bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial distribution of CD3- and CD8-positive lymphocytes as pretest for POLE wild-type in molecular subgroups of endometrial carcinoma
Authors: Jungen Samuel H. , Noti Luca , Christe Lucine , Galvan Jose A. , Zlobec Inti , Müller Michael D. , Imboden Sara , Siegenthaler Franziska , Carlson Joseph W. , Pellinen Teijo , Heredia-Soto Victoria , Ruz-Caracuel Ignacio , Hardisson David , Redondo Andres , Mendiola Marta , Rau Tilman T.
Published: March 2023

Introduction

Over the years, the molecular classification of endometrial carcinoma has evolved significantly. Both POLEmut and MMRdef cases share tumor biological similarities like high tumor mutational burden and induce strong lymphatic reactions. While therefore use case scenarios for pretesting with tumor-infiltrating lymphocytes to replace molecular analysis did not show promising results, such testing may be warranted in cases where an inverse prediction, such as that of POLEwt, is being considered. For that reason we used a spatial digital pathology method to quantitatively examine CD3+ and CD8+ immune infiltrates in comparison to conventional histopathological parameters, prognostics and as potential pretest before molecular analysis.

Methods

We applied a four-color multiplex immunofluorescence assay for pan-cytokeratin, CD3, CD8, and DAPI on 252 endometrial carcinomas as testing and compared it to further 213 cases as validation cohort from a similar multiplexing assay. We quantitatively assessed immune infiltrates in microscopic distances within the carcinoma, in a close distance of 50 microns, and in more distant areas.

Results

Regarding prognostics, high CD3+ and CD8+ densities in intra-tumoral and close subregions pointed toward a favorable outcome. However, TCGA subtyping outperforms prognostication of CD3 and CD8 based parameters. Different CD3+ and CD8+ densities were significantly associated with the TCGA subgroups, but not consistently for histopathological parameter. In the testing cohort, intra-tumoral densities of less than 50 intra-tumoral CD8+ cells/mm2 were the most suitable parameter to assume a POLEwt, irrespective of an MMRdef, NSMP or p53abn background. An application to the validation cohort corroborates these findings with an overall sensitivity of 95.5%.

Discussion

Molecular confirmation of POLEmut cases remains the gold standard. Even if CD3+ and CD8+ cell densities appeared less prognostic than TCGA, low intra-tumoral CD8+ values predict a POLE wild-type at substantial percentage rates, but not vice versa. This inverse correlation might be useful to increase pretest probabilities in consecutive POLE testing. Molecular subtyping is currently not conducted in one-third of cases deemed low-risk based on conventional clinical and histopathological parameters. However, this percentage could potentially be increased to two-thirds by excluding sequencing of predicted POLE wild-type cases, which could be determined through precise quantification of intra-tumoral CD8+ cells.
Anesthetic management of patients with sepsis/septic shock
Authors: Carsetti Andrea , Vitali Eva , Pesaresi Lucia , Antolini Riccardo , Casarotta Erika , Damiani Elisa , Adrario Erica , Donati Abele
Published: March 2023

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, while septic shock is a subset of sepsis with persistent hypotension requiring vasopressors to maintain a mean arterial pressure (MAP) of ≥65 mmHg and having a serum lactate level of >2 mmol/L, despite adequate volume resuscitation. Sepsis and septic shock are medical emergencies and time-dependent diseases with a high mortality rate for which early identification, early antibiotic therapy, and early source control are paramount for patient outcomes. The patient may require surgical intervention or an invasive procedure aiming to control the source of infection, and the anesthesiologist has a pivotal role in all phases of patient management. During the preoperative assessment, patients should be aware of all possible organ dysfunctions, and the severity of the disease combined with the patient's physiological reserve should be carefully assessed. All possible efforts should be made to optimize conditions before surgery, especially from a hemodynamic point of view. Anesthetic agents may worsen the hemodynamics of shock patients, and the anesthesiologist must know the properties of each anesthetic agent. All possible efforts should be made to maintain organ perfusion supporting hemodynamics with fluids, vasoactive agents, and inotropes if required.
Insights into remediation effects and bacterial diversity of different remediation measures in rare earth mine soil with SO42− and heavy metals
Authors: Yan Xiao , Gao Bowen , Wang Jianlei , Zhu Xuezhe , Zhang Mingjiang
Published: March 2023

The increased demand for rare earth resources has led to an increase in the development of rare earth mines (REMs). However, the production of high-concentration leaching agents (SO42−) and heavy metals as a result of rare earth mining has increased, necessitating the removal of contaminants. Here, a series of experiments with different remediation measures, including control (CK), sulfate-reducing bacteria (SRB) alone (M), chemicals (Ca(OH)2, 1.5 g/kg) plus SRB (CM-L), chemicals (Ca(OH)2, 3.0 g/kg) plus SRB (CM-M), and chemicals (Ca(OH)2, 4.5 g/kg) plus SRB (CM-H), were conducted to investigate the removal effect of SO42−, Pb, Zn, and Mn from the REM soil. Then, a high-throughput sequencing technology was applied to explore the response of bacterial community diversity and functions with different remediation measures. The results indicated that CM-M treatment had a more efficient removal effect for SO42−, Pb, Zn, and Mn than the others, up to 94.6, 88.3, 98.7, and 91%, respectively. Soil bacterial abundance and diversity were significantly affected by treatments with the inoculation of SRB in comparison with CK. The relative abundance of Desulfobacterota with the ability to transform SO42− into S2− increased significantly in all treatments, except for CK. There was a strong correlation between environmental factors (pH, Eh, SO42−, Pb, and Zn) and bacterial community structure. Furthermore, functional prediction analysis revealed that the SRB inoculation treatments significantly increased the abundance of sulfate respiration, sulfite respiration, and nitrogen fixation, while decreasing the abundance of manganese oxidation, dark hydrogen oxidation, and denitrification. This provides good evidence for us to understand the difference in removal efficiency, bacterial community structure, and function by different remediation measures that help select a more efficient and sustainable method to remediate contaminants in the REM soil.
A novel loop-mediated isothermal amplification-lateral flow dipstick method for Helicobacter pylori detection
Authors: Liu Wenwen , Lu Gang , Wang Yu , Chen Zhenghong , Gao Yunyun , Yin Zhipeng , Wu Yi , Lv Xiaoqian , Guo Pengbo , Zhao Yinghui
Published: March 2023

Introduction

To eradicate Helicobacter pylori (H. pylori) and reduce the risk of gastric cancer, a sensitive, specific, convenient, and simple detection method is needed. This study aimed to establish a novel loop-mediated isothermal amplification-lateral flow dipstick (LAMP-LFD) method for H. pylori detection.

Methods

LAMP primer design software was used to design primers for the conserved sites of the H. pylori ureB gene. UreB-FIP-labeled biotin was used for LAMP amplification, and FAM-labeled probes were specifically hybridized with LAMP amplification products, which were then detected by LFD. In addition, a clinical study was conducted to assess LAMP-LFD in 20 fecal samples.

Results

The results of the optimization indicated that H. pylori could be specifically detected by LFD without cross-reaction with other non-H. pylori bacteria when the LAMP was performed at 65°C for 60 min. The lower limit of the detection method was 102 copies/μL, which was 100 times the sensitivity of polymerase chain reaction (PCR). H. pylori-positive fecal samples were detected by LAMP-LFD in 13/20 patients.

Discussion

In conclusion, a new LAMP-LFD assay has been fully established and confirmed for H. pylori detection. The entire process can be completed in approximately 1.5 h, with the advantages of strong specificity, high sensitivity, and simple operation. This study provides a novel potential method for the detection of H. pylori in the clinical settings of primary hospitals and low-resource countries.
Predictive microbial feature analysis in patients with depression after acute ischemic stroke
Authors: Yao Shanshan , Xie Huijia , Wang Ya , Shen Nan , Chen Qionglei , Zhao Yiting , Gu Qilu , Zhang Junmei , Liu Jiaming , Sun Jing , Tong Qiuling
Published: March 2023

Introduction

Post-stroke depression (PSD) is the most common emotional problem following a stroke, which requires early diagnosis to improve the prognosis. Gut microbiota plays important role in the pathological mechanisms of acute ischemic stroke and influences the outcome of patients. However, the relationship between PSD and gut microbiota remains unknown. Here, we explored whether the microbial signatures of gut microbiota in the patients with stroke could be an appropriate predictor of PSD.

Methods

Fecal samples were collected from 232 acute ischemic stroke patients and determined by 16s rRNA sequencing. All patients then received 17-Hamilton Depression Rating Scale (HAMD-17) assessment 3 months after discharge, and were further divided into PSD group and non-PSD group. We analyzed the differences of gut microbiota between these groups. To identify gut microbial biomarkers, we then established microbial biomarker model.

Results

Our results showed that the composition of gut microbiota in the PSD patients differed significantly from that in non-PSD patients. The genus Streptococcus, Akkermansia, and Barnesiella were significantly increased in PSD patients compared to non-PSD, while the genus Escherichia-Shigella, Butyricicoccus, and Holdemanella were significantly decreased. Correlation analyses displayed that Akkermansia, Barnesiella, and Pyramidobacter were positively correlated with HAMD score, while Holdemanella was negatively correlated with HAMD score. The optimal microbial markers were determined, and the combination achieved an area under the curve (AUC) value of 0.705 to distinguish PSD from non-PSD.

Conclusions

Our findings suggest that PSD patients had distinct gut microbiota compared to non-PSD patients, and explore the potential of microbial markers, which might provide clinical decision-making in PSD.
Prefrontal EEG slowing, synchronization, and ERP peak latency in association with predementia stages of Alzheimer’s disease
Authors: Choi Jungmi , Ku Boncho , Doan Dieu Ni Thi , Park Junwoo , Cha Wonseok , Kim Jaeuk U. , Lee Kun Ho
Published: March 2023

Background

Early screening of elderly individuals who are at risk of dementia allows timely medical interventions to prevent disease progression. The portable and low-cost electroencephalography (EEG) technique has the potential to serve it.

Objective

We examined prefrontal EEG and event-related potential (ERP) variables in association with the predementia stages of Alzheimer’s disease (AD).

Methods

One hundred elderly individuals were recruited from the GARD cohort. The participants were classified into four groups according to their amyloid beta deposition (A+ or A−) and neurodegeneration status (N+ or N−): cognitively normal (CN; A−N−, n = 27), asymptomatic AD (aAD; A + N−, n = 15), mild cognitive impairment (MCI) with AD pathology (pAD; A+N+, n = 16), and MCI with non-AD pathology (MCI(−); A−N+, n = 42). Prefrontal resting-state eyes-closed EEG measurements were recorded for five minutes and auditory ERP measurements were recorded for 8 min. Three variables of median frequency (MDF), spectrum triangular index (STI), and positive-peak latency (PPL) were employed to reflect EEG slowing, temporal synchrony, and ERP latency, respectively.

Results

Decreasing prefrontal MDF and increasing PPL were observed in the MCI with AD pathology. Interestingly, after controlling for age, sex, and education, we found a significant negative association between MDF and the aAD and pAD stages with an odds ratio (OR) of 0.58. Similarly, PPL exhibited a significant positive association with these AD stages with an OR of 2.36. Additionally, compared with the MCI(-) group, significant negative associations were demonstrated by the aAD group with STI and those in the pAD group with MDF with ORs of 0.30 and 0.42, respectively.

Conclusion

Slow intrinsic EEG oscillation is associated with MCI due to AD, and a delayed ERP peak latency is likely associated with general cognitive impairment. MCI individuals without AD pathology exhibited better cortical temporal synchronization and faster EEG oscillations than those with aAD or pAD.

Significance

The EEG/ERP variables obtained from prefrontal EEG techniques are associated with early cognitive impairment due to AD and non-AD pathology. This result suggests that prefrontal EEG/ERP metrics may serve as useful indicators to screen elderly individuals’ early stages on the AD continuum as well as overall cognitive impairment.
Deep brain stimulation in posterior subthalamic area for Holmes tremor: Case reports with review of the literature
Authors: Kamo Hikaru , Oyama Genko , Ito Masanobu , Iwamuro Hirokazu , Umemura Atsushi , Hattori Nobutaka
Published: March 2023

Background

Holmes tremor (HT) is a refractory tremor associated with cortico-basal ganglia loops and cerebellothalamic tract abnormalities. Various drug treatments have been attempted; however, no treatment method has yet been established. Historically, thalamic deep brain stimulation (DBS) has been performed in medically refractory cases. Recently, the posterior subthalamic area (PSA) has been used for HT. Here, we report cases of HT and review the effectiveness and safety of PSA-DBS for HT.

Cases

We conducted a retrospective chart review of two patients with HT who underwent PSA-DBS. Improvement in tremors was observed 1 year after surgery without apparent complications.

Literature review

We identified 12 patients who underwent PSA-DBS for HT, including our cases. In six patients, PSA was targeted alone; for the rest, the ventralis intermediate nucleus (Vim) of the thalamus and PSA were simultaneously targeted. The Fahn–Tolosa–Marin Tremor Rating Scale improvement rates were 56.8% (range, 33.9–82.1%; n = 6) and 77.8% (range, 42.6–100%; n = 5) for the PSA-DBS and PSA+Vim-DBS, respectively.

Conclusion

Reasonable improvements in HT were observed after PSA-DBS. PSA might be an appropriate target for improving the symptoms of HT. Long-term observations, accumulation of cases, and randomized studies are required in future.
The neurophysiological approach to misophonia: Theory and treatment
Authors: Jastreboff Pawel J. , Jastreboff Margaret M.
Published: March 2023

Clinical observations of hundreds of patients who exhibited decreased tolerance to sound showed that many of them could not be diagnosed as having hyperacusis when negative reactions to a sound depend only on its physical characteristics. In the majority of these patients, the physical characteristics of bothersome sounds were secondary, and patients were able to tolerate other sounds with levels higher than sounds bothersome for them. The dominant feature determining the presence and strength of negative reactions are specific to a given patient's patterns and meaning of bothersome sounds. Moreover, negative reactions frequently depend on the situation in which the offensive sound is presented or by whom it is produced. Importantly, physiological and emotional reactions to bothersome sounds are very similar (even identical) for both hyperacusis and misophonia, so reactions cannot be used to diagnose and differentiate them. To label this non-reported phenomenon, we coined the term misophonia in 2001. Incorporating clinical observations into the framework of knowledge of brain functions allowed us to propose a neurophysiological model for misophonia. The observation that the physical characterization of misophonic trigger was secondary and frequently irrelevant suggested that the auditory pathways are working in identical manner in people with as in without misophonia. Descriptions of negative reactions indicated that the limbic and sympathetic parts of the autonomic nervous systems are involved but without manifestations of general malfunction of these systems. Patients with misophonia could not control internal emotional reactions (even when fully realizing that these reactions are disproportionate to benign sounds evoking them) suggesting that subconscious, conditioned reflexes linking the auditory system with other systems in the brain are the core mechanisms of misophonia. Consequently, the strength of functional connections between various systems in the brain plays a dominant role in misophonia, and the functional properties of the individual systems may be perfectly within the norms. Based on the postulated model, we proposed a treatment for misophonia, focused on the extinction of conditioned reflexes linking the auditory system with other systems in the brain. Treatment consists of specific counseling and sound therapy. It has been used for over 20 years with a published success rate of 83%.
Voltage-gated calcium channel subunit α2δ-1 in spinal dorsal horn neurons contributes to aberrant excitatory synaptic transmission and mechanical hypersensitivity after peripheral nerve injury
Authors: Koga Keisuke , Kobayashi Kenta , Tsuda Makoto , Kubota Kazufumi , Kitano Yutaka , Furue Hidemasa
Published: March 2023

Neuropathic pain, an intractable pain symptom that occurs after nerve damage, is caused by the aberrant excitability of spinal dorsal horn (SDH) neurons. Gabapentinoids, the most commonly used drugs for neuropathic pain, inhibit spinal calcium-mediated neurotransmitter release by binding to α2δ-1, a subunit of voltage-gated calcium channels, and alleviate neuropathic pain. However, the exact contribution of α2δ-1 expressed in SDH neurons to the altered synaptic transmission and mechanical hypersensitivity following nerve injury is not fully understood. In this study, we investigated which types of SDH neurons express α2δ-1 and how α2δ-1 in SDH neurons contributes to the mechanical hypersensitivity and altered spinal synaptic transmission after nerve injury. Using in situ hybridization technique, we found that Cacna2d1, mRNA coding α2δ-1, was mainly colocalized with Slc17a6, an excitatory neuronal marker, but not with Slc32a1, an inhibitory neuronal marker in the SDH. To investigate the role of α2δ-1 in SDH neurons, we used clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system and showed that SDH neuron-specific ablation of Cacna2d1 alleviated mechanical hypersensitivity following nerve injury. We further found that excitatory post-synaptic responses evoked by electrical stimulation applied to the SDH were significantly enhanced after nerve injury, and that these enhanced responses were significantly decreased by application of mirogabalin, a potent α2δ-1 inhibitor, and by SDH neuron-specific ablation of Cacna2d1. These results suggest that α2δ-1 expressed in SDH excitatory neurons facilitates spinal nociceptive synaptic transmission and contributes to the development of mechanical hypersensitivity after nerve injury.
Dried fruit intake causally protects against low back pain: A Mendelian randomization study
Authors: Huang Jian , Xie Zheng-Fu
Published: March 2023

Background

Low back pain is the leading cause of years lived with disability worldwide. The aim of this study was to evaluate whether dried fruit intake causally protects against low back pain using two-sample Mendelian randomization (MR).

Methods

We obtained summary-level data for dried fruit intake (N = 421,764) from the IEU Open GWAS Project. Forty-one independent genetic variants proxied dried fruit intake. The corresponding data for low back pain were derived from the FinnGen project (13,178 cases and 164,682 controls; discovery data) and the Neale lab (5,423 cases and 355,771 controls; replication data). We conducted univariable and multivariable MR analyses.

Results

In the univariable MR analysis, the inverse variance weighted estimate showed that greater dried fruit intake was associated with decreased risk of low back pain [odds ratio (OR) = 0.435, 95% confidence interval (CI): 0.287–0.659, P = 8.657 × 10−5]. Sensitivity analyses using the MR-Egger (OR = 0.078, 95% CI: 0.013–0.479, P = 0.009), maximum likelihood (OR = 0.433, 95% CI: 0.295–0.635, P = 1.801 × 10−5), weighted median (OR = 0.561, 95% CI: 0.325–0.967, P = 0.038) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) (OR = 0.454, 95% CI: 0.302–0.683, P = 4.535 × 10−4) methods showed consistent results. No evidence of directional pleiotropy was identified according to the Egger intercept (intercept P-value = 0.065) or applying the MR-PRESSO method (global test P-value = 0.164). The replication analysis yielded similar results. The multivariable MR revealed that the inverse association between dried fruit intake and low back pain was consistent after adjustment for fresh fruit intake, body mass index, current tobacco smoking, alcohol intake frequency, total body bone mineral density, serum 25-hydroxyvitamin D levels, and vigorous physical activity.

Conclusion

This MR study provides evidence to support that dried fruit intake causally protects against low back pain.
A discriminant analysis of plasma metabolomics for the assessment of metabolic responsiveness to red raspberry consumption
Authors: Barbe Valentin , de Toro-Martín Juan , San-Cristobal Rodrigo , Garneau Véronique , Pilon Geneviève , Couture Patrick , Roy Denis , Couillard Charles , Marette André , Vohl Marie-Claude
Published: March 2023

Background

Many studies show that the intake of raspberries is beneficial to immune-metabolic health, but the responses of individuals are heterogeneous and not fully understood.

Methods

In a two-arm parallel-group, randomized, controlled trial, immune-metabolic outcomes and plasma metabolite levels were analyzed before and after an 8-week red raspberry consumption. Based on partial least squares discriminant analysis (PLS-DA) on plasma xenobiotic levels, adherence to the intervention was first evaluated. A second PLS-DA followed by hierarchical clustering was used to classify individuals into response subgroups. Clinical immune and metabolic outcomes, including insulin resistance (HOMA-IR) and sensitivity (Matsuda, QUICKI) indices, during the intervention were assessed and compared between response subgroups.

Results

Two subgroups of participants, type 1 responders (n = 17) and type 2 responders (n = 5), were identified based on plasma metabolite levels measured during the intervention. Type 1 responders showed neutral to negative effects on immune-metabolic clinical parameters after raspberry consumption, and type 2 responders showed positive effects on the same parameters. Changes in waist circumference, waist-to-hip ratio, fasting plasma apolipoprotein B, C-reactive protein and insulin levels as well as Matsuda, HOMA-IR and QUICKI were significantly different between the two response subgroups. A deleterious effect of two carotenoid metabolites was also observed in type 1 responders but these variables were significantly associated with beneficial changes in the QUICKI index and in fasting insulin levels in type 2 responders. Increased 3-ureidopropionate levels were associated with a decrease in the Matsuda index in type 2 responders, suggesting that this metabolite is associated with a decrease in insulin sensitivity for those subjects, whereas the opposite was observed for type 1 responders.

Conclusion

The beneficial effects associated with red raspberry consumption are subject to inter-individual variability. Metabolomics-based clustering appears to be an effective way to assess adherence to a nutritional intervention and to classify individuals according to their immune-metabolic responsiveness to the intervention. This approach may be replicated in future studies to provide a better understanding of how interindividual variability impacts the effects of nutritional interventions on immune-metabolic health.
Ketogenic diet alleviates renal fibrosis in mice by enhancing fatty acid oxidation through the free fatty acid receptor 3 pathway
Authors: Qiu Yang , Hu Xiaofan , Xu Cong , Lu Chenqi , Cao Rui , Xie Yanan , Yang Jun
Published: March 2023

Introduction

The ketogenic diet (KD), as a dietary intervention, has gained importance in the treatment of solid organ structural remodeling, but its role in renal fibrosis has not been explored.

Methods

Male C57BL/6 mice were fed a normal diet or a KD for 6 weeks prior to unilateral ureteral obstruction (UUO), a well-established in vivo model of renal fibrosis in rodents. Seven days after UUO, serum and kidney samples were collected. Serum β-hydroxybutyrate (β-OHB) concentrations and renal fibrosis were assessed. NRK52E cells were treated with TGFβ1, a fibrosis-inducing cytokine, and with or without β-OHB, a ketone body metabolized by KD, to investigate the mechanism underlying renal fibrosis.

Results

KD significantly enhanced serum β-OHB levels in mice. Histological analysis revealed that KD alleviated structural destruction and fibrosis in obstructed kidneys and reduced the expression of the fibrosis protein markers α-SMA, Col1a1, and Col3a1. Expression of the rate-limiting enzymes involved in fatty acid oxidation (FAO), Cpt1a and Acox1, significantly decreased after UUO and were upregulated by KD. However, the protective effect of KD was abolished by etomoxir (a Cpt1a inhibitor). Besides, our study observed that KD significantly suppressed UUO-induced macrophage infiltration and the expression of IL-6 in the obstructive kidneys. In NRK52E cells, fibrosis-related signaling was increased by TGFβ1 and reduced by β-OHB. β-OHB treatment restored the impaired expression of Cpt1a. The effect of β-OHB was blocked by siRNA targeting free fatty acid receptor 3 (FFAR3), suggesting that β-OHB might function through the FFAR3-dependent pathway.

Discussion

Our results highlight that KD attenuates UUO-induced renal fibrosis by enhancing FAO via the FFAR3-dependent pathway, which provides a promising dietary therapy for renal fibrosis.
Deciphering the origin of total estrogenic activity of complex mixtures
Authors: Debon Emma , Gentili Bastien , Latado Hélia , Serrant Patrick , Badoud Flavia , Ernest Marion , Christinat Nicolas , Bessaire Thomas , Schilter Benoit , Marin-Kuan Maricel
Published: March 2023

Introduction

Identifying compounds with endocrine properties in food is getting increasingly important. Current chemical analysis methodology is mainly focused on the identification of known substances without bringing insight for biological activity. Recently, the application of bioassays has been promoted for their potential to detect unknown bioactive substances and to provide information on possible interactions between molecules. From the toxicological perspective, measuring endocrine activity cannot inform on endocrine disruption and/or health risks without sufficient knowledge on the nature of the responsible factors.

Methods

The present study addresses a promising approach using High Performance Thin-Layer Chromatography (HPTLC) coupled to bioassays were analyzed using the Liquid Chromatography Mass-Spectrometry (LC-MS). The estrogen receptor activation was assessed using the transcription activation Estrogen Receptor Alpha Chemical Activated LUciferase gene eXpression assay (ERα- CALUX) and the HPTLC coupled to the Estrogen Screen Yeast assay (p-YES).

Results

Seven isoflavones were identified in the soy isolates. Estrogen receptor activation was assessed for both, the identified isoflavones and the soy isolates with ERα-CALUX test. Correlation between the soy isolates extracts and the identified isoflavones was shown. Moreover, p-YES revealed the presence of an estrogenic bioactive zone. Analysis of the bioactive zone through LCHRMS highlighted signals corresponding to several isoflavones already detected in the isolates as well as two additional ones. For all detected isoflavones, an estrogenic activity dose-response was established in both bioassays.

Conclusion

Finally, genistein, daidzein, and naringenin were found as the most active substances. A concordance analysis integrating the analytical and bioassay data indicated that genistein and daidzein were the drivers of the estrogenic activity of these soy protein isolates. Altogether, these data suggest that the integration of HPTLC-bioassay together with chemical analysis is a powerful approach to characterize the endocrine activity of complex mixtures.
Tim3 and PD-1 as a therapeutic and prognostic targets in colorectal cancer: Relationship with sidedness, clinicopathological parameters, and survival
Authors: Mokhtari Zahra , Rezaei Marzieh , Sanei Mohammad Hossein , Dehghanian Amirreza , Faghih Zahra , Heidari Zahra , Tavana Shirin
Published: March 2023

Background

Colorectal cancer (CRC) is a heterogeneous disease that complicates predicting patients’ prognosis and their response to treatment. CRC prognosis is influenced by the tumor microenvironment (TME). The immune system is a critical component of the TME. Programmed cell death receptor 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (Tim3) are inhibitory immune checkpoints that regulate immune response and may provide prognostic power. However, the effect of their expressions and co-expressions on the CRC prognosis remains unclear. Accordingly, this study aimed to investigate the prognostic value of the CD8, CD3, PD-1, Tim3 expression, and PD-1/Tim3 co-expression in patients with CRC.

Materials and Methods

One hundred and thirty six patients with CRC who underwent curative surgery were enrolled in the study. Immunohistochemical staining was performed for PD-1, Tim3, CD8, and CD3, and the expression of each marker was evaluated in the center of the tumor (CT), invasive margin (IM), and adjacent normal-like tissue.

Result

Our results indicated that high expression of PD-1 in IM was significantly associated with lower TNM stage, T-stage, M-stage, lack of metastasis, the presence of tertiary lymphoid structure (TLS), lack of recurrence (in the left-sided tumors), and larger tumor size (in right-sided tumors) (P<0.05). High expression of PD-1 in IM was also associated with improved overall survival (OS) in a subgroup of patients with high CD8 expression. High Tim3 expression in CT was associated with higher M-stage (M1) (in left-sided CRCs) (P<0.05). It was also associated with decreased OS in total cohort and left-sided CRCs and represented an independent prognostic factor for CRC patients in multivariate analysis. PD-1 and Tim3 co-expression had no synergistic effects on predicting OS.

Conclusion

Our findings suggest that the clinicopathological and prognostic significance of immune system-related markers such as CD8, PD-1, and Tim3 depends on the primary tumor sides. We also showed that Tim3 could act as a prognostic factor and therapeutic target in CRC. This marker is probably a more preferred target for immunotherapy than PD-1, especially in left-sided CRCs.
Outcome of the first 200 patients with prostate cancer treated with MRI-Linac at Assuta MC
Authors: Gelbart Pridan Or , Ben David Merav Akiva , Zalmanov Svetlana , Lipski Yoav , Grinberg Vladislav , Levin Daphne , Apter Sara , Guindi Michal , Epstein Dan , Radus Roman , Arsenault Orit , Hod Keren , Tamami Qusai , Pfeffer Raphael
Published: March 2023

Background

We present our experience with MR-guided stereotactic body radiotherapy (SBRT) for 200 consecutive patients with prostate cancer with minimum 3-month follow-up.

Methods

Treatment planning included fusion of the 0.35-Tesla planning MRI with multiparametric MRI and PET-PSMA for Group Grade (GG) 2 or higher and contour review with an expert MRI radiologist. No fiducials or rectal spacers were used. Prescription dose was 36.25 Gy in 5 fractions over 2 weeks to the entire prostate with 3-mm margins. Daily plan was adapted if tumor and organs at risk (OAR) doses differed significantly from the original plan. The prostate was monitored during treatment that was automatically interrupted if the target moved out of the PTV range.

Results

Mean age was 72 years. Clinical stage was T1c, 85.5%; T2, 13%; and T3, 1.5%. In addition, 20% were GG1, 50% were GG2, 14.5% were GG3, 13% were GG4, and one patient was GG5. PSA ranged from 1 to 77 (median, 6.2). Median prostate volume was 57cc, and 888/1000 (88%) fractions required plan adaptation. The most common acute GU toxicity was Grade I, 31%; dysuria and acute gastrointestinal toxicity were rare. Three patients required temporary catheterization. Prostate size of over 100cc was associated with acute fatigue, urinary hesitance, and catheter insertion. Prostate Specific Antigen (PSA) decreased in 99% of patients, and one patient had regional recurrence.

Conclusion

MR-guided prostate SBRT shows low acute toxicity and excellent short-term outcomes. Real-time MRI ensures accurate positioning and SBRT delivery.
Epidemiology and mortality predictors for severe childhood community-acquired pneumonia in ICUs: A retrospective observational study
Authors: Cao Lu , Ji Zhaohua , Zhang Peng , Wang Jingwen
Published: March 2023

Background

To identify the epidemiology and mortality predictors of severe childhood community-acquired pneumonia (CAP) and evaluate the influence of medications on clinical outcomes in the real world.

Methods

We conducted a multicenter retrospective observational study among children aged ≤5 years with severe CAP, separately comparing the detailed information between those who experienced in-hospital death and those who survived in three different age groups. A multivariate logistic regression model was used to determine mortality predictors.

Results

A total of 945 children were recruited: 341 young children aged 2–59 months, 47 infants aged 29 days to 2 months, and 557 neonates aged less than 28 days. A total of 88 deaths occurred (9.3%). There was low adherence to antimicrobial guidelines in the group aged 2–59 months, and carbapenems widely served as initial empirical regimens. However, analysis of all three age groups showed that the efficacy of antibacterial drugs with initial empirical selection grades higher than those recommended by the guidelines was not better than that of antibacterial drugs with grades recommended by the guidelines. In multivariate analyses, very severe pneumonia (odds ratio (OR): 3.48; 95% confidence interval (CI): 1.36–8.93), lower birth weight (OR: 4.64; 95% CI: 1.78–12.20), severe underweight (OR: 6.06; 95% CI: 2.34–15.63), mechanical ventilation (OR: 2.58; 95% CI: 1.00–6.62; OR: 15.63; 95% CI 3.25–76.92), a higher number of comorbidities (OR: 8.40; 95% CI: 1.89–37.04), comorbidities including anemia (OR: 5.24; 95% CI: 2.33–11.76) and gastrointestinal hemorrhage (OR: 3.79; 95% CI: 1.36–10.53), and the use of sedative-hypnotics (OR: 2.60; 95% CI: 1.14–5.95) were independent risk factors for death; infants treated with probiotics had a lower mortality rate (OR: 0.14; 95% CI: 0.06–0.33).

Conclusions

Severe CAP remains a primary cause of death in children under 5 years of age. Clinical characteristics, comorbidities and medications are evidently associated with death. Importantly, we should pay particular attention to the identification of mortality predictors and establish prophylactic measures to reduce mortality.
Rapid ventricular overdrive pacing and other advanced flow-control techniques for the endovascular embolization of vein of galen malformations
Authors: Baranoski Jacob F. , Catapano Joshua S. , Albuquerque Felipe C. , Abruzzo Todd A.
Published: March 2023

Endovascular embolization is the primary strategy in the management for vein of Galen malformations (VOGM). However, despite significant advances in endovascular embolization technologies and techniques, VOGMs remain very technically challenging lesions largely due to the high-flow arteriovenous shunts present in these malformations. A variety of advanced flow-control techniques can be implemented to mitigate the risk of venous escape and increase the safety and efficacy of endovascular treatment. These techniques include regionally targeted strategies (transvenous embolization and balloon-assisted transarterial embolization) and global flow-control methods (pharmacologic cardiac arrest and rapid ventricular overdrive pacing). Each of these strategies are associated with unique advantages and disadvantages, highlighting the importance of a patient-specific approach when treating these challenging lesions.
Pediatric Crohn's disease diagnosis aid via genomic analysis and machine learning
Authors: Zheng Zhiwei , Zhan Sha , Zhou Yongmao , Huang Ganghua , Chen Pan , Li Baofei
Published: March 2023

Introduction

Determination of pediatric Crohn's disease (CD) remains a major diagnostic challenge. However, the rapidly emerging field of artificial intelligence has demonstrated promise in developing diagnostic models for intractable diseases.

Methods

We propose an artificial neural network model of 8 gene markers identified by 4 classification algorithms based on Gene Expression Omnibus database for diagnostic of pediatric CD.

Results

The model achieved over 85% accuracy and area under ROC curve value in both training set and testing set for diagnosing pediatric CD. Additionally, immune infiltration analysis was performed to address why these markers can be integrated to develop a diagnostic model.

Conclusion

This study supports further clinical facilitation of precise disease diagnosis by integrating genomics and machine learning algorithms in open-access database.
Spider venom-derived peptide JZTX-14 prevents migration and invasion of breast cancer cells via inhibition of sodium channels
Authors: Wu Wenfang , Yin Yuan , Feng Peihao , Chen Gong , Pan Liangyu , Gu Panyang , Zhou Siqin , Lin Fulong , Ji Siyu , Zheng Chunbing , Deng Meichun
Published: March 2023

Nav1.5 channel is crucial for the proliferation and migration of breast cancer cells. In this study, we investigated the anticancer effect of JZTX-14, a natural peptide considered an effective antagonist of Nav1.5. First, we successfully isolated and purified the 31 amino acid peptide JZTX-14 containing three pairs of disulfide bonds from spider venom and synthesised JZTX-14 by solid phase synthesis. We then predicted their physiochemical properties and structures in the peptide database. Further, we investigated the effects of natural and synthetic JZTX-14 on the proliferation and migration of MDA-MB-231 breast cancer cells via modulation of sodium current through the Nav1.5 channel. The results showed that both synthetic and natural JZTX-14 inhibited Nav1.5 currents, indicating the successful synthesis of JZTX-14. However, JZTX-14 did not affect MDA-MB-231 cell proliferation but inhibited its migration. Transcriptome analysis revealed that JZTX-14 downregulated S100A4 and FBXO2 and upregulated SERPINB2 in MDA-MB-231 cells. Western blot analysis demonstrated an increased level of the epithelial marker, E-cadherin, and decreased levels of the mesenchymal markers, N-cadherin and vimentin, and matrix metalloproteinase (MMP2), indicating the possible underlying mechanism of the inhibition of MDA-MB-231 cell migration by JZTX-14. This study provides a new target for inhibiting breast cancer metastasis and identifies a potent natural peptide for treating Triple-negative breast cancer.
An updated overview of anticancer effects of alternariol and its derivatives: underlying molecular mechanisms
Authors: Islam Muhammad Torequl , Martorell Miquel , González-Contreras Carlos , Villagran Marcelo , Mardones Lorena , Tynybekov Bekzat , Docea Anca Oana , Abdull Razis Ahmad Faizal , Modu Babagana , Calina Daniela , Sharifi-Rad Javad
Published: March 2023

Alternariol is a toxic metabolite of Alternaria fungi and studies have shown multiple potential pharmacological effects. To outline the anticancer effects and mechanisms of alternariol and its derivatives based on database reports, an updated search of PubMed/MedLine, ScienceDirect, Web of Science, and Scopus databases was performed with relevant keywords for published articles. The studies found to suggest that this mycotoxin and/or its derivatives have potential anticancer effects in many pharmacological preclinical test systems. Scientific reports indicate that alternariol and/or its derivatives exhibit anticancer through several pathways, including cytotoxic, reactive oxygen species leading to oxidative stress and mitochondrial dysfunction-linked cytotoxic effect, anti-inflammatory, cell cycle arrest, apoptotic cell death, genotoxic and mutagenic, anti-proliferative, autophagy, and estrogenic and clastogenic mechanisms. In light of these results, alternariol may be one of the hopeful chemotherapeutic agents.
Metabonomic analysis of the anti-hepatic fibrosis effect of Ganlong capsules
Authors: Lv ChangLing , Li YinRui , Ou Ling , Zhou Jie , Peng Fang , Wu DingYu
Published: March 2023

Context: Hepatic fibrosis is a progressive condition, often attributed to metabolic disorders, which may promote cirrhosis and liver cancer. Ganlong capsules derived from Periplaneta Americana have been shown to have a therapeutic effect on liver fibrosis but little is known about the molecular mechanisms involved.

Objective: To investigate the metabolic modulations produced by Ganlong capsules in liver fibrosis.

Methods: A carbon tetrachloride- (CCl4) treated rat model of liver fibrosis was constructed and Ganlong capsules administered. Levels of serum liver enzymes and pathological changes to the liver were evaluated. Non-targeted metabolomics of liver, serum and urine were used to investigate metabolic regulatory mechanisms.

Results:Ganlong capsules reduced serum levels of liver enzymes and improved pathological changes in the rat model of fibrosis. Non-targeted metabolomics showed that Ganlong capsules ameliorated pathways of glycerophospholipid, linoleic acid, pyrimidine, glycine, butyric acid, valine, serine, threonine and arachidonic acid metabolism and biosynthesis of leucine and isoleucine. Such pathways influence the development of CCl4-induced liver fibrosis.

Conclusion:Ganlong capsules had an anti-fibrotic hepatoprotective effect and regulated lipid, butyric acid, amino acid and arachidonic acid metabolism.
Association of thiamine administration and prognosis in critically ill patients with heart failure
Authors: Yang Rui , Huang Jiasheng , Zhao Yumei , Wang Jia , Niu Dongdong , Ye Enlin , Yue Suru , Hou Xuefei , Cui Lili , Wu Jiayuan
Published: March 2023

Background: Thiamine deficiency is common in patients with heart failure, and thiamine supplement can benefit these patients. However, the association between thiamine administration and prognosis among critically ill patients with heart failure remains unclear. Thus, this study aims to prove the survival benefit of thiamine use in critically ill patients with heart failure.

Methods: A retrospective cohort analysis was performed on the basis of the Medical Information Mart of Intensive Care-Ⅳ database. Critically ill patients with heart failure were divided into the thiamine and non-thiamine groups depending on whether they had received thiamine therapy or not during hospitalization. The association between thiamine supplement and in-hospital mortality was assessed by using the Kaplan−Meier (KM) method and Cox proportional hazard models. A 1:1 nearest propensity-score matching (PSM) and propensity score-based inverse probability of treatment weighting (IPW) were also performed to ensure the robustness of the findings.

Results: A total of 7,021 patients were included in this study, with 685 and 6,336 in the thiamine and non-thiamine groups, respectively. The kaplan−meier survival curves indicated that the thiamine group had a lower in-hospital mortality than the none-thiamine group. After adjusting for various confounders, the Cox regression models showed significant beneficial effects of thiamine administration on in-hospital mortality among critically ill patients with heart failure with a hazard ratio of 0.78 (95% confidence interval: 0.67–0.89) in the fully adjusted model. propensity-score matching and probability of treatment weighting analyses also achieved consistent results.

Conclusion: Thiamine supplement is associated with a decreased risk of in-hospital mortality in critically ill patients with heart failure who are admitted to the ICU. Further multicenter and well-designed randomized controlled trials with large sample sizes are necessary to validate this finding.
Random effects modelling versus logistic regression for the inclusion of cluster-level covariates in propensity score estimation: A Monte Carlo simulation and registry cohort analysis
Authors: Du Mike , Prats-Uribe Albert , Khalid Sara , Prieto-Alhambra Daniel , Strauss Victoria Y.
Published: March 2023

Purpose: Surgeon and hospital-related features, such as volume, can be associated with treatment choices and outcomes. Accounting for these covariates with propensity score (PS) analysis can be challenging due to the clustered nature of the data. We studied six different PS estimation strategies for clustered data using random effects modelling (REM) compared with logistic regression.

Methods: Monte Carlo simulations were used to generate variable cluster-level confounding intensity [odds ratio (OR) = 1.01–2.5] and cluster size (20–1,000 patients per cluster). The following PS estimation strategies were compared: i) logistic regression omitting cluster-level confounders; ii) logistic regression including cluster-level confounders; iii) the same as ii) but including cross-level interactions; iv), v), and vi), similar to i), ii), and iii), respectively, but using REM instead of logistic regression. The same strategies were tested in a trial emulation of partial versus total knee replacement (TKR) surgery, where observational versus trial-based estimates were compared as a proxy for bias. Performance metrics included bias and mean square error (MSE).

Results: In most simulated scenarios, logistic regression, including cluster-level confounders, led to the lowest bias and MSE, for example, with 50 clusters × 200 individuals and confounding intensity OR = 1.5, a relative bias of 10%, and MSE of 0.003 for (i) compared to 32% and 0.010 for (iv). The results from the trial emulation also gave similar trends.

Conclusion: Logistic regression, including patient and surgeon-/hospital-level confounders, appears to be the preferred strategy for PS estimation.