bluuebunny/crossref_metadata_2025 huggingface dataset:
Transauricular vagus nerve stimulation for patients with disorders of consciousness: A randomized controlled clinical trial
Authors: Zhou Yi-Fan , Kang Jun-Wei , Xiong Qi , Feng Zhen , Dong Xiao-Yang
Published: March 2023

Introduction

Disorders of consciousness (DoCs) are a frequent complication of brain injury disease, and effective treatments are currently lacking. Transauricular vagus nerve stimulation (tVNS) has been proposed as a promising therapeutic method for neurological disorders such as epilepsy and depression. In our previous study, we demonstrated that vagus nerve stimulation promoted recovery in rats with DoCs caused by traumatic brain injury. However, the clinical effect of vagus nerve stimulation on consciousness disorders is unclear. We aimed to investigate the therapeutic efficacy and safety of tVNS in patients with DoCs.

Methods

We conducted a randomized, double-blinded, sham-controlled trial. Patients (N = 60) with DoCs, including minimally conscious state (MCS) and vegetative state/unresponsive wakefulness syndrome, were enrolled and randomized to groups receiving either active or sham tVNS. A frequency of 20 Hz and pulse wave of 200 us was used in the active-tVNS protocol, which was performed in the auricular branch of the vagus nerve in the left outer ear. The sham-tVNS protocol was the same as the active-tVNS protocol although without current input. Both groups of patients also received conventional treatments. Consciousness was evaluated according to the Coma Recovery Scale-Revised before and after the 4-week intervention. We also recorded the type and number of behavioral responses. Safety was primarily assessed according to the incidence of treatment-emergent adverse events. Each patient's heart rate and blood pressure were monitored during all treatment sessions.

Results

Ultimately, 57 patients completed the study: 28 patients underwent active tVNS and 29 patients underwent sham tVNS. No significant differences were observed in Coma Recovery Scale-Revised scores between the active- and sham-tVNS groups before the tVNS sessions. Compared with patients in the sham-tVNS group (9.28 ± 4.38), patients with DoCs treated with active tVNS showed improved consciousness (10.93 ± 4.99), although not statistically significant. Further analysis revealed obvious differences between patients with MCS receiving active and sham tVNS, but no significant difference in patients with vegetative state/unresponsive wakefulness syndrome in both groups. All side effects were considered common medical conditions with no obvious correlation to tVNS.

Conclusion

These preliminary data provide early evidence that tVNS may be an effective and safe approach for promoting the recovery of consciousness, especially in patients with MCS.

Clinical trial registration

https://www.chictr.org.cn/edit.aspx?pid=175938&htm=4, identifier: ChiCTR2200066629.
Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients
Authors: Thapaliya Kiran , Marshall-Gradisnik Sonya , Barth Markus , Eaton-Fitch Natalie , Barnden Leighton
Published: March 2023

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID patients have overlapping neurological, autonomic, pain, and post-exertional symptoms. We compared volumes of brainstem regions for 10 ME/CFS (CCC or ICC criteria), 8 long COVID (WHO Delphi consensus), and 10 healthy control (HC) subjects on 3D, T1-weighted MRI images acquired using sub-millimeter isotropic resolution using an ultra-high field strength of 7 Tesla. Group comparisons with HC detected significantly larger volumes in ME/CFS for pons (p = 0.004) and whole brainstem (p = 0.01), and in long COVID for pons (p = 0.003), superior cerebellar peduncle (p = 0.009), and whole brainstem (p = 0.005). No significant differences were found between ME/CFS and long COVID volumes. In ME/CFS, we detected positive correlations between the pons and whole brainstem volumes with “pain” and negative correlations between the midbrain and whole brainstem volumes with “breathing difficulty.” In long COVID patients a strong negative relationship was detected between midbrain volume and “breathing difficulty.” Our study demonstrated an abnormal brainstem volume in both ME/CFS and long COVID consistent with the overlapping symptoms.
Lipid analysis of meat from Bactrian camel (Camelus bacterianus), beef, and tails of fat-tailed sheep using UPLC-Q-TOF/MS based lipidomics
Authors: Li Qingqing , Yang Li , Li Rongrong , Chen Gangliang , Dong Jing , Wu Linying , Fu Yinghua , Yang Jie
Published: March 2023

Introduction

As a source of low-cost and high-quality meat for human beings, the consumption of camel meat was increasing, and beef has similar texture and nutritional characteristics with camel meat. Camel hump and fatty-tails are important parts of fat storage for camels and fat-tailed lambs, respectively, which were to adapt and endure harsh environments. Considering their similar physiological functions, their fat composition might be similar. Lipidomics is a system-level analysis of lipids method, which play an important role in the determination and quantification of individual lipid molecular specie, food adulteration and labeling.

Methods

A GC/MS was used to analyze fatty acids composition of Xinjiang Bactrian camel meat, hump, beef, and fatty-tails. UPLC-Q-TOF/MS based on lipidomics approach was used to analyze lipid composition, characterize and examine the lipid differences in Xinjiang Bactrian camel meat, hump, beef, and fatty-tails.

Results and discussion

The major fatty acids of the four samples were C16:0, C18:0, and C18:1cis, and camel meat had a significant low SFA content and high MUFA content. A total of 342 lipid species were detected, 192, 64, and 79 distinguishing lipids were found in the groups camel hump compared to camel meat, camel meat compared to beef, and camel hump compared to fatty-tails, respectively. Lipid metabolisms of ether lipid, glycerophospholipid, glycerolipid, and sphingolipid were the most influential pathways revealed by KEGG analysis. The results contributed to enrich the lipid information of Bactrian camel meat, and indicated that UPLC-Q-TOF/MS based on lipidomics was an alternative method to distinguish meat samples.
Enzyme inactivation induced by thermal stabilization in highland barley and impact on lipid oxidation and aroma profiles
Authors: Zheng Qianna , Wang Zheng , Xiong Feiyang , Zhang Guoquan
Published: March 2023

Thermal stabilization is efficient for slowing lipid degradation and prolonging the shelf life of highland barley, but the impacts of different thermal stabilized treatments on highland barley and possible chemical reactions remain unclear. The effects of thermal stabilization treatments (bake, far-infrared, fry, microwave and steam) on the enzymes, lipids and aroma profiles of highland barley flour (HBF) were investigated in this study. Thermal stabilization significantly decreased the contents of ash and GABA. Baked HBF exhibited the lowest fatty acid value and peroxide value. Untreated HBF had higher lipase and lipoxygenase activities and fried mostly inactivated these enzymes. All thermal stabilization treatments increased the catalase activities and fried showed the higher level. Thus, fried might be an effective method to stabilize the HBF. The high temperatures during stabilizing triggered the complex reactions, leading to the loss of some volatile compounds, and in the meantime the formation of others such as furans and aldehydes. These productions contributed to the unique aroma profiles of different HBFs. Furthermore, a chemometric approach was used to analyze the changes of thermal stabilized treated HBFs and to identity six key volatile compounds, which provided important knowledge on possible chemical reactions caused by thermal stabilization. Overall, these results provide the theoretical basis for the wider application of thermal stabilization technologies in highland barley processing.
The I148M PNPLA3 variant mitigates niacin beneficial effects: How the genetic screening in non-alcoholic fatty liver disease patients gains value
Authors: Paolini Erika , Longo Miriam , Meroni Marica , Tria Giada , Cespiati Annalisa , Lombardi Rosa , Badiali Sara , Maggioni Marco , Fracanzani Anna Ludovica , Dongiovanni Paola
Published: March 2023

Background

The PNPLA3 p.I148M impact on fat accumulation can be modulated by nutrients. Niacin (Vitamin B3) reduced triglycerides synthesis in in vitro and in vivo NAFLD models.

Objectives

In this study, we aimed to investigate the niacin-I148M polymorphism crosstalk in NAFLD patients and examine niacin’s beneficial effect in reducing fat by exploiting hepatoma cells with different PNPLA3 genotype.

Design

We enrolled 172 (Discovery cohort) and 358 (Validation cohort) patients with non-invasive and histological diagnosis of NAFLD, respectively. Dietary niacin was collected from food diary, while its serum levels were quantified by ELISA. Hepatic expression of genes related to NAD metabolism was evaluated by RNAseq in bariatric NAFLD patients (n = 183; Transcriptomic cohort). Hep3B (148I/I) and HepG2 (148M/M) cells were silenced (siHep3B) or overexpressed (HepG2I148+) for PNPLA3, respectively.

Results

In the Discovery cohort, dietary niacin was significantly reduced in patients with steatosis ≥ 2 and in I148M carriers. Serum niacin was lower in subjects carrying the G at risk allele and negatively correlated with obesity. The latter result was confirmed in the Validation cohort. At multivariate analysis, the I148M polymorphism was independently associated with serum niacin, supporting that it may be directly involved in the modulation of its availability. siHep3B cells showed an impaired NAD biosynthesis comparable to HepG2 cells which led to lower niacin efficacy in clearing fat, supporting a required functional protein to guarantee its effectiveness. Conversely, the restoration of PNPLA3 Wt protein in HepG2I148+ cells recovered the NAD pathway and improved niacin efficacy. Finally, niacin inhibited de novo lipogenesis through the ERK1/2/AMPK/SIRT1 pathway, with the consequent SREBP1-driven PNPLA3 reduction only in Hep3B and HepG2I148M+ cells.

Conclusions

We demonstrated a niacin-PNPLA3 I148M interaction in NAFLD patients which possibly pave the way to vitamin B3 supplementation in those with a predisposing genetic background.
A comparison of machine learning models and Cox proportional hazards models regarding their ability to predict the risk of gastrointestinal cancer based on metabolic syndrome and its components
Authors: Tran Tao Thi , Lee Jeonghee , Gunathilake Madhawa , Kim Junetae , Kim Sun-Young , Cho Hyunsoon , Kim Jeongseon
Published: March 2023

Background

Little is known about applying machine learning (ML) techniques to identify the important variables contributing to the occurrence of gastrointestinal (GI) cancer in epidemiological studies. We aimed to compare different ML models to a Cox proportional hazards (CPH) model regarding their ability to predict the risk of GI cancer based on metabolic syndrome (MetS) and its components.

Methods

A total of 41,837 participants were included in a prospective cohort study. Incident cancer cases were identified by following up with participants until December 2019. We used CPH, random survival forest (RSF), survival trees (ST), gradient boosting (GB), survival support vector machine (SSVM), and extra survival trees (EST) models to explore the impact of MetS on GI cancer prediction. We used the C-index and integrated Brier score (IBS) to compare the models.

Results

In all, 540 incident GI cancer cases were identified. The GB and SSVM models exhibited comparable performance to the CPH model concerning the C-index (0.725). We also recorded a similar IBS for all models (0.017). Fasting glucose and waist circumference were considered important predictors.

Conclusions

Our study found comparably good performance concerning the C-index for the ML models and CPH model. This finding suggests that ML models may be considered another method for survival analysis when the CPH model’s conditions are not satisfied.
A systematic review and meta-analysis evaluating the impact of antibiotic use on the clinical outcomes of cancer patients treated with immune checkpoint inhibitors
Authors: Crespin Athéna , Le Bescop Clément , de Gunzburg Jean , Vitry Fabien , Zalcman Gérard , Cervesi Julie , Bandinelli Pierre-Alain
Published: March 2023

Background

Immune checkpoint inhibitors (ICIs) have considerably improved patient outcomes in various cancer types, but their efficacy remains poorly predictable among patients. The intestinal microbiome, whose balance and composition can be significantly altered by antibiotic use, has recently emerged as a factor that may modulate ICI efficacy. The objective of this systematic review and meta-analysis is to investigate the impact of antibiotics on the clinical outcomes of cancer patients treated with ICIs.

Methods

PubMed and major oncology conference proceedings were systematically searched to identify all studies reporting associations between antibiotic use and at least one of the following endpoints: Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR) and Progressive Disease (PD) Rate. Pooled Hazard Ratios (HRs) for OS and PFS, and pooled Odds Ratios (ORs) for ORR and PD were calculated. Subgroup analyses on survival outcomes were also performed to investigate the potential differential effect of antibiotics according to cancer types and antibiotic exposure time windows.

Results

107 articles reporting data for 123 independent cohorts were included, representing a total of 41,663 patients among whom 11,785 (28%) received antibiotics around ICI initiation. The pooled HRs for OS and PFS were respectively of 1.61 [95% Confidence Interval (CI) 1.48-1.76] and 1.45 [95% CI 1.32-1.60], confirming that antibiotic use was significantly associated with shorter survival. This negative association was observed consistently across all cancer types for OS and depending on the cancer type for PFS. The loss of survival was particularly strong when antibiotics were received shortly before or after ICI initiation. The pooled ORs for ORR and PD were respectively of 0.59 [95% CI 0.47-0.76] and 1.86 [95% CI 1.41-2.46], suggesting that antibiotic use was significantly associated with worse treatment-related outcomes.

Conclusion

As it is not ethically feasible to conduct interventional, randomized, controlled trials in which antibiotics would be administered to cancer patients treated with ICIs to demonstrate their deleterious impactversuscontrol, prospective observational studies and interventional trials involving microbiome modifiers are crucially needed to uncover the role of microbiome and improve patient outcomes. Such studies will reduce the existing publication bias by allowing analyses on more homogeneous populations, especially in terms of treatments received, which is not possible at this stage given the current state of the field. In the meantime, antibiotic prescription should be cautiously considered in cancer patients receiving ICIs.

Systematic review registration

https://www.crd.york.ac.uk/prospero/, identifier CRD42019145675.
Genomic, epigenomic, and transcriptomic signatures of prostate cancer between African American and European American patients
Authors: Stevens Claire , Hightower Alexandria , Buxbaum Sarah G. , Falzarano Sara M. , Rhie Suhn K.
Published: March 2023

Prostate cancer is the second most common cancer in men in the United States, and racial disparities are greatly observed in the disease. Specifically, African American (AA) patients have 60% higher incidence and mortality rates, in addition to higher grade and stage prostate tumors, than European American (EA) patients. In order to narrow the gap between clinical outcomes for these two populations, genetic and molecular signatures contributing to this disparity have been characterized. Over the past decade, profiles of prostate tumor samples from different ethnic groups have been developed using molecular and functional assays coupled with next generation sequencing or microarrays. Comparative genome-wide analyses of genomic, epigenomic, and transcriptomic profiles from prostate tumor samples have uncovered potential race-specific mutations, copy number alterations, DNA methylation, and gene expression patterns. In this study, we reviewed over 20 published studies that examined the aforementioned molecular contributions to racial disparities in AA and EA prostate cancer patients. The reviewed genomic studies revealed mutations, deletions, amplifications, duplications, or fusion genes differentially enriched in AA patients relative to EA patients. Commonly reported genomic alterations included mutations or copy number alterations of FOXA1, KMT2D, SPOP, MYC, PTEN, TP53, ZFHX3, and the TMPRSS2-ERG fusion. The reviewed epigenomic studies identified that CpG sites near the promoters of PMEPA1, RARB, SNRPN, and TIMP3 genes were differentially methylated between AA and EA patients. Lastly, the reviewed transcriptomic studies identified genes (e.g. CCL4, CHRM3, CRYBB2, CXCR4, GALR1, GSTM3, SPINK1) and signaling pathways dysregulated between AA and EA patients. The most frequently found dysregulated pathways were involved in immune and inflammatory responses and neuroactive ligand signaling. Overall, we observed that the genomic, epigenomic, and transcriptomic alterations evaluated between AA and EA prostate cancer patients varied between studies, highlighting the impact of using different methods and sample sizes. The reported genomic, epigenomic, and transcriptomic alterations do not only uncover molecular mechanisms of tumorigenesis but also provide researchers and clinicians valuable resources to identify novel biomarkers and treatment modalities to improve the disparity of clinical outcomes between AA and EA patients.
Hepatocellular carcinoma subtypes based on metabolic pathways reveals potential therapeutic targets
Authors: He Zehua , Chen Qingfeng , He Wanrong , Cao Junyue , Yao Shunhan , Huang Qingqiang , Zheng Yu
Published: March 2023

Introduction

Hepatocellular carcinoma (HCC) is an aggressive malignancy with steadily increasing incidence rates worldwide and poor therapeutic outcomes. Studies show that metabolic reprogramming plays a key role in tumor genesis and progression. In this study, we analyzed the metabolic heterogeneity of epithelial cells in the HCC and screened for potential biomarkers.

Methods

The hepatic single-cell RNA sequencing (scRNA-seq) datasets of HCC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Based on data intergration and measurement of differences among groups, the metabolic epithelial cell subpopulations were identified. The single-cell metabolic pathway was analyzed and the myeloid subpopulations were identified. Cell-cell interaction analysis and single-cell proliferation analysis were performed. The gene expression profiles of HCC patients were obtained from the GSE14520 dataset of GEO and TCGA-LIHC cohort of the UCSC Xena website. Immune analysis was performed. The differentially expressed genes (DEGs) were identified and functionally annotated. Tumor tissues from HCC patients were probed with anti-ALDOA, anti-CD68, anti-CD163, anti-CD4 and anti-FOXP3 antibodies. Results We analyzed the scRNA-seq data from 48 HCC patients and 14 healthy controls. The epithelial cells were significantly enriched in HCC patients compared to the controls (p = 0.011). The epithelial cells from HCC patients were classified into two metabolism-related subpopulations (MRSs) – pertaining to amino acid metabolism (MRS1) and glycolysis (MRS2). Depending on the abundance of these metabolic subpopulations, the HCC patients were also classified into the MRS1 and MRS2 subtype distinct prognoses and immune infiltration. The MRS2 group had significantly worse clinical outcomes and more inflamed tumor microenvironment (TME), as well as a stronger crosstalk between MRS2 cells and immune subpopulations that resulted in an immunosuppressive TME. We also detected high expression levels of ALDOA in the MRS2 cells and HCC tissues. In the clinical cohort, HCC patients with higher ALDOA expression showed greater enrichment of immunosuppressive cells including M2 macrophages and T regulatory cells.

Discussion

The glycolytic subtype of HCC cells with high ALDOA expression is associated with an immunosuppressive TME and predicts worse clinical outcomes, providing new insights into the metabolism and prognosis of HCC.
How smart is artificial intelligence in organs delineation? Testing a CE and FDA-approved Deep-Learning tool using multiple expert contours delineated on planning CT images
Authors: Strolin Silvia , Santoro Miriam , Paolani Giulia , Ammendolia Ilario , Arcelli Alessandra , Benini Anna , Bisello Silvia , Cardano Raffaele , Cavallini Letizia , Deraco Elisa , Donati Costanza Maria , Galietta Erika , Galuppi Andrea , Guido Alessandra , Ferioli Martina , Laghi Viola , Medici Federica , Ntreta Maria , Razganiayeva Natalya , Siepe Giambattista , Tolento Giorgio , Vallerossa Daria , Zamagni Alice , Morganti Alessio Giuseppe , Strigari Lidia
Published: March 2023

Background

A CE- and FDA-approved cloud-based Deep learning (DL)-tool for automatic organs at risk (OARs) and clinical target volumes segmentation on computer tomography images is available. Before its implementation in the clinical practice, an independent external validation was conducted.

Methods

At least a senior and two in training Radiation Oncologists (ROs) manually contoured the volumes of interest (VOIs) for 6 tumoral sites. The auto-segmented contours were retrieved from the DL-tool and, if needed, manually corrected by ROs. The level of ROs satisfaction and the duration of contouring were registered. Relative volume differences, similarity indices, satisfactory grades, and time saved were analyzed using a semi-automatic tool.

Results

Seven thousand seven hundred sixty-five VOIs were delineated on the CT images of 111 representative patients. The median (range) time for manual VOIs delineation, DL-based segmentation, and subsequent manual corrections were 25.0 (8.0-115.0), 2.3 (1.2-8) and 10.0 minutes (0.3-46.3), respectively. The overall time for VOIs retrieving and modification was statistically significantly lower than for manual contouring (p<0.001). The DL-tool was generally appreciated by ROs, with 44% of vote 4 (well done) and 43% of vote 5 (very well done), correlated with the saved time (p<0.001). The relative volume differences and similarity indexes suggested a better inter-agreement of manually adjusted DL-based VOIs than manually segmented ones.

Conclusions

The application of the DL-tool resulted satisfactory, especially in complex delineation cases, improving the ROs inter-agreement of delineated VOIs and saving time.
Gradual deterioration of fatty liver disease to liver cancer via inhibition of AMPK signaling pathways involved in energy-dependent disorders, cellular aging, and chronic inflammation
Authors: Meng Sha-Sha , Gu Hong-Wei , Zhang Ting , Li Yu-Sang , Tang He-Bin
Published: March 2023

Introduction

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer kind. According to recent research, a fatty liver increases the risk of hepatocellular cancer. Nevertheless, the AMPK signaling pathway is crucial. In addition, 5’-AMP-activated protein kinase (AMPK) is strongly linked to alterations in the tumor microenvironment, such as inflammation, hypoxia, and aging. The objective of this study is to evaluate the impact of the AMPK signaling pathway on the progression of fatty liver to HCC.

Methods

In this study, we established a mouse liver cancer model using high-fat diets and nano-nitrosamines (nano-DEN). In addition, we employed a transcriptomic technique to identify all mRNAs detected in liver samples at the 25th weekexpression of proteins linked with the LKB1-AMPK-mTOR signaling pathway, inflammation, aging, and hypoxia was studied in microarrays of liver cancer tissues from mice and humans. These proteins included p-AMPK, LKB1, mTOR, COX-2, β-catenin, HMGB1, p16, and HIF-1α.

Results

Data were collected at different times in the liver as well as in cancerous and paracancerous regions and analyzed by a multispectral imaging system. The results showed that most of the genes in the AMPK signaling pathway were downregulated. Prakk1 expression was upregulated compared to control group but downregulated in the cancerous regions compared to the paracancerous regions. Stk11 expression was downregulated in the cancerous regions. Mtor expression was upregulated in the cancerous regions. During liver cancer formation, deletion of LKB1 in the LKB1-AMPK-mTOR signaling pathway reduces phosphorylation of AMPK. It contributed to the upregulation of mTOR, which further led to the upregulation of HIF1α. In addition, the expression of β-catenin, COX-2, and HMGB1 were upregulated, as well as the expression of p16 was downregulated.

Discussion

These findings suggest that changes in the AMPK signaling pathway exacerbate the deterioration of disrupted energy metabolism, chronic inflammation, hypoxia, and cellular aging in the tumor microenvironment, promoting the development of fatty liver into liver cancer.
Intrafraction tumor motion monitoring and dose reconstruction for liver pencil beam scanning proton therapy
Authors: Nankali Saber , Worm Esben Schjødt , Thomsen Jakob Borup , Stick Line Bjerregaard , Bertholet Jenny , Høyer Morten , Weber Britta , Mortensen Hanna Rahbek , Poulsen Per Rugaard
Published: March 2023

Background

Pencil beam scanning (PBS) proton therapy can provide highly conformal target dose distributions and healthy tissue sparing. However, proton therapy of hepatocellular carcinoma (HCC) is prone to dosimetrical uncertainties induced by respiratory motion. This study aims to develop intra-treatment tumor motion monitoring during respiratory gated proton therapy and combine it with motion-including dose reconstruction to estimate the delivered tumor doses for individual HCC treatment fractions.

Methods

Three HCC-patients were planned to receive 58 GyRBE (n=2) or 67.5 GyRBE (n=1) of exhale respiratory gated PBS proton therapy in 15 fractions. The treatment planning was based on the exhale phase of a 4-dimensional CT scan. Daily setup was based on cone-beam CT (CBCT) imaging of three implanted fiducial markers. An external marker block (RPM) on the patient’s abdomen was used for exhale gating in free breathing. This study was based on 5 fractions (patient 1), 1 fraction (patient 2) and 6 fractions (patient 3) where a post-treatment control CBCT was available. After treatment, segmented 2D marker positions in the post-treatment CBCT projections provided the estimated 3D motion trajectory during the CBCT by a probability-based method. An external-internal correlation model (ECM) that estimated the tumor motion from the RPM motion was built from the synchronized RPM signal and marker motion in the CBCT. The ECM was then used to estimate intra-treatment tumor motion. Finally, the motion-including CTV dose was estimated using a dose reconstruction method that emulates tumor motion in beam’s eye view as lateral spot shifts and in-depth motion as changes in the proton beam energy. The CTV homogeneity index (HI) The CTV homogeneity index (HI) was calculated as D2% − D98%D50% ×100%.

Results

The tumor position during spot delivery had a root-mean-square error of 1.3 mm in left-right, 2.8 mm in cranio-caudal and 1.7 mm in anterior-posterior directions compared to the planned position. On average, the CTV HI was larger than planned by 3.7%-points (range: 1.0-6.6%-points) for individual fractions and by 0.7%-points (range: 0.3-1.1%-points) for the average dose of 5 or 6 fractions.

Conclusions

A method to estimate internal tumor motion and reconstruct the motion-including fraction dose for PBS proton therapy of HCC was developed and demonstrated successfully clinically.
Nondestructive label-free detection of peritumoral white matter damage using cross-polarization optical coherence tomography
Authors: Achkasova Ksenia A. , Moiseev Alexander A. , Yashin Konstantin S. , Kiseleva Elena B. , Bederina Evgenia L. , Loginova Maria M. , Medyanik Igor A. , Gelikonov Grigory V. , Zagaynova Elena V. , Gladkova Natalia D.
Published: March 2023

Introduction

To improve the quality of brain tumor resections, it is important to differentiate zones with myelinated fibers destruction from tumor tissue and normal white matter. Optical coherence tomography (OCT) is a promising tool for brain tissue visualization and in the present study, we demonstrate the ability of cross-polarization (CP) OCT to detect damaged white matter and differentiate it from normal and tumor tissues.

Materials and methods

The study was performed on 215 samples of brain tissue obtained from 57 patients with brain tumors. The analysis of the obtained OCT data included three stages: 1) visual analysis of structural OCT images; 2) quantitative assessment based on attenuation coefficients estimation in co- and cross-polarizations; 3) building of color-coded maps with subsequent visual analysis. The defining characteristics of structural CP OCT images and color-coded maps were determined for each studied tissue type, and then two classification tests were passed by 8 blinded respondents after a training.

Results

Visual assessment of structural CP OCT images allows detecting white matter areas with damaged myelinated fibers and differentiate them from normal white matter and tumor tissue. Attenuation coefficients also allow distinguishing all studied brain tissue types, while it was found that damage to myelinated fibers leads to a statistically significant decrease in the values of attenuation coefficients compared to normal white matter. Nevertheless, the use of color-coded optical maps looks more promising as it combines the objectivity of optical coefficient and clarity of the visual assessment, which leads to the increase of the diagnostic accuracy of the method compared to visual analysis of structural OCT images.

Conclusions

Alteration of myelinated fibers causes changes in the scattering properties of the white matter, which gets reflected in the nature of the received CP OCT signal. Visual assessment of structural CP OCT images and color-coded maps allows differentiating studied tissue types from each other, while usage of color-coded maps demonstrates higher diagnostic accuracy values in comparison with structural images (F-score = 0.85-0.86 and 0.81, respectively). Thus, the results of the study confirm the potential of using OCT as a neuronavigation tool during resections of brain tumors.
Prenatal marijuana exposure and visual perception in toddlers: Evidence of a sensory processing deficit
Authors: Bailey Beth A. , Osborne Jahla B.
Published: March 2023

Background

Research has identified a link between prenatal marijuana exposure and multiple outcomes in children, including cognitive development. Several studies have found specific differences in sensory processing and attention, with visual perception especially impacted in school age children. The current study explored whether this effect is evident at an earlier age, and thus our goal was to investigate the relationship between in-utero marijuana exposure and sensory processing capabilities in toddlers. We hypothesized that in-utero marijuana exposure throughout pregnancy would specifically predict visual sensory hyperactivity in children as young as 15 months of age.

Methods

Participants were 225 15-month-old children whose mothers were recruited during pregnancy. Substance exposure was prospectively collected and biochemically verified, with marijuana coded as no exposure, 1st trimester exposure only, or exposure throughout pregnancy. The Infant Toddler Sensory Profile evaluated 5 domains of sensory processing (visual, auditory, tactile, vestibular, oral).

Results

Prenatal marijuana exposure throughout pregnancy, but not when limited to the first trimester, predicted a two-fold increased likelihood of scoring in a range indicating high levels of seeking out and potentially over-attending to visual stimulation after controlling for potentially confounding factors including other prenatal exposures. Marijuana exposure was not significantly related to other processing domains.

Conclusion

Results indicate that links previously identified between prenatal marijuana exposure and visual function and attention may already be evident at 15 months of age, and also suggest an impact related to continuous/later pregnancy exposure. Our findings, as well as those from previous studies, all suggest visual processing differences for exposed children, differences that may predict emerging issues with visual attention and habituation. As legalization of marijuana continues to increase, further research is clearly needed to examine specific teratologic effects associated with use during pregnancy.
Current and future methods of probiotic therapy for necrotizing enterocolitis
Authors: Sajankila Nitin , Wala Samantha Jane , Ragan Mecklin Victoria , Volpe Samuel Grant , Dumbauld Zachary , Purayil Nanditha , Mihi Belgacem , Besner Gail E.
Published: March 2023

Necrotizing enterocolitis (NEC) is a complex intestinal disease that primarily affects premature neonates. Given its significant mortality and morbidity, there is an urgent need to develop improved prophylactic measures against the disease. One potential preventative strategy for NEC is the use of probiotics. Although there has been significant interest for decades in probiotics in neonatal care, no clear guidelines exist regarding which probiotic to use or for which patients, and no FDA-approved products exist on the market for NEC. In addition, there is lack of agreement regarding the benefits of probiotics in neonates, as well as some concerns about the safety and efficacy of available products. We discuss currently available probiotics as well as next-generation probiotics and novel delivery strategies which may offer an avenue to capitalize on the benefits of probiotics, while minimizing the risks. Thus, probiotics may still prove to be an effective prevention strategy for NEC, although further product development and research is needed to support use in the preterm population.
Cost-effectiveness analysis of PD-1 inhibitors combined with chemotherapy as first-line therapy for advanced esophageal squamous-cell carcinoma in China
Authors: Liu Shixian , Dou Lei , Li Shunping
Published: March 2023

Objective: This study was aimed to investigate the cost-effectiveness of all available programmed death 1 (PD-1) inhibitors combined with chemotherapy in the first-line treatment of advanced esophageal squamous-cell carcinoma (ESCC) from the Chinese healthcare system perspective.

Methods: A partitioned survival model with a 3-week cycle and a 10-year time horizon was constructed based on a network meta-analysis. The survival data and utility values were derived from clinical trials, and the direct medical costs were collected from public drug bidding database and published literature. Total costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. Scenario, one-way and probabilistic sensitivity analyses were performed to assess the uncertainty around model parameters.

Results: Compared with mono-chemotherapy, toripalimab, sintilimab and camrelizumab plus chemotherapy were cost-effective treatment regimens, while serplulimab, pembrolizumab and nivolumab plus chemotherapy were not cost-effective options. Toripalimab plus chemotherapy provided the highest QALYs of 0.95 with the lower cost of $8,110.53 compared to other competing alternatives. The robustness of the base-case results was confirmed by scenario and one-way sensitivity analysis. At a willingness-to-pay threshold of three times per capita gross domestic product ($38,351.20) in 2021, the probability of toripalimab plus chemotherapy being the optimal option was 74.25% compared with other six competing alternatives.

Conclusion: Toripalimab plus chemotherapy represented the most cost-effective option as the first-line therapy for advanced ESCC patients in China.
The influence of Hyssopus cuspidatus Boriss extract on lipid mediators metabolism network in asthmatic mice
Authors: Ling-Fei Kong , Xiao-Juan Rong , Pan Yan , Tuo Qin , Xiao-Hui Zhang , Yu-Tong Kang , Bo Cheng , Wen-Ling Su , Tian-Le Gao , Cai Tie
Published: March 2023

Current drugs do not provide an absolute cure or modify the course of asthma. Hyssopus cuspidatus Boriss extract (SXCF) has been used as Uyghur medicine for several years to treat bronchial asthma. However, very limited research has been conducted on the therapeutic mechanisms of SXCF. Disruptions in the metabolic network of lipid mediators (LMs) are closely linked to the development of asthma. Here, we explored the therapeutic mechanism of SXCF in asthma based on the metabolic network of LMs, aiming to contribute to the understanding of SXCF in asthma treatment at the molecular level. The UHPLC-MRM strategy was used for the quantitative detection of LMs in the lung tissue and in the peripheral circulatory system (serum). ELISA was used to detect IgE in serum and cytokines in BALF. The lung tissue sections were stained with H&E to observe the infiltration of inflammatory cells, and behavioural changes in mice were observed and recorded throughout the animal experiment. In contrast to the asthma group, the opposite result was observed in the SXCF groups, where the perturbed LMs metabolic network was partly restored in a dose-dependent manner with a significant elevation of anti-inflammatory metabolites, while pro-inflammatory lipids were decreased. As significant downregulation of IgE and pro-inflammatory cytokines was observed, IgE and cytokines analysis also supported the anti-inflammatory effects of SXCF. It was also noticed that SXCF treatment reduced the number of coughs and decreased the inflammatory cell infiltration around the bronchus in mice. These results suggested that SXCF has a significant ameliorative effect on ovalbumin (OVA)-induced asthma. The modulation of LMs is a possible underlying mechanism of the SXCF effects.
Prenatal exposure to acetaminophen and adolescent assessment of behavior: Discrepancies by age and reporter
Authors: Smith-Webb Rashida S. , Barnard-Mayers Ruby , Werler Martha M. , Parker Samantha E.
Published: March 2023

Acetaminophen, which is one of the most commonly used medications during pregnancy, has been linked to adverse neurodevelopmental outcomes among offspring during childhood. Less is known about associations with outcomes occurring later in adolescence.

Methods: We conducted a follow-up study of children born between 1996 and 2002. Data on illnesses and medications, including acetaminophen, during pregnancy were collected through a standardized interview after delivery. Behavioral assessments were conducted at two subsequent time points, childhood (ages 5–10) and adolescence (ages 11–17). Outcomes examined included internalizing, externalizing, and total behavior problems based on the parent-completed Child Behavior Checklist (CBCL), the teacher-completed Teacher Report Form (TRF), and the youth-completed Youth Self Report (YSR, adolescent follow-up only). Adjusted linear regression models were used to calculate mean differences (MD) and 95% confidence intervals (95% CI) in T-scores comparing those with prenatal acetaminophen exposure to those without. Stabilized inverse probability weights were used to account for attrition.

Results: Among the 216 mother-child dyads with completed parent and teacher behavioral assessments at both childhood and adolescence, prenatal acetaminophen exposure was not associated with behavioral problems according to either parent or teacher assessments. Modest increases in externalizing and total behavior problems were observed according to youth report (MD: 1.9). Compared to associations observed during the childhood follow-up, associations at adolescence were attenuated according to parent-report.

Conclusion: Reported associations between prenatal acetaminophen exposure and behavioral outcomes were not consistent over time nor between reporters.
Krüppel-like factor 15 in liver diseases: Insights into metabolic reprogramming
Authors: Chen Hao , Li Lan-Lan , Du Yan
Published: March 2023

Liver diseases, characterized by metabolic disorder, have become a global public health problem with high morbidity and mortality. Krüppel-like factor 15 (KLF15) is a zinc-finger transcription factor mainly enriched in liver. Increasing evidence suggests that hepatic KLF15 is activated rapidly during fasting, and contributes to the regulation of gluconeogenesis, lipid, amino acid catabolism, bile acids, endobiotic and xenobiotic metabolism. This review summarizes the latest advances of KLF15 in metabolic reprogramming, and explore the function of KLF15 in acute liver injury, hepatitis B virus, and autoimmune hepatitis. which aims to evaluate the potential of KLF15 as a therapeutic target and prognostic biomarker for liver diseases.
Autophagy-related gene LAPTM4B promotes the progression of renal clear cell carcinoma and is associated with immunity
Authors: Wang He , Wang Qibo , Wu Yaoyao , Lou Jianmin , Zhu Shaoxing , Xu Yipeng
Published: March 2023

Renal cell carcinoma (RCC) is a common urologic disease. Currently, surgery is the primary treatment for renal cancer; immunotherapy is not as effective a treatment strategy as expected. Hence, understanding the mechanism in the tumor immune microenvironment (TME) and exploring novel immunotherapeutic targets are considered important. Recent studies have demonstrated that autophagy could affect the immune environment of renal cell carcinoma and induce proliferation and apoptosis of cancer cells. By comparing lysosomal genes and regulating autophagy genes, we identified the LAPTM4B gene to be related to RCC autophagy. By analyzing the TCGA-KIRC cohort using bioinformatics, we found M2 macrophages associated with tumor metastasis to be significantly increased in the immune microenvironment of patients with high expression of LAPTM4B. GO/KEGG/GSEA/GSVA results showed significant differences in tumor autophagy- and metastasis-related pathways. Single-cell sequencing was used to compare the expression of LAPTM4B in different cell types and obtain the differences in lysosomal and autophagy pathway activities in different ccRCC cells. Subsequently, we confirmed the differential expression of LAPTM4B in renal cell carcinoma of different Fuhrman grades using western blotting. Downregulation of LAPTM4B expression significantly reduced the proliferation of renal cell carcinoma cells and promoted cell apoptosis through cell experiments. Overall, our study demonstrated that the autophagy-related gene LAPTM4B plays a critical role in the TME of RCC, and suggested that LAPTM4B is a potential therapeutic target for RCC immunotherapy.
The role of irreversible pan-HER tyrosine kinase inhibitors in the treatment of HER2-Positive metastatic breast cancer
Authors: Wu Zihong , Wang Jiamei , You Fengming , Li Xueke , Xiao Chong
Published: March 2023

Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is the leading cause of cancer death in women. For patients with HER2-positive MBC, after the failure of multiple lines of treatment, there is no optimal line of therapy. A series of clinical trials confirmed that treatment with irreversible pan-HER tyrosine kinase inhibitors (TKIs) in combination with chemotherapy significantly improves patients’ survival outcomes. This review focuses on the pathogenesis of HER2-positive breast cancer, current standard treatments, mechanisms of approved irreversible TKIs, and key clinical trials. The available findings suggest that irreversible pan-HER TKIs, such as pyrotinib and neratinib, in combination with chemotherapy, represent a beneficial salvage therapy for patients with HER2-positive MBC with manageable toxicity. However, further studies are needed to assess the efficacy and safety of this combination therapy.
Research progress of glutathione peroxidase family (GPX) in redoxidation
Authors: Pei Jun , Pan Xingyu , Wei Guanghui , Hua Yi
Published: March 2023

Maintaining the balance of a cell’s redox function is key to determining cell fate. In the critical redox system of mammalian cells, glutathione peroxidase (GPX) is the most prominent family of proteins with a multifaceted function that affects almost all cellular processes. A total of eight members of the GPX family are currently found, namely GPX1-GPX8. They have long been used as antioxidant enzymes to play an important role in combating oxidative stress and maintaining redox balance. However, each member of the GPX family has a different mechanism of action and site of action in maintaining redox balance. GPX1-4 and GPX6 use selenocysteine as the active center to catalyze the reduction of H2O2 or organic hydroperoxides to water or corresponding alcohols, thereby reducing their toxicity and maintaining redox balance. In addition to reducing H2O2 and small molecule hydroperoxides, GPX4 is also capable of reducing complex lipid compounds. It is the only enzyme in the GPX family that directly reduces and destroys lipid hydroperoxides. The active sites of GPX5 and GPX7-GPX8 do not contain selenium cysteine (Secys), but instead, have cysteine residues (Cys) as their active sites. GPX5 is mainly expressed in epididymal tissue and plays a role in protecting sperm from oxidative stress. Both enzymes, GPX7 and GPX8, are located in the endoplasmic reticulum and are necessary enzymes involved in the oxidative folding of endoplasmic reticulum proteins, and GPX8 also plays an important role in the regulation of Ca2+ in the endoplasmic reticulum. With an in-depth understanding of the role of the GPX family members in health and disease development, redox balance has become the functional core of GPX family, in order to further clarify the expression and regulatory mechanism of each member in the redox process, we reviewed GPX family members separately.
Intensive care photoplethysmogram datasets and machine-learning for blood pressure estimation: Generalization not guarantied
Authors: Weber-Boisvert Guillaume , Gosselin Benoit , Sandberg Frida
Published: March 2023

The large MIMIC waveform dataset, sourced from intensive care units, has been used extensively for the development of Photoplethysmography (PPG) based blood pressure (BP) estimation algorithms. Yet, because the data comes from patients in severe conditions—often under the effect of drugs—it is regularly noted that the relationship between BP and PPG signal characteristics may be anomalous, a claim that we investigate here. A sample of 12,000 records from the MIMIC waveform dataset was stacked up against the 219 records of the PPG-BP dataset, an alternative public dataset obtained under controlled experimental conditions. The distribution of systolic and diastolic BP data and 31 PPG pulse morphological features was first compared between datasets. Then, the correlation between features and BP, as well as between the features themselves, was analysed. Finally, regression models were trained for each dataset and validated against the other. Statistical analysis showed significant p<0.001 differences between the datasets in diastolic BP and in 20 out of 31 features when adjusting for heart rate differences. The eight features showing the highest rank correlation ρ > 0.40 to systolic BP in PPG-BP all displayed muted correlation levels ρ < 0.10 in MIMIC. Regression tests showed twice higher baseline predictive power with PPG-BP than with MIMIC. Cross-dataset regression displayed a practically complete loss of predictive power for all models. The differences between the MIMIC and PPG-BP dataset exposed in this study suggest that BP estimation models based on the MIMIC dataset have reduced predictive power on the general population.