bluuebunny/crossref_metadata_2025 huggingface dataset:
GWAS and genetic and phenotypic correlations of plasma metabolites with complete blood count traits in healthy young pigs reveal implications for pig immune response
Authors: Dervishi E. , Bai X. , Dyck M. K. , Harding J. C. S. , Fortin F. , Dekkers J. C. M. , Plastow G.
Published: March 2023

Introduction: In this study estimated genetic and phenotypic correlations between fifteen complete blood count (CBC) traits and thirty-three heritable plasma metabolites in young healthy nursery pigs. In addition, it provided an opportunity to identify candidate genes associated with variation in metabolite concentration and their potential association with immune response, disease resilience, and production traits.

Methods: The blood samples were collected from healthy young pigs and Nuclear Magnetic Resonance (NMR) was used to quantify plasma metabolites. CBC was determined using the ADVIA® 2120i Hematology System. Genetic correlations of metabolite with CBC traits and single step genome-wide association study (ssGWAS) were estimated using the BLUPF90 programs.

Results: Results showed low phenotypic correlation estimates between plasma metabolites and CBC traits. The highest phenotypic correlation was observed between lactic acid and plasma basophil concentration (0.36 ± 0.04; p < 0.05). Several significant genetic correlations were found between metabolites and CBC traits. The plasma concentration of proline was genetically positively correlated with hemoglobin concentration (0.94 ± 0.03; p < 0.05) and L-tyrosine was negatively correlated with mean corpuscular hemoglobin (MCH; −0.92 ± 0.74; p < 0.05). The genomic regions identified in this study only explained a small percentage of the genetic variance of metabolites levels that were genetically correlated with CBC, resilience, and production traits.

Discussion: The results of this systems approach suggest that several plasma metabolite phenotypes are phenotypically and genetically correlated with CBC traits, suggesting that they may be potential genetic indicators of immune response following disease challenge. Genomic analysis revealed genes and pathways that might interact to modulate CBC, resilience, and production traits.
Consistency of the anesthesia consciousness index versus the bispectral index during laparoscopic gastrointestinal surgery with sevoflurane anesthesia: A prospective multi-center randomized controlled clinical study
Authors: Zhan Jian , Chen Feng , Wu Zhuoxi , Duan Zhenxin , Deng Qiangting , Zeng Jun , Hou Lihong , Zhang Jun , Si Yongyu , Liu Kexuan , Wang Mingjun , Li Hong
Published: March 2023

Background

This study aimed to compare the consistency of anesthesia consciousness index (Ai) with that of bispectral index (BIS) in monitoring the depth of anesthesia (DOA) during sevoflurane anesthesia, to reveal the optimal cutoff values in different states of consciousness, and explore the stability of DOA monitoring during intraoperative injurious stimulation.

Methods

We enrolled 145 patients (97 men and 48 women) from 10 medical centers. General anesthesia was induced using intravenous anesthetics and maintained with sevoflurane. Ai and BIS values were recorded.

Results

The mean difference between the Ai and BIS was-0.1747 (95% confidence interval, −0.6660 to 0.3166; p = 0.4857). The regression equation of Ai and BIS from the Deming regression analysis was y = 5.6387 + 0.9067x (y is BIS, x is Ai), and the slope and intercept were statistically significant. Meanwhile, the receiver operating characteristic curve analysis of anesthesia-induced unconsciousness, loss of consciousness, and recovery of consciousness revealed that the accuracy of Ai and BIS were similar. In addition, the optimal cutoff values of the different states of consciousness were not sensitive to age, and both Ai and BIS had no correlation with hemodynamics.

Conclusion

We conclude that Ai and BIS show no systematic deviation in readings with high consistency, similar accuracy, and good stability; these insights provide more data for clinical application.
Language impairment in Parkinson’s disease: fMRI study of sentence reading comprehension
Authors: Novakova Lubomira , Gajdos Martin , Markova Jana , Martinkovicova Alice , Kosutzka Zuzana , Svantnerova Jana , Valkovic Peter , Csefalvay Zsolt , Rektorova Irena
Published: March 2023

Parkinson’s disease (PD) affects the language processes, with a significant impact on the patients’ daily communication. We aimed to describe specific alterations in the comprehension of syntactically complex sentences in patients with PD (PwPD) as compared to healthy controls (HC) and to identify the neural underpinnings of these deficits using a functional connectivity analysis of the striatum. A total of 20 patients PwPD and 15 HC participated in the fMRI study. We analyzed their performance of a Test of sentence comprehension (ToSC) adjusted for fMRI. A task-dependent functional connectivity analysis of the striatum was conducted using the psychophysiological interaction method (PPI). On the behavioral level, the PwPD scored significantly lower (mean ± sd: 77.3 ± 12.6) in the total ToSC score than the HC did (mean ± sd: 86.6 ± 8.0), p = 0.02, and the difference was also significant specifically for sentences with a non-canonical word order (PD-mean ± sd: 69.9 ± 14.1, HC-mean ± sd: 80.2 ± 11.5, p = 0.04). Using PPI, we found a statistically significant difference between the PwPD and the HC in connectivity from the right striatum to the supplementary motor area [SMA, (4 8 53)] for non-canonical sentences. This PPI connectivity was negatively correlated with the ToSC accuracy of non-canonical sentences in the PwPD. Our results showed disturbed sentence reading comprehension in the PwPD with altered task-dependent functional connectivity from the right striatum to the SMA, which supports the synchronization of the temporal and sequential aspects of language processing. The study revealed that subcortical-cortical networks (striatal-frontal loop) in PwPD are compromised, leading to impaired comprehension of syntactically complex sentences.
Effect of PCSK9 inhibition in combination with statin therapy on intracranial atherosclerotic stenosis: A high-resolution MRI study
Authors: Wu Lingshan , Kong Qianqian , Huang Hao , Xu Shabei , Qu Wensheng , Zhang Ping , Yu Zhiyuan , Luo Xiang
Published: March 2023

Introduction

Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke worldwide. Evolocumab, a proprotein convertase subtilisin/kexin type-9 inhibitor (PCSK9i), effectively lowers low-density lipoprotein (LDL) and produces favorable changes in coronary atherosclerosis. This study aimed to determine the effects of PCSK9i on intracranial plaques in moderate-intensity statin-treated individuals with ICAS.

Methods

This prospective, observational study monitored the imaging and clinical outcomes of individuals with ICAS who were consecutively treated with moderate-intensity statins with or without PCSK9i. Individuals underwent monthly visits and repeat high-resolution MRI (HR-MRI) at week 12. The primary outcome was a change in HR-MRI after 12 weeks of treatment and the secondary outcome was major vascular events during follow-up.

Results

Forty-nine individuals were studied (PCSK9i group: 26 individuals with 28 abnormal vascular regions; statin group: 23 with 27 regions). The PCSK9i group showed a significant reduction in the normalized wall index (0.83 vs. 0.86, p = 0.028) and stenosis degree (65.5 vs. 74.2%, p = 0.01). Similarly, a greater percentage of individuals with a good response to the efficacy of treatment were treated in the PCSK9i group than that in the statin group (75 vs. 44.4%, p = 0.021). The incidence of major vascular events was overall similar between the groups. The treatment options (OR = 8.441, p = 0.01) and prior diabetes (OR = 0.061, p = 0.001) were significantly associated with the efficacy of treatment.

Discussion

Statin and PCSK9i combination treatment stabilized intracranial atherosclerotic plaques more often compared to statins alone, as documented by HR-MRI. Further study is warranted to determine if combination treatment improves clinical outcomes in ICAS.
Case report: Anti-CNTN1 antibody-associated nodopathies disease with asymmetric onset
Authors: Li Qian , Chen Qing , Zhang Ting , Xu Ying , Kan Yanmin , Zhang Jing
Published: March 2023

Anti-contactin-1 (CNTN1) IgG4 antibody-associated nodopathies is an autoimmune antibody-mediated peripheral neuropathy with a unique clinical presentation, pathophysiology, electrophysiology, and therapeutic response. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. Here, a 62-year-old male patient presented with subacute unilateral limb onset, progressive exacerbation, marked weakness of the extremities, cranial, and autonomic nerve involvement. Neurophysiology showed slowed motor nerve conduction velocity (MCV), prolonged distal motor delay (DML), slowed sensory nerve conduction velocity (SCV), decreased sensory nerve activity potential (SNAP) amplitude, decreased amplitude of bilateral neuromotor conduction, abnormal cutaneous sympathetic response (SSR) in both lower extremities, axonal damage, prolonged F-wave latency, and discrete waves. In the initial phase, there was a response to intravenous immunoglobulin (IVIG), and corticosteroids and rituximab were also effective. After 1 year follow-up, the patient improved significantly. This article reports on a patient with nodular disease with anti-contactin-1 (CNTN1) IgG4 antibodies and reviews the literature to improve clinicians' understanding of the disease.
Clinical outcome, recanalization success, and time metrics in drip-and-ship vs. drive-the-doctor: A retrospective analysis of the HEI-LU-Stroke registry
Authors: Urbanek Christian , Jung Jasmin , Güney Resul , Potreck Arne , Nagel Simon , Grau Armin J. , Boujan Timan , Luckscheiter Andre , Bendszus Martin , Möhlenbruch Markus A. , Seker Fatih
Published: March 2023

Purpose

This study aimed at comparing clinical outcome, recanalization success and time metrics in the “drip and ship” (DS) vs. “drive the doctor” (DD) concept in a comparable setting.

Methods

This is a retrospective analysis of thrombectomy registries of a comprehensive stroke center (CSC) and a thrombectomy-capable stroke center (TSC). Patients, who were transferred from the TSC to the CSC, were classified as DS. Patients treated at the TSC by an interventionalist transferred from the CSC were classified as DD. Good outcome was defined as mRS 0–2 or equivalent to premorbid mRS at discharge. Recanalization (TICI 2b-3 or equivalent) and time metrics were compared in both groups.

Results

In total, 295 patients were included, of which 116 (39.3%) were treated in the DS concept and 179 (60.7%) in the DD concept. Good clinical outcome was similarly achieved in DS and DD (DS 25.0% vs. DD 31.3%, P = 0.293). mRS on discharge (DS median 4, DD median 4, P = 0.686), NIHSS improvement (DS median 4, DD median 5, P = 0.582) and NIHSS on discharge (DS median 9, DD median 7, P = 0.231) were similar in both groups. Successful reperfusion was achieved similarly in DS (75.9%) and DD as well (81.0%, P = 0.375). Time from onset to reperfusion (median DS 379 vs. DD 286 min, P = 0.076) and time from initial imaging to reperfusion were longer in DS compared to DD (median DS 246 vs. DD 162 min, P < 0.001).

Conclusion

The DD concept is time saving while achieving similar clinical outcome and recanalization results.
A systematic mini-review of epigenetic mechanisms associated with electroconvulsive therapy in humans
Authors: Castro Sayra Catalina Coral , Bicca Carla , Bicca Bruno , Araujo Stéfany , Viola Thiago Wendt
Published: March 2023

Introduction

Electroconvulsive therapy (ECT) is one of the most effective strategies for treating resistant major depression. Although the mechanism of action is not fully understood and studies are limited, epigenetics is a promising area for the development of biomarkers associated with ECT treatment response.

Aim

We reviewed studies available in the literature that explored the epigenetics of ECT in peripheral samples from patients with major depressive disorder (MDD).

Methods

A systematic review was performed following The PRISMA guidelines. The search was performed in seven electronic databases: Scopus, Web of Science, Medline, PsycINFO, Embase, Cochrane, and Cinahl.

Results

Nine studies were included. Seven assessed DNA methylation and three investigated microRNAs (miR). Overall, most studies were exploratory, with small sample sizes, and we found high heterogeneity between the study’s design, ECT protocols, molecular biology methods, and epigenetic findings. Investigated candidates with some evidence of association with ECT treatment response were BDNF, S100A10, RNF213M, TNKS, FKBP5, miR-126, miR-106a, and miR-24.

Conclusion

The present findings seem to support previous preclinical research, suggesting that epigenetic mechanisms play an important role in the molecular mechanism underlying ECT effects.
A computational model to simulate spectral modulation and speech perception experiments of cochlear implant users
Authors: Alvarez Franklin , Kipping Daniel , Nogueira Waldo
Published: March 2023

Speech understanding in cochlear implant (CI) users presents large intersubject variability that may be related to different aspects of the peripheral auditory system, such as the electrode–nerve interface and neural health conditions. This variability makes it more challenging to proof differences in performance between different CI sound coding strategies in regular clinical studies, nevertheless, computational models can be helpful to assess the speech performance of CI users in an environment where all these physiological aspects can be controlled. In this study, differences in performance between three variants of the HiRes Fidelity 120 (F120) sound coding strategy are studied with a computational model. The computational model consists of (i) a processing stage with the sound coding strategy, (ii) a three-dimensional electrode-nerve interface that accounts for auditory nerve fiber (ANF) degeneration, (iii) a population of phenomenological ANF models, and (iv) a feature extractor algorithm to obtain the internal representation (IR) of the neural activity. As the back-end, the simulation framework for auditory discrimination experiments (FADE) was chosen. Two experiments relevant to speech understanding were performed: one related to spectral modulation threshold (SMT), and the other one related to speech reception threshold (SRT). These experiments included three different neural health conditions (healthy ANFs, and moderate and severe ANF degeneration). The F120 was configured to use sequential stimulation (F120-S), and simultaneous stimulation with two (F120-P) and three (F120-T) simultaneously active channels. Simultaneous stimulation causes electric interaction that smears the spectrotemporal information transmitted to the ANFs, and it has been hypothesized to lead to even worse information transmission in poor neural health conditions. In general, worse neural health conditions led to worse predicted performance; nevertheless, the detriment was small compared to clinical data. Results in SRT experiments indicated that performance with simultaneous stimulation, especially F120-T, were more affected by neural degeneration than with sequential stimulation. Results in SMT experiments showed no significant difference in performance. Although the proposed model in its current state is able to perform SMT and SRT experiments, it is not reliable to predict real CI users' performance yet. Nevertheless, improvements related to the ANF model, feature extraction, and predictor algorithm are discussed.
Synergistic effects of transcutaneous vagus nerve stimulation and inhibitory control training on electrophysiological performance in healthy adults
Authors: Wang Chunchen , Zeng Lingwei , Cao Xinsheng , Dai Jing , Liu Yang , Gao Zhijun , Qin Yilong , Yang Lin , Wang Hang , Wen Zhihong
Published: March 2023

Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive nerve stimulation technique that exerts a positive “exogenous” online neuromodulatory effect on inhibitory control (IC). Additionally, IC training (ICT) is an effective approach for enhancing IC via the “endogenous” activation of brain regions implicated in this process. The aim of the present study was to examine the synergistic effects of tVNS and ICT on IC enhancement. For this, we measured the changes in neural activity in frontal, fronto-central, and central regions in the time domain of the N2 component and the frequency domain of alpha power during the stop signal task. A total of 58 participants were randomly divided into four groups that received five sessions of either ICT or sham ICT with either online tVNS or sham tVNS. No differences in N2 amplitude were detected after any of the interventions. However, N2 latency shortened after tVNS + ICT in frontal, fronto-central, and central regions. N2 latency shortened after the intervention of sham tVNS + ICT in frontal region. Moreover, alpha power after tVNS + ICT intervention was larger than those of the other interventions in frontal, fronto-central, and central regions. The obtained electrophysiological data suggested that combining tVNS with ICT has synergistic ameliorative effects on IC, and provide evidence supporting the IC-enhancing potential of tVNS combined with ICT.
Neuronal P2X4 receptor may contribute to peripheral inflammatory pain in rat spinal dorsal horn
Authors: Ducza László , Gajtkó Andrea , Hegedűs Krisztina , Bakk Erzsébet , Kis Gréta , Gaál Botond , Takács Roland , Szücs Péter , Matesz Klára , Holló Krisztina
Published: March 2023

Objective

Intense inflammation may result in pain, which manifests as spinal central sensitization. There is growing evidence that purinergic signaling plays a pivotal role in the orchestration of pain processing. Over the last decade the ionotropic P2X purino receptor 4 (P2X4) got into spotlight in neuropathic disorders, however its precise spinal expression was scantily characterized during inflammatory pain. Thus, we intended to analyze the receptor distribution within spinal dorsal horn and lumbar dorsal root ganglia (DRG) of rats suffering in inflammatory pain induced by complete Freund adjuvant (CFA).

Methods

CFA-induced peripheral inflammation was validated by mechanical and thermal behavioral tests. In order to ensure about the putative alteration of spinal P2X4 receptor gene expression qPCR reactions were designed, followed by immunoperoxidase and Western blot experiments to assess changes at a protein level. Colocalization of P2X4 with neuronal and glial markers was investigated by double immunofluorescent labelings, which were subsequently analyzed with IMARIS software. Transmission electronmicroscopy was applied to study the ultrastructural localization of the receptor. Concurrently, in lumbar DRG cells similar methodology has been carried out to complete our observations.

Results

The figures of mechanical and thermal behavioral tests proved the establishment of CFA-induced inflammatory pain. We observed significant enhancement of P2X4 transcript level within the spinal dorsal horn 3 days upon CFA administration. Elevation of P2X4 immunoreactivity within Rexed lamina I-II of the spinal gray matter was synchronous with mRNA expression, and confirmed by protein blotting. According to IMARIS analysis the robust protein increase was mainly detected on primary afferent axonterminals and GFAP-labelled astrocyte membrane compartments, but not on postsynaptic dendrites was also validated ultrastructurally within the spinal dorsal horn. Furthermore, lumbar DRG analysis demonstrated that peptidergic and non-peptidergic nociceptive subsets of ganglia cells were also abundantly positive for P2X4 receptor in CFA model.

Conclusion

Here we provide novel evidence about involvement of neuronal and glial P2X4 receptor in the establishment of inflammatory pain.
State-of-the-art therapeutic strategies for targeting cancer stem cells in prostate cancer
Authors: Ramesh Saravanan , Selvakumar Preethi , Ameer Mohamed Yazeer , Lian Sen , Abdullah Alzarooni Abdulqadir Ismail M. , Ojha Shreesh , Mishra Anshuman , Tiwari Ashutosh , Kaushik Ajeet , Jung Young Do , Chouaib Salem , Lakshmanan Vinoth-Kumar
Published: March 2023

The development of new therapeutic strategies is on the increase for prostate cancer stem cells, owing to current standardized therapies for prostate cancer, including chemotherapy, androgen deprivation therapy (ADT), radiotherapy, and surgery, often failing because of tumor relapse ability. Ultimately, tumor relapse develops into advanced castration-resistant prostate cancer (CRPC), which becomes an irreversible and systemic disease. Hence, early identification of the intracellular components and molecular networks that promote prostate cancer is crucial for disease management and therapeutic intervention. One of the potential therapeutic methods for aggressive prostate cancer is to target prostate cancer stem cells (PCSCs), which appear to be a primary focal point of cancer metastasis and recurrence and are resistant to standardized therapies. PCSCs have also been documented to play a major role in regulating tumorigenesis, sphere formation, and the metastasis ability of prostate cancer with their stemness features. Therefore, the current review highlights the origin and identification of PCSCs and their role in anti-androgen resistance, as well as stemness-related signaling pathways. In addition, the review focuses on the current advanced therapeutic strategies for targeting PCSCs that are helping to prevent prostate cancer initiation and progression, such as microRNAs (miRNAs), nanotechnology, chemotherapy, immunotherapy, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene-editing system, and photothermal ablation (PTA) therapy.
UCHL3 promotes hepatocellular carcinoma cell migration by de-ubiquitinating and stabilizing Vimentin
Authors: Ma Qiancheng , Lu Qiliang , Lei Xiangxiang , Zhao Jie , Sun Wen , Wang Jun , Zhu Qing , Huang Dongsheng
Published: March 2023

Background

Hepatocellular carcinoma (HCC) is a common malignant tumor associated with a poor prognosis. Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) has been reported to promote diverse tumors, but little is known about its role in HCC.

Methods

Expression levels of UCHL3 in Huh7 and Hep3B cells were measured by qRT-PCR. UCHL3, Vimentin protein levels, and ubiquitination levels were determined by Western blot assay. co-immunoprecipitation, Immunofluorescence, and IHC were used to detect the interaction and expression association between UCHL3 and Vimentin in the cells. Wound healing and Transwell assays were used to measure cell migration. Spheroid formation assay were used to assess stem-like properties.

Results

UCHL3 expression was found to be significantly elevated in HCC and associated with poor prognosis. UCHL3 promoted migration and stem-like properties of HCC cells. Vimentin was identified as a potential de-ubiquitination substrate of UCHL3 and UCHL3 interacted with and promoted the de-ubiquitination of Vimentin, enhancing its stability. Moreover, the suppression of UCHL3 by siRNA or the inhibition by TCID upregulated ubiquitinated Vimentin. Vimentin attenuated the suppression of cell migration caused by knockdown of UCHL3.

Conclusion

UCHL3 was highly expressed in HCC and functioned as an oncogene. Vimentin is a novel substrate of UCHL3 and its stabilization and de-ubiquitination enhanced HCC cell migration.
Pan-cancer investigation of C-to-U editing reveals its important role in cancer development and new targets for cancer treatment
Authors: Guo Mengbiao , Li Feng , Zhao Linghao , Fang Zhengwen , Yu Huichuan , Songyang Zhou , Xiong Yuanyan
Published: March 2023

RNA editing is prevalent in the transcriptome and is important for multiple cellular processes. C-to-U RNA editing sites (RES) are relatively rare and understudied in humans, compared to A-to-I editing. However, the functional impact of C-to-U editing in human cancers also remains elusive. Here, we conducted the first comprehensive survey of pan-cancer C-to-U RESs. Surprisingly, we found that the same subset of RESs were associated with multiple features, including patient survival, cancer stemness, tumor mutation burden (TMB), and tumor-infiltrated immune cell compositions (ICC), suggesting an RES-mediated close relationship between these features. For example, editing sites for GALM or IFI6 that led to higher expression were linked to lower survival and more cancer stemness. Also, TMB was found to be lower in prostate cancer cases with ICC-associated RESs in CAVIN1 or VWA8 or higher in prostate cancer cases with thymoma. With experimental support, we also found RESs in CST3, TPI1, or TNC that are linked to immune checkpoint blockade by anti-PD1. We also confirmed through experiments that two C-to-U RESs in CSNK2B or RPS14 had different effects on colon cancer cells. Patients with CSNK2B editing, which increased the expression of the oncogene CLDN18, had a lower response to drugs. On the other hand, drugs worked better on people who had RPS14 editing, which greatly increased ribosome production. In summary, our study demonstrated the important roles of C-to-U RESs across cancers and shed light on personalized cancer therapy.
Targeted therapy based on ubiquitin-specific proteases, signalling pathways and E3 ligases in non-small-cell lung cancer
Authors: Yang Yu-Chen , Zhao Can-Jun , Jin Zhao-Feng , Zheng Jin , Ma Li-Tian
Published: March 2023

Lung cancer is one of the most common malignant tumours worldwide, with the highest mortality rate. Approximately 1.6 million deaths owing to lung cancer are reported annually; of which, 85% of deaths occur owing to non-small-cell lung cancer (NSCLC). At present, the conventional treatment methods for NSCLC include radiotherapy, chemotherapy, targeted therapy and surgery. However, drug resistance and tumour invasion or metastasis often lead to treatment failure. The ubiquitin–proteasome pathway (UPP) plays an important role in the occurrence and development of tumours. Upregulation or inhibition of proteins or enzymes involved in UPP can promote or inhibit the occurrence and development of tumours, respectively. As regulators of UPP, ubiquitin-specific proteases (USPs) primarily inhibit the degradation of target proteins by proteasomes through deubiquitination and hence play a carcinogenic or anticancer role. This review focuses on the role of USPs in the occurrence and development of NSCLC and the potential of corresponding targeted drugs, PROTACs and small-molecule inhibitors in the treatment of NSCLC.
Targeted therapies for the treatment of soft tissue sarcoma
Authors: Fuchs Jeffrey W. , Schulte Brian C. , Fuchs Joseph R. , Agulnik Mark
Published: March 2023

Soft tissue sarcomas are rare malignant tumors derived from mesenchymal cells that have a high morbidity and mortality related to frequent occurrence of advanced and metastatic disease. Over the past two decades there have been significant advances in the use of targeted therapies for the treatment of soft tissue sarcoma. The ability to study various cellular markers and pathways related to sarcomagenesis has led to the creation and approval of multiple novel therapies. Herein, we describe the current landscape of targeted medications used in the management of advanced or metastatic soft tissue sarcomas, excluding GIST. We distinguish three categories: targeted therapies that have current US Food and Drug Administration (FDA) approval for treatment of soft tissue sarcoma, non-FDA approved targeted therapies, and medications in development for treatment of patients with soft tissue sarcoma.
Management of patients with recurrent/metastatic endometrial cancer: Consensus recommendations from an expert panel from Brazil
Authors: de Andrade Diocésio Alves Pinto , Guimarães Andréa Paiva Gadelha , de Melo Andréia Cristina , Nogueira-Rodrigues Angélica , Gomes Larissa Müller , Scaranti Mariana , Maia Joyce Maria Lisboa , Morelle Alessandra Menezes , Santos Candice Amorim de Araújo Lima , Souza Cristiano de Pádua , de Freitas Daniela , Callegaro Filho Donato , Paulino Eduardo , Júnior Elge Werneck Araújo , Pimenta Juliana Martins , Santos Marcela Bonalumi dos , de Almeida Michelle Samora , Souza Ronaldo Pereira , Cabral Samantha , Maluf Fernando Cotait
Published: March 2023

Background

Endometrial cancer is of increasing concern in several countries, including Brazil, in part because of an ageing population, declines in fertility, and the increasing prevalence of obesity. Although endometrial tumors had lagged behind other cancer types in terms of treatment improvements, molecular characterization of these tumors is paving the way for novel therapies and an expansion of the therapeutic arsenal. We aimed to help medical oncologists who manage patients with recurrent or metastatic endometrial cancer in the Brazilian healthcare setting.

Methods

The panel, composed of 20 medical oncologists, convened in November 2021 to address 50 multiple-choice questions on molecular testing and treatment choices. We classified the level of agreement among panelists as (1) consensus (≥75% choosing the same answer), (2) majority vote (50% to <75%), or (3) less than majority vote (<50%).

Results

Consensus was present for 25 of the 50 questions, whereas majority vote was present for an additional 23 questions. Key recommendations include molecular testing for every patient with recurrent/metastatic endometrial cancer; choice of first-line treatment according to microsatellite instability and HER2, with the addition of programmed death ligand 1 (PD-L1) and hormone receptors (HRs) for second-line therapy; carboplatin and paclitaxel as the preferred option in first-line treatment of HER2-negative disease, with the addition of trastuzumab in HER2-positive disease; pembrolizumab plus lenvatinib as a key option in second line, regardless of HER2, PD-L1 or HRs; and various recommendations regarding treatment choice for patients with distinct comorbidities.

Conclusion

Despite the existing gaps in the current literature, the vast majority of issues addressed by the panel provided a level of agreement sufficient to inform clinical practice in Brazil and in other countries with similar healthcare environments.
Effect of sarcopenia on postoperative ICU admission and length of stay after hepatic resection for Klatskin tumor
Authors: Jung Hyun Eom , Han Dai Hoon , Koo Bon-Nyeo , Kim Jeongmin
Published: March 2023

Background

Hepatic resection of Klatskin tumors usually requires postoperative intensive care unit (ICU) admission because of its high morbidity and mortality. Identifying surgical patients who will benefit most from ICU admission is important because of scarce resources but remains difficult. Sarcopenia is characterised by the loss of skeletal muscle mass and is associated with poor surgical outcomes.

Methods

We retrospectively analysed th.e relationship between preoperative sarcopenia and postoperative ICU admission and length of ICU stay (LOS-I) in patients who underwent hepatic resection for Klatskin tumors. Using preoperative computed tomography scans, the cross-sectional area of the psoas muscle at the level of the third lumbar vertebra was measured and normalised to the patient’s height. Using these values, the optimal cut-off for diagnosing sarcopenia was determined using receiver operating characteristic curve analysis for each sex.

Results

Of 330 patients, 150 (45.5%) were diagnosed with sarcopenia. Patients with preoperative sarcopenia presented significantly more frequently to the ICU (77.3% vs. 47.9%, p < 0.001) and had longer total LOS-I (2.45 vs 0.89 days, p < 0.001). Moreover, patients with sarcopenia showed a significantly higher postoperative length of hospital stay, severe complication rate, and in-hospital mortality.

Conclusions

Sarcopenia correlated with poor postoperative outcomes, especially with the increased requirement of postoperative ICU admission and prolonged LOS-I after hepatic resection in patients with Klatskin tumors.
The use of nanoparticles for targeted drug delivery in non-small cell lung cancer
Authors: Holder Jessica E. , Ferguson Christopher , Oliveira Elisabete , Lodeiro Carlos , Trim Carol M. , Byrne Lee J. , Bertolo Emilia , Wilson Cornelia M.
Published: March 2023

Lung cancer is a global health problem affecting millions of people each year. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with various conventional treatment available in the clinic. Application of these treatments alone often results in high rates of cancer reoccurrence and metastasis. In addition, they can cause damage to healthy tissues, resulting in many adverse effects. Nanotechnology has emerged as a modality for the treatment of cancer. When used in combination with nanoparticles, it is possible to improve the pharmacokinetic and pharmacodynamic profiles of pre-existing drugs used in cancer treatment. Nanoparticles have physiochemical properties such as small size which allowing passage through challenging areas of the body, and large surface area allows for higher doses of drugs to be brought to the tumor site. Nanoparticles can be functionalized which involves modifying the surface chemistry of the particles and allows for the conjugation of ligands (small molecules, antibodies, and peptides). Ligands can be chosen for their ability to target components that are specific to or are upregulated in cancer cells, such as targeting receptors on the tumor surface that are highly expressed in the cancer. This ability to precisely target the tumor can improve the efficacy of drugs and decrease toxic side effects. This review will discuss approaches used for targeting drugs to tumors using nanoparticles, provide examples of how this has been applied in the clinic and highlight future prospects for this technology.
Real-word adrenocorticotropic hormone treatment for childhood-onset nephrotic syndrome
Authors: Wang Ying , Dang Xiqiang , Wu Xiaochuan , Li Yongzhen , He Qingnan , Li Xiaoyan
Published: March 2023

Background

Current first-line anti-proteinuric treatments do not produce a satisfactory therapeutic effect in a considerable number of patients with nephrotic syndrome (NS). Interest in adrenocorticotropic hormone (ACTH) for the treatment of NS has recently been revived. The present study investigated the efficacy and safety of ACTH treatment in children with frequent relapsing NS (FRNS), steroid-dependent NS (SDNS), and steroid-resistant NS (SRNS).

Method

The ACTH treatment group was comprised of NS patients receiving ACTH treatment. Patients with serum cortisol concentrations <85.3 nmol/L and who had not received ACTH treatment previously were enrolled in the control group from January 2018 to January 2021. The maintenance dose of prednisone, the number of disease recurrences, the time of first disease relapse, immunosuppressant use, serum cortisol levels, and adverse events were recorded in both groups.

Results

Fifty-one patients were included in the ACTH group, and twenty-one patients were enrolled in the control group. Concurrent treatment with one or more immunosuppressive and/or cytotoxic treatments occurred in 92.2% and 85.7% of patients in the ACTH and control groups, respectively, throughout the study period. A greater reduction in the prednisone maintenance dose was observed in the ACTH group compared with the control group after 1 year of follow up (0.603 ± 0.445 mg/kg vs. 0.267 ± 0.500 mg/kg, p = 0.006). During the one-year study period, fewer participants experienced one or more disease relapses in the ACTH group (45.1%) compared to the control group (76.2%, odds ratio = 3.896, p = 0.016). The number of disease recurrences per patient in the ACTH group was less than that in the control group (median difference = −1, p = 0.006). The mean length of remission was 8.902 m and 7.905 m in the ACTH group and control group, respectively. A log-rank test showed a longer relapse free survival for patients in the ACTH group (p = 0.046), but the Breslow test showed no significant difference between groups (p = 0.104). Ten patients in the ACTH group successfully discontinued all drug therapies. No patients in the control group were able to discontinue drug therapy as of February 2022.

Conclusion

ACTH, combined with multiple drugs, is effective at reducing the prednisone maintenance dose and may effectively prevent disease relapses in childhood NS.
Pattern of linear growth and progression of bone maturation for girls with early-onset puberty: A mixed longitudinal study
Authors: Liu Shuangyi , Su Zhe , Pan Lili , Chen Jinfeng , Zhao Xiu , Wang Li , Zhang Longjiang , Su Qiru , Su Huiping
Published: March 2023

Background and objective

With a worldwide trend to earlier age of onset of puberty, the prevalence of early-onset puberty (EP) among girls has increased. The impact of EP on the pattern of linear growth and bone maturation is unclear. Accordingly, the objective of our study was to describe this pattern for girls with EP in Shenzhen, China.

Methods

A total of 498 untreated girls diagnosed with EP at Shenzhen Children's Hospital, China, between January 2016 and December 2021. A total of 1,307 anthropometric measurements and 1,307 left-hand radiographs were available for analysis. Artificial intelligence (AI) was used to determine bone age (BA). Participants were classified into groups according to chronological age (CA) and BA. The pattern of linear growth (height) and progression of bone maturation was described between groups using the Lambda-Mu-Sigma (LMS) method. Published height-for-CA and height-for-BA norm references for a healthy Chinese population were used for age-appropriate comparisons.

Results

The mean CA of appearance of first pubertal signs (breast buds) was 8.1 ± 0.5 years. Compared to norm-referenced data, girls with EP were significantly taller at a CA of 7–10 years. This was followed by a slowing in linear growth after a CA of 10 years, with 71 girls with EP having already achieved their target adult height. From 7 to 10 years of BA, the linear growth was slower in the EP group compared to norm-reference values. This was followed by a period of catch-up growth at 11.2 years of BA, with growth curves approaching norm-referenced values. The BA progressed rapidly from 7 to 8 years of age in about half of the girls with EP (median ΔBA/ΔCA >1.9), slowing, thereafter, until the period of catch-up growth at 11.2 years of BA.

Conclusions

BA provides a more reliable reference than CA to assess growth parameters among girls with EP. Our limited data set does indicate that EP does not negatively impact final adult height. Therefore, the growth curves from our study are relevant, providing a reference for pediatricians in this clinical population and, thus, preventing over-treatment for EP.
Cardioprotective effects of curcumin against myocardial I/R injury: A systematic review and meta-analysis of preclinical and clinical studies
Authors: Li Tianli , Jin Jialin , Pu Fenglan , Bai Ying , Chen Yajun , Li Yan , Wang Xian
Published: March 2023

Objective: Myocardial ischemia-reperfusion (I/R) injury is a complex clinical problem that often leads to further myocardial injury. Curcumin is the main component of turmeric, which has been proved to have many cardioprotective effects. However, the cardioprotective potential of curcumin remains unclear. The present systematic review and meta-analysis aimed to evaluate the clinical and preclinical (animal model) evidence regarding the effect of curcumin on myocardial I/R injury.

Methods: Eight databases and three register systems were searched from inception to 1 November 2022. Data extraction, study quality assessment, data analyses were carried out strictly. Then a fixed or random-effects model was applied to analyze the outcomes. SYRCLE’s-RoB tool and RoB-2 tool was used to assess the methodological quality of the included studies. RevMan 5.4 software and stata 15.1 software were used for statistical analysis.

Results: 24 animal studies, with a total of 503 animals, and four human studies, with a total of 435 patients, were included in this study. The meta-analysis of animal studies demonstrated that compared with the control group, curcumin significantly reduced myocardial infarction size (p < 0.00001), and improved the cardiac function indexes (LVEF, LVFS, LVEDd, and LVESd) (p < 0.01). In addition, the indexes of myocardial injury markers, myocardial oxidation, myocardial apoptosis, inflammation, and other mechanism indicators also showed the beneficial effect of curcumin (p < 0.05). In terms of clinical studies, curcumin reduced the incidence of cardiac dysfunction, myocardial infarction in the hospital and MACE in the short term, which might be related to its anti-inflammatory and anti-oxidative property. Dose-response meta-analysis predicted, 200 mg/kg/d bodyweight was the optimal dose of curcumin in the range of 10–200 mg/kg/d, which was safe and non-toxic according to the existing publications.

Conclusion: Our study is the first meta-analysis that includes both preclinical and clinical researches. We suggested that curcumin might play a cardioprotective role in acute myocardial infarction in animal studies, mainly through anti-oxidative, anti-inflammatory, anti-apoptosis, and anti-fibrosis effects. In addition, from the clinical studies, we found that curcumin might need a longer course of treatment and a larger dose to protect the myocardium, and its efficacy is mainly reflected on reducing the incidence of myocardial infarction and MACE. Our finding provides some meaningful advice for the further research.
Association of variations in the CAT and prognosis in lung cancer patients with platinum-based chemotherapy
Authors: Liu Jia-Si , Liu Jun-Yan , Xiao Qi , Li Xiang-Ping , Chen Juan , Liu Zhao-Qian
Published: March 2023

PURPOSE: To explore the relationship between ATM, ATR and CAT polymorphisms and prognosis of lung cancer patients received platinum-based chemotherapy.

METHODS: 404 patients with lung cancer who received platinum-chemotherapy were enrolled and DNA typing was performed. Cox regression analysis and stratification analyses was performed to assess relationships between OS and PFS with SNPs genotypes. The prognosis of lung adenocarcinomaand squamous cell carcinomapatients was analyzed with The Cancer Genome Atlas (TCGA) database according to the grouping of CAT expression.

RESULTS:CAT rs769217 was significantly related to PFS of patients with lung cancer who received platinum-chemotherapy. In the Additive model, rs769217 was associated with PFS (HR = 0.747, 95% CI = 0.581–0.960, p = 0.023). In the Dominant model, CT and TT genotypes led to lung cancer progression 0.738 times more than CC genotype. In stratification analyses of association between CAT rs769217 polymorphisms and PFS, the HR of patients at stage IV in additive model was 0.73, and HR was 0.745 (p = 0.034) in dominant model. For OS analyses, HR was 0.672 in the older lung cancer patients (>55 years old) in additive model. Meanwhile, in the Dominant model, it was found that the older patients with CT and TT genotypes had better prognosis, and the risk of death after receiving platinum-based chemotherapy was 0.692 times that of patients with CC genotype (p = 0.037). TCGA data shows that LUAD patients with high CAT expression have longer OS (p = 0.020).

CONCLUSION:CAT rs769217 is significantly related to PSF of platinum-based chemotherapy in lung cancer patients and may be a biomarker for predicting the prognosis of lung cancer patients with platinum-based chemotherapy.
Efficacy and safety of anticoagulation in atrial fibrillation patients with intracranial hemorrhage: A systematic review and meta-analysis
Authors: Zhou Qiang , Liu Xiang , Yang Xian , Huang Xiao-Hui , Wu Yan-Zi , Tao Ying-Ying , Wei Meng
Published: March 2023

Background: The benefits and risks of starting anticoagulation therapy, such as direct oral anticoagulations (DOACs) or warfarin, in atrial fibrillation (AF) patients with a history of intracranial hemorrhage (ICH) remain controversial. We performed a systematic review and meta-analysis to compare the safety and efficacy of starting oral anticoagulation (OAC) and non-oral anticoagulation in these patients.

Methods: PubMed, Cochrane Library, and Embase were searched from inception to 01 May 2022 for randomized controlled trials and cohort studies, reporting effectiveness and safety outcomes for anticoagulation therapy in atrial fibrillation patients with intracranial hemorrhage. The Newcastle-Ottawa Scale (NOS) and the Cochrane Collaboration tool were used to evaluate bias risks for all randomized controlled trials (RCTs) and cohort studies. An effects model was applied to calculate adjusted hazard ratios (aHRs) for randomized controlled trials and cohort studies.

Results: We analyzed data from two randomized controlled trials (304 patients) and seven Cohort studies (17,477 patients). Compared to non-oral anticoagulation, starting oral anticoagulation therapy reduced the risk of Ischemic Stroke/Systemic Embolism (SE) (aHR: 0.64, 95% CI: 0.55–0.57) and all-cause death (aHR: 0.53, 95% CI: 0.35–0.80) in atrial fibrillation patients and a prior history intracranial hemorrhage. Starting oral anticoagulation therapy did not increase the risk of recurrent intracranial hemorrhage (aHR: 1.07, 95% CI: 0.66–1.74), but increased the risk of major bleeding (aHR: 1.38, 95% CI: 1.00–1.91) than no oral anticoagulation therapy. The DOACs had a lower risk of Ischemic Stroke/SE (aHR: 0.84, 95% CI: 0.70–1.00), recurrent intracranial hemorrhage (aHR: 0.63, 95% CI: 0.49–0.82), and all-cause death (aHR: 0.65, 95% CI: 0.48–0.88) compared to warfarin. According to subgroup analyses, starting oral anticoagulation therapy have a higher risk of recurrent intracranial hemorrhage than non-oral anticoagulation therapy (aHR: 1.57, 95% CI: 1.36–1.81) for Asians.

Conclusion: After intracranial hemorrhage in atrial fibrillation patients, restarting or initiating oral anticoagulation therapy decreased the risk of Ischemic Stroke/SE and all-cause death but did not increase the risk for recurrent intracranial hemorrhage. Direct oral anticoagulations have better efficacy and safety than warfarin if oral anticoagulation therapy is started. However, starting oral anticoagulation increases the risk for recurrent intracranial hemorrhage in the Asian region.
Current possibilities and future opportunities provided by three-dimensional lung ECM-derived hydrogels
Authors: Nizamoglu Mehmet , Burgess Janette K.
Published: March 2023

Disruption of the complex interplay between cells and extracellular matrix (ECM), the scaffold that provides support, biochemical and biomechanical cues, is emerging as a key element underlying lung diseases. We readily acknowledge that the lung is a flexible, relatively soft tissue that is three dimensional (3D) in structure, hence a need exists to develop in vitro model systems that reflect these properties. Lung ECM-derived hydrogels have recently emerged as a model system that mimics native lung physiology; they contain most of the plethora of biochemical components in native lung, as well as reflecting the biomechanics of native tissue. Research investigating the contribution of cell:matrix interactions to acute and chronic lung diseases has begun adopting these models but has yet to harness their full potential. This perspective article provides insight about the latest advances in the development, modification, characterization and utilization of lung ECM-derived hydrogels. We highlight some opportunities for expanding research incorporating lung ECM-derived hydrogels and potential improvements for the current approaches. Expanding the capabilities of investigations using lung ECM-derived hydrogels is positioned at a cross roads of disciplines, the path to new and innovative strategies for unravelling disease underlying mechanisms will benefit greatly from interdisciplinary approaches. While challenges need to be addressed before the maximum potential can be unlocked, with the rapid pace at which this field is evolving, we are close to a future where faster, more efficient and safer drug development targeting the disrupted 3D microenvironment is possible using lung ECM-derived hydrogels.