bluuebunny/crossref_metadata_2025 huggingface dataset:
Unraveling the prognostic significance and molecular characteristics of tumor-infiltrating B lymphocytes in clear cell renal cell carcinoma through a comprehensive bioinformatics analysis
Authors: Yue Youwei , Cai Xinyi , Lu Changhao , Sechi Leonardo Antonio , Solla Paolo , Li Shensuo
Published: October 2023

Introduction

Clear cell renal cell carcinoma (ccRCC) is a prevalent subtype of kidney cancer that exhibits a complex tumor microenvironment, which significantly influences tumor progression and immunotherapy response. In recent years, emerging evidence has underscored the involvement of tumor-infiltrating B lymphocytes (TIL-Bs), a crucial component of adaptive immunity, and their roles in ccRCC as compared to other tumors. Therefore, the present study endeavors to systematically explore the prognostic and molecular features of TIL-Bs in ccRCC.

Methods

Initially, xCell algorithm was used to predict TIL-Bs in TCGA-KIRC and other ccRCC transcriptomic datasets. The Log-Rank test and Cox regression were applied to explore the relationship of B-cells with ccRCC survival. Then, we used WGCNA method to identify important modules related to TIL-Bs combining Consensus subcluster and scRNA-seq data analysis. To narrow down the prospective biomarkers, a prognostic signature was proposed. Next, we explored the feature of the signature individual genes and the risk-score. Finally, the potential associations of signature with clinical phenotypes and drugs were investigated.

Results

Preliminary, we found ccRCC survival was negatively associated with TIL-Bs, which was confirmed by other datasets. Afterwards, ten co-expression modules were identified and a distinct ccRCC cluster was subsequently detected. Moreover, we assessed the transcriptomic alteration of B-cell in ccRCC and a relevant B-cell subtype was also pinpointed. Based on two core modules (brown, red), a 10-gene signature (TNFSF13B, SHARPIN, B3GAT3, IL2RG, TBC1D10C, STAC3, MICB, LAG3, SMIM29, CTLA4) was developed in train set and validated in test sets. These biomarkers were further investigated with regards to their differential expression and correlation with immune characteristics, along with risk-score related mutations and pathways. Lastly, we established a nomogram combined tumor grade and discovered underlying drugs according to their sensitivity response.

Discussion

In our research, we elucidated the remarkable association between ccRCC and B-cells. Then, we detected several key gene modules, together with close patient subcluster and B-cell subtype,which could be responsible for the TIL-Bs in ccRCC. Moreover, we proposed a 10-gene signature and investigated its molecular features from multiple perspectives. Overall, understanding the roles of TIL-Bs could aid in the immunotherapeutic approaches for ccRCC, which deserve further research to clarify the implications for patient prognosis and treatment.
Direct interaction of the molecular chaperone GRP78/BiP with the Newcastle disease virus hemagglutinin-neuraminidase protein plays a vital role in viral attachment to and infection of culture cells
Authors: Han Chenxin , Xie Ziwei , Lv Yadi , Liu Dingxiang , Chen Ruiai
Published: October 2023

Introduction

Glucose Regulated Proteins/Binding protein (GRP78/Bip), a representative molecular chaperone, effectively influences and actively participates in the replication processes of many viruses. Little is known, however, about the functional involvement of GRP78 in the replication of Newcastle disease virus (NDV) and the underlying mechanisms.

Methods

The method of this study are to establish protein interactomes between host cell proteins and the NDV Hemagglutinin-neuraminidase (HN) protein, and to systematically investigate the regulatory role of the GRP78-HN protein interaction during the NDV replication cycle.

Results

Our study revealed that GRP78 is upregulated during NDV infection, and its direct interaction with HN is mediated by the N-terminal 326 amino acid region. Knockdown of GRP78 by small interfering RNAs (siRNAs) significantly suppressed NDV infection and replication. Conversely, overexpression of GRP78 resulted in a significant increase in NDV replication, demonstrating its role as a positive regulator in the NDV replication cycle. We further showed that the direct interaction between GRP78 and HN protein enhanced the attachment of NDV to cells, and masking of GRP78 expressed on the cell surface with specific polyclonal antibodies (pAbs) inhibited NDV attachment and replication.

Discussion

These findings highlight the essential role of GRP78 in the adsorption stage during the NDV infection cycle, and, importantly, identify the critical domain required for GRP78-HN interaction, providing novel insights into the molecular mechanisms involved in NDV replication and infection.
Safety and immunogenicity of BK-SE36/CpG malaria vaccine in healthy Burkinabe adults and children: a phase 1b randomised, controlled, double-blinded, age de-escalation trial
Authors: Ouédraogo Alphonse , Bougouma Edith Christiane , Palacpac Nirianne Marie Q. , Houard Sophie , Nebie Issa , Sawadogo Jean , Berges Gloria D. , Soulama Issiaka , Diarra Amidou , Hien Denise , Ouedraogo Amidou Z. , Konaté Amadou T. , Kouanda Seni , Myoui Akira , Ezoe Sachiko , Ishii Ken J. , Sato Takanobu , D’Alessio Flavia , Leroy Odile , Tiono Alfred B. , Cousens Simon , Horii Toshihiro , Sirima Sodiomon B.
Published: October 2023

Background

BK-SE36/CpG is a recombinant blood-stage malaria vaccine candidate based on the N-terminal Plasmodium falciparum serine repeat antigen5 (SE36), adsorbed to aluminium hydroxide gel and reconstituted, prior to administration, with synthetic oligodeoxynucleotides bearing CpG motifs. In healthy Japanese adult males, BK-SE36/CpG was well tolerated. This study assessed its safety and immunogenicity in healthy malaria-exposed African adults and children.

Methods

A double-blind, randomised, controlled, age de-escalating clinical trial was conducted in an urban area of Ouagadougou, Burkina Faso. Healthy participants (n=135) aged 21-45 years (Cohort 1), 5-10 years (Cohort 2) and 12-24 months (Cohort 3) were randomised to receive three vaccine doses (Day 0, 28 and 112) of BK-SE36/CpG or rabies vaccine by intramuscular injection.

Results

One hundred thirty-four of 135 (99.2%) subjects received all three scheduled vaccine doses. Vaccinations were well tolerated with no related Grade 3 (severe) adverse events (AEs). Pain/limitation of limb movement, headache in adults and fever in younger children (all mild to moderate in intensity) were the most frequently observed local and systemic AEs. Eighty-three of BK-SE36/CpG (91%) recipients and 37 of control subjects (84%) had Grade 1/2 events within 28 days post vaccination. Events considered by the investigator to be vaccine related were experienced by 38% and 14% of subjects in BK-SE36/CpG and control arms, respectively. Throughout the trial, six Grade 3 events (in 4 subjects), not related to vaccination, were recorded in the BK-SE36/CpG arm: 5 events (in 3 subjects) within 28 days of vaccination. All serious adverse events (SAEs) (n=5) were due to severe malaria (52-226 days post vaccination) and not related to vaccination. In all cohorts, BK-SE36/CpG arm had higher antibody titres after Dose 3 than after Dose 2. Younger cohorts had stronger immune responses (12–24-month-old > 5-10 years-old > 21-45 years-old). Sera predominantly reacted to peptides that lie in intrinsically unstructured regions of SE36. In the control arm, there were no marked fold changes in antibody titres and participants’ sera reacted poorly to all peptides spanning SE36.

Conclusion

BK-SE36/CpG was well-tolerated and immunogenic. These results pave the way for further proof-of-concept studies to demonstrate vaccine efficacy.

Clinical trial registration

https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1921, PACTR201701001921166.
Case Report: Limbic encephalitis following treatment with durvalumab for small-cell lung cancer
Authors: Moss Thomas T. , Stavem Knut , Aandahl Astrid , Gløersen Anne S. , Grønberg Bjørn H. , Neumann Kirill , Vedeler Christian A. , Lundqvist Christofer
Published: October 2023

Background

Durvalumab is an immune checkpoint Inhibitor (ICIs) that is used in the treatment of malignant tumors, such as lung cancer and melanoma. ICIs are associated with immune-related adverse events including autoimmune encephalitis, although both paraneoplastic phenomena and ICI treatment may lead to autoimmunity.

Case presentation

We describe a 72-year old male patient with small-cell lung cancer, who during adjuvant treatment with Durvalumab developed GABABR1 and GAD65 antibodies and both diabetes and autoimmune limbic encephalitis. Because he was followed prospectively as part of a treatment study, we had access to repeated serum samples and cognitive assessments over time prior to developing encephalitis and diabetes, in addition to later assessments. A high titer of GABABR1 antibodies appeared early, while GAD65 antibodies appeared later with a lower titer in parallel with the development of diabetes. As he subsequently developed clinical signs of encephalitis, verified by EEG and brain MRI, he also had CSF GABABR1 antibodies. Durvalumab was discontinued and steroid treatment with subsequent plasmapheresis were started, resulting in reduction of both CSF and serum antibody levels. Clinical signs of encephalitis gradually improved.

Conclusion

This case illustrates the importance of being aware of possible serious autoimmune adverse reactions, including neurological syndromes such as encephalitis, when treating patients with high risk of para-neoplasia with ICIs. In addition, the case shows the development of autoantibodies over time.
A multi-physics approach for modelling noise mitigation using an air-bubble curtain in impact pile driving
Authors: Peng Yaxi , Jarquin Laguna Antonio , Tsouvalas Apostolos
Published: October 2023

Underwater noise from offshore pile driving has raised significant concerns over its ecological impact on marine life. To protect the marine environment and maintain the sustainable development of wind energy, strict governmental regulations are imposed. Assessment and mitigation of underwater noise are usually required to ensure that sound levels stay within the noise thresholds. The air-bubble curtain system is one of the most widely applied noise mitigation techniques. This paper presents a multi-physics approach for modeling an air-bubble curtain system in application to offshore pile driving. The complete model consists of four modules: (i) a compressible flow model to account for the transport of compressed air from the offshore vessel to the perforated hose located in the seabed; (ii) a hydrodynamic model for capturing the characteristics of bubble clouds in varying development phases through depth; (iii) an acoustic model for predicting the sound insertion loss of the air-bubble curtain; and (iv) a vibroacoustic model for the prediction of underwater noise from pile driving which is coupled to the acoustic model in (iii) through a boundary integral formulation. The waterborne and soilborne noise transmission paths are examined separately, allowing us to explore the amount of energy channeled through the seabed and through the bubble curtain in the water column. A parametric study is performed to examine the optimal configuration of the double bubble curtain system for various soil conditions and pile configurations. Model predictions are compared with measured data. The model allows for a large number of simulations to examine different configurations of a single bubble curtain and a double big bubble curtain.
Latent diffusion augmentation enhances deep learning analysis of neuro-morphology in limbal stem cell deficiency
Authors: Gibson David , Tran Thai , Raveendran Vidhur , Bonnet Clémence , Siu Nathan , Vinet Micah , Stoddard-Bennett Theo , Arnold Corey , Deng Sophie X. , Speier William
Published: October 2023

Introduction

Limbal Stem Cell Deficiency (LSCD) is a blinding corneal disease characterized by the loss of function or deficiency in adult stem cells located at the junction between the cornea and the sclera (i.e., the limbus), namely the limbal stem cells (LSCs). Recent advances in in vivo imaging technology have improved disease diagnosis and staging to quantify several biomarkers of in vivo LSC function including epithelial thickness measured by anterior segment optical coherence tomography, and basal epithelial cell density and subbasal nerve plexus by in vivo confocal microscopy. A decrease in central corneal sub-basal nerve density and nerve fiber and branching number has been shown to correlate with the severity of the disease in parallel with increased nerve tortuosity. Yet, image acquisition and manual quantification require a high level of expertise and are time-consuming. Manual quantification presents inevitable interobserver variability.

Methods

The current study employs a novel deep learning approach to classify neuron morphology in various LSCD stages and healthy controls, by integrating images created through latent diffusion augmentation. The proposed model, a residual U-Net, is based in part on the InceptionResNetV2 transfer learning model.

Results

Deep learning was able to determine fiber number, branching, and fiber length with high accuracy (R2 of 0.63, 0.63, and 0.80, respectively). The model trained on images generated through latent diffusion on average outperformed the same model when trained on solely original images. The model was also able to detect LSCD with an AUC of 0.867, which showed slightly higher performance compared to classification using manually assessed metrics.

Discussion

The results suggest that utilizing latent diffusion to supplement training data may be effective in bolstering model performance. The results of the model emphasize the ability as well as the shortcomings of this novel deep learning approach to predict various nerve morphology metrics as well as LSCD disease severity.
Contrast enhanced CT on PET/CT imaging in clinical routine: an international survey
Authors: Annunziata Salvatore , Testart Nathalie , Auf der Springe Katharina , Cuzzocrea Marco , Nicod Lalonde Marie , Schaefer Niklaus , Prior John O. , Garibotto Valentina , Treglia Giorgio
Published: October 2023

Aim

To perform an international survey about PET/CT imaging with contrast enhanced CT (PET/ceCT) in clinical routine worldwide.

Methods

A questionnaire of ten questions was prepared for health professionals, addressing the following issues: (1) general demographic, hospital, and department information; (2) use and diffusion of PET/ceCT worldwide; (3) factors influencing the use of PET/ceCT. An invitation to the survey was sent to the corresponding authors of NM scientific articles indexed in SCOPUS in 2022 and dedicated to PET/CT imaging. Data were analysed per individual responder.

Results

191 individual responders worldwide participated in this survey. Most of the responders are using PET/ceCT in their center (74%). Interestingly, the relative use of PET/ceCT over the total PET/CT scans has an anti-Gaussian distribution (<20% ceCT and > 80% ceCT were most represented). Most of responders are using PET/ceCT in oncological settings (62%) and irrespectively from radiopharmaceuticals (62%). In most cases, PET/ceCT scans are reported by NM physicians alone or together by NM physicians and radiologists with an integrated report (31%).

Conclusion

PET/ceCT imaging is largely used worldwide. Local factors can affect the choice of PET/ceCT in respect to conventional PET/CT imaging. Further cost–benefit analysis could be useful to consider other possible influencing variables, such as technologies, dosimetry, department organization and economics.
Metagenomic and metabolomic analysis of changes in intestinal contents of rainbow trout (Oncorhynchus mykiss) infected with infectious hematopoietic necrosis virus at different culture water temperatures
Authors: Hai Qiang , Wang Jianfu , Kang Weiguo , Cheng Shuru , Li Jie , Lyu Nana , Li Yajun , Luo Zhiyuan , Liu Zhe
Published: October 2023

Infectious hematopoietic necrosis (IHN) is a major disease that limits the culture of rainbow trout. In practical production, it has been found that the temperature of the culture water is a crucial factor affecting its mortality. Currently, little is known about how temperature affects the immune response of rainbow trout gut microbiota and metabolites to IHNV. In this study, our main objective is to analyze the changes in gut microorganisms of rainbow trout (juvenile fish with a consistent genetic background) after 14 days of infection with IHNV (5 × 105 pfu/fish) at 12–13°C (C: injected with saline, A: injected with IHNV) and 16–17°C (D: injected with saline, B: injected with IHNV) using metagenomic and metabolomic analyses, and to screen for probiotics that are effective against IHNV. The results showed that infection with IHNV at 12–13°C caused Eukaryote loss. Compared to Group C, Group A showed a significant increase in harmful pathogens, such as Yersiniaceae, and a significant alteration of 4,087 gut metabolites. Compared to group D, group B showed a significant increase in the abundance of Streptococcaceae and Lactococcus lactis, along with significant changes in 4,259 intestinal metabolites. Compared with their respective groups, the levels of two immune-related metabolites, 1-Octadecanoyl-glycero-3-phosphoethanolamine and L-Glutamate, were significantly upregulated in groups A and B. Compared to group B, Group A showed significantly higher pathogenic bacteria including Aeromonas, Pseudomonas, and Yersiniaceae, while group B showed a significant increase in Streptococcaceae and Lactococcus lactis. Additionally, there were 4,018 significantly different metabolites between the two groups. Interestingly, 1-Octadecanoyl-sn-glycero-3-phosphoethanolamine and L-Glutamate were significantly higher in group A than in group B. Some of the different metabolites in C vs. A are correlated with Fomitopsis pinicola, while in D vs. B they were correlated with Lactococcus raffinolactis, and in A vs. B they were correlated with Hypsizygus marmoreus. This study exposed how rainbow trout gut microbiota and metabolites respond to IHNV at different temperatures, and screens beneficial bacteria with potential resistance to IHN, providing new insights and scientific basis for the prevention and treatment of IHN.
AVEN: a novel oncogenic biomarker with prognostic significance and implications of AVEN-associated immunophenotypes in lung adenocarcinoma
Authors: Fan Dengxia , Yang Moses , Lee Hye Jung , Lee Jeong Hee , Kim Hong Sook
Published: October 2023

Introduction: AVEN, an apoptosis and caspase activation inhibitor, has been associated with adverse clinical outcomes and poor prognosis in Acute myeloid leukemia (AML). Targeting AVEN in AML improves apoptosis sensitivity and chemotherapy efficacy, making it a promising therapeutic target. However, AVEN’s role has not been studied in solid tumors. Therefore, our study investigated AVEN as a prognostic biomarker in a more comprehensive manner and developed an AVEN-derived prognostic model in Lung adenocarcinoma (LUAD).

Method: Pan-cancer analysis was performed to examine AVEN expression in 33 cancer types obtained from the TCGA database. GEPIA analysis was used to determine the predictive value of AVEN in each cancer type with cancer-specific AVEN expression. Lung Adenocarcinomas (LUAD) patients were grouped into AVENhigh and AVENlow based on AVEN expression level. Differentially expressed genes (DEGs) and pathway enrichment analysis were performed to gain insight into the biological function of AVEN in LUAD. In addition, several deconvolution tools, including Timer, CIBERSORT, EPIC, xCell, Quanti-seq and MCP-counter were used to explore immune infiltration. AVEN-relevant prognostic genes were identified by Random Survival Forest analysis via univariate Cox regression. The AVEN-derived genomic model was established using a multivariate-Cox regression model and GEO datasets (GSE31210, GSE50081) were used to validate its prognostic effect.

Results: AVEN expression was increased in several cancer types compared to normal tissue, but its impact on survival was only significant in LUAD in the TCGA cohort. High AVEN expression was significantly correlated with tumor progression and shorter life span in LUAD patients. Pathway analysis was performed with 838 genes associated with AVEN expression and several oncogenic pathways were altered such as the Cell cycle, VEGFA-VEGFR2 pathway, and epithelial-mesenchymal-transition pathway. Immune infiltration was also analyzed, and less infiltrated B cells was observed in AVENhigh patients. Furthermore, an AVEN-derived genomic model was established, demonstrating a reliable and improved prognostic value in TCGA and GEO databases.

Conclusion: This study provided evidence that AVEN is accumulated in LUAD compared to adjacent tissue and is associated with poor survival, high tumor progression, and immune infiltration alteration. Moreover, the study introduced the AVEN-derived prognostic model as a promising prognosis tool for LUAD.
Prognostic factors and predictive nomogram models for early death in elderly patients with hepatocellular carcinoma: a population-based study
Authors: Zhou Hao , Chen Junhong , Liu Kai , Xu Hongji
Published: October 2023

Background: Owing to an aging society, there has been an observed increase in the average age of patients diagnosed with hepatocellular carcinoma (HCC). Consequently, this study is centered on identifying the prognostic factors linked with early death among this elderly demographic diagnosed with HCC. Additionally, our focus extends to developing nomograms capable of predicting such outcomes.

Methods: The Surveillance, Epidemiology and End Results (SEER) database underpinned this study, showcasing participants aged 75 and above diagnosed with HCC within the timeframe from 2010 to 2015. These participants were divided randomly, at a 7:3 ratio, into training and validation cohorts. Univariable and multivariable logistic regressions were applied to the training cohort in the identification of prognostic indicators of early death, forming the basis for nomogram development. To measure the efficacy of these nomograms within both cohorts, we resorted to Receiver Operating Characteristic (ROC) curves, along with GiViTI calibration belt and Decision Curve Analysis (DCA).

Results: The study involved 1,163 elderly individuals diagnosed with HCC, having reported instances of 397 all-cause early deaths and 356 HCC-specific early deaths. The sample group was divided into two cohorts: a training group consisting of 815 individuals, and a validation cohort, comprised of 348 individuals. Multifactorial analysis identified grade, T-stage, surgery, radiation, chemotherapy, bone and lung metastasis as significant predictors of mortality from all causes. Meanwhile, race, grade, T-stage, surgery, radiation, chemotherapy, and bone metastasis were revealed to be estimative factors for cancer-specific mortality. Subsequently, these factors were used to develop nomograms for prediction. GiViTI calibration belt corroborated the acceptable coherence of the nomograms, DCA confirmed their valuable clinical applicability, and ROC curves evidenced satisfactory discriminative capacity within both training and validation cohorts.

Conclusion: The nomograms utilized in this study proved instrumental in detecting early death among elderly individuals afflicted with HCC. This tool could potentially assist physicians in formulating individualized treatment strategies.
Social withdrawal and anxiety-like behavior have an impact on zebrafish adult neurogenesis
Authors: Perdikaris Panagiotis , Prouska Paulina , Dermon Catherine R.
Published: October 2023

Introduction

Accumulating evidence highlights the key role of adult neurogenesis events in environmental challenges, cognitive functions and mood regulation. Abnormal hippocampal neurogenesis has been implicated in anxiety-like behaviors and social impairments, but the possible mechanisms remain elusive.

Methods

The present study questioned the contribution of altered excitation/inhibition as well as excessive neuroinflammation in regulating the neurogenic processes within the Social Decision-Making (SDM) network, using an adult zebrafish model displaying NMDA receptor hypofunction after sub-chronic MK-801 administration. For this, the alterations in cell proliferation and newborn cell densities were evaluated using quantitative 5-Bromo-2′-Deoxyuridine (BrdU) methodology.

Results

In short-term survival experiments. MK-801-treated zebrafish displayed decreased cell proliferation pattern within distinct neurogenic zones of telencephalic and preoptic SDM nodes, in parallel to the social withdrawal and anxiety-like comorbidity. BrdU+ cells co-expressed the pro-inflammatory marker IL-1β solely in MK-801-treated zebrafish, indicating a role of inflammation. Following the cessation of drug treatment, significant increases in the BrdU+ cell densities were accompanied by the normalization of the social and anxiety-like phenotype. Importantly, most labeled cells in neurogenic zones showed a radial glial phenotype while a population of newborn cells expressed the early neuronal marker TOAD or mGLuR5, the latter suggesting the possible involvement of metabotropic glutamate receptor 5 in neurogenic events.

Discussion

Overall, our results indicate the role of radial glial cell proliferation in the overlapping pathologies of anxiety and social disorders, observed in many neuropsychiatric disorders and possibly represent potential novel targets for amelioration of these symptoms.
Gradients of thalamic connectivity in the macaque lateral prefrontal cortex
Authors: Borra Elena , Rizzo Marianna , Luppino Giuseppe
Published: October 2023

In the primate brain, the lateral prefrontal cortex (LPF) is a large, heterogeneous region critically involved in the cognitive control of behavior, consisting of several connectionally and functionally distinct areas. Studies in macaques provided evidence for distinctive patterns of cortical connectivity between architectonic areas located at different dorsoventral levels and for rostrocaudal gradients of parietal and frontal connections in the three main architectonic LPF areas: 46d, 46v, and 12r. In the present study, based on tracer injections placed at different dorsoventral and rostrocaudal cortical levels, we have examined the thalamic projections to the LPF to examine to what extent fine-grained connectional gradients of cortical connectivity are reflected in the topography of thalamo-LPF projections. The results showed mapping onto the nucleus medialis dorsalis (MD), by far the major source of thalamic input to the LPF, of rostral-to-caudal LPF zones, in which MD zones projecting to more caudal LPF sectors are located more rostral than those projecting to intermediate LPF sectors. Furthermore, the MD zones projecting to the rostral LPF sectors tended to be much more extensive in the rostrocaudal direction. One rostrolateral MD sector appeared to be a common source of projections to caudal prefrontal areas involved in the oculomotor frontal domain, a more caudal and ventral MD sector to a large extent of the ventral LPF, and middle and dorsal MD sectors to most of the dorsal LPF. Additional topographically organized projections to LPF areas originated from the nucleus pulvinaris medialis and projections from the nucleus anterior medialis selectively targeted more rostral sectors of LPF. Thus, the present data suggest that the topography of the MD-LPF projections does not adhere to simple topological rules, but is mainly organized according to functional criteria.
Three-stage pattern of rapid increase, plateau, and subsequent decline in vitamin D concentration during pregnancy among Chinese women: a large-scale survey
Authors: Wang Huabin , Zhang Feifang , Li Bingxian , Fu Miao , Shan Xiaoyun , Ma Yongjun
Published: October 2023

Background

There is an incomplete understanding of fluctuations in vitamin D (VitD) concentration during pregnancy among Chinese women. Furthermore, previous research has yielded conflicting results in this area. This study aims to investigate the changes in VitD status and deficiency in Chinese pregnant women across various age groups, gestational weeks, and as well as seasonal variations through conducting a large-scale survey.

Methods

A toal of 11,220 Chinese pregnant women between 2021 and April 2023 were included in this study. Generalized additive models (GAM), stratified analysis, and restricted cubic splines (RCS) were used to analyze changes in VitD status and deficiency risk during pregnancy.

Results

Of the participants, 45.2% had deficient concentration of 25-hydroxyvitamin D. VitD concentration and deficiency rate do not show linear changes with age and gestational weeks. With increasing gestational weeks, VitD concentration rapidly increased in women with gestational age < 20 weeks, remained stable between 20 and 30 weeks, and decreased beyond 30 weeks; however, the odds of VitD deficiency showed three different patterns: a rapid decline, a stable period, and a mild increase, respectively. Based on the stratified regression analysis, VitD deficiency odds increased by 16% with each additional week of gestation in pregnant women with gestational age > 30 weeks, OR = 1.16 (1.10–1.22), p < 0.001. Interaction effect analysis indicated that pregnant women over 35 years with gestational weeks between 20 and 30 had the lowest odds of VitD deficiency.

Conclusion

VitD concentration undergo three phases during pregnancy: rapid increase, plateau, and subsequent decrease. VitD deficiency odds was highest in pregnant women under 25 with gestational ages <20 and lowest in pregnant women over 35 with gestational ages between 20 and 30. The odds of deficiency increase slightly in pregnant women with gestational ages beyond 30 weeks, indicating that they may require additional VitD supplementation.
Effects of MRI radiomics combined with clinical data in evaluating lymph node metastasis in mrT1-3a staging rectal cancer
Authors: Dong Xue , Ren Gang , Chen Yanhong , Yong Huifang , Zhang Tingting , Yin Qiufeng , Zhang Zhongyang , Yuan Shijun , Ge Yaqiong , Duan Shaofeng , Liu Huanhuan , Wang Dengbin
Published: October 2023

Objective

To investigate the value of a clinical-MRI radiomics model based on clinical characteristics and T2-weighted imaging (T2WI) for preoperatively evaluating lymph node (LN) metastasis in patients with MRI-predicted low tumor (T) staging rectal cancer (mrT1, mrT2, and mrT3a with extramural spread ≤ 5 mm).

Methods

This retrospective study enrolled 303 patients with low T-staging rectal cancer (training cohort, n = 213, testing cohort n = 90). A total of 960 radiomics features were extracted from T2WI. Minimum redundancy and maximum relevance (mRMR) and support vector machine were performed to select the best performed radiomics features for predicting LN metastasis. Multivariate logistic regression analysis was then used to construct the clinical and clinical-radiomics combined models. The model performance for predicting LN metastasis was assessed by receiver operator characteristic curve (ROC) and clinical utility implementing a nomogram and decision curve analysis (DCA). The predictive performance for LN metastasis was also compared between the combined model and human readers (2 seniors).

Results

Fourteen radiomics features and 2 clinical characteristics were selected for predicting LN metastasis. In the testing cohort, a higher positive predictive value of 75.9% for the combined model was achieved than those of the clinical model (44.8%) and two readers (reader 1: 54.9%, reader 2: 56.3%) in identifying LN metastasis. The interobserver agreement between 2 readers was moderate with a kappa value of 0.416. A clinical-radiomics nomogram and decision curve analysis demonstrated that the combined model was clinically useful.

Conclusion

T2WI-based radiomics combined with clinical data could improve the efficacy in noninvasively evaluating LN metastasis for the low T-staging rectal cancer and aid in tailoring treatment strategies.
Exploring the therapeutic potential of targeting polycomb repressive complex 2 in lung cancer
Authors: Gao Min , Li Yongwen , Cao Peijun , Liu Hongyu , Chen Jun , Kang Shirong
Published: October 2023

The pathogenesis of lung cancer (LC) is a multifaceted process that is influenced by a variety of factors. Alongside genetic mutations and environmental influences, there is increasing evidence that epigenetic mechanisms play a significant role in the development and progression of LC. The Polycomb repressive complex 2 (PRC2), composed of EZH1/2, SUZ12, and EED, is an epigenetic silencer that controls the expression of target genes and is crucial for cell identity in multicellular organisms. Abnormal expression of PRC2 has been shown to contribute to the progression of LC through several pathways. Although targeted inhibition of EZH2 has demonstrated potential in delaying the progression of LC and improving chemotherapy sensitivity, the effectiveness of enzymatic inhibitors of PRC2 in LC is limited, and a more comprehensive understanding of PRC2’s role is necessary. This paper reviews the core subunits of PRC2 and their interactions, and outlines the mechanisms of aberrant PRC2 expression in cancer and its role in tumor immunity. We also summarize the important role of PRC2 in regulating biological behaviors such as epithelial mesenchymal transition, invasive metastasis, apoptosis, cell cycle regulation, autophagy, and PRC2-mediated resistance to LC chemotherapeutic agents in LC cells. Lastly, we explored the latest breakthroughs in the research and evaluation of medications that target PRC2, as well as the latest findings from clinical studies investigating the efficacy of these drugs in the treatment of various human cancers.
Olfactory neuroblastoma: diagnosis, management, and current treatment options
Authors: Tosoni Alicia , Di Nunno Vincenzo , Gatto Lidia , Corradi Giacomo , Bartolini Stefania , Ranieri Lucia , Franceschi Enrico
Published: October 2023

Olfactory neuroblastoma (ONB) is a rare neoplasm originating from the olfactory neuroepithelium representing 3-6% of tumors of the sinonasal tract. ONB require multi-disciplinary care. Historically, the gold standard surgical procedure for ONB has been open craniofacial resection. In the last years, endoscopic endonasal approaches have been largely introduced with lower complication rates, shorter hospital stay, and similar clinical outcome. Radiotherapy plays an important role in the management of ONB, however there are not generally accepted recommendations for its application. Although there is agreement that multimodal therapy is needed, the optimal use of chemotherapy is still unknown. The rarity of the disease, makes difficult to draw definitive conclusions about the role of systemic treatment in induction and concomitant setting.
Pembrolizumab and trastuzumab in combination with FLOT in the perioperative treatment of HER2-positive, localized esophagogastric adenocarcinoma—a phase II trial of the AIO study group (AIO STO 0321)
Authors: Tintelnot Joseph , Stein Alexander , Al-Batran Salah-Eddin , Ettrich Thomas , Götze Thorsten , Grün Barbara , Haag Georg Martin , Heuer Vera , Hofheinz Ralf-Dieter , Homann Nils , Bröring Tobias Sebastian , Cruz Mariana Santos , Kurreck Annika , Lorenzen Sylvie , Moosmann Nicolas , Müller Christian , Schuler Markus , Siegler Gabriele , Binder Mascha , Gökkurt Eray
Published: October 2023

Background

Esophagogastric adenocarcinoma (EGA) presents a substantial global health challenge as the number of cases continues to rise. The current standard approach for treating localized EGA involves a combination of triplet chemotherapy, which consists of a platinum compound, a fluoropyrimidine, and a taxane (known as FLOT), followed by surgery. In cases of metastatic EGA with HER2-positive status or in certain studies with localized EGA, the use of HER2-targeted antibodies such as trastuzumab has shown improved responses. Recently, the addition of programmed cell death protein 1 (PD-1) inhibitors, such as pembrolizumab, when combined with 5-FU, platinum-based chemotherapy, and trastuzumab, has demonstrated significant enhancements in response rates for HER2-positive metastatic EGA. However, there is currently insufficient evidence regarding this treatment approach in localized HER2-positive disease.

Methods

The PHERFLOT study is an open-label, single-arm, multicenter, exploratory phase II trial designed to assess the efficacy, safety, and tolerability of perioperative pembrolizumab, FLOT, and trastuzumab in patients with previously untreated localized HER2-positive EGA. In total, 30 patients will be recruited. The co-primary end points are pathological complete response rate and disease-free survival rate after 2 years. Secondary objectives include safety and tolerability, efficacy in terms of progression-free survival and objective response rate and translational markers, such as blood-based signatures (e.g., immune repertoire changes or emergence of anti-HER2 resistance variants) or microbiota signatures that may correlate with immune activation and therapy response.

Discussion

Recent evidence from phase II clinical trials demonstrated improved efficacy through the addition of trastuzumab to perioperative FLOT. Furthermore, in advanced or metastatic EGA, the combination of trastuzumab, FLOT, and the PD1-inhibitor pembrolizumab significantly improved treatment response. The PHERFLOT study aims to assess the efficacy and safety of this treatment approach in HER2-positive–localized EGA, potentially identifying a promising new perioperative regimen for localized EGA, which then needs to be confirmed within a randomized trial. Furthermore, the accompanying translational program of the study might help to improve the stratification of suitable patients and to identify potential translational targets for future clinical trials.

Clinical trial registration

https://clinicaltrials.gov, identifier NCT05504720.
TP53 Gene 72 Arg/Pro (rs1042522) single nucleotide polymorphism increases the risk and the severity of chronic lymphocytic leukemia
Authors: Ounalli Asma , Moumni Imen , Mechaal Amal , Chakroun Aya , Barmat Mbarka , Rhim Rim El Elj , Menif Samia , Safra Ines
Published: October 2023

Background

Genetic variations in TP53 gene are known to be important in chronic lymphocytic leukemia (CLL) and may cause its inactivation which is associated with an aggressive form of the disease. Single nucleotide polymorphism (rs1042522:G>C) in TP53 gene at codon 72 encodes for arginine (Arg) or proline (Pro) variant which results in amino acid substitution affecting the apoptotic potential of TP53 protein. The aim of this study was to assess the correlation between TP53 codon 72 polymorphism and risk susceptibility as well as severity of CLL among Tunisian patients.

Materials and methods

A case-control study was conducted in Tunisia from February 2019 to November 2021, 160 de novo CLL patients and 160 healthy volunteers matched in age and gender were involved. DNA was extracted from peripheral blood mononuclear cells and the rs1042522 was analyzed using PCR-RFLP.

Results

Pro variant was associated with higher susceptibility to CLL than Arg variant (p= 0.023). A significant association was found between Pro variant and prognostic classification of Binet stage C (p= 0.001), low hemoglobin level (p= 0.003) and low platelet count (p= 0.016).

Conclusion

We suggest that Pro variant may increase the risk of developing CLL in our population and could be associated with the severity of the disease.
Prognostic significance of the systemic immune-inflammation index in patients with extranodal natural killer/T-cell lymphoma
Authors: Hai Tao , Wu Wanchun , Ren Kexin , Li Na , Zou Liqun
Published: October 2023

Background

The systemic immune-inflammation index (SII) is based on the neutrophil, platelet, and lymphocyte counts, and has been identified as a prognostic marker in multiple types of cancer. However, the potential value of the SII for predicting survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTCL) has not been investigated thus far.

Method

This study included 382 patients with ENKTCL treated with asparaginase-base regimens from 2021 to 2017 in West China Hospital (Chengdu, China). Clinical and demographic variables, as well as the prognostic value of the SII, were analyzed using Cox proportional hazards regression analysis.

Results

The complete and objective response rates were 55.8% and 74.9%, respectively. Patients with high SII were associated with a lower rate of complete response, higher rate of B symptoms, and serum lactate dehydrogenase levels above or equal to the upper limits of normal (p < 0.01). Patients with low SII were linked to better overall survival and progression-free survival than those with high SII (p < 0.01). Patients with early-stage disease or prognostic model for natural killer lymphoma with Epstein–Barr virus, defined as the low-risk group, could be further stratified according to the SII (p < 0.01). Negative prognostic factors were determined using the Cox proportional hazards regression analysis, which identified four variables: Eastern Cooperative Oncology Group performance status score ≥2, Stage III/IV disease, positivity for Epstein–Barr virus DNA in plasma, and high SII. Predictive nomograms for the prediction of 3- and 5-year overall survival, as well as progression-free survival, were constructed based on those four variables. The nomograms demonstrated favorable discriminating power.

Conclusion

The SII is a novel prognostic marker for ENKTCL, which may be used for the prediction of poorer survival in low-risk patients.
Case report: Diagnosis and treatment of DGAT1 deficiency-induced congenital diarrhea in two cases and literature review
Authors: Li Jian , Sun Mei , Guo Jing , Xu Lingfen
Published: October 2023

Introduction

Congenital diarrhea is a rare inherited intestinal disease characterized by persistent and severe diarrhea and malabsorption in the first few weeks after birth, which can be life-threatening. Some congenital diarrheal diseases are associated with mutations in the diacylglycerol acyltransferase 1 (DGAT1) gene.

Case descriptions

This study delineated 2 cases of diarrhea and growth retardation, subsequently confirmed as congenital diarrhea via genetic testing, revealing that the etiology involved compound heterozygous mutations in the DGAT1 gene.

Diagnostic assessments

High-MCT milk powder did not obtain an ideal outcome, whereas low-fat diets improved the symptoms of diarrhea and increased the body weigths.

Disscussion

The two cases facilitated our understanding of the clinical features of, and treatments for, patients harboring a DGAT1 mutation and enriched the existing DGAT1 mutation database.
Research on task offloading optimization strategies for vehicular networks based on game theory and deep reinforcement learning
Authors: Wang Lei , Zhou Wenjiang , Xu Haitao , Li Liang , Cai Lei , Zhou Xianwei
Published: October 2023

With the continuous development of the 6G mobile network, computing-intensive and delay-sensitive onboard applications generate task data traffic more frequently. Particularly, when multiple intelligent agents are involved in tasks, limited computational resources cannot meet the new Quality of Service (QoS) requirements. To provide a satisfactory task offloading strategy, combining Multi-Access Edge Computing (MEC) with artificial intelligence has become a potential solution. In this context, we have proposed a task offloading decision mechanism (TODM) based on cooperative game and deep reinforcement learning (DRL). A joint optimization problem is presented to minimize both the overall task processing delay (OTPD) and overall task energy consumption (OTEC). The approach considers task vehicles (TaVs) and service vehicles (SeVs) as participants in a cooperative game, jointly devising offloading strategies to achieve resource optimization. Additionally, a proximate policy optimization (PPO) algorithm is designed to ensure robustness. Simulation experiments confirm the convergence of the proposed algorithm. Compared with benchmark algorithms, the presented scheme effectively reduces delay and energy consumption while ensuring task completion.
Gastrointestinal cell injury and perceived symptoms after running the Boston Marathon
Authors: Kelly Melani R. , Emerson Dawn M. , McDermott Brendon P. , Atkins Whitley C. , Butts Cory L. , Laursen R. Mark , Troyanos Christopher , Duckett Andrew , Siedlik Jacob
Published: October 2023

Gastrointestinal (GI) disturbances are a prevalent cause of marathon related complaints, and in extreme cases can promote life-threatening conditions such as exertional heat stroke. Our aim was to study intestinal cell injury [via intestinal fatty acid binding protein (I-FABP)] and perceived GI distress symptoms among marathon runners. We also examined potential risk factors (e.g., inadequate sleep) that could exacerbate GI disturbances in healthy, trained endurance runners. This was a parallel mixed-methods study design. 2019 Boston Marathon participants were recruited via email and subjects completed surveys before the race describing demographics and training history. Participants completed a GI questionnaire to assess presence and severity of symptoms, a survey regarding risk factors (e.g., recent illness, medications) that could promote GI disturbances, and provided a urine sample at three time points (immediately pre-race, post-race, and 24-h post-race). Due to weather, blood samples were only collected immediately and 24-h post-race. A total of 40 runners (males: n = 19, age = 44.9 ± 10.8 years; females: n = 21, age = 44.8 ± 10.6 years) completed this study. I-FABP significantly decreased from post-race (3367.5 ± 2633.5 pg/mL) to 24-h post-race (1657.3 ± 950.7 pg/mL, t (39) = −4.228, p < .001, d = −.669). There was a significant difference in overall GI symptom scores across the three time points (F (2, 39) = 41.37, p < .001). The highest average score occurred post-race (.84 ± .68), compared to pre-race (.09 ± .12) and 24-h post-race (.44 ± .28). Post-race I-FABP (r = .31, p = .048) and post-race urine specific gravity (r = .33, p = .041) were significantly correlated with post-race GI symptom scores. Our study provides further support to the individualized nature of GI disturbances, with participants experiencing a wide range of risk factors that can influence the extent of GI damage and perceived symptoms during and after exercise.