bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune response of heterologous versus homologous prime-boost regimens with adenoviral vectored and mRNA COVID-19 vaccines in immunocompromised patients
Authors: Chu Chang , Schönbrunn Anne , Fischer Dorothea , Liu Yvonne , Hocher Johann-Georg , Weinerth Jutta , Klemm Kristin , von Baehr Volker , Krämer Bernhard K. , Elitok Saban , Hocher Berthold
Published: June 2023

Due to rare but major adverse reactions to the AstraZeneca adenoviral ChAdOx1-S-nCoV-19 vaccine (ChAd), German health authorities recommended adults under 60 who received one dose of ChAd, to receive a second dose of the BioNTech mRNA BNT162b2 vaccine (BNT) as a booster. Studies in the general population suggest an enhanced efficacy of the heterologous (ChAd-BNT) compared to the homologous (BNT-BNT) vaccination regimen. However, an analysis of the efficacy in patient populations with a high risk of severe COVID-19 due to acquired immunodeficiency is still missing. We therefore compared both vaccination regimens in healthy controls, patients with gynecological tumors after chemotherapy, patients on dialysis and patients with rheumatic diseases concerning the humoral and cellular immune response. The humoral and cellular immune response differed substantially in healthy controls compared to patients with acquired immunodeficiency. Overall, the most significant differences between the two immunization regimens were found in neutralizing antibodies. These were always higher after a heterologous immunization. Healthy controls responded well to both vaccination regimens. However, the formation of neutralizing antibodies was more pronounced after a heterologous immunization. Dialysis patients, on the other hand, only developed an adequate humoral and particularly cellular immune response after a heterologous immunization. Tumor and rheumatic patients also - to a weaker extent compared to dialysis patients - benefited from a heterologous immunization. In conclusion, the heterologous COVID-19 vaccination regimens (ChAd-BNT) seem to have an advantage over the homologous vaccination regimens, especially in immunocompromised patients such as patients with end-stage kidney disease treated with hemodialysis.
eDNA metabarcoding vs metagenomics: an assessment of dietary competition in two estuarine pipefishes
Authors: Serite Conny P. , Emami-Khoyi Arsalan , Ntshudisane Ofentse K. , James Nicola C. , Jansen van Vuuren Bettine , Bodill Taryn , Cowley Paul D. , Whitfield Alan K. , Teske Peter R.
Published: June 2023

Understanding the dietary preferences of endangered species can be useful in implementing conservation strategies, including habitat restoration, translocation, and captive breeding. Environmental DNA (eDNA) from feces provides a non-invasive method for analysing animal diets. Currently, metabarcoding, a PCR-based approach, is the method of choice for analysing such data. However, this method has limitations, specifically PCR bias, which can result in the overestimation of the importance of certain taxa and failure to detect other taxa because they do not amplify. The present study compared metabarcoding with metagenomics, a PCR-free method, to assess the diversity of prey items in the feces of a critically endangered South African estuarine pipefish, Syngnathus watermeyeri, and its widely distributed congener S. temminckii to investigate potential dietary competition. The metabarcoding results showed a distinct difference between the diets of S. watermeyeri and S. temminckii, with the former mainly consuming calanoid copepods and the latter preferring caridean shrimp. In each case, a single species dominated the sequences generated by metabarcoding. Metagenomics produced more species identifications, and although the same trend was found regarding the preference of S. watermeyeri for copepods and that of S. temminckii for shrimp, this approach identified additional, albeit yet unidentified, copepod species as being important in the diet of S. watermeyeri. We conclude that the lower number of species identified using metabarcoding was most likely a result of amplification bias, resulting in key copepod species missing from the dietary analysis. These findings suggest that metagenomics is not only a useful complementary method for molecular dietary analysis, but may in some cases outperform metabarcoding. However, metagenomics is even more strongly affected by the lack of reference sequences than is metabarcoding, as the majority of sequences originate from genomic regions that have not yet been sequenced for the putative prey species in question.
An effective method to extract and purify radiolaria from tropical marine sediments
Authors: Zhang Qiang , Swann George E. A.
Published: June 2023

Radiolaria are the primary contributors to biogenic opal in the tropical ocean, and their isotope compositions are potentially useful tool for reconstructing the silicon cycle in mid-depth waters. To date little attention has been paid to their isotopic study, partly because of the difficulties in purifying radiolarian tests from marine sediments. In this study twelve surface sediment samples from the South China Sea and the western Indian Ocean were used in a density separation experiment, with the aim of enabling better separation of radiolarian tests from detrital grains and other siliceous organisms. The results show that sponge spicules, radiolarian tests and diatom frustules from tropical ocean sediments preferentially settle in heavy liquid solutions with different specific gravities, and are constrained to range in the densities from 1.95 to 2.1 g/cm3, 1.85 to 2.0 g/cm3 and 1.7 to 1.95 g/cm3, respectively. These density ranges for radiolarians and diatom frustules in the low-latitude ocean are much lower than that of amorphous silica, probably resulting from the decreased silicification of radiolarians and diatoms due to the limited silica availability in the highly-stratified tropical ocean. According to the components and density ranges of siliceous microfossils observed in this study, an optimized method with detailed procedures is proposed to extract and purify radiolarians from late Quaternary sediments in the tropical ocean that have not undergone substantial dissolution and diagenetic change. Using a combination of wet-chemical treatment, wet sieving, differential settling, and density separations, this method can yield clean radiolarian test in sufficient quantities from tropical ocean sediments for isotope/geochemical analysis.
Atmospheric radioactive nuclide deposition on the coast of the Maowei Sea, northern Beibu Gulf, China
Authors: Wang Xilong , Zhou Jiaodi , Su Kaijun , Du Jinzhou , Wei Longtao , Li Xing , Du Juan , Lu Dongliang
Published: June 2023

The natural radioisotopes 7Be, 210Pb, and 210Po, with different half-lives, are all particle-reactive and serve as natural tracers to study sources and transportation of sediments, sedimentation rates, and sediment chronology. Atmospheric deposition of these radioisotopes is the premise and foundation of their tracing application. The Maowei Sea is a semi-closed bay along the Beibu Gulf, which is an important gulf in the northwest of the South China Sea, but the atmospheric deposition of the abovementioned radioisotopes has not been systematically reported along the coast. In this research paper, the atmospheric depositional fluxes of 7Be, 210Pb, and 210Po were observed over a period from June 2018 to December 2021 on the coast of the Maowei Sea. The annual atmospheric depositional fluxes (Bq m-2 yr-1) of 7Be, 210Pb, and 210Po on the coast of the Maowei Sea were 496.80, 201.72, and 58.08, respectively. The distributions for 7Be and 210Pb depositional fluxes during a whole year (years 2019 and 2021) followed a bimodal pattern, with one peak from February to April and another peak from August to October, while the distribution for 210Po depositional flux showed only one peak during the year of 2019 and another during 2021. The deposition flux and activity of 7Be showed a strong positive correlation with the deposition flux and activity of 210Pb, respectively; the deposition flux and activity of 210Po also showed positive correlations with the deposition fluxes and activities of 210Pb and 7Be, respectively, indicating a similarly scavenging behavior from the atmosphere. A Pearson correlation matrix was used to illustrate the factors influencing the atmospheric depositions and found that precipitation, air quality index (AQI), and PM (both PM2.5 and PM10) were the major factors that influenced the deposition of these three radionuclides. Precipitation had significant positive correlations with the deposition fluxes of all three radionuclides, indicating that, for these radionuclides, rainfall was the main scavenging way from the atmosphere. The observations for specific single rainfall events and their air mass backward trajectory analyses showed that the air masses movement during the rainfall may be another important factor that impacted the depositional fluxes for 7Be, 210Pb, and 210Po.
CFD-DEM modeling of turbidity current propagation in channels with two different topographic configurations
Authors: Lu Yang , Liu Xiaolei , Sun Junkai , Xie Xiaotian , Li Dongyang , Guo Xingsen
Published: June 2023

Submarine turbidity currents are a special type of sediment gravity flow responsible for turbidite deposits, attracting great interests from scientists and engineers in marine and petroleum geology. This paper presents a fully coupled computational fluid dynamics (CFD) and discrete element method (DEM) model to quantitatively analyze the turbidity current propagation in channels with two different topographic configurations. An appropriate drag force model is first incorporated in the CFD-DEM scheme, and two benchmark cases, including a single-particle sedimentation case and an immersed granular collapse case, are conducted to verify the accuracy of the developed CFD-DEM model. The model is then employed to investigate the fluid and particle dynamics of turbidity currents flowing over a flat bed (FB), and three obstacle-placed beds with different heights (OPB, OPB_1 and OPB_2). The CFD-DEM results indicate that the front position of turbidity current in the FB case is well consistent with the classic lock-exchange experiment. Results also show that the presence of the obstacle can clearly diminish the inter-particle collisions and the particle kinetic energy, weaken the particle-fluid interactions, and further make more sediment particles settle in front of the obstacle. Increase of obstacle height can result in diverse flow morphology of particles and fluids, and intensify the influences of obstacle on particle dynamics of turbidity currents. We show that our models enable reproducing the typical process of turbidity current propagation, and further can provide more valuable insights in understanding the turbidite-related geological phenomena from the point of view of particulate flow.
WeChat official accounts’ posts on medication use of 251 community healthcare centers in Shanghai, China: content analysis and quality assessment
Authors: Liang Xujian , Yan Ming , Li Haixin , Deng Zhiling , Lu Yiting , Lu Panpan , Cai Songtao , Li Wanchao , Fang Lizheng , Xu Zhijie
Published: June 2023

Background

The dissemination of online health information (OHI) on medication use via WeChat Official Accounts (WOAs) is an effective way to help primary care practitioners (PCPs) address drug-related problems (DRPs) in the community. Although an increasing number of primary care institutions in China have published WOA posts on medication use, their content and quality have not yet been assessed.

Objective

This study aimed to explore the general features and content of WOA posts on medication use published by community healthcare centers (CHCs) in Shanghai, China and to assess their quality of content. It also aimed to explore the factors associated with the number of post views.

Methods

From June 1 to October 31, 2022, two coauthors independently screened WOA posts on medication use published throughout 2021 by the CHCs in Shanghai. Content analysis was performed to analyze their general features (format, length, and source, etc.) and content (types of medicines and diseases). The QUEST tool was used to assess the quality of the posts. We compared the differences among posts published by CHCs in central urban areas and suburban areas, and used multiple linear regression to explore the factors associated with the number of post views.

Results

A total of 236 WOAs of interest published 37,147 posts in 2021, and 275 (0.74%) of them were included in the study. The median number of post views was 152. Thirty percent of the posts were reviewed by the CHCs’ staff before publication and only 6% provided information on PCPs’ consultations. The most commonly mentioned medicines and diseases in the posts were Chinese patent medicines (37.1%) and respiratory diseases (29.5%). The posts frequently provided information on indications (77%) and usage (56%) but rarely on follow-up (13%) and storage (11%). Of the posts, 94.9% had a total QUEST score < 17 (full score = 28). The median number of post views and total post quality scores did not significantly differ among the CHCs in central urban and suburban areas. In the multiple linear regression model, the number of post views was associated with scores of complementarity (B = 56.47, 95% CI 3.05, 109.89) and conflict of interest (B = −46.40, 95% CI -56.21, −36.60).

Conclusion

The quantity and quality of WOA posts on medication use published by CHCs in China need improvement. The quality of posts may partially impact the dissemination effect, but intrinsic causal associations merit further exploration.
Chemo-radiotherapy with 177Lu-PLGA(RGF)-CXCR4L for the targeted treatment of colorectal cancer
Authors: Cruz-Nova Pedro , Gibbens-Bandala Brenda , Ancira-Cortez Alejandra , Ramírez-Nava Gerardo , Santos-Cuevas Clara , Luna-Gutiérrez Myrna , Ocampo-García Blanca
Published: June 2023

Introduction

More than 1.9 million new cases of colorectal cancer and 935,000 deaths were estimated to have occurred worldwide in 2020. Therapies for metastatic colorectal cancer include cytotoxic chemotherapy and targeted therapies in multiple lines of treatment. Nevertheless, the optimal use of these agents has not yet been resolved. Regorafenib (RGF) is an Food and Drug Administration (FDA)-authorized multikinase inhibitor indicated for patients with metastatic colorectal cancer, non-responding to priority lines of chemotherapy and immunotherapy. Nanoparticles have been used in specific applications, such as site-specific drug delivery systems, cancer therapy, and clinical bioanalytical diagnostics. C-X-C Chemokine receptor type 4 (CXCR4) is the most widely-expressed chemokine receptor in more than 23 human cancer types, including colorectal cancer. This research aimed to synthesize and preclinically evaluate a targeted nanosystem for colorectal cancer chemo-radiotherapy using RGF encapsulated in Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles coated with a CXCR4 ligand (CXCR4L) and 177Lu as a therapeutic β-emitter.

Methods

Empty PLGA and PLGA(RGF) nanoparticles were prepared using the microfluidic method, followed by the DOTA and CXCR4L functionalization and nanoparticle radiolabeling with 177Lu. The final nanosystem gave a particle size of 280 nm with a polydispersity index of 0.347. In vitro and in vivo toxicity effects were assessed using the HCT116 colorectal cancer cell line.

Results

177Lu-PLGA(RGF)-CXCR4L nanoparticles decreased cell viability and proliferation by inhibiting Erk and Akt phosphorylation and promoting apoptosis. Moreover, in vivo administration of 177Lu-PLGA(RGF)-CXCR4L significantly reduced tumor growth in an HCT116 colorectal cancer xenograft model. The biokinetic profile showed hepatic and renal elimination.

Discussion

Data obtained in this research justify additional preclinical safety trials and the clinical evaluation of 177Lu-PLGA(RGF)-CXCR4L as a potential combined treatment of colorectal cancer.
Tailoring the secretome composition of mesenchymal stem cells to augment specific functions of epidermal regeneration: an in vitro diabetic model
Authors: Hodge Jacob G. , Robinson Jennifer L. , Mellott Adam J.
Published: June 2023

Introduction

Wound healing consists of a dynamic series of events that are highly dependent on paracrine factors for proper progression through the phases of wound healing. Inappropriate progression through the phases is associated with insufficient epidermal regeneration (i.e., re-epithelialization) of wounds and subsequent propagation of chronic wounds, such as diabetic ulcers, which are associated with increased patient morbidity. Recently, investigation into the dynamic secretome of Adipose-derived Mesenchymal Stem Cells (ASCs), have shown promise in augmenting the wound healing response of chronic diabetic wounds. However, currently utilized 2D culture techniques are known to drastically alter the regenerative phenotype of ASCs. In this study a novel tissue-mimetic 3D system was utilized as a means to culture ASCs.

Methods

The capacity for the ASC secretome to augment epidermal regeneration activity was then evaluated after exposure of ASCs to “wound priming stimuli” in 2D and 3D. The priming stimuli consisted of coating the 2D and 3D systems with the wound matrix proteins, collagen type I, fibronectin, and fibrin. To understand the potential benefit of the ASC secretome in the context of diabetic wounds, keratinocytes (KCs) were exposed to super-physiological glucose levels to induce a diabetic-like phenotype (idKCs).

Results

Relative to KCs, idKC exhibited a 52% and 23% decline in proliferation and migration, respectively. Subsequently, analyses of the ASC secretome were performed. ASC conditioned media (ASC-CM) from tissue-mimetic culture demonstrated a > 50% increase secretion of proteins and a 2-fold increase in secreted EVs, relative to 2D culture. Interestingly, the different priming stimuli did not alter the total amount of protein or EVs secreted within the tissue-mimetic system. However, evaluation of specific soluble proteins via ELISA revealed significant differences in key epidermal regeneration factors, such as EGF, IGF-1, FGF-2, MMP-1, TIMP-1, and TGFβ-1. Additionally, the relative effect of ASC-EVs from the 2D and 3D system on idKCs epidermal regeneration functionality varied significantly, with EVs from 3D-Collagen culture providing the most significant benefit on idKC activity.

Discussion

Together, these data support the utilization of tissue-mimetic culture system to enhance the adaptability and secretory activity of MSC-like populations in order to generate tailored biologics, via priming stimuli, for specific wound healing applications.
Long non-coding RNAs in intracerebral hemorrhage
Authors: Zhang Chenyu , Zhang Ying , Wang Qi , Fang Zhenwei , Xu Xinyi , Zhao Mengnan , Xu Ting
Published: June 2023

Intracerebral hemorrhage (ICH), a subtype of stroke, can lead to long-term disability and is one of the leading causes of death. Unfortunately, the effectiveness of pharmacological therapy for ICH is still uncertain. Long non-coding RNA (lncRNA) was defined as an RNA molecule that consists of more than 200 nt without translational activity. As a vital class of diverse molecules, lncRNAs are involved in developmental and pathological processes and have been attractive for decades. LncRNAs have also become potential targets for therapies, as they were massively identified and profiled. In particular, emerging evidence has revealed the critical role of lncRNAs in ICH while attempts were made to treat ICH via regulating lncRNAs. But the latest evidence remains to be summarized. Thus, in this review, we will summarize the recent advances in lncRNA in ICH, highlighting the regulatory role of lncRNAs and their potential as therapeutic targets.
Identification of immunosuppressive signature subtypes and prognostic risk signatures in triple-negative breast cancer
Authors: Ding Ran , Wang Yuhan , Fan Jinyan , Tian Ziyue , Wang Shuang , Qin Xiujuan , Su Wei , Wang Yanbo
Published: June 2023

Purpose

Immune checkpoint blockade (ICB) therapy has transformed the treatment of triple-negative breast cancer (TNBC) in recent years. However, some TNBC patients with high programmed death-ligand 1 (PD-L1) expression levels develop immune checkpoint resistance. Hence, there is an urgent need to characterize the immunosuppressive tumor microenvironment and identify biomarkers to construct prognostic models of patient survival outcomes in order to understand biological mechanisms operating within the tumor microenvironment.

Patients and methods

RNA sequence (RNA-seq) data from 303 TNBC samples were analyzed using an unsupervised cluster analysis approach to reveal distinctive cellular gene expression patterns within the TNBC tumor microenvironment (TME). A panel of T cell exhaustion signatures, immunosuppressive cell subtypes and clinical features were correlated with the immunotherapeutic response, as assessed according to gene expression patterns. The test dataset was then used to confirm the occurrence of immune depletion status and prognostic features and to formulate clinical treatment recommendations. Concurrently, a reliable risk prediction model and clinical treatment strategy were proposed based on TME immunosuppressive signature differences between TNBC patients with good versus poor survival status and other clinical prognostic factors.

Results

Significantly enriched TNBC microenvironment T cell depletion signatures were detected in the analyzed RNA-seq data. A high proportion of certain immunosuppressive cell subtypes, 9 inhibitory checkpoints and enhanced anti-inflammatory cytokine expression profiles were noted in 21.4% of TNBC patients that led to the designation of this group of immunosuppressed patients as the immune depletion class (IDC). Although IDC group TNBC samples contained tumor-infiltrating lymphocytes present at high densities, IDC patient prognosis was poor. Notably, PD-L1 expression was relatively elevated in IDC patients that indicated their cancers were resistant to ICB treatment. Based on these findings, a set of gene expression signatures predicting IDC group PD-L1 resistance was identified then used to develop risk models for use in predicting clinical therapeutic outcomes.

Conclusion

A novel TNBC immunosuppressive tumor microenvironment subtype associated with strong PD-L1 expression and possible resistance to ICB treatment was identified. This comprehensive gene expression pattern may provide fresh insights into drug resistance mechanisms for use in optimizing immunotherapeutic approaches for TNBC patients.
The role of MRI after neochemoradiotherapy in predicting pathological tumor regression grade and clinical outcome in patients with locally advanced rectal adenocarcinoma
Authors: Niu Shaoqing , Chen Yan , Peng Fang , Wen Jie , Xiong Jianqi , Yang Zhuangzhuang , Peng Jianjun , Bao Yong , Ding Li
Published: June 2023

Objective

To evaluate the predictive value of tumor regression grade assessed by MRI (mr-TRG) after neoadjuvant chemoradiotherapy (neo-CRT) for postoperative pathological TRG (pTRG) and prognosis in patients with locally advanced rectal adenocarcinoma (LARC).

Materials and methods

This was a retrospective study from a single center experience. The patients who were diagnosed with LARC and received neo-CRT in our department between January 2016 and July 2021 were enrolled. The agreement between mrTRG and pTRG was assessed with the weighted κ test. Overall survival (OS), progress-free survival (PFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan-Meier analysis and log-rank test.

Results

From January 2016 to July 2021, 121 LARC patients received neo-CRT in our department. Among them, 54 patients had complete clinical data, including MRI of pre- and post-neo-CRT, postoperative tumor samples, and follow-up. The median follow-up time was 34.6 months (range: 4.4-70.6 months). The estimated 3-year OS, PFS, LRFS and DMFS were 78.5%, 70.7%, 89.0%, and 75.2%, respectively. The median time from the completion of neo-CRT to preoperative MRI and surgery was 7.1 weeks and 9.7 weeks, respectively. Out of 54 patients, 5 patients achieved mrTRG1 (9.3%), 37 achieved mrTRG2 (68.5%), 8 achieved mrTRG3 (14.8%), 4 achieved mrTRG4 (7.4%), and no patient achieved mrTRG5 after neo-CRT. Regarding pTRG, 12 patients achieved pTRG0 (22.2%), 10 achieved pTRG1 (18.5%), 26 achieved pTRG2 (48.1%), and 6 achieved pTRG3 (11.1%). The agreement between three-tier mrTRG (mrTRG1 vs. mrTRG2-3 vs. mrTRG4-5) and pTRG (pTRG0 vs. pTRG1-2 vs. pTRG3) was fair (weighted kappa=0.287). In a dichotomous classification, the agreement between mrTRG(mrTRG1 vs. mrTRG2-5)and pTRG(pTRG0 vs. pTRG1-3) also resulted in fair agreement (weighted kappa=0.391). The sensitivity, specificity, positive, and negative predictive values of favorable mrTRG (mrTRG 1-2) for pathological complete response (PCR) were 75.0%, 21.4%, 21.4%, and 75.0%, respectively. In univariate analysis, favorable mrTRG (mrTRG1-2) and downstaging N were significantly associated with better OS, while favorable mrTRG (mrTRG1-2), downstaging T, and downstaging N were significantly associated with superior PFS (p<0.05). In multivariate analysis, downstaging N was an independent prognostic factor for OS. Meanwhile, downstaging T and downstaging N remained independent prognostic factors for PFS.

Conclusions

Although the consistency between mrTRG and pTRG is only fair, favorable mrTRG after neo-CRT may be used as a potential prognostic factor for LARC patients.
A meta-analysis: the clinical value of PD-1 inhibitor or protein tyrosine kinase inhibitors in the treatment of advanced osteosarcoma
Authors: Shi Binhao , Chang Junli , Sun Xingyuan , Ma Xiaoping , Zhao Peng , Zhou Chujie , Wang Yongjun , Yang Yanping
Published: June 2023

Backgrounds

PD-1 inhibitors and TKIs have been used to treat advanced osteosarcoma, but there is still a lack of intuitive data for the comparison of their efficacy. We conducted a meta-analysis to evaluate their therapeutic benefits.

Methods

A systematic methodological search of five primary electronic databases was performed. Studies with a randomized design of any type about PD-1 inhibitors or TKIs for the treatment of advanced osteosarcoma were included. The primary outcomes mainly included CBR, PFS, OS and ORR, The CR, PR, SD and AEs were the secondary outcomes. The survival period (months) of patients was taken as the main analysis data. Random-effects models were used for meta-analysis.

Results

Eight immunocheckpoint inhibitors in 327 patients from 10 clinical trials were finally evaluated. For OS, TKIs [11.67 months (95% CI, 9.32-14.01)] show more obvious advantages than PD-1 inhibitors [6.37 months (95% CI, 3.96-8.78)]. For PFS, TKIs [4.79 months (95% CI, 3.33-6.24)] are longer than PD-1 inhibitors [1.46 months (95% CI, 1.23-1.69)]. Although there was no fatal event, attention should still be paid, especially during the combined application of PD-1 inhibitors with TKIs since their obvious AEs.

Conclusions

The findings of this study suggest that patients with advanced osteosarcoma, TKIs may be more beneficial than PD-1 inhibitors. TKIs combined with PD-1 inhibitors has a bright future in the treatment of advanced osteosarcoma, but we should always pay attention to the strong side effects.
The role of BHLHE40 in clinical features and prognosis value of PDAC by comprehensive analysis and in vitro validation
Authors: Liu Chao , Du Jiang , Zheng Jianwei , Zhang Ruizhe , Zhu Jialin , Xing Bofan , Dong Lin , Zhou Qianqian , Yao Xiaofeng , Gao Song , Wang Yu , Ren Yu , Zhou Xuan
Published: June 2023

Pancreatic ductal adenocarcinoma (PDAC) is the leading cause of cancer-related mortality, primarily due to the abundance of cancer-associated fibroblasts (CAFs), depleted effector T cells, and increased tumor cell stemness; hence, there is an urgent need for efficient biomarkers with prognostic and therapeutic potential. Here, we identified BHLHE40 as a promising target for PDAC through comprehensive analysis and weighted gene coexpression network analysis of RNA sequencing data and public databases, taking into account the unique characteristics of PDAC such as cancer-associated fibroblasts, infiltration of effector T cells, and tumor cell stemness. Additionally, we developed a prognostic risk model based on BHLHE40 and three other candidate genes (ITGA2, ITGA3, and ADAM9) to predict outcomes in PDAC patients. Furthermore, we found that the overexpression of BHLHE40 was significantly associated with T stage, lymph node metastasis, and American Joint Committee on Cancer (AJCC) stage in a cohort of 61 PDAC patients. Moreover, elevated expression levels of BHLHE40 were validated to promote epithelial–mesenchymal transition (EMT) and stemness-related proteins in BXPC3 cell lines. Compared to the parent cells, BXPC3 cells with BHLHE40 overexpression showed resistance to anti-tumor immunity when co-cultured with CD8+ T cells. In summary, these findings suggest that BHLHE40 is a highly effective biomarker for predicting prognosis in PDAC and holds great promise as a target for cancer therapy.
Facial nerve outcome score: a new score to predict long-term facial nerve function after vestibular schwannoma surgery
Authors: Di Perna Giuseppe , De Marco Raffaele , Baldassarre Bianca Maria , Lo Bue Enrico , Cofano Fabio , Zeppa Pietro , Ceroni Luca , Penner Federica , Melcarne Antonio , Garbossa Diego , Lanotte Michele Maria , Zenga Francesco
Published: June 2023

Introduction

Patients’ quality of life (QoL), facial nerve (FN), and cochlear nerve (CN) (if conserved) functions should be pursued as final outcomes of vestibular schwannoma (VS) surgery. In regard to FN function, different morphologic and neurophysiological factors have been related to postoperative outcomes. The aim of the current retrospective study was to investigate the impact of these factors on the short- and long-term FN function after VS resection. The combination of preoperative and intraoperative factors resulted in designing and validating a multiparametric score to predict short- and long-term FN function.

Methods

A single-center retrospective analysis was performed for patients harboring non-syndromic VS who underwent surgical resection in the period 2015–2020. A minimum follow-up period of 12 months was considered among the inclusion criteria. Morphological tumor characteristics, intraoperative neurophysiological parameters, and postoperative clinical factors, namely, House–Brackmann (HB) scale, were retrieved in the study. A statistical analysis was conducted to investigate any relationships with FN outcome and to assess the reliability of the score.

Results

Seventy-two patients with solitary primary VS were treated in the period of the study. A total of 59.8% of patients showed an HB value < 3 in the immediate postoperative period (T1), reaching to 76.4% at the last follow-up evaluation. A multiparametric score, Facial Nerve Outcome Score (FNOS), was built. The totality of patients with FNOS grade A showed an HB value < 3 at 12 months, decreasing to 70% for those with FNOS grade B, whereas 100% of patients with FNOS grade C showed an HB value ≥ 3. The ordinal logistic regression showed three times increasing probability to see an HB value ≥ 3 at 3-month follow-up for each worsening point in FNOS score [Exp(B), 2,999; p < 0.001] that was even more probable [Exp(B), 5.486; p < 0.001] at 12 months.

Conclusion

The FNOS score resulted to be a reliable score, showing high associations with FN function both at short- and long-term follow-up. Although multicenter studies would be able to increase its reproducibility, it could be used to predict the FN damage after surgery and the potential of restoring its function on the long-term period.
Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy
Authors: Zerella Jiarna R. , Homan Claire C. , Arts Peer , Brown Anna L. , Scott Hamish S. , Hahn Christopher N.
Published: June 2023

Transcription factors (TFs) play a critical role as key mediators of a multitude of developmental pathways, with highly regulated and tightly organized networks crucial for determining both the timing and pattern of tissue development. TFs can act as master regulators of both primitive and definitive hematopoiesis, tightly controlling the behavior of hematopoietic stem and progenitor cells (HSPCs). These networks control the functional regulation of HSPCs including self-renewal, proliferation, and differentiation dynamics, which are essential to normal hematopoiesis. Defining the key players and dynamics of these hematopoietic transcriptional networks is essential to understanding both normal hematopoiesis and how genetic aberrations in TFs and their networks can predispose to hematopoietic disease including bone marrow failure (BMF) and hematological malignancy (HM). Despite their multifaceted and complex involvement in hematological development, advances in genetic screening along with elegant multi-omics and model system studies are shedding light on how hematopoietic TFs interact and network to achieve normal cell fates and their role in disease etiology. This review focuses on TFs which predispose to BMF and HM, identifies potential novel candidate predisposing TF genes, and examines putative biological mechanisms leading to these phenotypes. A better understanding of the genetics and molecular biology of hematopoietic TFs, as well as identifying novel genes and genetic variants predisposing to BMF and HM, will accelerate the development of preventative strategies, improve clinical management and counseling, and help define targeted treatments for these diseases.
Hypercalcemia of malignancy caused by parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumors (PTHrP-PNETs): Case Report
Authors: Pitts Stephanie , Mahipal Amit , Bajor David , Mohamed Amr
Published: June 2023

Parathyroid hormone-related protein (PTHrP) secretion is occasionally detected in various solid tumors such as renal cell carcinoma and lung cancers. It is considered quite rare for neuroendocrine tumors with only few published case reports. We reviewed the current literature and summarized a case report of a patient with metastatic pancreatic neuroendocrine tumor (PNET) presenting with hypercalcemia due to elevation of PTHrP. The patient had histological confirmation of well-differentiated PNET and developed hypercalcemia years after his initial diagnosis. In our case report, evaluation showed intact parathyroid hormone (PTH) in the setting of concomitant elevation of PTHrP. The patient’s hypercalcemia and PTHrP levels were improved by using a long-acting somatostatin analogue. In addition, we reviewed the current literature regarding the optimal management of malignant hypercalcemia due to PTHrP-producing PNETs.
Phenotypes, bedside examination, and video head impulse test in vestibular migraine of childhood compared with probable vestibular migraine and recurrent vertigo in childhood
Authors: Teggi Roberto , Colombo Bruno , Familiari Marco , Cangiano Iacopo , Bussi Mario , Filippi Massimo
Published: June 2023

Introduction

Vestibular impairment and vertigo in the pediatric population have an estimated prevalence ranging between 0.4% and 5.6% and are a topic of interest in recent years. The Bárány Society has recently reclassified migraine-related vertigo syndromes as vestibular migraine of childhood (VMC), probable vestibular migraine of childhood (probable VMC), and recurrent vertigo of childhood (RVC).

Methods

Applying the criteria established by the Bárány Society, we retrospectively analyzed data on 95 pediatric patients suffering from episodic vertigo that were recruited from 2018 to 2022. In applying the revised criteria, 28 patients had VMC, 38 had probable VMC, and 29 had RVC.

Results

Visuo-vestibular symptoms (external vertigo) or internal vertigo were reported by 20 of 28 VMC patients (71.4%) compared to 8 of 38 probable VMC patients (21%) (P < .001). None of the RVC patients reported external vertigo. Duration of vertigo was demonstrably longer in the VMC patients than in the probable VMC (P < .001) and RVC (P < .001) patients. Cochlear symptoms were reported by 28.6% of VMC patients and by 13.1% of probable VMC patients. No cochlear symptoms were reported by any RVC patients. Familial cases for headache and episodic vertigo showed no significant difference between groups.

Discussion

The most frequent finding during bedside examination in all three groups was central positional nystagmus. Differences in the duration of attacks and in accompanying symptoms may underline different pathophysiological mechanisms.
Assistance of metagenomics next-generation sequencing for diagnosis of adenovirus pericarditis with pericardial effusion in a child: a case report and literature review
Authors: Lin Liangkang , Xu Min , Zhang Haiyang
Published: June 2023

Human adenoviruses (HAdVs) can cause infection at any age but are most common in the pediatric population, especially young children and infants, with a peak incidence in infants and children from 6 months to 5 years of age. Adenovirus infection can cause severe pneumonia, but pericarditis from adenovirus infection was rare. This article reports a case of a 2-year-old patient with pericarditis caused by adenovirus infection and a moderate pericardial effusion. We detected positive adenovirus nucleic acid in the patient’s blood by polymerase chain reaction assay. In addition, HAdVs were identified by metagenomics next-generation sequencing (mNGS) in blood and pericardial effusion. According to the test results and clinical practice, active symptomatic and supportive treatment was given, and finally the child recovered and was discharged from the hospital. Comprehensive and accurate diagnosis of pathogens is a prerequisite for effective treatment, and mNGS provides an effective means for diagnosing rare adenovirus myocarditis in children.
Maternal consumption and perinatal exposure to non-nutritive sweeteners: should we be concerned?
Authors: Concha Francisca , Sambra Verónica , Cáceres Paola , López-Arana Sandra , Carvajal Bielka , Gotteland Martín
Published: June 2023

The context for this review is the rapid increase in the use of non-nutritive sweeteners (NNSs) instead of sugar in foods and beverages, a situation so prevalent in some countries that consumers are finding it increasingly challenging to access foods without NNSs. The benefits of consuming NNSs on obesity and diabetes are now being questioned, and studies have shown that they may exert physiological activities, sometimes independently of sweet taste receptor stimulation. Few studies, limited mainly to North American and European countries, have described the consumption of NNSs by pregnant or lactating women and infants. Most focus on beverages rather than foods, but all agree that consumption levels have increased dramatically. Although some studies report a negative impact of NNSs on the risk of preterm birth, increased birth weight and decreased gestational age, the level of evidence is low. Several studies have also reported increased weight gain in infancy, associated with maternal NNS intake. Interestingly, several NNSs have been detected in amniotic fluid and breast milk, usually (but not always) at concentrations below their established detection limit in humans. Unfortunately, the impact of chronic exposure of the fetus/infant to low levels of multiple NNSs is unknown. In conclusion, there is a stark contrast between the galloping increase in the consumption of NNSs and the small number of studies evaluating their impact in at-risk groups such as pregnant and lactating women and infants. Clearly, more studies are needed, especially in Latin America and Asia, to fill these gaps and update recommendations.
Community-acquired and healthcare-associated Staphylococcus aureus infections in a pediatric hospital in southern Brazil over 8 years: how common is MRSA?
Authors: Fassbind Derrick Alexandre , Rezende Raíssa Queiroz , Dias Cícero Armídio Gomes , Motta Fabrizio
Published: June 2023

Backgrounds

Both healthcare-associated and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections are relevant in children. The objective of our study was to evaluate their impact in a pediatric hospital in southern Brazil.

Methods

Data from patients under 18 years of age with S. aureus infections between January 2013 and December 2020 were retrospectively analyzed. Data were collected regarding infection site, infection type (community-acquired or healthcare-associated), susceptibility to oxacillin [methicillin-susceptible S. aureus (MSSA) or MRSA] and other antimicrobials. We analyzed the evolution of the susceptibility rates for the isolates over this period.

Results

A total of 563 patients were included, among whom the prevalences of community- and hospital-acquired MRSA infections were 46.1% and 8.1%, respectively. No significant change occurred in these prevalences over the study period. In community-acquired infections, MSSA was significantly more associated with osteoarticular infections and MRSA was more associated with respiratory and intra-abdominal infections. In healthcare-associated infections, there was an association between MSSA and primary bloodstream infections and between MRSA, skin/soft tissue infections, and respiratory infections. Community-acquired MRSA were highly susceptible to trimethoprim-sulfamethoxazole (96.1%), clindamycin (88.4%), and doxycycline (99.0%).

Conclusion

Our study draws attention to the high rates of MRSA in community-acquired staphylococcal infections in this population, indicating a need to review initial protocols for severe staphylococcal infections according to local epidemiology.
Revisiting the neuroinflammation hypothesis in Alzheimer’s disease: a focus on the druggability of current targets
Authors: Wong-Guerra Maylin , Calfio Camila , Maccioni Ricardo B. , Rojo Leonel E.
Published: June 2023

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease and disability in the elderly; it is estimated to account for 60%–70% of all cases of dementia worldwide. The most relevant mechanistic hypothesis to explain AD symptoms is neurotoxicity induced by aggregated amyloid-β peptide (Aβ) and misfolded tau protein. These molecular entities are seemingly insufficient to explain AD as a multifactorial disease characterized by synaptic dysfunction, cognitive decline, psychotic symptoms, chronic inflammatory environment within the central nervous system (CNS), activated microglial cells, and dysfunctional gut microbiota. The discovery that AD is a neuroinflammatory disease linked to innate immunity phenomena started in the early nineties by several authors, including the ICC´s group that described, in 2004, the role IL-6 in AD-type phosphorylation of tau protein in deregulating the cdk5/p35 pathway. The “Theory of Neuroimmunomodulation”, published in 2008, proposed the onset and progression of degenerative diseases as a multi-component “damage signals” phenomena, suggesting the feasibility of “multitarget” therapies in AD. This theory explains in detail the cascade of molecular events stemming from microglial disorder through the overactivation of the Cdk5/p35 pathway. All these knowledge have led to the rational search for inflammatory druggable targets against AD. The accumulated evidence on increased levels of inflammatory markers in the cerebrospinal fluid (CSF) of AD patients, along with reports describing CNS alterations caused by senescent immune cells in neuro-degenerative diseases, set out a conceptual framework in which the neuroinflammation hypothesis is being challenged from different angles towards developing new therapies against AD. The current evidence points to controversial findings in the search for therapeutic candidates to treat neuroinflammation in AD. In this article, we discuss a neuroimmune-modulatory perspective for pharmacological exploration of molecular targets against AD, as well as potential deleterious effects of modifying neuroinflammation in the brain parenchyma. We specifically focus on the role of B and T cells, immuno-senescence, the brain lymphatic system (BLS), gut-brain axis alterations, and dysfunctional interactions between neurons, microglia and astrocytes. We also outline a rational framework for identifying “druggable” targets for multi-mechanistic small molecules with therapeutic potential against AD.
Constructing a cancer stem cell related prognostic model for predicting immune landscape and drug sensitivity in colorectal cancer
Authors: Chen Jianfang , Wu Shuang , Peng Yu , Zhao Yang , Dong Yan , Ran Fengwei , Geng Haofei , Zhang Kang , Li Jianjun , Huang Shuo , Wang Zhe
Published: June 2023

Background: Colorectal cancer (CRC) ranks the second malignancy with high incidence and mortality worldwide. Cancer stem cells (CSCs) function critically in cancer progression and metastasis via the interplay with immune cells in tumor microenvironment. This study aimed to identify important CSC marker genes and parsed the role of these marker genes in CRC.

Materials and methods: CRC samples’ single-cell RNA sequencing data and bulk transcriptome data were utilized. Seurat R package annotated CSCs and identified CSC marker genes. Consensus clustering subtyped CRC samples based on CSC marker genes. Immune microenvironment, pathway and oxidative stress analysis was performed using ESTIMATE, MCP-counter analysis and ssGSEA analysis. A prognostic model was established by Lasso and stepAIC. Sensitivity to chemotherapeutic drugs was determined by the biochemical half maximal inhibitory concentration with pRRophetic R package.

Results: We identified a total of 29 CSC marker genes related to disease-specific survival (DSS). Two clusters (CSC1 and CSC2) were determined, and CSC2 showed shorter DSS, a larger proportion of late-stage samples, and higher oxidative stress response. Two clusters exhibited differential activation of biological pathways associated with immune response and oncogenic signaling. Drug sensitivity analysis showed that 44 chemotherapy drugs were more sensitive to CSC2 that those in CSC1. We constructed a seven-gene prognostic model (DRD4, DPP7, UCN, INHBA, SFTA2, SYNPO2, and NXPH4) that was effectively to distinguish high-risk and low-risk patients. 14 chemotherapy drugs were more sensitive to high-risk group and 13 chemotherapy drugs were more sensitive to low-risk group. Combination of higher oxidative stress and risk score indicated dismal prognosis.

Conclusion: The CSC marker genes we identified may help to further decipher the role of CSCs in CRC development and progression. The seven-gene prognostic model could serve as an indicator for predicting the response to immunotherapy and chemotherapy as well as prognosis of CRC patients.