literature search following stringent study inclusion–exclusion criteria. The Newcastle–Ottawa Scale and GRADE tools were used to assess the quality of evidence in studies and the study outcome. Cohen's κ value was estimated to access the reviewer's agreement. RevMan 5.4.1 was used to perform the meta-analyses. Weighted mean difference and Meta p-value was assessed for 25(OH)D serum levels. Meta-odds ratio and Z-test p-value were evaluated to estimate the allelic susceptibility of VDR variants.

Results

A total of 8 out of 12 studies were evaluated for “25(OH)D” serum level, while four studies were found eligible for SNPs (Bsm1, Apa1, Fok1, and Taq1) of VDR. Significantly higher levels [WMD = 5.49, p < 0.00001] of 25(OH)D were observed in healthy controls than in patients with CD. rs2228570-T (Fok1) [Meta-OR = 1.52, p = 0.02] was confirmed to be predisposing allele for CD.

Conclusion

Reduced serum level of 25(OH)D and association of Fok1 T-allele of VDR confirmed in this study plays a critical role in immunomodulation and maintaining barrier integrity, which is majorly implicated in CD.
Bilberry-containing supplements on severe dry eye disease in young and middle-aged adults: A 3-month pilot analysis
Authors: Yu Wing Y. , Chan Lily Y. L. , Chung Aden , Lee Paul H. , Woo George C.
Published: January 2023

Purpose

To explore the effect of bilberry and fish oil combination supplement on a small clinical sample patient-base with severe dry eyes.

Methods

Twenty-four subjects were recruited with twelve randomly assigned to the intervention and control groups, respectively. Inclusion criteria included severe dry eye symptoms determined by scores >33 from the Ocular Surface Disease Index (OSDI) questionnaire. The intervention group was instructed to take an oral supplement with key ingredients of 600 mg bilberry extract and 240 mg docosahexaenoic acid-refined fish oil once daily for 3 months. The control group did not take any supplements. Mean changes in OSDI score, non-invasive tear break-up time (NITBUT), phenol red thread test (PRT), and percentage of meibomian gland openings were used as outcome measures. Testing was done at baseline, 1-month, and 3-month follow-up. Comparison between the treatment and control groups, and the younger adult and middle-age groups were performed.

Results

The mean baseline values for the treatment and control groups were not clinically different. The OSDI score, NITBUT, PRT, and percentage of meibomian gland openings improved after taking the supplements for 3 months. The OSDI score, NITBUT, and PRT showed clinical improvements between the intervention and control groups. These improvements were consistent between the two age groups.

Conclusion

This study suggested preliminary improvements in signs and symptoms of severe dry eyes that were independent of age after taking dietary supplementation of bilberry extract and fish oil for 3 months. Further studies using more device-based measures and a placebo supplement are warranted.
Improved methods for mare milk analysis: Extraction and quantification of mare milk carbohydrates and assessment of FTIR-based macronutrient quantification
Authors: Pyles Morgan B. , Brock Kristin , Schendel Rachel R. , Lawrence Laurie M.
Published: January 2023

Accurately determining the macronutrient profile of mare milk is a precursor to studying how milk composition affects foals’ growth and development. This study optimized and validated an extraction and quantification method for mare milk oligosaccharides, which make up a portion of the carbohydrate fraction of mare milk. Mare milk was extracted with chloroform and methanol, and oligosaccharides were selectively isolated from the carbohydrate fraction using porous-graphitized carbon solid-phase-extraction (SPE). Good recovery rates for milk oligosaccharides (between 70 and 100%) were achieved with the optimized method. This study also compared the use of Fourier-Transform infrared (FTIR) spectroscopy versus wet chemistry quantification methods for protein, fat, and lactose. The FTIR method produced statistically equivalent protein contents to the wet chemistry method, along with substantial savings in both analyst time and consumable consumption. FTIR analysis slightly underestimated the fat content of mare milk relative to the official wet chemistry method, with the difference between the methods increasing at higher fat contents. FTIR also overestimated the lactose content of mare milk and appeared to generate “lactose” values that included the milk oligosaccharides and thus represented the total carbohydrate (lactose and milk oligosaccharides) content of mare milk.
Metabolomics analysis reveals amelioration effects of yellowhorn tea extract on hyperlipidemia, inflammation, and oxidative stress in high-fat diet-fed mice
Authors: Ta Na , A. Lisha , E. Erdunduleng , Qi Rigeer , Mu Xiyele , Feng Lan , Ba Genna , Li Yonghui , Zhang Junqing , Bai Laxinamujila , Fu Minghai
Published: January 2023

Yellowhorn tea (YT) is traditionally used as a lipid-lowering beverage in Mongolian minorities. However, the pharmacological effects of YT extract and its specific metabolic changes in hyperlipidemia models are not fully understood. The aim of this study was to identify biomarkers using untargeted metabolomics techniques and to investigate the mechanisms underlying the changes in metabolic pathways associated with lipid lowering, anti-inflammation and anti-oxidant in hyperlipidemic mice. A high-fat diet (HFD)-induced hyperlipidemic mouse model was established. YT extract was administered as oral gavage at 0.15, 0.3, and 0.6 g/kg doses for 10 weeks. HFD-induced hyperlipidemia and the therapeutic effect of YT extract were evaluated based on histopathology and by assessing blood lipid levels. Liver inflammatory factors and oxidative stress indices were determined using enzyme-linked immunosorbent assays. Liver metabolites were evaluated using untargeted metabolomics. Biochemical and histological examinations showed that YT extract significantly reduced body-weight gain (p < 0.01) and fat deposition in tissues. YT extract significantly reduced the levels of serum and liver triglyceride and total cholesterol; inflammatory factors [interleukin (IL)-6, IL-1β, and tumor necrosis factor-α]; malondialdehyde; and leptin (p < 0.05) in hyperlipidemic mice. YT extract also significantly increased the levels of oxidative stress indicators (superoxide dismutase, catalase, and glutathione peroxidase) and adiponectin. Metabolomics studies revealed several endogenous molecules were altered by the high-fat diet and recovery following intervention with YT extract. The metabolites that were significantly different in the liver after YT intake included citicoline, acetylcholine, pyridoxine, and NAD. Pathway analysis indicated that YT extract ameliorated HFD-induced hyperlipidemia in mice via three major metabolic pathways, namely, glycerophospholipid metabolism, vitamin B6 metabolism, and nicotinate and nicotinamide metabolism. This study demonstrates YT extract has profound effects on the alleviation of HFD-induced hyperlipidemia, inflammation and oxidative stress.
A genome-wide association study of germline variation and melanoma prognosis
Authors: Chat Vylyny , Dagayev Sasha , Moran Una , Snuderl Matija , Weber Jeffrey , Ferguson Robert , Osman Iman , Kirchhoff Tomas
Published: January 2023

Background

The high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers.

Methods

We performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naïve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression.

Results

We found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05–4.81), p=1.48×10-7; and rs77480547 in SH3BP4: HR=3.02 (2.02–4.52), p=7.58×10-8, both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone.

Conclusions

Our study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma.
The risk and latency evaluation of secondary primary malignancies of cervical cancer patients who received radiotherapy: A study based on the SEER database
Authors: Chen Mengjie , Pan Xinbin , Wang He , Yao Desheng
Published: January 2023

Objectives

To study the risk factors for the onset of secondary primary malignancies (SPM) and the latency between SPM and cervical cancer after radiotherapy.

Methods

We selected patients with cervical cancer who underwent radiotherapy between 2000 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) database. And the data of patients with cervical cancer who underwent radiotherapy in Guangxi Medical University Cancer Hospital during January 1,1997 to December 31,2016 were collected and analyzed. The factors associated with SPM onset and latency were then estimated by nomograms based on logistic regression and a complete risk model. Dynamic risk plots were performed by Poisson regression.

Results

A total of 32,313 cases of cervical cancer who underwent radiotherapy were downloaded from the SEER database; of these, 19,439 cases had a complete dataset and were included in the final analysis. In total, 561 cases suffered from SPM; the remaining 18,878 did not. And a total of 1486 cases of cervical cancer who underwent radiotherapy from Guangxi Medical University Cancer Hospital were analyzed, 27 cases caught SPM and the rest of 1459 cases did not. Patients with SPM were older than those without SPM(p=0.000); significant associations were also identified between SPM and white race(p=0.000), localized stage (p=0.000), squamous carcinoma (SCC)(p=0.003), surgery(p=0.000), and combination radiotherapy (p=0.026). A logistic regression nomogram showed that older age (HR:1.015, 95%CI:1.009-1.021, p=0.000), localized stage (HR:4.056, 95%CI: 2.625-6.269, p=0.000) and regional stage (HR: 3.181, 95%CI:2.094-4.834, p=0.000), white (HR: 1.722, 95%CI:1.145-2.590, p=0.000) and black race (HR: 1.889, 95%CI:1.327-2.689, p=0.000), and the receipt of surgery (HR: 1.381, 95%CI:1.151-1.657, p=0.000) were all independent risk factors for the onset of SPM. The largest proportion of cases involved SPM in the female reproductive system. A dynamic risk plot showed that age, race, stage, and surgery had impacts on the latency of SPM onset. A competing risk regression analysis nomogram showed that age (HR: 1.564, 95%CI: 1.272-1.920, p=0.000), surgery (HR: 1.415, 95%CI: 1.140-1.760, p=0.002), localized stage (HR: 8.035, 95%CI: 4.502-14.340, p=0.000) and regional stage (HR: 4.904, 95%CI: 2.790-8.620, p=0.000), and black race (HR: 1.786, 95%CI: 1.161-2.750, p=0.008) all had significant impacts on the cumulative incidence and latency of SPM.

Conclusions

Advanced age, the receipt of surgery, earlier stages, and white and black race were identified as risk factors for SPM onset and influenced latency in patients with cervical cancer after radiotherapy.
Real-world experiences of CNS-directed chemotherapy followed by autologous stem cell transplantation for secondary CNS involvement in relapsed or refractory diffuse large B-cell lymphoma
Authors: Jeong Sun Young , Yoon Sang Eun , Cho Duck , Kang Eun Suk , Cho Junhun , Kim Won Seog , Kim Seok Jin
Published: January 2023

Introduction

Secondary central nervous system (CNS) involvement is a rare but fatal event in patients with diffuse large B cell lymphoma (DLBCL). Some studies have suggested autologous stem cell transplantation (ASCT) for patients responding to salvage therapies, although its role is not clear.

Methods

We analyzed DLBCL patients with secondary CNS involvement who received salvage therapies with curative intent and who underwent high-dose chemotherapy followed by ASCT. We analyzed the post-ASCT outcome in terms of CNS and/or systemic relapse and overall survival (OS) according to type of secondary CNS involvement and salvage treatment.

Results

A total of 43 patients who achieved complete or partial response after salvage treatments, mainly high-dose methotrexate (MTX)-containing chemotherapy, was treated with busulphan-thiotepa followed by ASCT between 2009 to 2019. Fifteen patients experienced grade III/IV febrile neutropenia, but all adverse events were manageable. At the median follow-up of 14.7 months after ASCT, 17 patients did not relapse, however, 26 patients had relapsed, comprising isolated CNS relapse (n = 12), systemic relapse (n = 12), and both (n = 2). Patients with systemic relapse had significantly shorter OS than those with isolated CNS relapse (42.7 vs, 11.1 months, p = 0.002). Of the 26 patients who relapsed after ASCT, six patients were rescued by subsequent salvage treatments. Finally, 21 patients were alive at the time of analysis.

Discussion

In conclusion, consolidative ASCT might be beneficial for secondary CNS involvement in relapsed or refractory DLBCL patients if they responded to CNS-directed salvage chemotherapy and were eligible for transplantation.
Case report: Hyperosmolar hyperglycemic syndrome secondary to PEG-asparaginase-induced hypertriglyceridemia and pancreatitis
Authors: Mudd Todd William , Fox Ashley Danielle , Ghaly Mark , Keruakous Amany
Published: January 2023

Pegylated (PEG)-asparaginase is an established treatment for acute lymphoblastic leukemias that exhibits an antitumor effect by depleting asparagine, an amino acid essential for leukemia cell protein synthesis. Pancreatitis with hypertriglyceridemia is a well-established toxidrome associated with PEG-asparaginase. However, impaired pancreatic synthetic function and hormone release have rarely been reported as a result of PEG-asparaginase pancreatitis. In this report, we present a 22-year-old woman recently diagnosed with T-acute lymphoblastic leukemia (T-ALL), who presented to the hospital with progressive weakness, confusion, blurry vision, hallucinations, and abdominal pain after induction treatment with daunorubicin, vincristine, PEG-asparaginase, and dexamethasone following the AYA protocol. She was found to have hypertriglyceridemia, acute pancreatitis, and hyperosmolar hyperglycemic syndrome. While pancreatitis and hypertriglyceridemia are commonly reported side effects of PEG-asparaginase, HHS related to these conditions has been sparsely reported. Providers should maintain awareness of this association and consider routine serial glucose monitoring of patients receiving PEG-asparaginase.