bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying Optimal Surgical Intervention-Based Chemotherapy for Gastric Cancer Patients With Liver Metastases
Authors: Sun Min , Ding Hangliang , Zhu Zhiqiang , Wang Shengsheng , Gu Xinsheng , Xia Lingyun , Li Tian
Published: December 2021

Background

This study aimed at evaluating the effects of surgical treatments-based chemotherapy in the treatment of gastric cancer with liver metastases (GCLM). It has not been established whether Liver-directed treatment (LDT) options such as hepatectomy and gastrectomy plus chemotherapy (HGCT), radiofrequency ablation and gastrectomy plus chemotherapy (RFAG), transarterial chemoembolization and gastrectomy plus chemotherapy (TACEG), gastrectomy plus chemotherapy (GCT) enhance the survival of GCLM patients.

Methods

We performed systematic literature searches in PubMed, EMBASE, and Cochrane library from inception to September 2021. We created a network plot to comprehensively analyze the direct and indirect evidence, based on a frequentist method. A contribution plot was used to determine inconsistencies, a forest plot was used to evaluate therapeutic effects, the publication bias was controlled by funnel plot, while the value of surface under the cumulative ranking curves (SUCRA) was calculated to estimate rank probability.

Results

A total of 23 retrospective studies were identified, involving 5472 GCLM patients. For OS and 1-, 2-, 3-year survival rate of all trials, meta-analysis of the direct comparisons showed significant better for HGCT treatments compared with GCT or PCT. In the comparison of the 5 treatments for 1-, 2-, 3-year survival rate, HGCT and RFAG were found to be more effective than GCT and PCT, respectively. By OS and 2-, 3-year survival rate analysis, RFAG was identified as the best option, followed by HGCT, TACEG, GCT and PCT. By 1-year survival rate analysis, HGCT and RFAG were identified as the most effective options.

Conclusion

HGCT and RFAG has remarkable survival benefits for GCLM patients when compared to TACEG, GCT and PCT. HGCT was found to exhibit superior therapeutic effects for GCLM patients for 1-year survival rate while RFAG was found to be a prospective therapeutic alternative for OS and 2-, 3-year survival rate.

Systematic Review Registration

identifier [10.37766/inplasy2020.12.0009].
Rare Metastasis to the Submandibular Gland in Oral Squamous Cell Carcinoma
Authors: Zhou Ping , Chen Jing-Xin , Zhou Yuan , Lian Chen-Lu , Yan Bing , Wu San-Gang
Published: December 2021

Purpose

In the current recommendation of neck dissection in oral squamous cell carcinoma (OSCC), the submandibular gland (SMG) should also be removed. This study aimed to investigate the incidence and the patterns of SMG involvement in OSCC patients.

Methods

Patients initially diagnosed with OSCC between January 2018 and October 2020 were included. The distribution of lymph nodes metastasis in level IB was analyzed.

Results

We included 145 patients who underwent primary surgery and neck dissection in this study. All patients had level IB lymph node dissection and simultaneous removal of the SMG. Of these patients, only one patient (0.7%) had involvement in SMG by directly infiltrating from the primary tumor. A total of 18 positive lymph nodes were found in level IB in 16 patients, and no positive lymph nodes were located in the SMG. There were 6 lymph nodes located in the lateral part of the SMG and 12 lymph nodes located in the anterior of the SMG. Patients with tumors located in the buccal mucosa and N3 stage were the independent predictive factors associated with level IB nodal metastasis.

Conclusion

Involvement of SMG in OSCC is quite rare. Preservation of the SMG during neck dissection in selected patients with OSCC seems to be feasible and oncologically safe.
Account for the Full Extent of Esophagus Motion in Radiation Therapy Planning: A Preliminary Study of the IRV of the Esophagus
Authors: Feng Aihui , Gu Hengle , Chen Hua , Shao Yan , Wang Hao , Duan Yanhua , Huang Ying , Zhou Tao , Xu Zhiyong
Published: December 2021

Objective

Accounting for esophagus motion in radiotherapy planning is an important basis for accurate assessment of toxicity. In this study, we calculated how much the delineations of the esophagus should be expanded based on three-dimensional (3D) computed tomography (CT), four-dimensional (4D) average projection (AVG), and maximum intensity projection (MIP) scans to account for the full extent of esophagus motion during 4D imaging acquisition.

Methods and Materials

The 3D and 4D CT scans of 20 lung cancer patients treated with conventional radiotherapy and 20 patients treated with stereotactic ablative radiation therapy (SBRT) were used. Radiation oncologists contoured the esophagus on the 3DCT, AVG, MIP and 25% exhale scans, and the combination of the esophagus in every phase of 4DCT. The union of all 4D phase delineations (U4D) represented the full extent of esophagus motion during imaging acquisition. Surface distances from U4D to 3D, AVG, and MIP volumes were calculated. Distances in the most extreme surface points (1.5 cm most superoinferior, 10% most right/left/anteroposterior) were used to derive margins accounting only for systematic (delineation) errors.

Results

Esophagus delineations on the MIP were the closest to the full extent of motion, requiring only 6.9 mm margins. Delineations on the AVG and 3D scans required margins up to 7.97 and 7.90 mm, respectively. The largest margins were for the inferior, right, and anterior aspects for the delineations on the 3D, AVG, and MIP scans, respectively.

Conclusion

Delineations on 3D, AVG, or MIP scans required extensions for representing the esophagus’s full extent of motion, with the MIP requiring the smallest margins. Research including daily imaging to determine the random components for the margins and dosimetric measurements to determine the relevance of creating a planning organ at risk volume (PRV) of the esophagus is required.
Gustave Roussy Immune Score as a Novel Prognostic Scoring System for Colorectal Cancer Patients: A Propensity Score Matching Analysis
Authors: Tian Shan , Cao Yinghao , Duan Yanran , Liu Qi , Peng Pailan
Published: December 2021

Aim

The Gustave Roussy Immune Score (GRIm-Score) was originally designed to select cancer patients for immunotherapy, and later was reported to be a novel prognostic scoring system in lung cancer and esophageal cancer. This study was aimed to determine the prognostic role and predictive performance of GRIm-Score in colorectal cancer (CRC) CRC patients.

Methods

We conducted a single-institution study of 1,579 adult CRC patients receiving surgical removal, and those patients were divided into low GRIm-Score group (scores 0, 1) and high GRIm-Score group (scores 2, 3). Propensity score matching (PSM) was executed to balance the potential confounding factors between the two groups. Survival and time-dependent receiver operating characteristic (Td-ROC) analyses were applied to depict the prognostic role and predictive significance of GRIm-Score in CRC patients.

Results

There were 200 cases CRC patients in high GRIm-Score group and 1,379 cases in low GRIm-Score group. CRC patients with high GRIm-Score correspond with higher level of CEA, CA125, and inflammatory indexes, such as NLR, PLR, SII, PNI, and ALRI. Correlation analysis exhibited that GRIm-Score correlated well with the established inflammatory indexes. Survival analysis revealed that CRC patients in high GRIm-Score group showed worse overall survival (OS, P <0.0001) and disease-free survival (DFS, P <0.0001) compared with those in low GRIm-Score group. Results from multivariate Cox regression implicated that high GRIm-Score was not only a potent prognostic index for unfavorable OS (HR = 1.622, 95%CI: 1.118–2.355, P = 0.0109), but also a potent risk factor for worse DFS (HR = 1.743, 95%CI: 1.188–2.558, P = 0.0045). Td-ROC analysis demonstrated that GRIm-Score exhibited the superior discriminatory power in the prediction of OS and DFS when compared to SII, PNI, and ALRI. Such strong associations between high levels of preoperative GRIm-Score and unfavorable survival outcomes remained robust after PSM analysis.

Conclusion

GRIm-Score, a novel inflammatory and nutritional risk scoring system, is a potent prognostic index in CRC patients receiving surgical removal. GRIm-Score can be used as an effective and simplified risk stratification tool for postoperative survival prediction of CRC patients.
Cerebral Structural Abnormalities and Their Associations With Peripheral Cytokine Levels in a Group of Untreated Patients With Nasopharyngeal Carcinoma
Authors: Wang Yan , Zhang Wenjing , Wu Xin , Luo Xinmei , Li Siyi , Zhu Guannan , Liu Jie , Gong Qiyong , Jiang Yu , Lui Su
Published: December 2021

The current study is to characterize the alterations of peripheral cytokines and anatomical brain changes, and their relationships in untreated nasopharyngeal carcinoma (NPC) patients with depressive symptoms. Twenty-nine newly diagnosed NPC patients without any treatment and 46 matched healthy comparisons were recruited, scanned with high-resolution T1 images and assessed psychologically using Hamilton Rating Scale for Depression (HAMD). Serum levels of interleukin-1 beta (IL-1β), IL-2, IL-6, IL-8, IL-10, interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-β) were measured by quantitative chemiluminescence assay. Inter-group comparisons of anatomical brain measures were performed, and regions with significant inter-group differences were correlated to HAMD scores and cytokines in NPC patients. A subgroup analysis especially within NPC patients with depression was conducted to precisely characterize the associations among serum cytokines, brain changes and depressive symptoms. Relative to healthy subjects, NPC patients showed significantly decreased cortical thickness in the left parahippocampal gyrus, increased surface area in the right superior parietal lobule and precentral gyrus, and increased gray matter volume in the right postcentral gyrus, bilateral caudate nucleus and right thalamus, as well as significantly elevated IL-1β, IL-2 and IL-10. The elevated IL-2 and IL-10 were negatively correlated with surface area in right superior parietal lobule, whilst IL-1β level was positively correlated to HAMD scores. In patients with depression, specific brain changes and evaluated IL-1β were identified, and the IL-1β interacted with right precentral gyrus to significantly affect the depressive symptoms. Our findings provide novel evidence indicating potential effects of inflammation on brain structure and behavior in NPC patients.
Oral Squamous Cell Carcinoma in Young Patients Show Higher Rates of EGFR Amplification: Implications for Novel Personalized Therapy
Authors: Satgunaseelan Laveniya , Porazinski Sean , Strbenac Dario , Istadi Aji , Willet Cali , Chew Tracy , Sadsad Rosemarie , Palme Carsten E. , Lee Jenny H. , Boyer Michael , Yang Jean Y. H. , Clark Jonathan R. , Pajic Marina , Gupta Ruta
Published: December 2021

There is an increasing worldwide incidence of patients under 50 years of age presenting with oral squamous cell carcinoma (OSCC). The molecular mechanisms driving disease in this emerging cohort remain unclear, limiting impactful treatment options for these patients. To identify common clinically actionable targets in this cohort, we used whole genome and transcriptomic sequencing of OSCC patient samples from 26 individuals under 50 years of age. These molecular profiles were compared with those of OSCC patients over 50 years of age (n=11) available from TCGA. We show for the first time that a molecular signature comprising of EGFR amplification and increased EGFR RNA abundance is specific to the young subset of OSCC patients. Furthermore, through functional assays using patient tumor-derived cell lines, we reveal that this EGFR amplification results in increased activity of the EGFR pathway. Using a panel of clinically relevant EGFR inhibitors we determine that an EGFR-amplified patient-derived cell line is responsive to EGFR inhibition, suggesting EGFR amplification represents a valid therapeutic target in this subset of OSCC patients. In particular, we demonstrate sensitivity to the second-generation EGFR tyrosine kinase inhibitor afatinib, which offers a new and promising therapeutic avenue versus current EGFR-targeting approaches. We propose that testing for EGFR amplification could easily be integrated into current diagnostic workflows and such measures could lead to more personalized treatment approaches and improved outcomes for this younger cohort of OSCC patients.
Cost-Effectiveness Analysis of Pembrolizumab Plus Pemetrexed and Platinum Versus Chemotherapy Alone as First-Line Treatment in Metastatic Non-Squamous Non–Small Cell Lung Cancer: A Reconstruction of Partitioned Survival Model Based on Time Dependent Pricing Mechanism of Patient Assistance Program
Authors: Cai Yuanyi , Hui Wen , Zhu Min , Zhang Mingyue , Gao Zhixiang , Wu Huazhang
Published: December 2021

Objectives

A new patient assistance program (PAP) for pembrolizumab was started in China in 2021. The researchers aimed to evaluate the economic outcomes of pembrolizumab plus pemetrexed and platinum versus chemotherapy alone in the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, based on the pricing mechanism of PAP.

Material and Methods

Survival analysis and partitioned survival model were performed to evaluate the incremental cost-effectiveness ratio (ICER) in the pembrolizumab group compared with the chemotherapy group. Survival probabilities were extracted from the data of the KEYNOTE-189 trial. Cost and utility data were gathered from published literature. The pricing mechanism of PAP was set in each cycle in the partitioned survival model, according to the progression-free survival (PFS) data of the KEYNOTE-189 trial, which included PFS-1 and PFS-2. Deterministic sensitivity analysis and probabilistic sensitivity analysis were conducted.

Results

The ICER of the pembrolizumab group versus chemotherapy group was $65,272/quality-adjusted life year (QALY), which still exceeded the willingness-to-pay threshold of three times per capita gross domestic product (GDP) of China ($33,581.22), although PAP was calculated. Sensitivity analysis implied that the price of chemotherapeutic drugs combined with pembrolizumab was one of the main influencing factors of ICER.

Conclusions

Due to various prices set by PAP and the payment for combined chemotherapy, the economic advantage of pembrolizumab plus chemotherapy in the first-line treatment of non-small cell lung cancer (NSCLC) is still not achieved in China.
Predicting Breast Cancer Gene Expression Signature by Applying Deep Convolutional Neural Networks From Unannotated Pathological Images
Authors: Phan Nam Nhut , Huang Chi-Cheng , Tseng Ling-Ming , Chuang Eric Y.
Published: December 2021

We proposed a highly versatile two-step transfer learning pipeline for predicting the gene signature defining the intrinsic breast cancer subtypes using unannotated pathological images. Deciphering breast cancer molecular subtypes by deep learning approaches could provide a convenient and efficient method for the diagnosis of breast cancer patients. It could reduce costs associated with transcriptional profiling and subtyping discrepancy between IHC assays and mRNA expression. Four pretrained models such as VGG16, ResNet50, ResNet101, and Xception were trained with our in-house pathological images from breast cancer patient with recurrent status in the first transfer learning step and TCGA-BRCA dataset for the second transfer learning step. Furthermore, we also trained ResNet101 model with weight from ImageNet for comparison to the aforementioned models. The two-step deep learning models showed promising classification results of the four breast cancer intrinsic subtypes with accuracy ranging from 0.68 (ResNet50) to 0.78 (ResNet101) in both validation and testing sets. Additionally, the overall accuracy of slide-wise prediction showed even higher average accuracy of 0.913 with ResNet101 model. The micro- and macro-average area under the curve (AUC) for these models ranged from 0.88 (ResNet50) to 0.94 (ResNet101), whereas ResNet101_imgnet weighted with ImageNet archived an AUC of 0.92. We also show the deep learning model prediction performance is significantly improved relatively to the common Genefu tool for breast cancer classification. Our study demonstrated the capability of deep learning models to classify breast cancer intrinsic subtypes without the region of interest annotation, which will facilitate the clinical applicability of the proposed models.
circRNAs: Insight Into Their Role in Tumor-Associated Macrophages
Authors: Duan Saili , Wang Shan , Huang Tao , Wang Junpu , Yuan Xiaoqing
Published: December 2021

Currently, it is well known that the tumor microenvironment not only provides energy support for tumor growth but also regulates tumor signaling pathways and promotes the proliferation, invasion, metastasis, and drug resistance of tumor cells. The tumor microenvironment, especially the function and mechanism of tumor-associated macrophages (TAMs), has attracted great attention. TAMs are the most common immune cells in the tumor microenvironment and play a vital role in the occurrence and development of tumors. circular RNA (circRNA) is a unique, widespread, and stable form of non-coding RNA (ncRNA), but little is known about the role of circRNAs in TAMs or how TAMs affect circRNAs. In this review, we summarize the specific manifestations of circRNAs that affect the tumor-associated macrophages and play a significant role in tumor progression. This review helps improve our understanding of the association between circRNAs and TAMs, thereby promoting the development and progress of potential clinical targeted therapies.
Xp11.2 Translocation Renal Cell Carcinoma With TFE3 Rearrangement: Distinct Morphological Features and Prognosis With Different Fusion Partners
Authors: Ge Yan , Lin Xingtao , Zhang Qingling , Lin Danyi , Luo Luqiao , Wang Huiling , Li Zhi
Published: December 2021

Background

Renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion is a rare and new subtype of RCC and was classified by the WHO in 2004. Since then, multiple 5′ fusion partners for TFE3 have been reported; however, the impact of individual fusion variant on specific clinicopathologic features of Xp11.2 RCCs has not been well defined.

Methods

Four Xp11.2 translocation RCCs were identified by morphological, immunostaining, and fluorescence in situ hybridization (FISH) assays from 200 patients who attended Guangdong General Hospital between January 2017 and January 2020. All these four cases were further analyzed by RNA sequencing to explore their TFE3 gene fusion partners. The clinicopathologic features, including clinical manifestations, pathological findings, treatment strategies, clinical outcomes, and follow-up information on Xp11.2 translocation RCCs, were recorded and evaluated.

Results

These four cases affected one male and three females. The median age was 13 years at the time of diagnosis (range = 4–20 years). All the examined tumors were unilateral and unifocal. The largest diameter of these tumors ranged from 2.0 to 10.0 cm, and the average was 5.55 cm. Regional lymph node or distant metastasis developed in two patients. Three cases demonstrated known fusions: ASPCR1–TFE3 (two cases) and PRCC–TFE3 (one case). However, one case showed an unreported VCP–TFE3 fusion gene in Xp11.2 translocation RCCs. Immunohistochemistry results revealed tumor cells diffusely positive for TFE3, but have no consistency in other markers. Moreover, there were different clinical prognoses among the different variant TFE3 rearrangements; RCC patients with VCP–TFE3 translocation had worse prognosis compared to those with other fusion types. Follow-up were available for all the patients and ranged from 3 to 36 months. Three patients were without evidence of disease progression, while that with VCP–TFE3 fusion died of the disease 3 months after the diagnosis.

Conclusion

In conclusion, our data expand the list of TFE3 gene fusion partners and the clinicopathologic features of Xp11.2 RCCs with specific TFE3 gene fusions. We identified a novel VCP–TFE3 fusion in Xp11.2 translocation RCCs for the first time, which has unique morphology and worse prognosis than those with other variant TFE3 rearrangements. Integration of morphological, immunohistochemical, and molecular methods is often necessary for the precise diagnosis and optimal clinical management of malignant tumors.
Concurrent Newborn Hearing and Genetic Screening in a Multi-Ethnic Population in South China
Authors: Tang Xiangrong , Liu Lihua , Liang Sulan , Liang Meie , Liao Tao , Luo Shiqiang , Yan Tizhen , Chen Jianping
Published: December 2021

Hearing loss is a common sensory deficit in humans with intricate genomic landscape and mutational signature. Approximately 1–3 out of 1,000 newborns have hearing loss and up to 60% of these cases have a genetic etiology. In this study, we conducted the concurrent newborn hearing and genetic screening in 20 mutations (18 pathogenic variants in GJB2, SLC26A4, and MT-RNR1 and 2 uncertain clinical significance variants in GJB3) for 9,506 normal newborns (4,977 [52.4%] males) from 22 ethnic population in South China. A total of 1,079 (11.4%) newborns failed to pass the initial hearing screening; 160 (1.7%) infants failed to pass the re-screening, and 135 (1.4%) infants presented the diagnostic hearing loss. For the genetic screening, 220 (2.3%) newborns who presented at least one of the screened mutations were more likely to fail the hearing screening and have diagnostic hearing loss than mutation-negative newborns. In comparison to the differences of distribution of mutations, we did not identify any significant difference in the prevalence of screened mutations between Han group (n = 5,265) and Zhuang group (n = 3,464), despite the lack of number of minority ethnic groups. Studies including larger number of minority ethnic populations are needed in the future.
Joint Modeling of Singleton Preterm Birth and Perinatal Death Using Birth Registry Cohort Data in Northern Tanzania
Authors: Mboya Innocent B. , Mahande Michael J. , Obure Joseph , Mwambi Henry G.
Published: December 2021

Understanding independent and joint predictors of adverse pregnancy outcomes is essential to inform interventions toward achieving sustainable development goals. We aimed to determine the joint predictors of preterm birth and perinatal death among singleton births in northern Tanzania based on cohort data from the Kilimanjaro Christian Medical Center (KCMC) zonal referral hospital birth registry between 2000 and 2017. We determined the joint predictors of preterm birth and perinatal death using the random-effects models to account for the correlation between these outcomes. The joint predictors of higher preterm birth and perinatal death risk were inadequate (<4) antenatal care (ANC) visits, referred for delivery, experiencing pre-eclampsia/eclampsia, postpartum hemorrhage, low birth weight, abruption placenta, and breech presentation. Younger maternal age (15–24 years), premature rupture of membranes, placenta previa, and male children had higher odds of preterm birth but a lessened likelihood of perinatal death. These findings suggest ANC is a critical entry point for delivering the recommended interventions to pregnant women, especially those at high risk of experiencing adverse pregnancy outcomes. Improved management of complications during pregnancy and childbirth and the postnatal period may eventually lead to a substantial reduction of adverse perinatal outcomes and improving maternal and child health.
Case Report: Prolonged CSF PCR Positivity in a Neonate With GBS Meningitis
Authors: Alruqaie Nourah , Falatah Yara , Alzahrani Fawaz , Alharbi Musaed
Published: December 2021

Bacterial meningitis is one of the critical diseases that needs to be diagnosed and treated promptly. Recent diagnostics of high sensitivity and specificity rates, such as PCR, helped with such presentation, especially in cases with prior antibiotics that led to culture negativity. However, the time window of PCR positivity is not well-studied, with scattered reports of different periods of positivity. Here, we report a case of neonatal GBS meningitis with positive PCR for more than 80 days from starting antibiotics.
Prevalence of and Risk Factors for Sagittal Posture Abnormalities in Children Born With Esophageal Atresia: A Prospective Cohort Study
Authors: Bisson Benoit , Gottrand Laurence , Aumar Madeleine , Nicolas Audrey , Sfeir Rony , Labreuche Julien , Thevenon André , Gottrand Frederic
Published: December 2021

Introduction: Scoliosis is a well-described complication of esophageal atresia (EA) caused by the associated spine malformations and/or thoracotomy. However, the sagittal posture abnormalities in patients with EA have not been described. The aim of this study was to evaluate the prevalence of and risk factors for sagittal posture abnormalities at the age of 6 years in patients operated on for EA.

Methods: A prospective cohort of 123 patients with EA was examined by the same rehabilitation doctor at the time of a multidisciplinary visit scheduled at the age of 6 years. Children presenting with scoliosis (n = 4) or who missed the consultation (n = 33) were excluded. Univariate and multivariate logistic regression models with Firth's penalized-likelihood approach were used to identify risk factors associated with sagittal posture anomalies. Candidate risk factors included neonatal characteristics, associated malformations, atresia type, postoperative complications, psychomotor development retardation, orthopedic abnormalities, and neurological hypotonia.

Results: The prevalence rates of sagittal posture abnormalities were 25.6% (n = 22; 95% CI, 16.7–36.1%). Multivariate analysis showed that minor orthopedic abnormalities (OR: 4.02, 95% CI: 1.29–13.43, P = 0.021), and VACTERL (OR: 3.35, 95% CI: 1.09–10.71, P = 0.042) were significant risk factors for sagittal posture abnormalities.

Conclusion: This study shows that sagittal posture anomalies occur frequently in children operated on at birth for EA and are not directly linked to the surgical repair. These children should be screened and treated using postural physiotherapy, especially those with VACTERL and minor orthopedic abnormalities.
Predictors of Developmental and Respiratory Outcomes Among Preterm Infants With Bronchopulmonary Dysplasia
Authors: Morag Iris , Barkai Efrat , Wazana Yaara , Elizur Arnon , Levkovitz Stern Orly , Staretz-Chacham Orna , Pinchevski-Kadir Shiran , Ofek Shlomai Noa
Published: December 2021

Objectives:To examine the importance of perinatal and postnatal environmental factors on developmental and respiratory outcomes among preterm infants with bronchopulmonary dysplasia (BPD).

Methods:Preterm infants (<32 weeks of gestation) born at a single tertiary medical center between 2012 and 2015 were included. Development was assessed at 12 months corrected age. Parents retrospectively completed a health and lifestyle questionnaire reviewing their child's health during the first 2 years of life. A linear regression model was applied to assess the effect of various perinatal and postnatal factors on development. A machine-learning algorithm was trained to assess factors affecting inhaler use.

Results:Of 398 infants meeting the inclusion criteria, 208 qualified for the study: 152 (73.1%) with no BPD, 40 (19.2%) with mild BPD, and 16 (7.7%) with moderate-severe BPD. Those in the moderate-severe group were more likely to be male, have mothers who were less educated, and require longer ventilation periods and less time to regain birth weight. They were also more likely to have mothers with asthma/allergies and to have a parent who smoked. Those in the moderate-severe BPD group exhibited significantly lower developmental scores (85.2 ± 16.4) than the no-BPD group (99.3 ± 10.9) and the mild BPD group (97.8 ± 11.7,p< 0.008) as well as more frequent inhaler use (p= 0.0014) than those with no or mild BPD. In addition to perinatal factors, exposure to breast milk, income level and daycare attendance positively affected development. Exposure to cigarette smoke, allergies among family members and daycare attendance proved to be important factors in inhaler use frequency.

Conclusions:Postnatal environmental factors are important in predicting and modifying early childhood outcomes among preterm infants.
Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients
Authors: Miranda Carla , Galleguillos Macarena , Torres Roberto , Tardón Karla , Cáceres Dante D. , Lee Kuen , Redal María A. , Varela Nelson M. , Quiñones Luis A.
Published: December 2021

Tamoxifen (TAM), a selective oestrogen receptor modulator, is one of the most used treatments in oestrogen receptor-positive (ER+) early and metastatic breast cancer (BC) patients. The response to TAM has a high degree of inter-individual variability. This is mainly due to genetic variants in CYP2D6 gene, as well as other genes encoding proteins involved in the TAM pharmacokinetic and/or pharmacodynamic. Therefore, prediction of the TAM response using these genetic factors together with other non-genetic variables may be relevant to improve breast cancer treatment. Thus, in this work, we used genetic polymorphisms and clinical variables for TAM response modelling. One hundred sixty-two ER + BC patients with 2 years of TAM treatment were retrospectively recruited, and the genetic polymorphisms CYP2D6*4, CYP3A4*1B (CYP3A4*1.001), CYP3A5*3, UGT2B7*2, UGT2B15*2, SULT1A1*2, and ESRA V364E were analyzed by PCR-RFLP. Concomitantly, the therapeutic response was obtained from clinical records for association with genotypes using univariate and multivariate biostatistical models. Our results show that UGT2B15*1/*2 genotype protects against relapse (OR = 0.09; p = 0.02), CYP3A5*3/*3 genotype avoids endometrial hyperplasia (OR = 0.07; p = 0.01), SULT1A1*1/*2 genotype avoids vaginal bleeding (OR = 0.09; p = 0.03) and ESRA 364E/364E genotype increases the probability of vaginal bleeding (OR = 5.68; p = 0.02). Logistic regression models, including genomic and non-genomic variables, allowed us to obtain preliminary predictive models to explain relapse (p = 0.010), endometrial hyperplasia (p = 0.002) and vaginal bleeding (p = 0.014). Our results suggest that the response to TAM treatment in ER + BC patients might be associated with the presence of the studied genetic variants in UGT2B15, CYP3A5, SULT1A1 and ESRA genes. After clinical validation protocols, these models might be used to help to predict a percentage of BC relapse and adverse reactions, improving the individual response to TAM-based treatment.
Social Isolation: How Can the Effects on the Cholinergic System Be Isolated?
Authors: Myslivecek Jaromir
Published: December 2021

Social species form organizations that support individuals because the consequent social behaviors help these organisms survive. The isolation of these individuals may be a stressor. We reviewed the potential mechanisms of the effects of social isolation on cholinergic signaling and vice versa how changes in cholinergic signaling affect changes due to social isolation.There are two important problems regarding this topic. First, isolation schemes differ in their duration (1–165 days) and initiation (immediately after birth to adulthood). Second, there is an important problem that is generally not considered when studying the role of the cholinergic system in neurobehavioral correlates: muscarinic and nicotinic receptor subtypes do not differ sufficiently in their affinity for orthosteric site agonists and antagonists. Some potential cholinesterase inhibitors also affect other targets, such as receptors or other neurotransmitter systems. Therefore, the role of the cholinergic system in social isolation should be carefully considered, and multiple receptor systems may be involved in the central nervous system response, although some subtypes are involved in specific functions. To determine the role of a specific receptor subtype, the presence of a specific subtype in the central nervous system should be determined using search in knockout studies with the careful application of specific agonists/antagonists.
Untargeted and Targeted Metabolomics Reveal the Underlying Mechanism of Aspirin Eugenol Ester Ameliorating Rat Hyperlipidemia via Inhibiting FXR to Induce CYP7A1
Authors: Xiao-Rong Lu , Ning Ma , Xi-Wang Liu , Shi-Hong Li , Zhe Qin , Li-Xia Bai , Ya-Jun Yang , Jian-Yong Li
Published: December 2021

Hyperlipidemia is an important lipid disorder and a risk factor for health. Aspirin eugenol ester (AEE) is a novel synthetic compound which is made up of two chemical structural units from aspirin and eugenol. Therapeutic effect of AEE on hyperlipidemia has been confirmed in animal model. But the action mechanism of AEE on hyperlipidemia is still poorly understood. In this study, we investigated the effects of AEE on liver and feces metabolic profile through UPLC-Q-TOF/MS-based untargeted metabolomics in hyperlipidemia hamster induced with high fat diet (HFD), and the effects of AEE on the expression of genes and proteins related to cholesterol and bile acid (BA) in HFD-induced hyperlipidemia SD rat. The concentrations of 26 bile acids (BAs) in the liver from hyperlipidemia SD rat were also quantified with the application of BA targeted metabolomics. The results of untargeted metabolomics showed that the underlying mechanism of AEE on hyperlipidemia was mainly associated with amino acid metabolism, glutathione metabolism, energy metabolism, BA metabolism, and glycerophospholipid metabolism. AEE induced the expression of the BA-synthetic enzymes cholesterol 7α-hydroxylase (CYP7A1) by the inhibition of BA nuclear receptor farnesoid X receptor (FXR) in liver, which resulted in accelerating the conversion of cholesterol into bile acids and excrete in feces. The results of BA targeted metabolomics showed that AEE elevated the glycine-conjugated BA level and decreased the tauro-conjugated BA level. In conclusion, this study found that AEE decreased FXR and increased CYP7A1 in the liver, which might be the possible molecular mechanisms and targets of AEE for anti-hyperlipidemia therapies.
Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking
Authors: Zou Wei , Shi Birui , Zeng Ting , Zhang Yan , Huang Baolin , Ouyang Bo , Cai Zheng , Liu Menghua
Published: December 2021

The kidneys are a pair of important organs that excretes endogenous waste and exogenous biological agents from the body. Numerous transporters are involved in the excretion process. The levels of these transporters could affect the pharmacokinetics of many drugs, such as organic anion drugs, organic cationic drugs, and peptide drugs. Eleven drug transporters in the kidney (OAT1, OAT3, OATP4C1, OCT2, MDR1, BCRP, MATE1, MATE2-K, OAT4, MRP2, and MRP4) have become necessary research items in the development of innovative drugs. However, the levels of these transporters vary between different species, sex-genders, ages, and disease statuses, which may lead to different pharmacokinetics of drugs. Here, we review the differences of the important transports in the mentioned conditions, in order to help clinicians to improve clinical prescriptions for patients. To predict drug-drug interactions (DDIs) caused by renal drug transporters, the molecular docking method is used for rapid screening of substrates or inhibitors of the drug transporters. Here, we review a large number of natural products that represent potential substrates and/or inhibitors of transporters by the molecular docking method.
Human Retinal Progenitor Cells Derived Small Extracellular Vesicles Delay Retinal Degeneration: A Paradigm for Cell-free Therapy
Authors: Chen Min , Ren Chunge , Ren Bangqi , Fang Yajie , Li Qiyou , Zeng Yuxiao , Li Yijian , Chen Fang , Bian Baishijiao , Liu Yong
Published: December 2021

Retinal degeneration is a leading cause of irreversible vision impairment and blindness worldwide. Previous studies indicate that subretinal injection of human retinal progenitor cells (hRPCs) can delay the progression of retinal degeneration, preserve retinal function, and protect photoreceptor cells from death, albeit the mechanism is not well understood. In this study, small extracellular vesicles derived from hRPCs (hRPC-sEVs) were injected into the subretinal space of retinal dystrophic RCS rats. We find that hRPC-sEVs significantly preserve the function of retina and thickness of the outer nuclear layer (ONL), reduce the apoptosis of photoreceptors in the ONL, and suppress the inflammatory response in the retina of RCS rats. In vitro, we have shown that hRPC-sEV treatment could significantly reserve the low-glucose preconditioned apoptosis of photoreceptors and reduce the expression of pro-inflammatory cytokines in microglia. Pathway analysis predicted the target genes of hRPC-sEV microRNAs involved in inflammation related biological processes and significantly enriched in processes autophagy, signal release, regulation of neuron death, and cell cycle. Collectively, our study suggests that hRPC-sEVs might be a favorable agent to delay retinal degeneration and highlights as a new paradigm for cell-free therapy.
Anti-Hyperalgesic Properties of Menthol and Pulegone
Authors: Hilfiger Louis , Triaux Zélie , Marcic Christophe , Héberlé Eléa , Emhemmed Fathi , Darbon Pascal , Marchioni Eric , Petitjean Hugues , Charlet Alexandre
Published: December 2021

Context: Menthol, the main monoterpene found in Mentha piperita L. (M. piperita) is known to modulate nociceptive threshold and is present in different curative preparations that reduce sensory hypersensitivities in pain conditions. While for pulegone, a menthol-like monoterpene, only a limited number of studies focus on its putative analgesic effects, pulegone is the most abundant monoterpene present in Calamintha nepeta (L.) Savi (C. nepeta), a plant of the Lamiaceae family used in traditional medicine to alleviate rheumatic disorders, which counts amongst chronic inflammatory diseases.

Objectives: Here, we analyzed the monoterpenes composition of C. nepeta and M. piperita. We then compared the putative anti-hyperalgesic effects of the main monoterpenes found, menthol and pulegone, in acute inflammatory pain conditions.

Methods:C. nepeta and M. piperita extracts were obtained through pressurized liquid extraction and analyzed by gas chromatography-mass spectrometry. The in vitro anti-inflammatory activity of menthol or pulegone was evaluated by measuring the secretion of the tumour necrosis factor alpha (TNF α) from LPS-stimulated THP-1 cells. The in vivo anti-hyperalgesic effects of menthol and pulegone were tested on a rat inflammatory pain model.

Results: Pulegone and menthol are the most abundant monoterpene found in C. nepeta (49.41%) and M. piperita (42.85%) extracts, respectively. In vitro, both pulegone and menthol act as strong anti-inflammatory molecules, with EC50 values of 1.2 ± 0.2 and 1.5 ± 0.1 mM, respectively, and exert cytotoxicity with EC50 values of 6.6 ± 0.3 and 3.5 ± 0.2 mM, respectively. In vivo, 100 mg/kg pulegone exerts a transient anti-hyperalgesic effect on both mechanical (pulegone: 274.25 ± 68.89 g, n = 8; vehicle: 160.88 ± 35.17 g, n = 8, p < 0.0001), thermal heat (pulegone: 4.09 ± 0.62 s, n = 8; vehicle: 2.25 ± 0.34 s, n = 8, p < 0.0001), and cold (pulegone: 2.25 ± 1.28 score, n = 8; vehicle: 4.75 ± 1.04 score, n = 8, p = 0.0003). In a similar way, 100 mg/kg menthol exerts a transient anti-hyperalgesic effect on both mechanical (mechanical: menthol: 281.63 ± 45.52 g, n = 8; vehicle: 166.25 ± 35.4 g, n = 8, p < 0.0001) and thermal heat (menthol: 3.65 ± 0.88 s, n = 8; vehicle: 2.19 ± 0.26 s, n = 8, <0.0001).

Conclusion: Here, we show that both pulegone and menthol are anti-inflammatory and anti-hyperalgesic monoterpenes. These results might open the path towards new compound mixes to alleviate the pain sensation.
Excretion and Residual Concentration Correlations of Salbutamol Between Edible Tissues and Living Samples in Pigs and Goats
Authors: Sun Lei , Zhu Minjuan , Shi Jingfei , Mi Kun , Ma Wenjing , Xu Xiangyue , Wang Hanyu , Pan Yuanhu , Tao Yanfei , Liu Zhenli , Huang Lingli
Published: December 2021

Illegal use of salbutamol (SAL), a β-adrenergic leanness-enhancing agent, has posed potential threat to human health in China. The excretion and depletion of SAL in pigs and goats were investigated, and the concentration correlations between edible tissues and living samples were analyzed to find out a suitable living sample for pre-slaughter monitoring of SAL in pigs and goats. After a single oral dosage of 1.2 mg/kg SAL, approximately 70% of the dose was excreted by pigs and goats from their excreta. When pigs and goats were supplied feed containing SAL (20 mg/kg) for 14 consecutive days, high concentrations of SAL were observed in the liver and kidneys, and the longest persistence was observed in hair. Unlike pigs, SAL was presented primarily as conjugated SAL in goats. Excellent concentration correlations of SAL were observed between urine and edible tissues both in pigs and goats, and in addition, good correlations also were found between hair and edible tissues in pigs and between feces and edible tissues in goats. Hence, urine and hair could accurately predict SAL concentrations in edible tissues of pigs, whereas feces and urine were satisfactory for predicting SAL concentrations in edible tissues of goats. These data make it possible for pre-slaughter monitoring of SAL residues in the edible tissues of pigs and goats.
Bilateral Paraventricular Nucleus Upregulation of Extracellular Superoxide Dismutase Decreases Blood Pressure by Regulation of the NLRP3 and Neurotransmitters in Salt-Induced Hypertensive Rats
Authors: Su Qing , Yu Xiao-Jing , Wang Xiao-Min , Li Hong-Bao , Li Ying , Bai Juan , Qi Jie , Zhang Nianping , Liu Kai-Li , Zhang Yan , Zhu Guo-Qing , Kang Yu-Ming
Published: December 2021

Aims: Long-term salt diet induces the oxidative stress in the paraventricular nucleus (PVN) and increases the blood pressure. Extracellular superoxide dismutase (Ec-SOD) is a unique antioxidant enzyme that exists in extracellular space and plays an essential role in scavenging excessive reactive oxygen species (ROS). However, the underlying mechanism of Ec-SOD in the PVN remains unclear.

Methods: Sprague–Dawley rats (150–200 g) were fed either a high salt diet (8% NaCl, HS) or normal salt diet (0.9% NaCl, NS) for 6 weeks. Each group of rats was administered with bilateral PVN microinjection of AAV-Ec-SOD (Ec-SOD overexpression) or AAV-Ctrl for the next 6 weeks.

Results: High salt intake not only increased mean arterial blood pressure (MAP) and the plasma noradrenaline (NE) but also elevated the NAD(P)H oxidase activity, the NAD(P)H oxidase components (NOX2 and NOX4) expression, and ROS production in the PVN. Meanwhile, the NOD-like receptor protein 3 (NLRP3)–dependent inflammatory proteins (ASC, pro-cas-1, IL-β, CXCR, CCL2) expression and the tyrosine hydroxylase (TH) expression in the PVN with high salt diet were higher, but the GSH level, Ec-SOD activity, GAD67 expression, and GABA level were lower than the NS group. Bilateral PVN microinjection of AAV-Ec-SOD decreased MAP and the plasma NE, reduced NAD(P)H oxidase activity, the NOX2 and NOX4 expression, and ROS production, attenuated NLRP3-dependent inflammatory expression and TH, but increased GSH level, Ec-SOD activity, GAD67 expression, and GABA level in the PVN compared with the high salt group.

Conclusion: Excessive salt intake not only activates oxidative stress but also induces the NLRP3-depensent inflammation and breaks the balance between inhibitory and excitability neurotransmitters in the PVN. Ec-SOD, as an essential anti-oxidative enzyme, eliminates the ROS in the PVN and decreases the blood pressure, probably through inhibiting the NLRP3-dependent inflammation and improving the excitatory neurotransmitter release in the PVN in the salt-induced hypertension.
Medicinal Plants Used by Traditional Healers in Algeria: A Multiregional Ethnobotanical Study
Authors: Belhouala Khadidja , Benarba Bachir
Published: December 2021

Traditional medicine is the cornerstone that boosts scientific research to explore new therapeutic approaches. The study aimed to assess the traditional knowledge and use of medicinal plants to treat various ailments by Algerian traditional healers. Forty traditional healers were face-to-face interviewed in three different Algerian areas (West, Kabylia, and Sahara). The data collected were analyzed using quantitative indices such as fidelity level (FL) and informant consensus factor (FIC). A total of 167 species belonging to 70 families were recorded. Lamiaceae (13%), Asteraceae (13%), Apiaceae (7%), and Rosaceae and Fabaceae (5% each) were the most cited families. The survey revealed that leaves were the most used parts of the plants (29%). Furthermore, decoction (35%), raw (24%), and infusion (19%) were the common modes for the remedies’ preparation. Here, 15% of the total species were newly reported as medicinal plants. Besides, it was reported for the first time a total of 47 new therapeutic uses for 20 known plant species. Of 17 ailments categories, cancer was presented by 44 species, showing the highest FICof 0.46.Marrubium vulgareL., Artemisia herba-albaAsso., Zingiber officinaleRoscoe., andJuniperus phoeniceaL. recorded the maximum fidelity value of 100%. Therefore, our study reveals strong ethnomedicinal knowledge shared by local populations living in the three regions studied. The medicinal species with a high FL could be promising candidates for identifying new bioactive molecules.
A Phase 1, Dose-Ranging Study to Assess Safety and Psychoactive Effects of a Vaporized 5-Methoxy-N, N-Dimethyltryptamine Formulation (GH001) in Healthy Volunteers
Authors: Reckweg Johannes , Mason Natasha L. , van Leeuwen Cees , Toennes Stefan W. , Terwey Theis H. , Ramaekers Johannes G.
Published: December 2021

5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a tryptamine with ultra-rapid onset and short duration of psychedelic effects. Prospective studies for other tryptamines have suggested beneficial effects on mental health outcomes. In preparation for a study in patients with depression, the present study GH001-HV-101 aimed to assess the impact of four different dose levels of a novel vaporized 5-MeO-DMT formulation (GH001) administered via inhalation as single doses of 2 (N = 4), 6 (N = 6), 12 (N = 4) and 18 mg (N = 4), and in an individualized dose escalation regimen (N = 4) on the safety, tolerability, and the dose-related psychoactive effects in healthy volunteers (N = 22). The psychedelic experience was assessed with a novel Peak Experience Scale (PES), the Mystical Experience Questionnaire (MEQ), the Ego Dissolution Inventory (EDI), the Challenging Experience Questionnaire (CEQ), and the 5-Dimensional Altered States of Consciousness Questionnaire (5D-ASC). Further aims were to assess the impact of 5-MeO-DMT on cognitive functioning, mood, and well-being. Higher doses of 5-MeO-DMT produced significant increments in the intensity of the psychedelic experience ratings as compared to the lowest 2 mg dose on all questionnaires, except the CEQ. Prominent effects were observed following single doses of 6, 12, and 18 mg on PES and MEQ ratings, while maximal effects on PES, MEQ, EDI, and 5D-ASC ratings were observed following individualized dose escalation of 5-MeO-DMT. Measures of cognition, mood, and well-being were not affected by 5-MeO-DMT. Vital signs at 1 and 3 h after administration were not affected and adverse events were generally mild and resolved spontaneously. Individualized dose escalation of 5-MeO-DMT may be preferable over single dose administration for clinical applications that aim to maximize the experience to elicit a strong therapeutic response.