bluuebunny/crossref_metadata_2025 huggingface dataset:
Skin cancer in solid organ transplant recipients: still an open problem
Authors: Granata Simona , Tessari Gianpaolo , Stallone Giovanni , Zaza Gianluigi
Published: April 2023

In the last two decades, the optimization of organ preservation and surgical techniques, and the personalized immunosuppression have reduced the rate of acute rejections and early post-transplant complications. However, long-term graft survival rates have not improved over time, and evidence suggest a role of chronic calcineurin inhibitor toxicity in this failure. Solid organ transplant recipients may develop chronic dysfunction/damage and several comorbidities, including post-transplant malignancies. Skin cancers, mostly non-melanoma skin cancers (squamous cell carcinoma and basal cell carcinoma), are the most common malignancies in Caucasian solid organ transplant recipients. Several factors, together with immunosuppression, may contribute to the susceptibility for skin cancers which, although often treatable, could be associated with a much higher mortality rate than in the general population. The rapid identification and treatment (including reduction of immunosuppression and early surgical treatments) have an important role to avoid an aggressive behavior of these malignancies. Organ transplant recipients with a history of skin cancer should be followed closely for developing new and metastatic lesions. Additionally, patient education on the daily use of sun-protective measures and the recognition of the early signs (self-diagnosis) of coetaneous malignancies are useful preventive measures. Finally, clinicians should make themselves aware of the problem and build, in every clinical follow-up center, collaborative network involving transplant clinicians, dermatologists and surgeons who should work together to easily identify and rapidly treat these complications.

In this review, we discuss the current literature regarding the epidemiology, risk factors, diagnosis, preventive strategies and treatments of skin cancer in organ transplantation.
Microbial community and soil enzyme activities driving microbial metabolic efficiency patterns in riparian soils of the Three Gorges Reservoir
Authors: Yang Yining , Chen Yao , Li Zhe , Zhang Yuanyuan , Lu Lunhui
Published: April 2023

Riparian zones represent important transitional areas between aquatic and terrestrial ecosystems. Microbial metabolic efficiency and soil enzyme activities are important indicators of carbon cycling in the riparian zones. However, how soil properties and microbial communities regulate the microbial metabolic efficiency in these critical zones remains unclear. Thus, microbial taxa, enzyme activities, and metabolic efficiency were conducted in the riparian zones of the Three Gorges Reservoir (TGR). Microbial carbon use efficiency and microbial biomass carbon had a significant increasing trend along the TGR (from upstream to downstream); indicating higher carbon stock in the downstream, microbial metabolic quotient (qCO2) showed the opposite trend. Microbial community and co-occurrence network analysis revealed that although bacterial and fungal communities showed significant differences in composition, this phenomenon was not found in the number of major modules. Soil enzyme activities were significant predictors of microbial metabolic efficiency along the different riparian zones of the TGR and were significantly influenced by microbial α-diversity. The bacterial taxa Desulfobacterota, Nitrospirota and the fungal taxa Calcarisporiellomycota, Rozellomycota showed a significant positive correlation with qCO2. The shifts in key microbial taxa unclassified_k_Fungi in the fungi module #3 are highlighted as essential factors regulating the microbial metabolic efficiency. Structural equation modeling results also revealed that soil enzyme activities had a highly significant negative effect on microbial metabolism efficiency (bacteria, path coefficient = −0.63; fungi, path coefficient = −0.67).This work has an important impact on the prediction of carbon cycling in aquatic-terrestrial ecotones.
The SMC-like RecN protein is at the crossroads of several genotoxic stress responses in Escherichia coli
Authors: Camus Adrien , Espinosa Elena , Zapater Baras Pénélope , Singh Parul , Quenech’Du Nicole , Vickridge Elise , Modesti Mauro , Barre François Xavier , Espéli Olivier
Published: April 2023

Introduction

DNA damage repair (DDR) is an essential process for living organisms and contributes to genome maintenance and evolution. DDR involves different pathways including Homologous recombination (HR), Nucleotide Excision Repair (NER) and Base excision repair (BER) for example. The activity of each pathway is revealed with particular drug inducing lesions, but the repair of most DNA lesions depends on concomitant or subsequent action of the multiple pathways.

Methods

In the present study, we used two genotoxic antibiotics, mitomycin C (MMC) and Bleomycin (BLM), to decipher the interplays between these different pathways in E. coli. We combined genomic methods (TIS and Hi-SC2) and imaging assays with genetic dissections.

Results

We demonstrate that only a small set of DDR proteins are common to the repair of the lesions induced by these two drugs. Among them, RecN, an SMC-like protein, plays an important role by controlling sister chromatids dynamics and genome morphology at different steps of the repair processes. We further demonstrate that RecN influence on sister chromatids dynamics is not equivalent during the processing of the lesions induced by the two drugs. We observed that RecN activity and stability requires a pre-processing of the MMC-induced lesions by the NER but not for BLM-induced lesions.

Discussion

Those results show that RecN plays a major role in rescuing toxic intermediates generated by the BER pathway in addition to its well-known importance to the repair of double strand breaks by HR.
Analysis of genetic structure and function of clustered regularly interspaced short palindromic repeats loci in 110 Enterococcus strains
Authors: Tao Shuan , Zhou Dongdong , Chen Huimin , Li Na , Zheng Lin , Fang Yewei , Xu Yao , Jiang Qi , Liang Wei
Published: April 2023

Clustered regularly interspaced short palindromic repeats (CRISPR) and their CRISPR-associated proteins (Cas) are an adaptive immune system involved in specific defenses against the invasion of foreign mobile genetic elements, such as plasmids and phages. This study aims to analyze the gene structure and to explore the function of the CRISPR system in the Enterococcus genome, especially with regard to drug resistance. The whole genome information of 110 enterococci was downloaded from the NCBI database to analyze the distribution and the structure of the CRISPR-Cas system including the Cas gene, repeat sequences, and spacer sequence of the CRISPR-Cas system by bioinformatics methods, and to find drug resistance-related genes and analyze the relationship between them and the CRISPR-Cas system. Multilocus sequence typing (MLST) of enterococci was performed against the reference MLST database. Information on the drug resistance of Enterococcus was retrieved from the CARD database, and its relationship to the presence or absence of CRISPR was statistically analyzed. Among the 110 Enterococcus strains, 39 strains (35.45%) contained a complete CRISPR-Cas system, 87 CRISPR arrays were identified, and 62 strains contained Cas gene clusters. The CRISPR system in the Enterococcus genome was mainly type II-A (59.68%), followed by type II-C (33.87%). The phylogenetic analysis of the cas1 gene sequence was basically consistent with the typing of the CRISPR-Cas system. Of the 74 strains included in the study for MLST typing, only 19 (25.68%) were related to CRISPR-Cas typing, while the majority of the strains (74.32%) of MLST typing were associated with the untyped CRISPR system. Additionally, the CRISPR-Cas system may only be related to the carrying rate of some drug-resistant genes and the drug-resistant phenotype. In conclusion, the distribution of the enterococcus CRISPR-Cas system varies greatly among different species and the presence of CRISPR loci reduces the horizontal transfer of some drug resistance genes.
Plasticity in parental behavior and vasopressin: responses to co-parenting, pup age, and an acute stressor are experience-dependent
Authors: Hiura Lisa C. , Lazaro Vanessa A. , Ophir Alexander G.
Published: April 2023

Introduction

The impact of variation in parental caregiving has lasting implications for the development of offspring. However, the ways in which parents impact each other in the context of caregiving is comparatively less understood, but can account for much of the variation observed in the postnatal environment. Prairie voles (Microtus ochrogaster) demonstrate a range of postnatal social groups, including pups raised by biparental pairs and by their mothers alone. In addition to the challenges of providing parental care, prairie vole parents often experience acute natural stressors (e.g., predation, foraging demands, and thermoregulation) that could alter the way co-parents interact.

Methods

We investigated how variation in the experience of raising offspring impacts parental behavior and neurobiology by administering an acute handling stressor on prairie vole families of single mothers and biparental parents over the course of offspring postnatal development.

Results

Mothers and fathers exhibited robust behavioral plasticity in response to the age of their pups, but in sex-dependent ways. Pup-directed care from mothers did not vary as a function of their partner’s presence, but did covary with the number of hypothalamic vasopressin neurons in experience-dependent ways. The relationship between vasopressin neuron numbers and fathers’ behaviors was also contingent upon the stress handling manipulation, suggesting that brain-behavior associations exhibit stress-induced plasticity.

Conclusion

These results demonstrate that the behavioral and neuroendocrine profiles of adults are sensitive to distinct and interacting experiences as a parent, and extend our knowledge of the neural mechanisms that may facilitate parental behavioral plasticity.
Beyond the γ-aminobutyric acid hypothesis of schizophrenia
Authors: Fujihara Kazuyuki
Published: April 2023

Abnormalities in the γ-aminobutyric acid (GABA) system have been reported in the postmortem brains of individuals with schizophrenia. In particular, the reduction of one of the GABA-synthesizing enzymes, the 67-kDa isoform of glutamate decarboxylase (GAD67), has garnered interest among researchers because of its role in the formation of γ-oscillations and its potential involvement in the cognitive dysfunction observed in schizophrenia. Although several animal models have been generated to simulate the alterations observed in postmortem brain studies, they exhibit inconsistent behavioral phenotypes, leading to conflicting views regarding their contributions to the pathogenesis and manifestation of schizophrenia symptoms. For instance, GAD67 knockout rats (also known as Gad1 knockout rats) exhibit marked impairments in spatial working memory, but other model animals do not. In this review, we summarize the phenotypic attributes of these animal models and contemplate the potential for secondary modifications that may arise from the disruption of the GABAergic nervous system.
Artificial intelligence for diffusion MRI-based tissue microstructure estimation in the human brain: an overview
Authors: Faiyaz Abrar , Doyley Marvin M. , Schifitto Giovanni , Uddin Md Nasir
Published: April 2023

Artificial intelligence (AI) has made significant advances in the field of diffusion magnetic resonance imaging (dMRI) and other neuroimaging modalities. These techniques have been applied to various areas such as image reconstruction, denoising, detecting and removing artifacts, segmentation, tissue microstructure modeling, brain connectivity analysis, and diagnosis support. State-of-the-art AI algorithms have the potential to leverage optimization techniques in dMRI to advance sensitivity and inference through biophysical models. While the use of AI in brain microstructures has the potential to revolutionize the way we study the brain and understand brain disorders, we need to be aware of the pitfalls and emerging best practices that can further advance this field. Additionally, since dMRI scans rely on sampling of the q-space geometry, it leaves room for creativity in data engineering in such a way that it maximizes the prior inference. Utilization of the inherent geometry has been shown to improve general inference quality and might be more reliable in identifying pathological differences. We acknowledge and classify AI-based approaches for dMRI using these unifying characteristics. This article also highlighted and reviewed general practices and pitfalls involving tissue microstructure estimation through data-driven techniques and provided directions for building on them.
Hematoma-induced Twiddler-like phenomenon as a presentation of DBS hardware failure: Case report
Authors: Holland Marshall T. , Alvarado-Gonzalez Abraham , Wong Joshua K. , Almeida Leonardo Brito de , Wagle Shukla Aparna , Deeb Wissam , Patterson Addie , Okun Michael S. , Foote Kelly D.
Published: April 2023

Deep brain stimulators (DBS) may fail for a multitude of reasons. We present a 79-year-old Parkinson's disease patient who suffered a DBS failure following impulse generator (IPG) replacement surgery due to the IPG flipping within an expanded capsular pocket. This creation of the pocket was unintentional, and the pocket formed around an undiagnosed postoperative hemorrhage. The syndrome could be considered “Twiddler-like” because it resulted in device flipping. There were, however, many characteristic differences between our case and classical Twiddler's syndrome. DBS neurostimulator failure due to hematoma induced device flipping should be suspected when device interrogation is impossible or there are abnormally high impedances across multiple DBS lead contacts. A plain film X-ray series should be ordered and can be useful in providing radiological evidence of device flipping. In cases like ours the extensive braiding encountered in Twiddler's syndrome may be absent. Anchoring the IPG to a deep fascial layer as well as the use of an antimicrobial pouch are two methods that may be employed to prevent or to treat this complication.
Conditional deletion of KCC2 impairs synaptic plasticity and both spatial and nonspatial memory
Authors: Kreis Anna , Issa Farah , Yerna Xavier , Jabbour Caren , Schakman Olivier , de Clippele Marie , Tajeddine Nicolas , Pierrot Nathalie , Octave Jean-Noël , Gualdani Roberta , Gailly Philippe
Published: April 2023

The postsynaptic inhibition through GABAA receptors (GABAAR) relies on two mechanisms, a shunting effect due to an increase in the postsynaptic membrane conductance and, in mature neurons, a hyperpolarization effect due to an entry of chloride into postsynaptic neurons. The second effect requires the action of the K+–Cl− cotransporter KCC2 which extrudes Cl− from the cell and maintains its cytosolic concentration very low. Neuronal chloride equilibrium seems to be dysregulated in several neurological and psychiatric conditions such as epilepsy, anxiety, schizophrenia, Down syndrome, or Alzheimer’s disease. In the present study, we used the KCC2 Cre-lox knockdown system to investigate the role of KCC2 in synaptic plasticity and memory formation in adult mice. Tamoxifen-induced conditional deletion of KCC2 in glutamatergic neurons of the forebrain was performed at 3  months of age and resulted in spatial and nonspatial learning impairment. On brain slices, the stimulation of Schaffer collaterals by a theta burst induced long-term potentiation (LTP). The lack of KCC2 did not affect potentiation of field excitatory postsynaptic potentials (fEPSP) measured in the stratum radiatum (dendrites) but increased population spike (PS) amplitudes measured in the CA1 somatic layer, suggesting a reinforcement of the EPSP-PS potentiation, i.e., an increased ability of EPSPs to generate action potentials. At the cellular level, KCC2 deletion induced a positive shift in the reversal potential of GABAAR-driven Cl− currents (EGABA), suggesting an intracellular accumulation of chloride subsequent to the downregulation of KCC2. After treatment with bumetanide, an antagonist of the Na+-K+-Cl− cotransporter NKCC1, spatial memory impairment, chloride accumulation, and EPSP-PS potentiation were rescued in mice lacking KCC2. The presented results emphasize the importance of chloride equilibrium and GABA-inhibiting ability in synaptic plasticity and memory formation.
Small-angle neutron scattering study of neutron-irradiated and post-irradiation annealed VVER-1000 reactor pressure vessel weld material
Authors: Ulbricht A. , Dykas J. , Chekhonin P. , Altstadt E. , Bergner F.
Published: April 2023

Post-irradiation annealing of neutron-irradiated reactor pressure vessel steels is a matter of both technical and scientific interest. Small-angle neutron scattering (SANS), while being sensitive to nm-sized irradiation-induced solute-atom clusters, provides macroscopically representative and statistically reliable measures of cluster volume fraction, number density and size. In the present study, SANS was applied to uncover the size distribution of clusters in as-irradiated samples of a VVER-1000 weld and their gradual dissolution as function of the post-irradiation annealing temperature. The same samples were used to measure Vickers hardness. The results are consistent with Mn-Ni-Si-rich clusters of less than 2 nm radius to be the dominant source of both scattering and hardening. Annealing gave rise to small but significant partial recovery at 350°C and almost complete recovery at 475°C. The dispersed-barrier hardening model was applied to bridge the gap between the characteristics of nano-features and macro-hardness.
CONUT score is associated with short-term prognosis in patients with severe acute pancreatitis: a propensity score matching cohort study
Authors: Shi Lvyuan , Li Ping , Wang Lietao , Wan Dingyuan , Wang Daojin , Yan Xin , He Min , Zhang Zhongwei
Published: April 2023

Background

The Controlling Nutritional Status (CONUT) score was designed to assess the immune-nutritional status in patients. This study aimed to investigate the role of the CONUT score in the short-term prognosis of severe acute pancreatitis.

Methods

This was a retrospective cohort study. 488 patients with severe acute pancreatitis at the Department of Critical Care Medicine of the West China Hospital of Sichuan University (Chengdu, China) were enrolled in the study. Baseline data were collected from the West China Hospital of Sichuan University database. The primary outcome during follow-up was all-cause mortality. The secondary outcomes were 28 day mortality, renal insufficiency, length of stay (LOS) in the ICU, and length of stay (LOS) in the hospital. Patients were divided into two groups based on a median CONUT score of 7, and baseline differences between the two groups were eliminated by propensity matching. Univariate Cox regression analyses were performed to estimate the association between CONUT score and outcomes. The Kaplan–Meier method was used to estimate the survival rate of patients.

Results

CONUT score was an independent predictor of all-cause mortality (hazard ratio [HR]:2.093; 95%CI: 1.342–3.263; p < 0.001) and 28 day mortality (hazard ratio [HR]:1.813; 95%CI: 1.135–2.896; p < 0.013). CONUT score was not statistically significant in predicting the incidence of renal insufficiency. The high CONUT group had significantly higher all-cause mortality (p < 0.001), and 28 day mortality (p < 0.011) than the low CONUT group.

Conclusion

The CONUT score is an independent predictor of short-term prognosis in patients with severe acute pancreatitis, and timely nutritional support is required to reduce mortality in patients with severe acute pancreatitis.
Comparison of ultrasound−based ADNEX model with magnetic resonance imaging for discriminating adnexal masses: a multi-center study
Authors: Hu Yanli , Chen Bo , Dong Hongmei , Sheng Bo , Xiao Zhibo , Li Jia , Tian Wei , Lv Furong
Published: April 2023

Objectives

The ADNEX model offered a good diagnostic performance for discriminating adnexal tumors, but research comparing the abilities of the ADNEX model and MRI for characterizing adnexal tumors has not been reported to our knowledge. The aim of this study was to evaluate the diagnostic accuracy of the ultrasound-based ADNEX (Assessment of Different NEoplasias in the adneXa) model in comparison with that of magnetic resonance imaging (MRI) for differentiating benign, borderline and malignant adnexal masses.

Methods

This prospective study included 529 women with adnexal masses who underwent assessment via the ADNEX model and subjective MRI analysis before surgical treatment between October 2019 and April 2022 at two hospitals. Postoperative histological diagnosis was considered the gold standard.

Results

Among the 529 women, 92 (17.4%) masses were diagnosed histologically as malignant tumors, 67 (12.7%) as borderline tumors, and 370 (69.9%) as benign tumors. For the diagnosis of malignancy, including borderline tumors, overall agreement between the ADNEX model and MRI pre-operation was 84.9%. The sensitivity of the ADNEX model of 0.91 (95% confidence interval [CI]: 0.85–0.95) was similar to that of MRI (0.89, 95% CI: 0.84–0.94; P=0.717). However, the ADNEX model had a higher specificity (0.90, 95% CI: 0.87–0.93) than MRI (0.81, 95% CI: 0.77–0.85; P=0.001). The greatest sensitivity (0.96, 95% CI: 0.92–0.99) and specificity (0.94, 95% CI: 0.91–0.96) were achieved by combining the ADNEX model and subjective MRI assessment. While the total diagnostic accuracy did not differ significantly between the two methods (P=0.059), the ADNEX model showed greater diagnostic accuracy for borderline tumors (P<0.001).

Conclusion

The ultrasound-based ADNEX model demonstrated excellent diagnostic performance for adnexal tumors, especially borderline tumors, compared with MRI. Accordingly, we recommend that the ADNEX model, alone or with subjective MRI assessment, should be used for pre-operative assessment of adnexal masses.
Cancer-associated fibroblasts in gynecological malignancies: are they really allies of the enemy?
Authors: Villegas-Pineda Julio César , Ramírez-de-Arellano Adrián , Bueno-Urquiza Lesly Jazmín , Lizarazo-Taborda Mélida del Rosario , Pereira-Suárez Ana Laura
Published: April 2023

Molecular and cellular components of the tumor microenvironment are essential for cancer progression. The cellular element comprises cancer cells and heterogeneous populations of non-cancer cells that satisfy tumor needs. Immune, vascular, and mesenchymal cells provide the necessary factors to feed the tumor mass, promote its development, and favor the spread of cancer cells from the primary site to adjacent and distant anatomical sites. Cancer-associated fibroblasts (CAFs) are mesenchymal cells that promote carcinogenesis and progression of various malignant neoplasms. CAFs act through the secretion of metalloproteinases, growth factors, cytokines, mitochondrial DNA, and non-coding RNAs, among other molecules. Over the last few years, the evidence on the leading role of CAFs in gynecological cancers has notably increased, placing them as the cornerstone of neoplastic processes. In this review, the recently reported findings regarding the promoting role that CAFs play in gynecological cancers, their potential use as therapeutic targets, and the new evidence suggesting that they could act as tumor suppressors are analyzed and discussed.
ERBB family fusions are recurrent and actionable oncogenic targets across cancer types
Authors: Schubert Laura , Elliott Andrew , Le Anh T. , Estrada-Bernal Adriana , Doebele Robert C. , Lou Emil , Borghaei Hossein , Demeure Michael J. , Kurzrock Razelle , Reuss Joshua E. , Ou Sai-Hong Ignatius , Braxton David R. , Thomas Christian A. , Darabi Sourat , Korn Wolfgang Michael , El-Deiry Wafik S. , Liu Stephen V.
Published: April 2023

Purpose

Gene fusions involving receptor tyrosine kinases (RTKs) define an important class of genomic alterations with many successful targeted therapies now approved for ALK, ROS1, RET and NTRK gene fusions. Fusions involving the ERBB family of RTKs have been sporadically reported, but their frequency has not yet been comprehensively analyzed and functional characterization is lacking on many types of ERBB fusions.

Materials and methods

We analyzed tumor samples submitted to Caris Life Sciences (n=64,354), as well as the TCGA (n=10,967), MSK IMPACT (n=10,945) and AACR GENIE (n=96,324) databases for evidence of EGFR, ERBB2 and ERBB4 gene fusions. We also expressed several novel fusions in cancer cell lines and analyzed their response to EGFR and HER2 tyrosine kinase inhibitors (TKIs).

Results

In total, we identified 1,251 ERBB family fusions, representing an incidence of approximately 0.7% across all cancer types. EGFR, ERBB2, and ERBB4 fusions were most frequently found in glioblastoma, breast cancer and ovarian cancer, respectively. We modeled two novel types of EGFR and ERBB2 fusions, one with a tethered kinase domain and the other with a tethered adapter protein. Specifically, we expressed EGFR-ERBB4, EGFR-SHC1, ERBB2-GRB7 and ERBB2-SHC1, in cancer cell lines and demonstrated that they are oncogenic, regulate downstream signaling and are sensitive to small molecule inhibition with EGFR and HER2 TKIs.

Conclusions

We found that ERBB fusions are recurrent mutations that occur across multiple cancer types. We also establish that adapter-tethered and kinase-tethered fusions are oncogenic and can be inhibited with EGFR or HER2 inhibitors. We further propose a nomenclature system to categorize these fusions into several functional classes.
m6A modification on the fate of colorectal cancer: functions and mechanisms of cell proliferation and tumorigenesis
Authors: Jiang Xiaohan , Jin Ziyao , Yang Yuzhong , Zheng Xiang , Chen Shaohua , Wang Shuaijie , Zhang Xuemei , Qu Nanfang
Published: April 2023

N6-methyladenosine (m6A) is the most pervasive RNA modification in eukaryotic cells. The dynamic and reversible m6A modification of RNA plays a critical role in the occurrence and progression of tumors by regulating RNA metabolism, including translocation, mRNA stability or decay, pre-mRNA splicing, and lncRNA processing. Numerous studies have shown that m6A modification is involved in the development of various cancers. This review aims to summarize the significant role of m6A modification in the proliferation and tumorigenesis of CRC, as well as the potential of modulating m6A modification for tumor treatment. These findings may offer new therapeutic strategies for clinical implementation of m6A modification in CRC in the near future.
Immunogenic sonodynamic therapy for inducing immunogenic cell death and activating antitumor immunity
Authors: Wang Ting , Peng Wangrui , Du Meng , Chen Zhiyi
Published: April 2023

Immunotherapy is widely regarded as a promising treatment for cancer. However, the immune effector phase suppression of tumor microenvironment (TME) and the generation of immune-related adverse events limit its application. Research indicates that sonodynamic therapy (SDT) can effectively activate antitumor immunity while killing tumor cells. SDT produces cytotoxic substances of tumors, and then cell apoptosis and immunogenic death occur by selectively activating the sonosensitizer under ultrasound. In recent years, various SDT alone as well as SDT in combination with other therapies have been developed to induce immunogenic cell death (ICD) and enhance immunotherapy. This paper overviews the research progress of SDT and nanotechnology in recent years, including the strategies involving SDT alone, SDT-based synergistic induction of antitumor immunity, and immunotherapy based on SDT for multimodal immunotherapy. Finally, the prospects and challenges of these SDT-based therapies in cancer immunotherapy are discussed.
Terminal fucosylation of haptoglobin in cancer-derived exosomes during cholangiocarcinoma progression
Authors: Choi Hyewon , Ju Sungeun , Kang Keunsoo , Seo Moon-Hyeong , Kim Jin-Man , Miyoshi Eiji , Yeo Min-Kyung , Park Seung-Yeol
Published: April 2023

Background

Cholangiocarcinoma (CCA) is a silent tumor with a high mortality rate due to the difficulty of early diagnosis and prediction of recurrence even after timely surgery. Serologic cancer biomarkers have been used in clinical practice, but their low specificity and sensitivity have been problematic. In this study, we aimed to identify CCA-specific glycan epitopes that can be used for diagnosis and to elucidate the mechanisms by which glycosylation is altered with tumor progression.

Methods

The serum of patients with various cancers was fractioned into membrane-bound and soluble components using serial ultracentrifugation. Lectin blotting was conducted to evaluate glycosylation. Proteins having altered glycosylation were identified using proteomic analysis and further confirmed using immunoblotting analysis. We performed HPLC, gene analysis, real-time cargo tracking, and immunohistochemistry to determine the origin of CCA glycosylation and its underlying mechanisms. Extracellular vesicles (EV) were isolated from the sera of 62 patients with CCA at different clinical stages and inflammatory conditions and used for glycan analysis to assess their clinical significance.

Results

The results reveal that glycosylation patterns between soluble and membrane-bound fractions differ significantly even when obtained from the same donor. Notably, glycans with α1-3/4 fucose and β1-6GlcNAc branched structures increase specifically in membrane-bound fractions of CCA. Mechanically, it is primarily due to β-haptoglobin (β-Hp) originating from CCA expressing fucosyltransferase-3/4 (FUT 3/4) and N-acetylglucosaminyltransferase-V (MGAT5). Newly synthesized β-Hp is loaded into EVs in early endosomes via a KFERQ-like motif and then secreted from CCA cells to induce tumor progression. In contrast, β-Hp expressed by hepatocytes is secreted in a soluble form that does not affect CCA progression. Moreover, evaluation of EV glycosylation in CCA patients shows that fucosylation level of EV-Hp gradually increases with tumor progression and decreases markedly when the tumors are eliminated by surgery.

Conclusion

This study suggests that terminal fucosylation of Hp in cancer-derived exosomes can be a novel glycan marker for diagnosis and prognosis of CCA. These findings highlight the potential of glycan analysis in different fractions of serum for biomarker discover for other diseases. Further research is needed to understand the role of fucosylated EVs on CCA progression.
Youth baseline and state pain-related injustice appraisals are associated with emotional responses of anger and sadness: An experimental study
Authors: Daenen Frederick , Wauters Aline , Van Ryckeghem Dimitri M.L. , Trost Zina , Vervoort Tine
Published: April 2023

Background

Youth pain-related injustice appraisals are associated with adverse functioning; however, mechanisms by which injustice appraisals exert their impact have yet to be elucidated. Adult injustice literature suggests anger, sadness, and attention bias to anger (AB) as potential mechanisms. This study examined the effects of injustice appraisals in a healthy youth sample by applying a justice violation manipulation. We hypothesized the justice violation condition to lead to worse pain outcomes with effects mediated by anger, sadness, and AB as compared to the control condition. We further explored associations between both baseline and state injustice appraisals and anger, sadness, and AB across conditions.

Methods

A 2 × 2 time by condition design was used to test hypotheses. 133 healthy youth aged 9–16 years old completed two cold pressor tasks (CPTs). In the experimental (i.e., justice violation) group, participants were initially told to complete one CPT, but were told afterwards to perform it again due to experimenter negligence. In the control group, no justice violation occurred. Baseline injustice appraisals and pain catastrophizing were assessed with the Injustice Experience Questionnaire and Pain Catastrophizing Scale for Children; state outcomes (i.e., injustice, catastrophizing, anger, sadness) were assessed after CPTs. AB was indexed using a dot-probe task.

Results

Findings indicated no effects of the justice violation on pain outcomes or associated mechanisms, nor on injustice appraisals, suggesting manipulation failure. However, across conditions, baseline and state injustice appraisals were positively associated with anger and sadness, but not with AB.

Conclusions

Despite the experimental justice violation failing to elicit differential injustice appraisals across conditions, the current study supports both anger and sadness as key emotional responses associated with pain-related injustice appraisals in a healthy youth sample.
A novel compound heterozygous mutation of the CLCN7 gene is associated with autosomal recessive osteopetrosis
Authors: Wang Xia , Wang Yingcan , Xu Ting , Fan Yanjie , Ding Yifeng , Qian Jihong
Published: April 2023

Osteopetrosis is a genetic condition of the skeleton characterized by increased bone density caused by osteoclast formation and function defects. Osteopetrosis is inherited in the form of autosomal dominant and autosomal recessive manner. We report autosomal recessive osteopetrosis (ARO; OMIM 611490) in a Chinese case with a history of scarce leukocytosis, vision and hearing loss, frequent seizures, and severe intellectual and motor disability. Whole-exome sequencing (WES) followed by Sanger sequencing revealed novel compound heterozygous mutations in the chloride channel 7 (CLCN7) gene [c.982-1G > C and c.1208G > A (p. Arg403Gln)] in the affected individual, and subsequent familial segregation showed that each parent had transmitted a mutation. Our results confirmed that mutations in the CLCN7 gene caused ARO in a Chinese family. Additionally, our study expanded the clinical and allelic spectrum of the CLCN7 gene and enhanced the applications of WES technology in determining the etiology of prenatal diagnoses in fetuses with ultrasound anomalies.
Value assessment of PD-1/PD-L1 inhibitors in the treatment of oesophageal and gastrointestinal cancers
Authors: Ou Shun-Long , Luo Jing , Wei Hua , Qin Xiao-Li , Jiang Qian
Published: April 2023

Background: Evidence of efficacy and safety of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) checkpoint inhibitors in oesophageal cancer (EC), gastric cancer (GC) and colorectal cancer (CRC) was inconsistent, obscuring their clinical application and decision-making. The aim of this study was to comprehensively evaluate the value of PD-1/PD-L1 inhibitors in EC, GC and CRC to select valuable PD-1/PD-L1 inhibitors, and to assess the association between the value and cost of PD-1/PD-L1 inhibitors.

Methods: A comprehensive search of trials of PD-1/PD-L1 inhibitors in EC, GC and CRC was performed in Chinese and English medical databases with a cut-off date of 1 July 2022. Two authors independently applied the ASCO-VF and ESMO-MCBS to assess the value of PD-1/PD-L1 inhibitors. A receiver operating characteristic (ROC) curve was generated to establish the predictive value of the ASCO-VF score to meet the threshold of the ESMO-MCBS grade. Spearman’s correlation was used to calculate the relationship between the cost and value of drugs.

Results: Twenty-three randomized controlled trials were identified: ten (43.48%) in EC, five (21.74%) in CRC, and eight (34.78%) in GC or gastroesophageal junction cancer (GEJC). For advanced diseases, ASCO-VF scores ranged from −12.5 to 69, with a mean score of 26.5 (95% CI 18.4–34.6). Six (42.9%) therapeutic regimens met the ESMO-MCBS benefit threshold grade. The area under the ROC curve was 1.0 (p = 0.002). ASCO-VF scores and incremental monthly cost were negatively correlated (Spearman’s ρ = −0.465, p = 0.034). ESMO-MCBS grades and incremental monthly cost were negatively correlated (Spearman’s ρ = −0.211, p = 0.489).

Conclusion: PD-1/PD-L1 inhibitors did not meet valuable threshold in GC/GEJC. Pembrolizumab met valuable threshold in advanced microsatellite instability–high CRC. The value of camrelizumab and toripalimab may be more worth paying in EC.
Chemotherapeutic and targeted drugs-induced immunogenic cell death in cancer models and antitumor therapy: An update review
Authors: Zhai Jiaqi , Gu Xi , Liu Yang , Hu Yueting , Jiang Yi , Zhang Zhenyong
Published: April 2023

As traditional strategies for cancer treatment, some chemotherapy agents, such as doxorubicin, oxaliplatin, cyclophosphamide, bortezomib, and paclitaxel exert their anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells. ICD induces anti-tumor immunity through release of, or exposure to, damage-related molecular patterns (DAMPs), including high mobility group box 1 (HMGB1), calreticulin, adenosine triphosphate, and heat shock proteins. This leads to activation of tumor-specific immune responses, which can act in combination with the direct killing functions of chemotherapy drugs on cancer cells to further improve their curative effects. In this review, we highlight the molecular mechanisms underlying ICD, including those of several chemotherapeutic drugs in inducing DAMPs exposed during ICD to activate the immune system, as well as discussing the prospects for application and potential role of ICD in cancer immunotherapy, with the aim of providing valuable inspiration for future development of chemoimmunotherapy.
The safety concerns regarding immune checkpoint inhibitors in liver cancer patients rising mainly from CHB
Authors: Lou Shike , Cao Zhujun , Chi Wanqing , Wang Xiaoyin , Feng Mingyang , Lin Lanyi , Ding Yezhou , Liu Kehui , Qu Lihong , Zhao Gangde , Bao Shisan , Wang Hui
Published: April 2023

Aim: To analyze the safety of immune checkpoint inhibitors in primary liver cancer patients and to identify the risk factors for immune-related adverse events (irAEs).

Methods: The study enrolled 106 patients with primary liver cancer, including 81 with hepatocellular carcinoma and 25 with intrahepatic cholangiocarcinoma. We analyzed the differences between groups in irAE occurrence, including those with and without targeted drugs and those who received interventional therapy.

Results: The incidence of irAEs was 39%, with thyroid function, liver function, and skin events being the most common. There was no correlation among irAE incidence and the liver cancer type, stage, or severity; grade of Child–Pugh score; and Barcelona Clinical Liver Cancer classification. However, being overweight was a significant risk factor for irAEs, correlating with high body mass index. The combination of targeted drugs and/or transcatheter arterial chemoembolization therapy did not increase the incidence of irAEs.

Conclusion: Being overweight is a potential risk factor for irAEs in primary liver cancer patients. However, there is no correlation between irAE incidence and the liver cancer type, stage, or severity or a combination of targeted drugs or transarterial chemoembolization therapy.
Protective effects of ginsenosides Rg1 and Rb1 against cognitive impairment induced by simulated microgravity in rats
Authors: Jiang Ning , Lv Jingwei , Zhang Yiwen , Sun Xinran , Yao Caihong , Wang Qiong , He Qinghu , Liu Xinmin
Published: April 2023

Microgravity experienced during space flight is known to exert several negative effects on the learning ability and memory of astronauts. Few effective strategies are currently available to counteract these effects. Rg1 and Rb1, the major steroidal components of ginseng, have shown potent neuroprotective effects with a high safety profile. The present study aimed to investigate the effects of Rg1 and Rb1 on simulated microgravity-induced learning and memory dysfunction and its underlying mechanism in the hindlimb suspension (HLS) rat model. Administration of Rg1 (30 and 60 μmol/kg) and Rb1 (30 and 60 μmol/kg) for 2 weeks resulted in a significant amelioration of impaired spatial and associative learning and memory caused by 4-week HLS exposure, measured using the Morris water maze and Reward operating conditioning reflex (ROCR) tests, respectively. Furthermore, Rg1 and Rb1 administration alleviated reactive oxygen species production and enhanced antioxidant enzyme activities in the prefrontal cortex (PFC). Rg1 and Rb1 also assisted in the recovery of mitochondrial complex I (NADH dehydrogenase) activities, increased the expression of Mfn2 and decreased the fission marker dynamin-related protein (Drp)-1expression. Additionally, Rg1 and Rb1 treatment increased the SYN, and PSD95 protein expressions and decreased the ratio of Bax:Bcl-2 and reduced the expression of cleaved caspase-3 and cytochrome C. Besides these, the BDNF-TrkB/PI3K-Akt pathway was also activated by Rg1 and Rb1 treatment. Altogether, Rg1 and Rb1 treatment attenuated cognitive deficits induced by HLS, mitigated mitochondrial dysfunction, attenuated oxidative stress, inhibited apoptosis, increased synaptic plasticity, and restored BDNF-TrkB/PI3K-Akt signaling.
Water refilling along vessels at initial stage of willow cuttage revealed by move contrast CT
Authors: Xu Mingwei , Li Ke , Xue Yanling , Wang Feixiang , Liu Zhixuan , Song Zenghao , Xiao Tiqiao
Published: April 2023

Cuttage is a widely used technique for plant propagation, whose success relies on the refilling for water transport recovery. However, requirements for refilling characterization studies, including large penetration depth, fast temporal resolution and high spatial resolution, cannot be reached simultaneously via conventional imaging techniques. So far, the dynamic process of water refilling along the vessels at the initial stage of cuttage, as well as its characteristics, remains unclear. Hereby, we developed a move contrast X-ray microtomography method which achieves 3D dynamic non-destructive imaging of water refilling at the initial stage of willow branch cuttage, without the aid of any contrast agent. Experimental results indicate three primary refilling modalities in vessels: 1) the osmosis type, mainly manifested by the osmosis of tissue through the vessel wall into the cavity; 2) the linear type, revealed as the tissue permeates to a certain extent where the liquid column in the vessels is completely formed; and 3) an osmosis-linear mixed type refilling as an intermediate state. Further analysis also exhibits a “temporal-spatial relay” mode of refilling between adjacent vessels. Since the vessel length is quite limited, the cavitation and the relay refilling mode of vessels can be an important way to achieve long-distance water transport.
Effect of the combination of 25-hydroxyvitamin D3 and higher level of calcium and phosphorus in the diets on bone 3D structural development in pullets
Authors: White Dima , Chen Chongxiao , Kim Woo Kyun
Published: April 2023

Bone issues such as osteoporosis are major concerns for the laying hen industry. A study was conducted to improve bone-health in pullets. A total of 448 one-day-old Hyline W36 pullets were randomly assigned to four treatments (8 rep; 14 birds/rep) until 17 weeks (wks). Dietary treatments were: 1) vitamin D3 at (2,760 IU/kg) (D), 2) vitamin D3 (2,760 IU/kg)+62.5 mg 25-(OH)D3/ton (H25D), 3) vitamin D3 (2,760 IU/kg) + 62.5 mg 25-(OH)D3/ton + high Ca&P (H25D + Ca/P), and 4) vitamin D3 (2,760 IU/kg) + high Ca&P (D + Ca/P). The high calcium (Ca) and phosphorus (P) diet was modified by increasing both high calcium and phosphorus by 30% (2:1) for the first 12 wks and then only increasing P for 12–17 wks to reduce the Ca to P ratio. At 17 wk, growth performance was measured, whole body composition was measured by dual energy x-ray absorptiometry (DEXA), and femur bones were scanned using Micro-computed tomography (Micro-CT) for bone 3D structure analyses. The data were subjected to a one-way ANOVA using the GLM procedure, with means deemed significant at p < 0.05. There was no significant outcome for growth performance or dual energy x-ray absorptiometry parameters. Micro-computed tomography results indicated that the H25D + Ca/P treatment had lower open pore volume space, open porosity, total volume of pore space, and total porosity in the cortical bone compared to the D + Ca/P. It also showed that a higher cortical bone volume/tissue volume (BV/TV) in the H25D + Ca/P than in the D + Ca/P. Furthermore, the H25D + Ca/P treatment had the lowest trabecular pattern factor and structure model index compared to the other treatments, which indicates its beneficial effects on trabecular structural development. Moreover, the H25D + Ca/P had a higher trabecular percentage compared to the D and 25D, which suggests the additional high calcium and phosphorus supplementation on top of 25D increased trabecular content in the cavity. In conclusion, the combination of 25D with higher levels of high calcium and phosphorus could improve cortical bone quality in pullets and showed a beneficial effect on trabecular bone 3D structural development. Thus, combination of a higher bio-active form of vitamin D3 and higher levels of high calcium and phosphorus could become a potential feeding strategy to improve bone structural integrity and health in pullets.
Ultrasound assessments of organs and blood vessels before and after 40 days isolation in a cavern (deep time experiment 2021)
Authors: Arbeille Philippe , Zuj Kathryn A. , Besnard Stephane , Mauvieux Benoit , Hingrand Corentin , Delaunay Pierre-Louis , Hughson Richard L. , Clot Christian
Published: April 2023

Introduction: Spaceflight simulation studies like confinement in small volume habitat with limited physical activity have reported even after 60 days an abnormal arterial wall adaptation with increase thickness or stiffness. The purpose of the current study was to determine the effects on blood vessel and organ structure of 40 days of isolation in a huge habitat with intensive physical activity.

Method: Data were collected from 14 individuals (7 male) who isolated in a cavern for 40-days while performing normal daily activities without time references. Ultrasound assessments were performed pre- and post-isolation using a teleoperated system with eight different acoustic windows to obtain 19 measurements on 12 different organ/vascular structures which included the common carotid artery, femoral artery, tibial artery, jugular vein, portal vein, bile duct, kidney, pancreas, abdominal aorta, cervical and lumbar vertebral distance, and Achilles tendon.

Results: Common carotid artery measures, including the intima media thickness, stiffness index, and the index of reflectivity measured from the radiofrequency signal, were not changed with isolation. Similarly, no differences were found for femoral artery measurements or measurements of any of the other organs/vessels assessed. There were no sex differences for any of the assessments.

Discussion: Results from this study indicate a lack of physiological effects of 40-days of isolation in a cavern, contrary to what observed in previous 60 days confinement. This suggests a potential protective effect of sustained physical activity, or reduced environmental stress inside the huge volume of the confined facility.