bluuebunny/crossref_metadata_2025 huggingface dataset:
Epididymal epithelial degeneration and lipid metabolism impairment account for male infertility in occludin knockout mice
Authors: Liu Bao Ying , Zhang Bao Li , Gao Da Yuan , Li Qing , Xu Xin Yu , Shum Winnie
Published: November 2022

Occludin (OCLN) is a tight junction protein and Ocln deletion mutation causes male infertility in mice. However, the role of OCLN in male reproductive system remains unknown. In this study, we used an interdisciplinary approach to elucidate the underlying mechanism of male infertility in related to OCLN function, includingOclnknockout mice as well as a combined omics analysis and immunofluorescent labelling. Our results showed that the epididymis ofOcln-null mice displayed a phenomenon resembling epididymal sperm granuloma, which occurred especially in the junctional region between caput and corpus epididymidis. Sperm motility and fertilisation capacity were also impaired in theseOcln-null mice, accompanied by enlarged tubules in the proximal regions and degeneration in the distal regions of epididymis. Cellular localization analysis showed that OCLN immunofluorescence was enriched only in the apical junction of epithelial principal cells in the proximal regions of epididymis. Integrative omics analysis revealed the downregulation of gene clusters enriched in acid secretion and fatty acid metabolism in theOcln-null epididymis, especially the enzymes related to the unsaturated arachidonic acid pathway. The number of proton-pump V-ATPase-expression clear cells, a key player of luminal acidification in the epididymis, declined drastically from prepubertal age before sperm arrival but not in the early postnatal age. This was accompanied by programmed cell death of clear cells and increased pH in the epididymal fluid of OCLN-deficient mice. The lipidomics results showed significantly increased levels of specific DAGs conjugated to unsaturated fatty acids in the Ocln-mutant. Immunofluorescent labelling showed that the arachidonic acid converting enzyme PTGDS and phospholipase PLA2g12a were prominently altered in the principal cells and luminal contents of theOcln-mutant epididymis. Whereas the carboxylate ester lipase CES1, originally enriched in the WT basal cells, was found upregulated in theOcln-mutant principal cells. Overall, this study demonstrates that OCLN is essential for maintaining caput-to-corpus epithelial integrity, survival of acid-secreting clear cells, and unsaturated fatty acid catabolism in the mouse epididymis, thereby ensuring sperm maturation and male fertility.
Calculation of inter-provincial differences in the appropriate proportioning of land transfer income to support rural revitalization
Authors: Wang Yubo , Xue Yuyu
Published: November 2022

This research examined the suitability and regional differences of the distribution ratio of land transfer income aimed at supporting rural revitalization by calculating the distribution ratio of 31 provincial-level administrative divisions (abbreviated as 31PLAD), while providing a reference template for land transfer incomes. Herein, we collated and calculated the fiscal expenditure of five dimensions of each province (city, district) in 2005, 2010, 2015, and 2020, and then predicted the situation of the next period (that is, 2025) using GM (1, 1). Further, we used a time series to calculate the land transfer income of each province in 2025. After combining these two, the possible support of land transfer income in all dimensions of rural revitalization across the 31PLAD in 2025 was calculated. Then, according to the Dagum Gini coefficient method, the regional differences of each dimension across the 31PLAD were observed. The financial expenditure of the 31PLAD across the five dimensions studied revealed that the expenditure of industrial prosperity and its proportion is higher, followed by the dimensions of ecological livability and rural civilization. The expenditure of the other dimensions, except for that of affluence in Regions I and II, is better than that of the same dimension in the region. The overall differences among the 31PLAD represent low industrial prosperity, high affluent life, similar overall differences between rural civilization and effective governance, and relatively large differences in ecological livability. Our findings provide relevant suggestions that would help support rural revitalization effectively. After focusing on the first four dimensions of rural revitalization, we suggest measures to promote the development of other dimensions within industrial prosperity and the linkage and cross-development of all dimensions so as to achieve complete rural revitalization. Further, we specify local policies and regulations for using land transfer income to make overall plans and proper arrangements. According to the industrial development and changes found among the 31PLAD, the necessary support path ahead is clear. According to the forecast trend and changes in the income difference found in this study, the PLAD could use these to plan objectives, clarify fund management, establish relevant supervision systems, and develop policy communication methods, among other measures.
Transcriptome analysis reveals key drought-stress-responsive genes in soybean
Authors: Li Mingqian , Li Hainan , Sun Anni , Wang Liwei , Ren Chuanyou , Liu Jiang , Gao Xining
Published: November 2022

Drought is the most common environmental stress and has had dramatic impacts on soybean (Glycine max L.) growth and yield worldwide. Therefore, to investigate the response mechanism underlying soybean resistance to drought stress, the drought-sensitive cultivar “Liaodou 15” was exposed to 7 (mild drought stress, LD), 17 (moderate drought stress, MD) and 27 (severe drought stress, SD) days of drought stress at the flowering stage followed by rehydration until harvest. A total of 2214, 3684 and 2985 differentially expressed genes (DEGs) in LD/CK1, MD/CK2, and SD/CK3, respectively, were identified by RNA-seq. Weighted gene co-expression network analysis (WGCNA) revealed the drought-response TFs such as WRKY (Glyma.15G021900, Glyma.15G006800), MYB (Glyma.15G190100, Glyma.15G237900), and bZIP (Glyma.15G114800), which may be regulated soybean drought resistance. Second, Glyma.08G176300 (NCED1), Glyma.03G222600 (SDR), Glyma.02G048400 (F3H), Glyma.14G221200 (CAD), Glyma.14G205200 (C4H), Glyma.19G105100 (CHS), Glyma.07G266200 (VTC) and Glyma.15G251500 (GST), which are involved in ABA and flavonoid biosynthesis and ascorbic acid and glutathione metabolism, were identified, suggesting that these metabolic pathways play key roles in the soybean response to drought. Finally, the soybean yield after rehydration was reduced by 50% under severe drought stress. Collectively, our study deepens the understanding of soybean drought resistance mechanisms and provides a theoretical basis for the soybean drought resistance molecular breeding and effectively adjusts water-saving irrigation for soybean under field production.
Vanadyl sulfate-enhanced oncolytic virus immunotherapy mediates the antitumor immune response by upregulating the secretion of pro-inflammatory cytokines and chemokines
Authors: Alluqmani Nouf , Jirovec Anna , Taha Zaid , Varette Oliver , Chen Andrew , Serrano Daniel , Maznyi Glib , Khan Sarwat , Forbes Nicole E. , Arulanandam Rozanne , Auer Rebecca C. , Diallo Jean-Simon
Published: November 2022

Oncolytic viruses (OVs) are promising anticancer treatments that specifically replicate in and kill cancer cells and have profound immunostimulatory effects. We previously reported the potential of vanadium-based compounds such as vanadyl sulfate (VS) as immunostimulatory enhancers of OV immunotherapy. These compounds, in conjunction with RNA-based OVs such as oncolytic vesicular stomatitis virus (VSVΔ51), improve viral spread and oncolysis, leading to long-term antitumor immunity and prolonged survival in resistant tumor models. This effect is associated with a virus-induced antiviral type I IFN response shifting towards a type II IFN response in the presence of vanadium. Here, we investigated the systemic impact of VS+VSVΔ51 combination therapy to understand the immunological mechanism of action leading to improved antitumor responses. VS+VSVΔ51 combination therapy significantly increased the levels of IFN-γ and IL-6, and improved tumor antigen-specific T-cell responses. Supported by immunological profiling and as a proof of concept for the design of more effective therapeutic regimens, we found that local delivery of IL-12 using VSVΔ51 in combination with VS further improved therapeutic outcomes in a syngeneic CT26WT colon cancer model.
Research progress of 3D printing combined with thermoplastic foaming
Authors: Sun Bin , Wu Lixin
Published: November 2022

Thermoplastic foam additive manufacturing is a brand-new industry that perfectly combines the advantages of polymer foaming with AM. The 3D printing industry currently suffers from limited available materials and monolithic part manufacturing, and 3D printed foam offers a new way of thinking to address these challenges. Designing multifunctional components with additive manufacturing gives designers great flexibility, while foaming reduces the weight of materials and costs. The combination of the two allows for the creation of lightweight structural and functional items with differentiated physical properties. This one-of-a-kind and innovative approach can be achieved in the printed section. 3D printing foam, on the other hand, is still in its infancy. This review examines the respective functions and applications of additive manufacturing and foaming, and then attempts to summarize four commonly used 3D printing methods at this stage:1) cellular scaffolds; 2) composite printing foam; 3) post-foaming of printed solid scaffolds; 4) in-situ foam 3D printing. Among these methods, in-situ foam 3D printing is the technique that properly merges the foaming and fused filament fabrication processes. Although in the early stages of research and not yet fully established, this foam 3D printing technique seems to be the trend to replace other foaming processes.
Capsule endoscopy in Crohn's disease surveillance: A monocentric, retrospective analysis in Italy
Authors: Calabrese Carlo , Gelli Dania , Rizzello Fernando , Gionchetti Paolo , Torrejon Torres Rafael , Saunders Rhodri , Davis Jason
Published: November 2022

Background

Crohn's disease (CD) is a potentially debilitating condition that burdens Italian healthcare substantially. The symptomatic management relies on prompt therapy adjustment to reduce flares and follow-up diagnostic inputs to maximise remission. Capsule endoscopy (CE) has introduced advantages in CD diagnostics, allowing the direct inspection of the entire gastrointestinal mucosa. The diagnostic procedure is comparable in effort to standard ileocolonoscopy (IC) but requires no anaesthesia. Whether CE follow-up improves clinical outcomes remains to be defined.

Objectives

To provide a preliminary evaluation of CE in terms of clinical outcomes with respect to the standard of care ileocolonoscopy/MRE in Italy.

Methods

This retrospective analysis utilises anonymised, monocentric data from the S. Orsola-Malpighi Hospital IBD database in Bologna, Italy, collected between 1999 and 2019. Out of 421 adult patient records, 100 were included in the analysis (50 per arm, matched per demographic and clinical characteristics). The CE represented the intervention arm, whereas ileocolonoscopy/magnetic resonance enterography was the standard of care. The use of biologics, symptomatology course, and surgery were the outcomes.

Results

The two techniques performed similarly overall. In general, no significant difference emerged in the use of biologics. The use of biologics appears reduced in the CE group, only in L4 patients after the first follow-up year. Similarly, surgery was seemingly less frequent among L4 patients in the CE group. No difference was found between groups in flare occurrence and duration. CE patients might have experienced longer and earlier first remissions, but no long-term difference persisted.

Conclusions

The CE group showed an apparent reduction in biologics and surgery, limiting to L4 diagnoses. More extensive, prospective, multicentre, randomised studies must corroborate these preliminary findings.
Oxidation reactions of cellular and acellular hemoglobins: Implications for human health
Authors: Alayash Abdu I.
Published: November 2022

Oxygen reversibly binds to the redox active iron, a transition metal in human Hemoglobin (Hb), which subsequently undergoes oxidation in air. This process is akin to iron rusting in non-biological systems. This results in the formation of non-oxygen carrying methemoglobin (ferric) (Fe3+) and reactive oxygen species (ROS). In circulating red blood cells (RBCs), Hb remains largely in the ferrous functional form (HbF2+) throughout the RBC's lifespan due to the presence of effective enzymatic and non-enzymatic proteins that keep the levels of metHb to a minimum (1%–3%). In biological systems Hb is viewed as a Fenton reagent where oxidative toxicity is attributed to the formation of a highly reactive hydroxyl radical (OH•) generated by the reaction between Hb's iron (Fe2+) and hydrogen peroxide (H2O2). However, recent research on both cellular and acellular Hbs revealed that the protein engages in enzymatic-like activity when challenged with H2O2, resulting in the formation of a highly reactive ferryl heme (Fe4+) that can target other biological molecules before it self-destructs. Accumulating evidence from several in vitro and in vivo studies are summarized in this review to show that Hb's pseudoperoxidase activity is physiologically more dominant than the Fenton reaction and it plays a pivotal role in the pathophysiology of several blood disorders, storage lesions associated with old blood, and in the toxicity associated with the infusion of Hb-derived oxygen therapeutics.
Understanding the research advances on lumpy skin disease: A comprehensive literature review of experimental evidence
Authors: Liang Zhengji , Yao Kaishen , Wang Shasha , Yin Juanbin , Ma Xiaoqin , Yin Xiangping , Wang Xiangwei , Sun Yuefeng
Published: November 2022

Lumpy skin disease is caused by lumpy skin disease virus (LSDV), which can induce cattle with high fever and extensive nodules on the mucosa or the scarfskin, seriously influencing the cattle industry development and international import and export trade. Since 2013, the disease has spread rapidly and widely throughout the Russia and Asia. In the past few decades, progress has been made in the study of LSDV. It is mainly transmitted by blood-sucking insects, and various modes of transmission with distinct seasonality. Figuring out how the virus spreads will help eradicate LSDV at its source. In the event of an outbreak, selecting the most effective vaccine to block and eliminate the threat posed by LSDV in a timely manner is the main choice for farmers and authorities. At present, a variety of vaccines for LSDV have been developed. The available vaccine products vary in quality, protection rate, safety and side effects. Early detection of LSDV can help reduce the cost of disease. In addition, because LSDV has a huge genome, it is currently also used as a vaccine carrier, forming a new complex with other viral genes through homologous recombination. The vaccine prepared based on this can have a certain preventive effect on many kinds of diseases. Clinical detection of disease including nucleic acid and antigen level. Each method varies in convenience, accuracy, cost, time and complexity of equipment. This article reviews our current understanding of the mode of transmission of LSDV and advances in vaccine types and detection methods, providing a background for further research into various aspects of LSDV in the future.
Seroprevalence of human brucellosis among the tribal and non-tribal population residing in an eastern state of India: Findings from the state-wide serosurvey
Authors: Parai Debaprasad , Sahoo Subrat Kumar , Pattnaik Matrujyoti , Swain Aparajita , Peter Annalisha , Samanta Lopamudra Jena , Pradhan Rashmita , Choudhary Hari Ram , Nahak Kanhu Charan , Pati Sanghamitra , Bhattacharya Debdutta
Published: November 2022

Background

Brucellosis is a neglected zoonotic disease found predominantly in lower- and middle-income countries (LMICs), causing significant public health concern in India. The objective of this study was to assess the prevalence of human brucellosis in Odisha, India among community members involved in animal husbandry as a common practice.

Method

This cross-sectional study included 817 adult participants from 11 districts in Odisha. Four districts from the Northern division, four districts from the Central division, and three districts from the Southern division were selected for the study. Blood samples were collected during a COVID-19 serosurvey in Odisha conducted from 1st to 17th September 2021. Immunoglobulin-G (IgG) antibodies were measured against Brucella using a commercial ELISA kit. Point estimates at 95% confidence intervals (CIs) and adjusted odds ratio were calculated.

Results

The overall prevalence of anti-Brucella IgG antibodies was calculated at 16.65% (95% CI: 14.19–19.42). The highest seropositivity was found in Sambalpur district (29.73%; 95% CI: 16.43–47.16) and the lowest was determined in Mayurbhanj district (4.44%; 95% CI: 0.99–15.60). Compared to males, females were more prone to contracting the disease (AOR: 1.13; 95% CI: 1.05–1.67). Participants from rural settings had higher prevalence of anti-Brucella IgG antibodies than urban dwellers (AOR: 4.53; 95% CI: 1.73–11.86).

Conclusion

This study revealed that human brucellosis was associated with sociodemographic factors like gender, living settings, and household numbers. To prevent brucellosis, screening should be initiated, infected humans should be treated early, and the public should be educated about risk factors and preventive measures.
Effects of heat stress on growth performance, carcass traits, serum metabolism, and intestinal microflora of meat rabbits
Authors: Liu Hongli , Zhang Bin , Li Fan , Liu Lei , Yang Tongao , Zhang Haihua , Li Fuchang
Published: November 2022

To investigate the effects of heat stress on meat rabbits, we assigned 80 rabbits to the moderate temperature group (24 ± 1°C; Control group) and the continuous high-temperature group (HT group), then monitored the effects using growth performance, carcass characteristics, biochemical assays, UPLC–MS/MS-based metabolomics, and microbiome. The results showed that after continuous high-temperature exposure, the average daily gain, average daily feed intake, and thymus index were significantly decreased (p < 0.05). Contents of HSP70, ALP, and Cortisol in serum were significantly increased, while TP, GLU, T3, and T4 were significantly decreased (p < 0.05). Nine kinds of differential metabolites were screened by serum metabolomics, which can be used as biomarkers of heat stress in meat rabbits. The selected differential metabolites were analyzed by KEGG annotation and enrichment analysis. The results showed that 14 pathways affected by heat stress were identified by KEGG pathway enrichment analysis, including Sphingolipid metabolism, Pyrimidine metabolism, Citrate cycle (TCA cycle)), aminoacyl-tRNA biosynthesis, and so on. The analysis of the effect of heat stress on the cecal microflora of meat rabbits showed that the abundance of cecal Proteus in the HT group was significantly higher than that in the moderate Control group. The number of Candidatus-saccharimonas in the cecum microflora was significantly higher than that in the moderate temperature group (p < 0.05) which may be related to inflammatory diseases in the heat stress group. These findings indicated that the heat-stressed rabbits were in negative energy balance, which affected protein metabolism, and subsequently affected growth performance and carcass characteristics.
Time-dependent alterations in the rat nigrostriatal system after intrastriatal injection of fibrils formed by α–Syn and tau fragments
Authors: Yang Xiaoman , Wang Jialing , Zeng Weiqi , Zhang Xiaoqian , Yang Xiaomei , Xu Yu , Xu Yan , Cao Xuebing
Published: November 2022

Introduction

Accurate demonstration of phosphorylated α-synuclein aggregation and propagation, progressive nigrostriatal degeneration and motor deficits will help further research on elucidating the mechanisms of Parkinson’s Disease. α-synucleinN103 and tauN368, cleaved by activated asparagine endopeptidase in Parkinson’s Disease, robustly interacted with each other and triggered endogenous α-synuclein accumulation in a strong manner. However, the detailed pathophysiological process caused by the complex remains to be established.

Methods

In this study, rats were unilaterally inoculated with 15 or 30 μg of this complex or vehicle (phosphate buffered saline, PBS). Over a 6-month period post injection, we then investigated the abundance of pSyn inclusions, nigrostriatal degeneration, and changes in axonal transport proteins to identify the various dynamic pathological changes caused by pSyn aggregates in the nigrostriatal system.

Results

As expected, rats displayed a dose-dependent increase in the amount of α-synuclein inclusions, and progressive dopaminergic neurodegeneration was observed throughout the study, reaching 30% at 6 months post injection. Impairments in anterograde axonal transport, followed by retrograde transport, were observed prior to neuron death, which was first discovered in the PFFs model.

Discussion

The current results demonstrate the value of a novel rat model of Parkinson’s disease characterized by widespread, “seed”-initiated endogenous α-Syn pathology, impaired axonal transport, and a neurodegenerative cascade in the nigrostriatal system. Notably, the present study is the first to examine alterations in axonal transport proteins in a PFF model, providing an appropriate foundation for future research regarding the mechanisms leading to subsequent neurodegeneration. As this model recapitulates some essential features of Parkinson’s disease, it provides an important platform for further research on specific pathogenic mechanisms and pre-clinical evaluations of novel therapeutic strategies.
Data-driven clustering of combined Functional Motor Disorders based on the Italian registry
Authors: Mostile Giovanni , Geroin Christian , Erro Roberto , Luca Antonina , Marcuzzo Enrico , Barone Paolo , Ceravolo Roberto , Mazzucchi Sonia , Pilotto Andrea , Padovani Alessandro , Romito Luigi Michele , Eleopra Roberto , Dallocchio Carlo , Arbasino Carla , Bono Francesco , Bruno Pietro Antonio , Demartini Benedetta , Gambini Orsola , Modugno Nicola , Olivola Enrica , Bonanni Laura , Albanese Alberto , Ferrazzano Gina , De Micco Rosa , Zibetti Maurizio , Calandra-Buonaura Giovanna , Petracca Martina , Morgante Francesca , Esposito Marcello , Pisani Antonio , Manganotti Paolo , Stocchi Fabrizio , Coletti Moja Mario , Di Vico Ilaria Antonella , Tesolin Lucia , De Bertoldi Francesco , Ercoli Tommaso , Defazio Giovanni , Zappia Mario , Nicoletti Alessandra , Tinazzi Michele
Published: November 2022

Introduction

Functional Motor Disorders (FMDs) represent nosological entities with no clear phenotypic characterization, especially in patients with multiple (combined FMDs) motor manifestations. A data-driven approach using cluster analysis of clinical data has been proposed as an analytic method to obtain non-hierarchical unbiased classifications. The study aimed to identify clinical subtypes of combined FMDs using a data-driven approach to overcome possible limits related to “a priori” classifications and clinical overlapping.

Methods

Data were obtained by the Italian Registry of Functional Motor Disorders. Patients identified with multiple or “combined” FMDs by standardized clinical assessments were selected to be analyzed. Non-hierarchical cluster analysis was performed based on FMDs phenomenology. Multivariate analysis was then performed after adjustment for principal confounding variables.

Results

From a study population of n = 410 subjects with FMDs, we selected n = 188 subjects [women: 133 (70.7%); age: 47.9 ± 14.4 years; disease duration: 6.4 ± 7.7 years] presenting combined FMDs to be analyzed. Based on motor phenotype, two independent clusters were identified: Cluster C1 (n = 82; 43.6%) and Cluster C2 (n = 106; 56.4%). Cluster C1 was characterized by functional tremor plus parkinsonism as the main clinical phenotype. Cluster C2 mainly included subjects with functional weakness. Cluster C1 included older subjects suffering from anxiety who were more treated with botulinum toxin and antiepileptics. Cluster C2 included younger subjects referring to different associated symptoms, such as pain, headache, and visual disturbances, who were more treated with antidepressants.

Conclusion

Using a data-driven approach of clinical data from the Italian registry, we differentiated clinical subtypes among combined FMDs to be validated by prospective studies.
Therapist reactions to patient personality: A pilot study of clinicians’ emotional and neural responses using three clinical vignettes from in treatment series
Authors: Tanzilli Annalisa , Trentini Cristina , Grecucci Alessandro , Carone Nicola , Ciacchella Chiara , Lai Carlo , Sabogal-Rueda Miguel David , Lingiardi Vittorio
Published: November 2022

Introduction

Therapists’ responses to patients play a crucial role in psychotherapy and are considered a key component of the patient–clinician relationship, which promotes successful treatment outcomes. To date, no empirical research has ever investigated therapist response patterns to patients with different personality disorders from a neuroscience perspective.

Methods

In the present study, psychodynamic therapists (N = 14) were asked to complete a battery of instruments (including the Therapist Response Questionnaire) after watching three videos showing clinical interactions between a therapist and three patients with narcissistic, histrionic/borderline, and depressive personality disorders, respectively. Subsequently, participants’ high-density electroencephalography (hdEEG) was recorded as they passively viewed pictures of the patients’ faces, which were selected from the still images of the previously shown videos. Supervised machine learning (ML) was used to evaluate whether: (1) therapists’ responses predicted which patient they observed during the EEG task and whether specific clinician reactions were involved in distinguishing between patients with different personality disorders (using pairwise comparisons); and (2) therapists’ event-related potentials (ERPs) predicted which patient they observed during the laboratory experiment and whether distinct ERP components allowed this forecast.

Results

The results indicated that therapists showed distinct patterns of criticized/devalued and sexualized reactions to visual depictions of patients with different personality disorders, at statistically systematic and clinically meaningful levels. Moreover, therapists’ late positive potentials (LPPs) in the hippocampus were able to determine which patient they observed during the EEG task, with high accuracy.

Discussion

These results, albeit preliminary, shed light on the role played by therapists’ memory processes in psychotherapy. Clinical and neuroscience implications of the empirical investigation of therapist responses are discussed.
Screening for Alzheimer's disease using prefrontal resting-state functional near-infrared spectroscopy
Authors: Keles Hasan Onur , Karakulak Ece Zeynep , Hanoglu Lutfu , Omurtag Ahmet
Published: November 2022

Introduction

Alzheimer's disease (AD) is neurodegenerative dementia that causes neurovascular dysfunction and cognitive impairment. Currently, 50 million people live with dementia worldwide, and there are nearly 10 million new cases every year. There is a need for relatively less costly and more objective methods of screening and early diagnosis.

Methods

Functional near-infrared spectroscopy (fNIRS) systems are a promising solution for the early Detection of AD. For a practical clinically relevant system, a smaller number of optimally placed channels are clearly preferable. In this study, we investigated the number and locations of the best-performing fNIRS channels measuring prefrontal cortex activations. Twenty-one subjects diagnosed with AD and eighteen healthy controls were recruited for the study.

Results

We have shown that resting-state fNIRS recordings from a small number of prefrontal locations provide a promising methodology for detecting AD and monitoring its progression. A high-density continuous-wave fNIRS system was first used to verify the relatively lower hemodynamic activity in the prefrontal cortical areas observed in patients with AD. By using the episode averaged standard deviation of the oxyhemoglobin concentration changes as features that were fed into a Support Vector Machine; we then showed that the accuracy of subsets of optical channels in predicting the presence and severity of AD was significantly above chance. The results suggest that AD can be detected with a 0.76 sensitivity score and a 0.68 specificity score while the severity of AD could be detected with a 0.75 sensitivity score and a 0.72 specificity score with ≤5 channels.

Discussion

These scores suggest that fNIRS is a viable technology for conveniently detecting and monitoring AD as well as investigating underlying mechanisms of disease progression.
A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply
Authors: Zou Wei , Kim Haram , Diffenderfer Eric S. , Carlson David J. , Koch Cameron J. , Xiao Ying , Teo BoonKeng K. , Kim Michele M. , Metz James M. , Fan Yi , Maity Amit , Koumenis Costas , Busch Theresa M. , Wiersma Rodney , Cengel Keith A. , Dong Lei
Published: November 2022

Introduction

Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning.

Methods

The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries.

Results

Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 μm vasculature spacing and 18.9 μM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect.

Conclusion

We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments.
Development of a breast cancer case management information platform (BC-CMIP) module based on patient-perceived value
Authors: Liang Yinyin , Gao Yan , Yin Guobing , Chen Wenjun , Gan Xiuni
Published: November 2022

Objective

To construct a content module for a breast cancer case management information platform (BC-CMIP) based on patient-perceived value (PPV).

Methods

A questionnaire was used to investigate the service needs of breast cancer patients and their families for the information platform. Based on the value dimensions of PPV, the module content of the BC-CMIP was initially constructed, and the Delphi method was used to justify and revise the module content. Excel 2019 and SPSS 26.0 were used for statistical analysis.

Results

The information platform includes the patient side and the medical side. The index content includes four primary indicators: functional value, emotional value, efficiency value and social value; it can realize all patient case management needs, such as diagnosis and treatment services, health education, telemedicine, treatment tracking, psychological support, case assessment and positive warning.

Conclusion

Based on the PPV, the module design of the BC-CMIP is reasonable and comprehensive, and it can scientifically and effectively meet the health needs of patients and provide a theoretical basis for subsequent platform development and application.
“Friends and foes” of multiple myeloma measurable/minimal residual disease evaluation by next generation flow
Authors: Pacelli Paola , Raspadori Donatella , Bestoso Elena , Gozzetti Alessandro , Bocchia Monica
Published: November 2022

Next Generation Flow (NGF) represents a gold standard for the evaluation of Minimal Residual Disease (MRD) in Multiple Myeloma (MM) patients at any stage of treatment. Although the assessment of MRD is still not universally employed in clinical practice, numerous studies have demonstrated the strength of MRD as a reliable predictor of long-term outcome, and its potential to supersede the prognostic value of CR. The possibility to acquire millions of events, in combination with the use of standard reagents and a good expertise in the analysis of rare populations, led to high chance of success and a sensitivity of 10-6 that is superimposable to the one of Next Generation Sequencing molecular techniques. Some minor bias, correlated to the protocols applied, to the quality of samples and to the high heterogeneity of plasma cells phenotype, may be overcome using standard protocols and having at disposition personnel expertise for MRD analysis. With the use of NGF we can today enter a new phase of the quantification of residual disease, switching from the definition of “minimal” residual disease to “measurable” residual disease. This review takes account of the principle “friends and foes” of Myeloma “Measurable” Residual Disease evaluation by NGF, to give insights into the potentiality of this technique. The optimization of the quality of BM samples and the analytic expertise that permits to discriminate properly the rare pathologic clones, are the keys for obtaining results with a high clinical value that could be of great impact and relevance in the future.
High grade glioma radiation therapy on a high field 1.5 Tesla MR-Linac - workflow and initial experience with daily adapt-to-position (ATP) MR guidance: A first report
Authors: Tseng Chia-Lin , Chen Hanbo , Stewart James , Lau Angus Z. , Chan Rachel W. , Lawrence Liam S. P. , Myrehaug Sten , Soliman Hany , Detsky Jay , Lim-Fat Mary Jane , Lipsman Nir , Das Sunit , Heyn Chinthaka , Maralani Pejman J. , Binda Shawn , Perry James , Keller Brian , Stanisz Greg J. , Ruschin Mark , Sahgal Arjun
Published: November 2022

Purpose

This study reports the workflow and initial clinical experience of high grade glioma (HGG) radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow.

Materials and methods

Ten HGG patients treated with radiation within the first year of the MRL’s clinical operation, between October 2019 and August 2020, were identified from a prospective database. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the relative FHR volumes (n = 281 contours) and migration distances (maximum linear displacement of the volume). Research mpMRIs were acquired on the MRL during radiation and changes in selected functional parameters were investigated within the FHR.

Results

All patients completed radiotherapy to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction with or without post-beam research imaging was 42.9 minutes (range, 25.0–69.0 minutes) and 37.3 minutes (range, 24.0–51.0 minutes), respectively. Three patients (30%) required re-planning between fractions 9 to 12 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30-day post-first fraction time points 3, 3, and 4 patients, respectively, had a FHR volume that changed by at least 20% relative to the first fraction. Research mpMRIs were successfully acquired on the MRL. The median apparent diffusion coefficient (ADC) within the FHR and the volumes of FLAIR were significantly correlated when data from all patients and time points were pooled (R=0.68, p<.001).

Conclusion

We report the first clinical series of HGG patients treated with radiotherapy on the MRL. The ATP workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of mpMRIs was feasible on the MRL during routine treatment workflow. Prospective clinical outcomes data is anticipated from the ongoing UNITED phase 2 trial to further refine the role of MR-guided adaptive radiotherapy.
Ferroptosis-related molecular patterns reveal immune escape, inflammatory development and lipid metabolism characteristics of the tumor microenvironment in acute myeloid leukemia
Authors: Zhong Fang-Min , Yao Fang-Yi , Liu Jing , Zhang Hai-Bin , Zhang Jing , Zhang Nan , Lin Jin , Li Shu-Qi , Li Mei-Yong , Jiang Jun-Yao , Cheng Ying , Xu Shuai , Wen Wen , Yang Yu-Lin , Zhang Xue-Ru , Cheng Xue-Xin , Huang Bo , Wang Xiao-Zhong
Published: November 2022

Background

An increasing number of studies have revealed the influencing factors of ferroptosis. The influence of immune cell infiltration, inflammation development and lipid metabolism in the tumor microenvironment (TME) on the ferroptosis of tumor cells requires further research and discussion.

Methods

We explored the relationship between ferroptosis-related genes and acute myeloid leukemia (AML) from the perspective of large sample analysis and multiomics, used multiple groups to identify and verify ferroptosis-related molecular patterns, and analyzed the sensitivity to ferroptosis and the state of immune escape between different molecular pattern groups. The single-sample gene set enrichment analysis (ssGSEA) algorithm was used to quantify the phenotypes of ferroptosis-related molecular patterns in individual patients. HL-60 and THP-1 cells were treated with ferroptosis inducer RSL3 to verify the therapeutic value of targeted inhibition of GPX4.

Results

Three ferroptosis-related molecular patterns and progressively worsening phenotypes including immune activation, immune exclusion and immunosuppression were found with the two different sequencing approaches. The FSscore we constructed can quantify the development of ferroptosis-related phenotypes in individual patients. The higher the FSscore is, the worse the patient’s prognosis. The FSscore is also highly positively correlated with pathological conditions such as inflammation development, immune escape, lipid metabolism, immunotherapy resistance, and chemotherapy resistance and is negatively correlated with tumor mutation burden. Moreover, RSL3 can induce ferroptosis of AML cells by reducing the protein level of GPX4.

Conclusions

This study revealed the characteristics of immunity, inflammation, and lipid metabolism in the TME of different AML patients and differences in the sensitivity of tumor cells to ferroptosis. The FSscore can be used as a biomarker to provide a reference for the clinical evaluation of the pathological characteristics of AML patients and the design of personalized treatment plans. And GPX4 is a potential target for AML treatment.
Case report: Cerebrospinal fluid-derived circulating tumor DNA diagnoses and guides the treatment of a lung adenocarcinoma case with leptomeningeal metastasis
Authors: Bai Yujun , Yu Qingxi , Liu Ning , Liu Jingwen , Wang Di , Liu Xiaoli , Yuan Shuanghu
Published: November 2022

Leptomeningeal metastasis (LM) occurs in 3~5% of non-small cell lung cancer (NSCLC) patients. Diagnosis of patients with LM and disease monitoring remains challenging due to the low sensitivity and specificity of the commonly used approaches, such as cerebrospinal fluid (CSF) cytology and magnetic resonance imaging (MRI). Therefore, new approaches are necessary to improve the detection of LM. Recent studies have shown that circulating tumor DNA (ctDNA) in CSF can be used to detect and monitor LM, but whether it can serve as an early diagnostic biomarker prior to cytological and radiographic evidence of LM involvement requires further evaluation. Here we report a lung adenocarcinoma patient who had detectable oncogenic mutations in the CSF ctDNA prior to confirmation of LM by CSF cytology and MRI, highlighting the potential application of CSF ctDNA in early detection of LM.
Adolescent triple-negative breast cancer with germline pathogenic variants in both BRCA1 and TP53 genes: A case report
Authors: Chen Dongmei , Zhang Chenyang , Yuan Mengqi , Zhang Ying , Liu Qing , Wan Donggui
Published: November 2022

Almost 5-10% of breast cancer results from inherited genetic pathogenic variants. Patients with pathogenic variants in high-penetrance genes such as TP53, BRCA1 and BRCA2 are susceptible to breast cancer. Moreover, nearly 80% of BRCA pathogenic variants carriers are diagnosed with breast cancer at a young age before menopause. There is currently no report of early onset breast cancer with germline pathogenic variants in both BRCA1 and TP53 genes. Here, we report a case of a 14-years-old female diagnosed with triple-negative breast cancer with a family history of malignant tumors. The cancer metastasized to multiple lymph nodes 1 year and 4 months after surgery, and the progression-free survival after subsequent chemotherapy and surgery has been 2 years and 10 months. The patient’s white blood cells were screened against a panel of 11 cancer-related genes, and both germline pathogenic variants in BRCA1 and TP53 were identified. Genetic tests of her family members revealed the same pathogenic variants in BRCA1 in her father and brother, but BRCA1 pathogenic variants wasn’t shown in other family members. The case indicates that genetic testing needs be performed in early onset breast cancer to confirm inherited risk, and if a germline pathogenic variant is identified, tailored therapeutic interventions and preventive interventions should be taken and genetic testing is recommended for relatives.
Case report: Identification of three novel compound heterozygous SGLT2 variants in three Chinese pediatric patients with familial renal glucosuria
Authors: Huang Huimei , Wu Xiantao , He Qing , Liang Xuqin , Ding Yi , Li Zhijuan , Ren Zhanping , Bao Ying
Published: November 2022

Familial renal glucosuria (FRG) is a rare genetic condition featured by isolated glucosuria without hyperglycemia or other kidney diseases. It is caused by pathogenic mutations of the SGLT2 (Sodium-Glucose Cotransporter 2) gene, whose protein product is responsible for reabsorbing the majority of glucose in the early proximal convoluted tubule. Hitherto, quite an array of variants of SGLT2 have been identified in patients of FRG. In this study, we performed whole exome sequencing on three Chinese pediatric patients with FRG and uncovered three compound heterozygous variants of SGLT2: c.1333C > T (p.Q445X) and c.1130–5 C > G; c.1438G > T (p.V480F) and c.346G > A (p.V116M); c.1175C > G (p.S392C) and c.1333C > T (p.Q445X). Among the total of five variants, c.1333C > T (p.Q445X), c.1438G > T (p.V480F) and c.1175C > G (p.S392C) represented novel variants that had not been reported in any genetic databases. All five variants had extremely low allele frequencies and the amino acids loci affected by missense variants were highly conserved in vertebrate species. Bioinformatic tools predicted that all five variants might disrupt the function of SGLT2, which were likely to be causal for FRG in these patients. Our findings expand the variant spectrum of SGLT2 associated with FRG and provide novel insights into mechanism of action of this transporter, which will aid in the development of novel SGLT2 inhibitors for treatment of type 2 diabetes and cardiovascular diseases.
Testis- specific Y-encoded- like protein 1 and cholesterol metabolism: Regulation of CYP1B1 expression through Wnt signaling
Authors: Zhu Xiujuan , Gao Huanyao , Qin Sisi , Liu Duan , Cairns Junmei , Gu Yayun , Yu Jia , Weinshilboum Richard M. , Wang Liewei
Published: November 2022

The cytochromes P450 (CYPs) represent a large gene superfamily that plays an important role in the metabolism of both exogenous and endogenous compounds. We have reported that the testis-specific Y-encoded-like proteins (TSPYLs) are novel CYP gene transcriptional regulators. However, little is known of mechanism(s) by which TSPYLs regulate CYP expression or the functional consequences of that regulation. The TSPYL gene family includes six members, TSPYL1 to TSPYL6. However, TSPYL3 is a pseudogene, TSPYL5 is only known to regulates the expression of CYP19A1, and TSPYL6 is expressed exclusively in the testis. Therefore, TSPYL 1, 2 and 4 were included in the present study. To better understand how TSPYL1, 2, and 4 might influence CYP expression, we performed a series of pull-downs and mass spectrometric analyses. Panther pathway analysis of the 2272 pulled down proteins for all 3 TSPYL isoforms showed that the top five pathways were the Wnt signaling pathway, the Integrin signaling pathway, the Gonadotropin releasing hormone receptor pathway, the Angiogenesis pathway and Inflammation mediated by chemokines and cytokines. Specifically, we observed that 177 Wnt signaling pathway proteins were pulled down with the TSPYLs. Subsequent luciferase assays showed that TSPYL1 knockdown had a greater effect on the activation of Wnt signaling than did TSPYL2 or TSPYL4 knockdown. Therefore, in subsequent experiments, we focused our attention on TSPYL1. HepaRG cell qRT-PCR showed that TSPYL1 regulated the expression of CYPs involved in cholesterol-metabolism such as CYP1B1 and CYP7A1. Furthermore, TSPYL1 and β-catenin regulated CYP1B1 expression in opposite directions and TSPYL1 appeared to regulate CYP1B1 expression by blocking β-catenin binding to the TCF7L2 transcription factor on the CYP1B1 promoter. In β-catenin and TSPYL1 double knockdown cells, CYP1B1 expression and the generation of CYP1B1 downstream metabolites such as 20-HETE could be restored. Finally, we observed that TSPYL1 expression was associated with plasma cholesterol levels and BMI during previous clinical studies of obesity. In conclusion, this series of experiments has revealed a novel mechanism for regulation of the expression of cholesterol-metabolizing CYPs, particularly CYP1B1, by TSPYL1 via Wnt/β-catenin signaling, raising the possibility that TSPYL1 might represent a molecular target for influencing cholesterol homeostasis.