bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic patterns of postprandial metabolic responses to three dietary challenges
Authors: Weinisch Patrick , Fiamoncini Jarlei , Schranner Daniela , Raffler Johannes , Skurk Thomas , Rist Manuela J. , Römisch-Margl Werner , Prehn Cornelia , Adamski Jerzy , Hauner Hans , Daniel Hannelore , Suhre Karsten , Kastenmüller Gabi
Published: September 2022

Food intake triggers extensive changes in the blood metabolome. The kinetics of these changes depend on meal composition and on intrinsic, health-related characteristics of each individual, making the assessment of changes in the postprandial metabolome an opportunity to assess someone's metabolic status. To enable the usage of dietary challenges as diagnostic tools, profound knowledge about changes that occur in the postprandial period in healthy individuals is needed. In this study, we characterize the time-resolved changes in plasma levels of 634 metabolites in response to an oral glucose tolerance test (OGTT), an oral lipid tolerance test (OLTT), and a mixed meal (SLD) in healthy young males (n = 15). Metabolite levels for samples taken at different time points (20 per individual) during the challenges were available from targeted (132 metabolites) and non-targeted (502 metabolites) metabolomics. Almost half of the profiled metabolites (n = 308) showed a significant change in at least one challenge, thereof 111 metabolites responded exclusively to one particular challenge. Examples include azelate, which is linked to ω-oxidation and increased only in OLTT, and a fibrinogen cleavage peptide that has been linked to a higher risk of cardiovascular events in diabetes patients and increased only in OGTT, making its postprandial dynamics a potential target for risk management. A pool of 89 metabolites changed their plasma levels during all three challenges and represents the core postprandial response to food intake regardless of macronutrient composition. We used fuzzy c-means clustering to group these metabolites into eight clusters based on commonalities of their dynamic response patterns, with each cluster following one of four primary response patterns: (i) “decrease-increase” (valley-like) with fatty acids and acylcarnitines indicating the suppression of lipolysis, (ii) “increase-decrease” (mountain-like) including a cluster of conjugated bile acids and the glucose/insulin cluster, (iii) “steady decrease” with metabolites reflecting a carryover from meals prior to the study, and (iv) “mixed” decreasing after the glucose challenge and increasing otherwise. Despite the small number of subjects, the diversity of the challenges and the wealth of metabolomic data make this study an important step toward the characterization of postprandial responses and the identification of markers of metabolic processes regulated by food intake.
Association of dietary pattern and Tibetan featured foods with high-altitude polycythemia in Naqu, Tibet: A 1:2 individual-matched case-control study
Authors: Cui Jiaxue , Zhaxi Duoji , Sun Xianzhi , Teng Nan , Wang Ruiqi , Diao Yizhuo , Jin Chenxin , Chen Yongxing , Xu Xiaoguang , Li Xiaofeng
Published: September 2022

This study focused on the association of dietary patterns and Tibetan featured foods with high-altitude polycythemia (HAPC) in Naqu, Tibet, to explore the risk factors of HAPC in Naqu, Tibet, to raise awareness of the disease among the population and provide evidence for the development of prevention and treatment interventions. A 1:2 individual-matched case-control study design was used to select residents of three villages in the Naqu region of Tibet as the study population. During the health examination and questionnaire survey conducted from December 2020 to December 2021, a sample of 1,171 cases was collected. And after inclusion and exclusion criteria and energy intake correction, 100 patients diagnosed with HAPC using the “Qinghai criteria” were identified as the case group, while 1,059 patients without HAPC or HAPC -related diseases were identified as the control group. Individuals were matched by a 1:2 propensity score matching according to gender, age, body mass index (BMI), length of residence, working altitude, smoking status, and alcohol status. Dietary patterns were determined by a principal component analysis, and the scores of study subjects for each dietary pattern were calculated. The effect of dietary pattern scores and mean daily intake (g/day) of foods in the Tibetan specialty diet on the prevalence of HAPC was analyzed using conditional logistic regression. After propensity score matching, we found three main dietary patterns among residents in Naqu through principal component analysis, which were a “high protein pattern,” “snack food pattern,” and “vegetarian food pattern.” All three dietary patterns showed a high linear association with HAPC (p < 0.05) and were risk factors for HAPC. In the analysis of the relationship between Tibetan featured foods and the prevalence of HAPC, the results of the multifactorial analysis following adjustment for other featured foods showed that there was a positive correlation between the average daily intake of tsampa and the presence of HAPC, which was a risk factor. Additionally, there was an inverse correlation between the average daily intake of ghee tea and the presence of HAPC, which was a protective factor.
Association between omega-3/6 fatty acids and cholelithiasis: A mendelian randomization study
Authors: Sun Qi , Gao Ning , Xia Weiliang
Published: September 2022

Background

Omega-3 and omega-6 may be protective factors for cholelithiasis. However, this relationship has not yet been demonstrated clearly. Therefore, we attempted to identify these causal relationships.

Materials and methods

The omega-3/6 fatty acid discovery dataset was obtained from UK Biobank and contained 114,999 individuals. The validation set was derived from an independent genome-wide association study (GWAS) and contained 13,544 individuals. The cholelithiasis dataset was derived from FinnGen and contained 19,023 cases and 195,144 controls. The inverse variance weighting (IVW) method was used as the main method of analysis in this study. Multiple methods of analysis were also used in the repeated methods, including the MR-Egger, weighted median, MR-pleiotropic residual sum (MR-PRESSO), outliers, and maximum likelihood methods. In addition, we used multiple sensitivity analyses to identify the potential pleiotropy.

Result

In the discovery stage, the results of the random effect IVW analysis showed that higher omega-3 levels were correlated inversely with the risk of cholelithiasis (β = –0.22, 95% CI [–0.32 to –0.12], P = 1.49 × 10–5). When the replication analysis was performed using another set of instrumental variables (IVs), the causal relationship between omega-3 fatty acids and cholelithiasis remained stable (β = –0.42, 95% CI [–0.66 to –0.18], P = 5.49 × 10–4), except for the results obtained using the MR-Egger method, which were not significant. The results of the IVW approach showed that each SD increase in omega-6 levels was associated negatively with the risk of cholelithiasis, both in the discovery (β = –0.21, 95% CI [–0.35 to –0.06], P = 4.37 × 10–3) and the validation phases (β = –0.21, 95% CI [–0.40 to –0.02], P = 3.44 × 10–2).

Conclusion

The results of our MR study suggest that omega-3/6 is associated with cholelithiasis risk. Attention to the risk of cholelithiasis in individuals with low serum omega-3/6 levels is necessary.
Dynamics of biochemical attributes and enzymatic activities of pasteurized and bio-preserved tender coconut water during storage
Authors: Pandiselvam R. , Prithviraj V. , Manikantan M. R. , Beegum P. P. Shameena , Ramesh S. V. , Kothakota Anjineyulu , Mathew A. C. , Hebbar K. B. , Maerescu Cristina Maria , Criste Florin Leontin , Socol Claudia Terezia
Published: September 2022

The potential of bio-preservatives, namely, nisin, natamycin, and polylysine, as viable alternatives to chemical preservatives for storage of tender coconut water (TCW) during refrigerated storage (5 ± 2°C) was explored. Bio-preservative treatments were carried out after optimized heat treatment (85°C for 5 min) of TCW to establish its storage characteristics. Various concentrations (up to 125 ppm) of bio-preservatives were used for the preservation, and quality parameters of resultant TCW were assessed based on physicochemical characteristics and Food and Agriculture Organization (FAO) guidelines and statistical analysis applied. Analysis of variance (ANOVA) and post-hoc test revealed that pH and overall acceptability (OA) are the major governing factors that determine spoilage of TCW (p < 0.05). Overall, the polylysine combination was found to be most effective in ensuring quality retention of TCW. It was concluded that pasteurized TCW shelf life could be extended up to 20 days using bio-preservatives.
Prediction models for monitoring selenium and its associated heavy-metal accumulation in four kinds of agro-foods in seleniferous area
Authors: Jiao Linshu , Zhang Liuquan , Zhang Yongzhu , Wang Ran , Liu Xianjin , Lu Baiyi
Published: September 2022

Se-rich agro-foods are effective Se supplements for Se-deficient people, but the associated metals have potential risks to human health. Factors affecting the accumulation of Se and its associated metals in Se-rich agro-foods were obscure, and the prediction models for the accumulation of Se and its associated metals have not been established. In this study, 661 samples of Se-rich rice, garlic, black fungus, and eggs, four typical Se-rich agro-foods in China, and soil, matrix, feed, irrigation, and feeding water were collected and analyzed. The major associated metal for Se-rich rice and garlic was Cd, and that for Se-rich black fungus and egg was Cr. Se and its associated metal contents in Se-rich agro-foods were positively correlated with Se and metal contents in soil, matrix, feed, and matrix organic contents. The Se and Cd contents in Se-rich rice grain and garlic were positively and negatively correlated with soil pH, respectively. Eight models for predicting the content of Se and its main associated metals in Se-rich rice, garlic, black fungus, and eggs were established by multiple linear regression. The accuracy of the constructed models was further validated with blind samples. In summary, this study revealed the main associated metals, factors, and prediction models for Se and metal accumulation in four kinds of Se-rich agro-foods, thus helpful in producing high-quality and healthy Se-rich.
Identification and immune characteristics of molecular subtypes related to fatty acid metabolism in idiopathic pulmonary fibrosis
Authors: Yang Fan , Ma Zhaotian , Li Wanyang , Kong Jingwei , Zong Yuhan , Wendusu Bilige , Wu Qinglu , Li Yao , Dong Guangda , Zhao Xiaoshan , Wang Ji
Published: September 2022

Background

Although fatty acid metabolism has been confirmed to be involved in the pathological process of idiopathic pulmonary fibrosis (IPF), systematic analyses on the immune process mediated by fatty acid metabolism-related genes (FAMRGs) in IPF remain lacking.

Methods

The gene expression data of 315 patients with IPF were obtained from Gene Expression Omnibus database and were divided into the training and verification sets. The core FAMRGs of the training set were identified through weighted gene co-expression network analysis. Then, the fatty acid metabolism-related subtypes in IPF were identified on the basis of k-means unsupervised clustering. The scores of fatty acid metabolism and the expression of the fibrosis biomarkers in different subtypes were compared, and functional enrichment analysis was carried out on the differentially expressed genes between subtypes. A random forest model was used to select important FAMRGs as diagnostic markers for distinguishing between subtypes, and a line chart model was constructed and verified by using other datasets and rat models with different degrees of pulmonary fibrosis. The difference in immune cell infiltration among subtypes was evaluated with CIBERSORT, and the correlation between core diagnostic markers and immune cells were analyzed.

Results

Twenty-four core FAMRGs were differentially expressed between the training set and normal samples, and IPF was divided into two subtypes. Significant differences were observed between the two subtypes in biological processes, such as linoleic acid metabolism, cilium movement, and natural killer (NK) cell activation. The subtype with high fatty acid metabolism had more severe pulmonary fibrosis than the other subtype. A reliable construction line chart model based on six diagnostic markers was constructed, and ABCA3 and CYP24A1 were identified as core diagnostic markers. Significant differences in immune cell infiltration were found between the two subtypes, and ABCA3 and CYP24A1 were closely related to NK cells.

Conclusion

Fatty acid metabolism and the immune process that it mediates play an important role in the occurrence and development of IPF. The analysis of the role of FAMRGs in IPF may provide a new potential therapeutic target for IPF.
Contemporary Chinese dietary pattern: Where are the hidden risks?
Authors: Xiang Hong , Tao Xufeng , Guan Xi , Yin Tianyi , Li Junchen , Dong Deshi , Shang Dong
Published: September 2022

Background

With the rapid improvement in economy and lifestyle, dietary risk-related diseases have become a public health problem worldwide. However, the health effects of dietary risk over time have not been fully clarified in China. Here, we explored the temporal trends in the death burden of unhealthy dietary habits in China and benchmark dietary risk challenges in China to G20 member states.

Method

Sex–age-specific burdens due to dietary risk in China were extracted from the Global Burden of Disease (GBD) Study 2019, including annual numbers and age-standardized rates (ASRs) of death, disability-adjusted life years (DALYs), and summary exposure values (SEVs) during 1990–2019. The variation trend of ASRs was evaluated by estimated annual percentage changes (EAPCs).

Result

Between 1990 and 2019, the number of dietary risk-based death and DALYs increased significantly in China with an overall downward trend of ASDR and ASR-DALYs. Ischemic heart disease was the first cause of death from diet, followed by stroke and colon and rectum cancers. Chinese men were at greater risk than women for diet-related death and DALYs. Further analysis showed that a high sodium diet has always been the “No. 1 killer” that threatens the health of Chinese residents. The death burden of dietary risk demonstrated an increasing trend with age, and the peak was reached in people over 75 years. Compared with other G20 countries, Japan and South Korea have the most similar dietary patterns to China with the character of high sodium intake. Notably, decreased whole grain intake, as the primary dietary risk attributable to death and DALYs burden in the United States and European countries, had already ranked second in China's dietary risks.

Conclusion

China's dietary burden cannot be ignored. Chinese residents should pay more attention to the collocation of dietary nutrients, especially men and 75+ years (elderly) people. Targeted dietary adjustments can significantly reduce deaths and DALYs in China.
LncRNA SNHG6 sponges miR-101 and induces tamoxifen resistance in breast cancer cells through induction of EMT
Authors: Khan Mohammad Imran , Ahmad Aamir
Published: September 2022

Acquired resistance is a major clinical challenge for tamoxifen-based therapy. In this study, we focused on lncRNA SNHG6 which plays a role in chemoresistance of cancer cells, but has never been investigated in the context of tamoxifen resistance. We found elevated levels of SNHG6 in tamoxifen-resistant estrogen receptor (ER)-positive MCF-7 cells (MCF7TR), relative to naïve MCF-7 cells, as well as in tamoxifen-resistant T47D cells (T47DTR), relative to naïve T47D cells, which correlated with induced vimentin, ZEB1/2 and decreased e-cadherin, thus implicating a role of EMT in SNHG6-mediated tamoxifen resistance. Downregulation of SNHG6, using specific siRNA, sensitized MCF7TR as well as T47DTR cells to tamoxifen along with markedly reduced proliferation, invasion and anchorage-independent clonogenicity. Further, SNHG6 was found to sponge and inhibit miR-101 as the endogenous expression levels of SNHG6 and miR-101 inversely correlated in paired parental and tamoxifen-resistant cells and, moreover, silencing of SNHG6 in tamoxifen-resistant cells resulted in de-repression of miR-101, along with reversal of EMT. SNHG6 expression also directly correlated with increased stem cells markers Sox2, Oct4 and EZH2. miR-101 levels, manipulated by transfections with pre/anti-miR-101 oligos, directly affected tamoxifen sensitivity of ER-positive cells with pre-miR-101 sensitizing MCF7TR and T47DTR cells to tamoxifen whereas anti-miR-101 inducing resistance of parental MCF-7 and T47D cells to tamoxifen. Further, miR-101 was found to attenuate SNHG6-mediated effects on tamoxifen resistance, EMT as well as stem cell markers, thereby making a case for SNHG6-miR-101 axis in tamoxifen resistance of ER-positive breast cancer cells. Thus, lncRNA SNHG6 is a novel modulator of tamoxifen resistance through its sponging of miR-101 and the resulting effects on EMT.
MOF negatively regulates estrogen receptor α signaling via CUL4B-mediated protein degradation in breast cancer
Authors: Zhang Xu , Yang Yang , Li Danyang , Wu Zhen , Liu Haoyu , Zhao Ziyan , Zhu Hongying , Xie Fei , Li Xiangzhi
Published: September 2022

Estrogen receptor α (ERα) is the dominant tumorigenesis driver in breast cancer (BC), and ERα-positive BC (ERα+ BC) accounts for more than two-thirds of BC cases. MOF (males absent on the first) is a highly conserved histone acetyltransferase that acetylates lysine 16 of histone H4 (H4K16) and several non-histone proteins. Unbalanced expression of MOF has been identified, and high MOF expression predicted a favorable prognosis in BC. However, the association of MOF with ERα and the regulatory mechanisms of MOF in ERα signaling remain elusive. Our study revealed that the expression of MOF is negatively correlated with that of ERα in BC. In ERα+ BC cells, MOF overexpression downregulated the protein abundance of ERα in both cytoplasm and nucleus, thus attenuating ERα-mediated transactivation as well as cellular proliferation and in vivo tumorigenicity of BC cells. MOF promoted ERα protein degradation through CUL4B-mediated ubiquitin–proteasome pathway and induced HSP90 hyperacetylation that led to the loss of chaperone protection of HSP90 to ERα. We also revealed that suppression of MOF restored ERα expression and increased the sensitivity of ERα-negative BC cells to tamoxifen treatment. These results provide a new insight into the tumor-suppressive role of MOF in BC via negatively regulating ERα action, suggesting that MOF might be a potential therapeutic target for BC.
Negotiating decisions on aggressive cancer care at end-of-life between patients, family members, and physicians – A qualitative interview study
Authors: Haun Markus W. , Wildenauer Alina , Hartmann Mechthild , Bleyel Caroline , Becker Nikolaus , Jäger Dirk , Friederich Hans-Christoph , Tönnies Justus
Published: September 2022

Background

Patients with advanced cancer do receive increasingly aggressive end-of-life care, despite it does often not prolong survival time but entails decreased quality of life for patients. This qualitative study explores the unfolding of aggressive end-of-life care in clinical practice focusing on the decision-making process and the quality of end-of-life care from family members’ perspective.

Materials and methods

We conducted semi-structured interviews with 16 family members (six of cancer patients with and ten without aggressive end-of-life care) at the National Center for Tumor Diseases Heidelberg, Germany. We conducted a content analysis applying a theoretical framework to differentiate between ‘decision-making’ (process of deciding for one choice among many options) and ‘decision-taking’ (acting upon this choice).

Results

While patients of the aggressive care group tended to make and take decisions with their family members and physicians, patients of the other group took the decision against more aggressive treatment alone. Main reason for the decision in favor of aggressive care was the wish to spend more time with loved ones. Patients took decisions against aggressive care given the rapid decline in physical health and to spare relatives difficult decisions and arising feelings of guilt and self-reproach.

Conclusion

Treatment decisions at end-of-life are always individual. Nevertheless, treatment courses with aggressive end-of-life care and those without differ markedly. To account for a longitudinal perspective on the interplay between patients, family members, and physicians, cohort studies are needed. Meanwhile, clinicians should validate patients and family members considering refraining from aggressive end-of-life care and explore their motives.

Clinical trial registration

https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022837, identifier DRKS00022837.
The Bigger the Better? Analysis of Surgical Complications and Outcome of the Retrosigmoid Approach in 449 Oncological Cases
Authors: Aftahy Amir Kaywan , Jörger Ann-Kathrin , Hillebrand Sandra , Harder Felix N. , Wiestler Benedikt , Bernhardt Denise , Combs Stephanie E. , Meyer Bernhard , Negwer Chiara , Gempt Jens
Published: September 2022

Introduction

Exposure of the posterior skull base and the cerebellopontine angle is challenging due to important neurovascular structures. The retrosigmoid approach (RSA) has become the standard method used in surgery. We report our experiences with RSAs regarding technical obstacles, complications, and approach-related outcomes.

Materials and Methods

We performed a retrospective chart review at a tertiary neurosurgical center between January 2007 and September 2020. We included all patients undergoing surgery for oncologic lesions through RSAs, concentrating on surgical technique, postoperative outcome, and complications.

Results

A total of 449 RSAs were included. The median age at the time of surgery was 58 years; 168 (37.4%) were male and 281 (62.6%) were female. The median approach surface was 7.8 cm2. The median tumor volume was 5.9 cm3. The median Clavien–Dindo grade was 2, the total complication rate was 28.7%, and gross total resection (GTR) was 78.8%. Findings revealed that tumor volume had no significant impact on postoperative complications in general (p = 0.086) but had a significant impact on postoperative hemorrhage (p = 0.037) and hydrocephalus (p = 0.019). Tumor volume was significant for several preoperative symptoms (p < 0.001). The extent of the approach had no significant impact on complications in general (p = 0.120) but was significant regarding postoperative cerebrospinal fluid (CSF) leaks (p = 0.008). Craniotomy size was not significant regarding GTR (p = 0.178); GTR rate just missed significant correlation with tumor volume (p = 0.056). However, in the case of vestibular schwannomas, the size of craniotomy was important for GTR (p = 0.041).

Conclusion

Tumor volume has an important impact on preoperative symptoms as well as on postoperative complications. Although the extent of the craniotomy barely missed significance regarding GTR, a correlation can be assumed. Thus, the extent of craniotomy should be taken into presurgical consideration, especially in the case of postoperative CSF leaks. Regarding vestibular schwannomas, craniotomy size plays an important role in achieving satisfactory oncological outcomes. Different approaches should be selected where necessary regarding superior resection rates.
Reclassification of endometrial cancer and identification of key genes based on neural-related genes
Authors: Chen Fan , Qin Tiansheng , Zhang Yigan , Wei Linzhen , Dang Yamei , Liu Peixia , Jin Weilin
Published: September 2022

Endometrial cancer (EC) is the most common gynecologic malignancy, and its incidence has been increasing every year. Nerve signaling is part of the tumor microenvironment and plays an active role in tumor progression and invasion. However, the relationship between the expression of neural-related genes (NRGs) and prognosis in endometrial cancer remains unknown. In this study, we obtained RNA sequencing data of EC from The Cancer Genome Atlas (TCGA). Endometrial cancer was classified into two subtypes based on the expression of neural-associated genes (NRGs), with statistical differences in clinical stage, pathological grading, and prognosis. A prognostic prediction model was established by LASSO-Cox analysis, and the results showed that high expression of NRGs was associated with poor survival prognosis. Further, CHRM2, GRIN1, L1CAM, and SEMA4F were found to be significantly associated with clinical stage, immune infiltration, immune response, and important signaling pathways in endometrial cancer. The reclassification of endometrial cancer based on NRG expression would be beneficial for future clinical practice. The genes CHRM2, GRIN1, L1CAM, and SEMA4F might serve as potential biomarkers of EC prognosis.
Burden of thyroid cancer in North Africa and Middle East 1990–2019
Authors: Nejadghaderi Seyed Aria , Moghaddam Sahar Saeedi , Azadnajafabad Sina , Rezaei Negar , Rezaei Nazila , Tavangar Seyed Mohammad , Jamshidi Hamidreza , Mokdad Ali H. , Naghavi Mohsen , Farzadfar Farshad , Larijani Bagher ,   GBD 2019 NAME Thyroid Cancer Collaborators
Published: September 2022

Background

Thyroid cancer is the leading cause of mortality and morbidity among cancers of the endocrine system. We aimed to describe the trends of thyroid cancer burden in North Africa and Middle East for 1990–2019.

Methods

Data on burden of thyroid cancer in North Africa and Middle East from 1990 to 2019 were obtained from the Global Burden of Disease (GBD) Study 2019. Decomposition analysis was used to estimate the effects of population growth, aging, and change in incident numbers on overall change of thyroid cancer incidence. Also, we used the comparative risk assessment framework of GBD to determine the burden of thyroid cancer attributable to a high body mass index (BMI).

Results

In 2019, the age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) of thyroid cancer were 3.5 (2.9–4) and 0.5 (0.5–0.7) per 100,000, respectively. The highest age-standardized incidence, deaths, and disability-adjusted life year (DALY) rate were in Lebanon, Afghanistan, and United Arab Emirates, respectively. The ASIR of thyroid cancer in region was about 2.5 times higher among women, which had a positive association with increasing age. In 2019, the age-standardized deaths attributable to a high BMI was 16.7% of all deaths due to thyroid cancer. In 1990–2019, the overall change in thyroid cancer incident cases was a 396% increase which was mostly driven by the increase in disease-specific incidence rate (256.8%).

Conclusions

Women, the elderly above about 60 years old, and countries with a higher sociodemographic index showed higher incidence rates of thyroid cancer. Regarding our findings, it is recommended to establish preventive plans by modification in life style like weight reduction programs.
Characterizing metastatic uveal melanoma patients who develop symptomatic brain metastases
Authors: Wei Alexander Z. , Uriel Matan , Porcu Agata , Manos Michael P. , Mercurio Ann C. , Caplan Michael M. , Hulse Liam , Seedor Rino S. , Holovatska Marta , Francis Jasmine , Khan Shaheer A. , McDonnell Diana E. , Bogomolny Dmitry , Sato Takami , Marr Brian P. , Haq Rizwan , Orloff Marlana , Shoushtari Alexander , Carvajal Richard D.
Published: September 2022

Metastatic uveal melanoma (mUM) is an advanced ocular malignancy characterized by a hepatotropic pattern of spread. As the incidence of brain metastases (BM) in mUM patients has been thought to be low, routine CNS surveillance has not been recommended. Notably, no formal assessment of BM incidence in mUM has to date been published to support this clinical practice. We aimed to determine the true rate of BM in mUM and to clarify the clinical and genomic risk factors associated with BM patients through a collaborative multicenter, retrospective research effort. Data collected from 1,845 mUM patients in databases across four NCI-designated comprehensive cancer centers from 2006-2021 were retrospectively analyzed to identify patients with BM. Brain imaging in most cases were performed due to onset of neurological symptoms and not for routine surveillance. An analysis of demographics, therapies, gene expression profile, tumor next generation sequencing (NGS) data, time to metastasis (brain or other), and survival in the BM cohort was completed. 116/1,845 (6.3%) mUM patients were identified with BM. The median age at time of UM diagnosis was 54 years old (range: 18-77). The median time to any metastasis was 4.2 years (range: 0-30.8). The most common initial metastatic site was the liver (75.9%). 15/116 (12.9%) BM patients presented with BM at the time of initial metastatic diagnosis. Median survival after a diagnosis of BM was 7.6 months (range: 0.4-73.9). The median number of organs involved at time of BM diagnosis was 3 (range: 1-9). DecisionDX-UM profiling was completed on 13 patients: 10-Class 2, 2-Class 1B, and 1-Class 1A. NGS and cytogenetic data were available for 34 and 21 patients, respectively. BM was identified in 6.3% of mUM cases and was associated with high disease burden and a median survival of under 8 months once diagnosed. Since most patients in this cohort were symptomatic, the incidence of asymptomatic BM remains unknown. These data suggest the use of routine brain imaging in all mUM patients at risk for developing BM for early detection.
To bind or not to bind: Cistromic reprogramming in prostate cancer
Authors: Shen Michelle , Demers Léa-Kristine , Bailey Swneke D. , Labbé David P.
Published: September 2022

The term “cistrome” refers to the genome-wide location of regulatory elements associated with transcription factor binding-sites. The cistrome of key regulatory factors in prostate cancer etiology are substantially reprogrammed and altered during prostatic transformation and disease progression. For instance, the cistrome of the androgen receptor (AR), a ligand-inducible transcription factor central in normal prostate epithelium biology, is directly impacted and substantially reprogrammed during malignant transformation. Accumulating evidence demonstrates that additional transcription factors that are frequently mutated, or aberrantly expressed in prostate cancer, such as the pioneer transcription factors Forkhead Box A1 (FOXA1), the homeobox protein HOXB13, and the GATA binding protein 2 (GATA2), and the ETS-related gene (ERG), and the MYC proto-oncogene, contribute to the reprogramming of the AR cistrome. In addition, recent findings have highlighted key roles for the SWI/SNF complex and the chromatin-modifying helicase CHD1 in remodeling the epigenome and altering the AR cistrome during disease progression. In this review, we will cover the role of cistromic reprogramming in prostate cancer initiation and progression. Specifically, we will discuss the impact of key prostate cancer regulators, as well as the role of epigenetic and chromatin regulators in relation to the AR cistrome and the transformation of normal prostate epithelium. Given the importance of chromatin-transcription factor dynamics in normal cellular differentiation and cancer, an in-depth assessment of the factors involved in producing these altered cistromes is of great relevance and provides insight into new therapeutic strategies for prostate cancer.
Modified immunoscore improves the prediction of progression-free survival in patients with non-muscle-invasive bladder cancer: A digital pathology study
Authors: Bieri Uwe , Enderlin Dominik , Buser Lorenz , Wettstein Marian S. , Eberli Daniel , Moch Holger , Hermanns Thomas , Poyet Cédric
Published: September 2022

Tumour-infiltrating lymphocytes (TIL), known to be of prognostic value in various solid tumours, have been in the focus of research in the last years. TIL are often quantified via IMMUNOSCORE ® (IS), a scoring system based on TIL cell densities. Recent studies were able to replicate these findings for muscle-invasive bladder cancer (MIBC), however data regarding non-muscle-invasive bladder cancer (NMIBC) are scarce. This study aimed to evaluate the value of a modified Immunoscore (mIS) as a predictive marker for NMIBC prognosis using tissue-micro-arrays (TMAs). We analysed two TMAs containing 316 samples from 158 patients with NMIBC, stained for CD3, CD8, CD45RO and FOXP3. Stained TIL were captured by digital pathology, cumulated, averaged, and reported as density (stained cells per mm²). The mIS was then constructed based on density of all four immune-cell types. Clinical, pathological and follow-up data were collected retrospectively. Univariable and multivariable cox regression analysis was performed to assess the potential value of mIS as a predictor for progression free survival (PFS) and recurrence-free-survival (RFS). Patients within “European Organisation for Research and Treatment of Cancer” (EORTC) risk groups were further substratified in high mIS and low mIS subgroups. Finally log-rank test was used to compare the different survival curves. The median age in our cohort was 68 years (Interquartile Range (IQR): 60 - 76), and 117 (74%) patients were male. A total of 26 patients (16.5%) were classified as EORTC low risk, 45 (28.5%) as intermediate risk and 87 (55.1%) as high risk. Patients in the EORTC high risk group with low mIS showed a shorter PFS in comparison to high mIS (HR 2.9, CI 0.79 – 11.0, p=0.082). In contrast, no predictive potential regarding PFS was observed in intermediate or low risk groups. Furthermore, mIS was not able to predict RFS in any EORTC risk group. mIS could be utilized to predict prognosis more accurately in high-risk patients with NMIBC by identifying those with higher or lower risk of progression. Therefore, mIS could be used to allocate these highrisk patients to more streamlined follow-up or more aggressive treatment strategies.
Synthetic CT generation for MRI-guided adaptive radiotherapy in prostate cancer
Authors: Hsu Shu-Hui , Han Zhaohui , Leeman Jonathan E. , Hu Yue-Houng , Mak Raymond H. , Sudhyadhom Atchar
Published: September 2022

Current MRI-guided adaptive radiotherapy (MRgART) workflows require fraction-specific electron and/or mass density maps, which are created by deformable image registration (DIR) between the simulation CT images and daily MR images. Manual density overrides may also be needed where DIR-produced results are inaccurate. This approach slows the adaptive radiotherapy workflow and introduces additional dosimetric uncertainties, especially in the presence of the magnetic field. This study investigated a method based on a conditional generative adversarial network (cGAN) with a multi-planar method to generate synthetic CT images from low-field MR images to improve efficiency in MRgART workflows for prostate cancer. Fifty-seven male patients, who received MRI-guided radiation therapy to the pelvis using the ViewRay MRIdian Linac, were selected. Forty-five cases were randomly assigned to the training cohort with the remaining twelve cases assigned to the validation/testing cohort. All patient datasets had a semi-paired DIR-deformed CT-sim image and 0.35T MR image acquired using a true fast imaging with steady-state precession (TrueFISP) sequence. Synthetic CT images were compared with deformed CT images to evaluate image quality and dosimetric accuracy. To evaluate the dosimetric accuracy of this method, clinical plans were recalculated on synthetic CT images in the MRIdian treatment planning system. Dose volume histograms for planning target volumes (PTVs) and organs-at-risk (OARs) and dose distributions using gamma analyses were evaluated. The mean-absolute-errors (MAEs) in CT numbers were 30.1 ± 4.2 HU, 19.6 ± 2.3 HU and 158.5 ± 26.0 HU for the whole pelvis, soft tissue, and bone, respectively. The peak signal-to-noise ratio was 35.2 ± 1.7 and the structural index similarity measure was 0.9758 ± 0.0035. The dosimetric difference was on average less than 1% for all PTV and OAR metrics. Plans showed good agreement with gamma pass rates of 99% and 99.9% for 1%/1 mm and 2%/2 mm, respectively. Our study demonstrates the potential of using synthetic CT images created with a multi-planar cGAN method from 0.35T MRI TrueFISP images for the MRgART treatment of prostate radiotherapy. Future work will validate the method in a large cohort of patients and investigate the limitations of the method in the adaptive workflow.
GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide
Authors: Parik Sweta , Fernández-García Juan , Lodi Francesca , De Vlaminck Karen , Derweduwe Marleen , De Vleeschouwer Steven , Sciot Raf , Geens Wietse , Weng Linqian , Bosisio Francesca Maria , Bergers Gabriele , Duerinck Johnny , De Smet Frederick , Lambrechts Diether , Van Ginderachter Jo A. , Fendt Sarah-Maria
Published: September 2022

Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma. This response is, however, blunted in recurring glioblastoma from the same patient. Further, we describe that disrupting cellular fatty acid homeostasis in favor of accumulation of saturated fatty acids such as palmitate synergizes with temozolomide treatment. Pharmacological inhibition of SCD and/or FADS2 allows palmitate accumulation and thus greatly augments temozolomide efficacy. This effect was independent of common GBM prognostic factors and was effective against cancer cells from recurring glioblastoma. In summary, we provide evidence that intracellular accumulation of saturated fatty acids in conjunction with temozolomide based chemotherapy induces death in glioblastoma cells derived from patients.
Combining prostate-specific antigen density with prostate imaging reporting and data system score version 2.1 to improve detection of clinically significant prostate cancer: A retrospective study
Authors: Lei Yin , Li Tian Jie , Gu Peng , Yang Yu kun , Zhao Lei , Gao Chao , Hu Juan , Liu Xiao Dong
Published: September 2022

Globally, Prostate cancer (PCa) is the second most common cancer in the male population worldwide, but clinically significant prostate cancer (CSPCa) is more aggressive and causes to more deaths. The authors aimed to construct the risk category based on Prostate Imaging Reporting and Data System score version 2.1 (PI-RADS v2.1) in combination with Prostate-Specific Antigen Density (PSAD) to improve CSPCa detection and avoid unnecessary biopsy. Univariate and multivariate logistic regression and receiver-operating characteristic (ROC) curves were performed to compare the efficacy of the different predictors. The results revealed that PI-RADS v2.1 score and PSAD were independent predictors for CSPCa. Moreover, the combined factor shows a significantly higher predictive value than each single variable for the diagnosis of CSPCa. According to the risk stratification model constructed based on PI-RADS v2.1 score and PSAD, patients with PI-RADS v2.1 score of ≤2, or PI-RADS V2.1 score of 3 and PSA density of <0.15 ng/mL2, can avoid unnecessary of prostate biopsy and does not miss clinically significant prostate cancer.
Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC
Authors: Xia Yixue , Gao Binghong , Zhang Xue
Published: September 2022

Most of the primary hepatocellular carcinoma (HCC) develops from Viral Hepatitis including Hepatitis B virus, Hepatitis C Virus, and Nonalcoholic Steatohepatitis. Herein, T cells play crucial roles combined with chronic inflammation and chronic viral infection. However, T cells are gradually exhausted under chronic antigenic stimulation, which leads to T cell exhaustion in the tumor microenvironment, and the exhaustion is associated with mitochondrial dysfunction in T cells. Meanwhile, mitochondria play a crucial role in altering T cells’ metabolism modes to achieve desirable immunological responses, wherein mitochondria maintain quality control (MQC) and promote metabolism regulation in the microenvironment. Although immune checkpoint inhibitors have been widely used in clinical practice, there are some limitations in the therapeutic effect, thus combining immune checkpoint inhibitors with targeting mitochondrial biogenesis may enhance cellular metabolic adaptation and reverse the exhausted state. At present, several studies on mitochondrial quality control in HCC have been reported, however, there are gaps in the regulation of immune cell function by mitochondrial metabolism, particularly the modulating of T cell immune function. Hence, this review summarizes and discusses existing studies on the effects of MQC on T cell populations in liver diseases induced by HCC, it would be clued by mitochondrial quality control events.
The roles of small extracellular vesicles as prognostic biomarkers and treatment approaches in triple-negative breast cancer
Authors: Zhou Yueyuan , Xiao Zhongdang , Zhu Wei
Published: September 2022

Triple-negative breast cancer (TNBC) is a particularly aggressive and invasive breast cancer subtype and is associated with poor clinical outcomes. Treatment approaches for TNBC remain limited partly due to the lack of expression of well-known molecular targets. Small extracellular vesicles (sEVs) carrying a variety of bioactive contents play an important role in intercellular communications. The biomolecules including nucleic acids, proteins, and metabolites can be transferred locally or systematically to recipient cells and regulate their biological states and are involved in physiological and pathological processes. Recently, despite the extensive attraction to the physiological functions of sEVs, few studies focus on the roles of sEVs in TNBC. In this review, we will summarize the involvement of sEVs in the tumor microenvironment of TNBC. Moreover, we will discuss the potential roles of sEVs as diagnostic markers and treatment therapy in this heterogeneous breast cancer subtype. We finally summarize the clinical application of sEVs in TNBC.
Elevated plasma D-dimer levels are associated with the poor prognosis of critically ill children
Authors: Wang Guan , Liu Junhui , Xu Rui , Liu Xinjie
Published: September 2022

Background

D-dimer has been shown as a valuable predictor for the prognosis of sepsis. But the prognostic association of an elevated D-dimer with adverse outcomes of all critical illnesses in pediatric intensive care unit (PICU) has received far less emphasis.

Methods

This was a single-center retrospective study, including 7,648 critical patients aged between 28 days and 18 years from the pediatric intensive care (PIC) database from 2010 to 2018. The primary outcome was the in-hospital mortality rate.

Results

Higher levels of D-dimer, INR, PT, APTT, and lower Fib were observed in the non-survivor group (all P < 0.001). D-dimer, INR, PT and APTT were independent risk factors for prognosis in critically ill children. There was the highest AUROC in D-dimer for predicting in-hospital mortality of critically ill patients compared with INR, PT, APTT, and Fib (D-dimer: 0.77 vs. INR: 0.73 vs. PT: 0.73 vs. APTT: 0.64 vs. Fib: 0.60). The cut-off value, sensitivity, and specificity of D-dimer were 1.53, 0.65, and 0.77, respectively. Subgroup analysis showed a stable evaluation effectiveness of D-dimer for predicting in-hospital mortality of critically ill patients in the age and gender groups.

Conclusions

We found poorer coagulation function in the non-survivors compared with the survivors. Among the coagulation indicators, D-dimer was most strongly associated with in-hospital mortality of unselected critically ill children.
New insights in understanding biliary atresia from the perspectives on maternal microchimerism
Authors: Muraji Toshihiro , Masuya Ryuta , Harumatsu Toshio , Kawano Takafumi , Muto Mitsuru , Ieiri Satoshi
Published: September 2022

Biliary atresia (BA) is a fibroinflammatory cholangiopathy and portal venopathy. It is of unknown etiology and is associated with systemic immune dysregulation, in which the first insult begins before birth. Maternal microchimerism is a naturally occurring phenomenon during fetal life in which maternal alloantigens promote the development of tolerogenic fetal regulatory T-cells in utero. However, maternal cells may alter the fetus’s response to self-antigens and trigger an autoimmune response under certain histocompatibility combinations between the mother and the fetus. A recent report on a set of dizygotic discordant twins with BA, one of whose placentae showed villitis of unknown etiology, implies a certain immune-mediated conflict between the fetus with BA and the mother. Maternal chimeric cells persist postnatally for various time spans and can cause cholangitis, which ultimately leads to liver failure. In contrast, patients who eliminate maternal chimeric cells may retain their liver function.
Efficacy and Prognosis of Hyperbaric Oxygen as Adjuvant Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Meta-Analysis Study
Authors: Gong Xiu-Bing , Feng Rui-Hua , Dong Hong-Mei , Liu Wen-Hua , Gu Ya-Nan , Jiang Xiang-Yue , Lou Ye-Hao , Xu Jun , Dou Qing-Li
Published: September 2022

Background

Preclinical and clinical evidence suggests that hyperbaric oxygen therapy (HBOT) may benefit newborns. The effectiveness of HBOT for neonatal hypoxic-ischemic encephalopathy (HIE) remains controversial. We conducted a meta-analysis to evaluate the efficacy and prognosis of HBOT in neonates with HIE.

Methods

A systematic search of eight databases was performed for available articles published between January 1, 2015, and September 30, 2020, to identify randomized controlled clinical trials (RCTs) on HBOT for neonatal HIE. Methodological quality assessment was performed by applying the simple procedure detailed by the Cochrane collaboration. Afterward, quality assessment and data analysis were performed using Revman 5.3 software. STATA 15 software was used to detect publication bias as well as for sensitivity analysis.

Results

A total of 46 clinical RCTs were selected for the study and included 4,199 patients with neonatal HIE. The results indicated that HBOT significantly improved the total efficiency (TEF) of treatment for neonatal HIE patients [odds ratio (OR) = 4.61, 95% confidence interval (CI) (3.70, 5.75), P < 0.00001] and reduced the risk of sequelae (OR = 0.23, 95% CI (0.16, 0.33), P < 0.00001) and the neonatal behavioral neurological assessment (NBNA) scores [mean difference (MD) = 4.51, 95%CI (3.83,5.19, P < 0.00001)].

Conclusion

In light of the effectiveness of HBOT neonatal HIE, this meta-analysis suggested that HBOT can be a potential therapy for the treatment of neonatal HIE. Due to the heterogeneity of studies protocol and patient selection being only from China, more research is needed before this therapy can be widely implemented in the clinic.

Protocol Registration

PROSPERO (ID: CRD42020210639). Available online at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020210639.