bluuebunny/crossref_metadata_2025 huggingface dataset:
Localization of the Center of the Intramuscular Nerve Dense Region of the Suboccipital Muscles: An Anatomical Study
Authors: Wang Jie , Li Yanrong , Wang Meng , Yang Shengbo
Published: April 2022

Purpose

This study aimed to determine the body surface puncture position and depth of the center of the intramuscular nerve dense region in the suboccipital muscle to provide morphological guidance for accurate botulinum toxin A injection to treat headaches caused by increased suboccipital muscle tension.

Methods

Twenty-four cadavers aged 66.5 ± 5.3 years were studied. The curve line connecting occipital eminence or mastoid process and spinous process of the 7th cervical vertebrae was considered the longitudinal reference line (L) and horizontal reference line (H), respectively. Sihler's staining, barium sulfate labeling, and CT were employed. The body surface projection point of the center of the intramuscular nerve dense region was designated as P. The projection of the center of the intramuscular nerve dense region was in the opposite direction across the transverse plane and was recorded as P'. The intersections of the vertical line through point P and lines L and H were designated as PL and PH. The percentage position of the PH and PL points on the H and L lines and the depths of the center of intramuscular nerve dense regions were identified.

Results

Sihler's staining showed one intramuscular nerve-dense region in each suboccipital muscle. The PH of the center of the intramuscular nerve dense region was located at 51.40, 45.55, 20.55, and 43.50%. The PL was located at 31.38, 30.08, 16.91, and 52.94%. The depth of the center of the intramuscular nerve dense region was at 22.26, 22.54, 13.14, and 27.30%. These percentage values are all the means.

Conclusion

Accurately defining the body surface position and depth of the center of intramuscular nerve dense region in suboccipital muscles will help to improve botulinum toxin A to target localization efficiency for treating tension-type headache.
Processing Self-Related Information Under Non-attentional Conditions Revealed by Visual MMN
Authors: Cheng Sizhe , Li Xinhong , Zhan Qingchen , Wang Yapei , Guo Yaning , Huang Wei , Cao Yang , Feng Tingwei , Wang Hui , Wu Shengjun , An Fei , Wang Xiuchao , Zhao Lun , Liu Xufeng
Published: April 2022

Mismatch negativity (MMN) of event-related potentials (ERPs) is a biomarker reflecting the preattentional change detection under non-attentional conditions. This study was performed to explore whether high self-related information could elicit MMN in the visual channel, indicating the automatic processing of self-related information at the preattentional stage. Thirty-five participants were recruited and asked to list 25 city names including the birthplace. According to the difference of relevance reported from the participants, we divided names of the different cities into high (birthplace as deviants), medium (Xi’an, where participants’ university is located, as deviants), and low (totally unrelated cities as standard stimuli) self-related information. Visual MMN (vMMN) was elicited by high self-related information but not by medium self-related information, with an occipital–temporal scalp distribution, indicating that, under non-attentional condition, high self-related information can be effectively processed automatically in the preattentional stage compared with low self-related information. These data provided new electrophysiological evidence for self-related information processing.
How to Decide the Number of Gait Cycles in Different Low-Pass Filters to Extract Motor Modules by Non-negative Matrix Factorization During Walking in Chronic Post-stroke Patients
Authors: Chujo Yuta , Mori Kimihiko , Kitawaki Tomoki , Wakida Masanori , Noda Tomoyuki , Hase Kimitaka
Published: April 2022

The motor modules during human walking are identified using non-negative matrix factorization (NNMF) from surface electromyography (EMG) signals. The extraction of motor modules in healthy participants is affected by the change in pre-processing of EMG signals, such as low-pass filters (LPFs); however, the effect of different pre-processing methods, such as the number of necessary gait cycles (GCs) in post-stroke patients with varying steps, remains unknown. We aimed to specify that the number of GCs influenced the motor modules extracted in the consideration of LPFs in post-stroke patients. In total, 10 chronic post-stroke patients walked at a self-selected speed on an overground walkway, while EMG signals were recorded from the eight muscles of paretic lower limb. To verify the number of GCs, five GC conditions were set, namely, 25 (reference condition), 20, 15, 10, and 5 gate cycles with three LPFs (4, 10, and 15 Hz). First, the number of modules, variability accounted for (VAF), and muscle weightings extracted by the NNMF algorithm were compared between the conditions. Next, a modified NNMF algorithm, in which the activation timing profiles among different GCs were unified, was performed to compare the muscle weightings more robustly between GCs. The number of motor modules was not significantly different, regardless of the GCs. The difference in VAF and muscle weightings in the different GCs decreased with the LPF of 4 Hz. Muscle weightings in 15 GCs or less were significantly different from those in 25 GCs using the modified NNMF. Therefore, we concluded that the variability extracted motor modules by different GCs was suppressed with lower LPFs; however, 20 GCs were needed for more representative extraction of motor modules during walking in post-stroke patients.
Repetitive Transcranial Magnetic Stimulation Induces Quantified Functional and Structural Changes in Subcortical Stroke: A Combined Arterial Spin Labeling Perfusion and Diffusion Tensor Imaging Study
Authors: Jin Yu , Bai Xi , Jiang Binghu , Guo Zhiwei , Mu Qiwen
Published: April 2022

Purpose

To explore the changes of cerebral blood flow (CBF) and fractional anisotropy (FA) in stroke patients with motor dysfunction after repetitive transcranial magnetic stimulation (rTMS) treatment, and to better understand the role of rTMS on motor rehabilitation of subcortical stroke patients from the perfusion and structural level.

Materials and Methods

In total, 23 first-episode acute ischemic stroke patients and sixteen healthy controls (HCs) were included. The patients were divided into the rTMS and sham group. The rehabilitation assessments and examination of perfusion and structural MRI were performed before and after rTMS therapy for each patient. Voxel-based analysis was used to detect the difference in CBF and FA among all three groups. The Pearson correlation analysis was conducted to evaluate the relationship between the CBF/FA value and the motor scales.

Results

After rTMS, significantly increased CBF was found in the ipsilesional supplementary motor area, postcentral gyrus, precentral gyrus, pons, medulla oblongata, contralesional midbrain, superior cerebellar peduncle, and middle cerebellar peduncle compared to that during the prestimulation and in the sham group, these fasciculi comprise the cortex-pontine-cerebellum-cortex (CPC) loop. Besides, altered CBF in the ipsilesional precentral gyrus, postcentral gyrus, and pons was positively associated with the improved Fugl-Meyer assessment (FMA) scores. Significantly decreased FA was found in the contralesional precentral gyrus, increased FA was found in the ipsilesional postcentral gyrus, precentral gyrus, contralesional supplementary motor area, and bilateral cerebellum, these fasciculi comprise the corticospinal tract (CST). The change of FMA score was positively correlated with altered FA value in the ipsilesional postcentral gyrus and negatively correlated with altered FA value in the contralesional precentral gyrus.

Conclusion

Our results suggested that rTMS could facilitate the motor recovery of stroke patients. High frequency could promote the improvement of functional activity of ipsilesional CPC loop and the recovery of the microstructure of CST.
Tractography in Type 2 Diabetes Mellitus With Subjective Memory Complaints: A Diffusion Tensor Imaging Study
Authors: Wang Jun , Ma Laiyang , Liu Guangyao , Bai Wenjuan , Ai Kai , Zhang Pengfei , Hu Wanjun , Zhang Jing
Published: April 2022

The brain white matter (WM) structural injury caused by type 2 diabetes mellitus (T2DM) has been linked to cognitive impairment. However, the focus was mainly on the mild cognitive impairment (MCI) stage in most previous studies, with little attention made to subjective memory complaints (SMC). The main purpose of the current study was to investigate the characteristics of WM injury in T2DM patients and its correlation with SMC symptoms. In a group of 66 participants (33 HC and 33 T2DM-S), pointwise differences along WM tracts were identified using the automated fiber quantification (AFQ) approach. Then we investigated the utility of DTI properties along major WM tracts as features to distinguish patients with T2DM-S from HC via the support vector machine (SVM). Based on AFQ analysis, 10 primary fiber tracts that represent the subtle alterations of WM in T2DM-S were identified. Lower fractional anisotropy (FA) in the right SLF tract (r = −0.538, p = 0.0013), higher radial diffusivity (RD) in the thalamic radiation (TR) tract (r = 0.433, p = 0.012), and higher mean diffusivity (MD) in the right inferior fronto-occipital fasciculus (IFOF) tract (r = 0.385, p = 0.0029) were significantly associated with a long period of disease. Decreased axial diffusivity (AD) in the left arcuate was associated with HbA1c (r = −0.368, p = 0.049). In addition, we found a significant negative correlation between delayed recall and abnormal MD in the left corticospinal tract (r = −0.546, p = 0.001). The FA of the right SLF tracts and bilateral arcuate can be used to differentiate the T2DM-S and the HC at a high accuracy up to 88.45 and 87.8%, respectively. In conclusion, WM microstructure injury in T2DM may be associated with SMC, and these abnormalities identified by DTI can be used as an effective biomarker.
Direct Regulation of Hyperpolarization-Activated Cyclic-Nucleotide Gated (HCN1) Channels by Cannabinoids
Authors: Mayar Sultan , Memarpoor-Yazdi Mina , Makky Ahmad , Eslami Sarokhalil Romina , D'Avanzo Nazzareno
Published: April 2022

Cannabinoids are a broad class of molecules that act primarily on neurons, affecting pain sensation, appetite, mood, learning, and memory. In addition to interacting with specific cannabinoid receptors (CBRs), cannabinoids can directly modulate the function of various ion channels. Here, we examine whether cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the most prevalent phytocannabinoids in Cannabis sativa, can regulate the function of hyperpolarization-activated cyclic-nucleotide-gated (HCN1) channels independently of CBRs. HCN1 channels were expressed in Xenopus oocytes since they do not express CBRs, and the effects of cannabinoid treatment on HCN1 currents were examined by a two-electrode voltage clamp. We observe opposing effects of CBD and THC on HCN1 current, with CBD acting to stimulate HCN1 function, while THC inhibited current. These effects persist in HCN1 channels lacking the cyclic-nucleotide binding domain (HCN1ΔCNBD). However, changes to membrane fluidity, examined by treating cells with TX-100, inhibited HCN1 current had more pronounced effects on the voltage-dependence and kinetics of activation than THC, suggesting this is not the primary mechanism of HCN1 regulation by cannabinoids. Our findings may contribute to the overall understanding of how cannabinoids may act as promising therapeutic molecules for the treatment of several neurological disorders in which HCN function is disturbed.
Excitatory and Inhibitory Synaptic Imbalance Caused by Brain-Derived Neurotrophic Factor Deficits During Development in a Valproic Acid Mouse Model of Autism
Authors: Qi Chuchu , Chen Andi , Mao Honghui , Hu Erling , Ge Junye , Ma Guaiguai , Ren Keke , Xue Qian , Wang Wenting , Wu Shengxi
Published: April 2022

Environmental factors, such as medication during pregnancy, are one of the major causes of autism spectrum disorder (ASD). Valproic acid (VPA) intake during pregnancy has been reported to dramatically elevate autism risk in offspring. Recently, researchers have proposed that VPA exposure could induce excitatory or inhibitory synaptic dysfunction. However, it remains to be determined whether and how alterations in the excitatory/inhibitory (E/I) balance contribute to VPA-induced ASD in a mouse model. In the present study, we explored changes in the E/I balance during different developmental periods in a VPA mouse model. We found that typical markers of pre- and postsynaptic excitatory and inhibitory function involved in E/I balance markedly decreased during development, reflecting difficulties in the development of synaptic plasticity in VPA-exposed mice. The expression of brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the formation and maturation of glutamatergic and GABAergic synapses during postnatal development, was severely reduced in the VPA-exposed group. Treatment with exogenous BDNF during the critical E/I imbalance period rescued synaptic functions and autism-like behaviors, such as social defects. With these results, we experimentally showed that social dysfunction in the VPA mouse model of autism might be caused by E/I imbalance stemming from BDNF deficits during the developmental stage.
Pequi (Caryocar brasiliense) Waste Extract as a Synergistic Agent in the Microbial and Physicochemical Preservation of Low-Sodium Raw Goat Cheese
Authors: Moreira Rodrigo V. , Vieira Carla P. , Galvan Diego , Castro Vinicius S. , Lima Rayssa S. , Mutz Yhan S. , Delgado Karina F. , Rosario Anisio Iuri L. , Mano Sérgio B. , Costa Marion P. , Conte-Junior Carlos A.
Published: April 2022

The growth of spoilage and pathogenic bacteria during storage represents significant losses in marketing raw milk cheeses. Thus, reducing NaCl in these products is challenging, as sodium has a critical antimicrobial role. Despite advances in non-thermal technologies, the short shelf life still limits the availability of raw goat cheese. Thus, combined preservation methods can be promising because their synergies can extend shelf life more effectively. In this context, Principal Component Analysis (PCA) was applied to variables to investigate the effect of pequi waste extract (PWE), a native Brazilian fruit, combined with UV-C radiation (CEU) and vacuum packaging (CEV) on the preservation of low-sodium raw goat cheese. CEV samples had lower loadings for Staphylococcus subsp. and Enterobacteriaceae than other treatments in PC2, having a count’s reduction up to 3-fold (P < 0.05) compared to vacuum alone. In contrast, CEU showed an increase of up to 1.2-fold on staphylococcal count compared to UV-C alone. Still, the addition of PWE to UV-C-treated cheeses resulted in 8.5% protein loss. Furthermore, PWE, especially in CEV, delayed post-acidification during storage. It made CEV up to 4.5 and 1.6-fold more stable for color and texture, respectively than vacuum alone. These data strongly suggest that PWE may be a novel and promising synergistic agent in the microbial and physicochemical preservation of low-sodium raw milk cheese when combined with the vacuum.
The Association Between Bangladeshi Adults’ Demographics, Personal Beliefs, and Nutrition Literacy: Evidence From a Cross-Sectional Survey
Authors: Banna Md. Hasan Al , Hamiduzzaman Mohammad , Kundu Satyajit , Ara Tasnu , Abid Mohammad Tazrian , Brazendale Keith , Seidu Abdul-Aziz , Disu Tasnim Rahman , Mozumder N. H. M. Rubel , Frimpong James Boadu , Khan Md Shafiqul Islam
Published: April 2022

Background

Poverty and health illiteracy, combined with inappropriate systems to track disease and infection rates, contribute to children-and-mothers’ poor adherence to nutrient-rich foods intake in Bangladesh. Although risk factors for child and pregnant women malnutrition have been explored, the relationship between Bangladeshi adults’ nutrition literacy and their demographics and personal beliefs remains unknown. The purpose of this study was to examine the association between adults’ nutrition literacy, demographics and personal beliefs in a large sample of Bangladeshi adults.

Methods

Four hundred adults from two districts (Dhaka and Chattogram) of Bangladesh participated in a cross-sectional survey. Data were collected by interviews using a structured questionnaire containing the Nutrition Literacy Scale. Multiple linear regression models were employed to analyze associations between nutrition literacy and related factors.

Results

The mean nutrition literacy score was 21.6 (SD: 3.7; range: 11–32) on a scale of 32. Multiple linear regression revealed that being a businessman (β = 1.66, p = 0.013) or private employee (β = 1.08, p = 0.030), having a higher family income (β = 1.17, p = 0.009), and a higher educational level were positively associated with higher nutrition literacy scores compared to their counterparts. Participants who had ever completed a nutrition-related course (β = 4.95, p < 0.001), and who perceived themselves as having a need for accessing nutrition-related information were positively associated with the higher nutrition literacy compared to their counterparts.

Conclusion

Findings from this study suggest the need for an integrated response plan involving educational interventions and accessible dietary plans targeting adult populations to enhance their nutritional literacy.
The Impacts of Ramadan Intermittent Fasting on Saliva Flow-Rate and Metabolic Data: A Systematic Review
Authors: Besbes Amira , Khemiss Mehdi , Bragazzi Nicola , Ben Saad Helmi
Published: April 2022

The aim of this systematic review was to report the impacts of Ramadan intermittent fasting (RIF) on salivary flow-rate (SFR) and metabolic parameters. A thorough literature search was carried out using the databases PubMed and Scopus from their inception up to 15 July 2021. The Boolean connectors used in PubMed were (Saliva [Mesh] AND Fasting [Mesh]). The same keywords were used in Scopus. Inclusion criteria were defined using PICOS. The research included all original studies involving “healthy” adults and published in English. Methodological quality assessment was performed utilizing the Joanna Briggs Institute Critical Appraisal Tool, which allows attributing scores from 1 to 11 to the selected studies. Two authors carried out the literature search, study selection, and data extraction. Differences on issues were resolved by a third author if necessary. The systematic review protocol was registered within the “Open Science Framework” (Doi: 10.17605/OSF.IO/DE7BH). Six articles met the inclusion criteria. All studies were heterogeneous and had a high score of bias and several methodological differences. The following parameters were collected: SFR, melatonin, cortisol, glucose, immunoglobulin A (IgA), uric-acid, alkaline phosphatase (ALP), and aspartate aminotransferase (AST). The SFR decreased by 10% during Ramadan in fasting subjects. The circadian pattern of melatonin remained unchanged during Ramadan, but melatonin levels dropped significantly from baseline. The salivary cortisol levels were unchanged or increased during Ramadan. The salivary glucose levels were decreased. ALP increased significantly, whilst uric-acid and AST decreased significantly. Salivary IgA decreased during the last week of Ramadan. To conclude, there is a trend toward a decrease in SFR and the content of the majority of the biomarkers investigated, with the exception of ALP and uric-acid. These changes cannot be easily attributed to any single factor (hydration status, dietary habits, physical activity, or hygiene habits).

Systematic Review Registration: [https://osf.io/de7bh/], identifier [Doi: 10.17605/OSF.IO/DE7B].
Application Effect of ICG Fluorescence Real-Time Imaging Technology in Laparoscopic Hepatectomy
Authors: Chen Hao , Wang Yumin , Xie Zhiguo , Zhang Luyuan , Ge Yongsheng , Yu Jihai , Zhang Chuanhai , Jia Weidong , Ma Jinliang , Liu Wenbin
Published: April 2022

This study aimed to evaluate the efficiency and safety of indocyanine green (ICG) fluorescence real-time imaging-guided technology in laparoscopic hepatectomy. A retrospective analysis of patients with primary liver cancer in the First Affiliated Hospital of USTC from January 2018 to October 2021, including 48 cases of fluorescence-guided laparoscopic hepatectomy (FGLH) and 60 cases of traditional laparoscopic hepatectomy (LH), was conducted. R0 resection rate, operation time, intraoperative blood loss, complications, hospital stay, and other intraoperative and postoperative indicators of the two groups were analyzed to determine the clinical feasibility and safety of ICG fluorescence real-time imaging-guided technology in laparoscopic hepatectomy. Related databases were searched for retrospective cohort studies and randomized controlled trials comparing FGLH with LH, studies were screened according to preset inclusion and exclusion criteria, literature quality was evaluated, and data were extracted. RevMan 5.3 software was used to conduct a meta-analysis on the extracted data. The results of our clinical data and meta-analysis showed that compared with LH, FGLH increased the R0 resection rate, shortened the operation time and postoperative hospital stay, and reduced blood loss and the occurrence of postoperative complications. Compared with LH, FGLH has a better application effect in laparoscopic hepatectomy, and it is worthy of promotion as it is safe and feasible.
Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair
Authors: Kelm Jeremy M. , Samarbakhsh Amirreza , Pillai Athira , VanderVere-Carozza Pamela S. , Aruri Hariprasad , Pandey Deepti S. , Pawelczak Katherine S. , Turchi John J. , Gavande Navnath S.
Published: April 2022

The vast majority of cancer patients receive DNA-damaging drugs or ionizing radiation (IR) during their course of treatment, yet the efficacy of these therapies is tempered by DNA repair and DNA damage response (DDR) pathways. Aberrations in DNA repair and the DDR are observed in many cancer subtypes and can promotede novocarcinogenesis, genomic instability, and ensuing resistance to current cancer therapy. Additionally, stalled or collapsed DNA replication forks present a unique challenge to the double-strand DNA break (DSB) repair system. Of the various inducible DNA lesions, DSBs are the most lethal and thus desirable in the setting of cancer treatment. In mammalian cells, DSBs are typically repaired by the error prone non-homologous end joining pathway (NHEJ) or the high-fidelity homology directed repair (HDR) pathway. Targeting DSB repair pathways using small molecular inhibitors offers a promising mechanism to synergize DNA-damaging drugs and IR while selective inhibition of the NHEJ pathway can induce synthetic lethality in HDR-deficient cancer subtypes. Selective inhibitors of the NHEJ pathway and alternative DSB-repair pathways may also see future use in precision genome editing to direct repair of resulting DSBs created by the HDR pathway. In this review, we highlight the recent advances in the development of inhibitors of the non-phosphatidylinositol 3-kinase-related kinases (non-PIKKs) members of the NHEJ, HDR and minor backup SSA and alt-NHEJ DSB-repair pathways. The inhibitors described within this review target the non-PIKKs mediators of DSB repair including Ku70/80, Artemis, DNA Ligase IV, XRCC4, MRN complex, RPA, RAD51, RAD52, ERCC1-XPF, helicases, and DNA polymerase θ. While the DDR PIKKs remain intensely pursued as therapeutic targets, small molecule inhibition of non-PIKKs represents an emerging opportunity in drug discovery that offers considerable potential to impact cancer treatment.
Case Report: Immune Checkpoint Inhibitors as a Single Agent in the Treatment of Metastatic Cervical Cancer
Authors: Anipindi Manasa , Smith Ryan J. , Gilani Madiha
Published: April 2022

The incidence of cervical cancer has decreased in recent years due to widespread vaccination and routine screenings. It can be treated successfully, and the prognosis is also excellent if detected early. However, the 5-year survival rate for patients with stage IV cervical cancer is only 17% even with aggressive systemic chemotherapy. With the Food and Drug Administration (FDA)’s approval of immunotherapy, the prognosis has improved. We present a patient with stage IV cervical cancer who could not tolerate platinum-based chemotherapy and bevacizumab, so she was started on an immune checkpoint inhibitor, as her tumor was 100% programmed cell death ligand-1 (PD-L1) positive. She survived more than 2 years since the diagnosis of stage IV cervical cancer without any significant side effects. Based on our patient’s response, the use of immune checkpoint inhibitors as a single agent needs further research and probably can be considered in patients with stage 4 cervical cancer who cannot tolerate standard chemotherapy.
Percutaneous Radiofrequency Ablation Is an Effective Method for Local Control of Liver Metastases From Lung Cancer
Authors: Zhang Zhong-Yi , Jiang An-Na , Yang Wei , Yan Kun , Wu Wei , Wang Song , Jiang Bin-Bin , Sun Li-Qi , Zhao Kun , Chen Min-Hua
Published: April 2022

Objective

To investigate the clinical value of percutaneous radiofrequency ablation (RFA) for liver metastasis from lung cancer (LCLM).

Materials and Methods

We retrospectively enrolled 58 patients who underwent RFA for LCLM between January 2014 and December 2019. Primary lung cancer histology included 38 adenocarcinomas, 15 squamous carcinomas, and 5 small cell carcinomas. For 83 metastatic lesions (mean tumor diameter 3.3 ± 1.1 cm, range 0.9–5.0 cm), 65 RFA sessions were performed. Before RFA, 17 and 41 patients presented no and stable extrahepatic metastasis, respectively, whereas 18 and 40 patients had synchronous and metachronous liver metastasis, respectively. Survival was analyzed using the Kaplan-Meier method. Cox proportional hazards model was used for multivariable analysis.

Results

The technical success rate was 96.3% (80/83 lesions). Local tumor progression was observed in 8 (9.8%, 8/82) lesions of 57 (14.0%, 8/57) patients at 4–12 months after RFA. New liver metastases occurred in 27 (46.6%) patients. The overall survival (OS) rates at 1, 2, 3, and 5 years after RFA were 55.2%, 26.0%, 22.0%, and 14.4%, respectively. The median OS after RFA and after liver metastasis were 14.0 ± 1.6 and 20.0 ± 1.5 months, respectively. Based on the univariable analysis, tumor size (p=0.017), histological type (p=0.015), and timing of liver metastasis (p=0.046) were related to OS. In further multivariable analyses, squamous carcinoma (hazard ratio= 2.269, 95% confidence interval: 1.186-4.339, p=0.013) was an independent unfavorable prognostic factor for OS. Based on the univariable analysis, histological type (p=0.010) was identified as parameters significantly related to local tumor progression (LTP)-free survival. Further multivariable analyses revealed that squamous carcinoma (hazard ratio=2.394, 95% confidence interval: 1.260–4.550, p=0.008) was an independent unfavorable prognostic factor for LTP-free survival.

Conclusion

RFA is a safe therapeutic option for LCLM with acceptable local tumor control, especially in patients with a tumor size ≤3 cm, adenocarcinoma/small cell carcinoma, and metachronous liver metastases.
Maternal Exposure to Polychlorinated Biphenyls and Asthma, Allergic Rhinitis and Atopic Dermatitis in the Offspring: The Environmental Health Fund Birth Cohort
Authors: Berlin Maya , Flor-Hirsch Hadar , Kohn Elkana , Brik Anna , Keidar Rimona , Livne Ayelet , Marom Ronella , Ovental Amit , Mandel Dror , Lubetzky Ronit , Factor-Litvak Pam , Tovbin Josef , Betser Moshe , Moskovich Miki , Hazan Ariela , Britzi Malka , Gueta Itai , Berkovitch Matitiahu , Matok Ilan , Hamiel Uri
Published: April 2022

Background: Polychlorinated biphenyls (PCBs) are persistent organic pollutants banned for use worldwide. Due to their biodegradation resistance, they accumulate along the food chain and in the environment. Maternal exposure to PCBs may affect the fetus and the infant. PCBs are immunotoxic and may damage the developing immune system. PCBs are associated with elevated IgE antibodies in cord blood and are considered to be predictive of atopic reactions. Several studies on the association between prenatal exposure to PCBs and atopic reactions were previously published, albeit with conflicting results.

Objectives: To examine the association between maternal PCBs levels and atopic reactions in their offspring.

Methods: During the years 2013–2015, a prospective birth cohort was recruited at the delivery rooms of Shamir Medical Center (Assaf Harofeh) and “Dana Dwek” Children’s Hospital. Four PCBs congeners were investigated: PCBs 118, 138, 153, and 180. In 2019, when children reached the age of 4–6 years, mothers were interviewed using the ISAAC questionnaire to assess symptoms of atopic reactions, including asthma, allergic rhinitis, and atopic dermatitis.

Results: One hundred and fifty mother-child dyads were analyzed. No significant differences were found in the median serum PCBs concentrations of each studied congener or total PCBs for asthma, allergic rhinitis, atopic dermatitis diagnosis, or parent-reported symptoms. No association was found between exposure to total PCBs and the risk for asthma symptoms or diagnosis, adjusted to maternal age and family member with atopic condition: aOR = 0.94, 95%CI: (0.88; 0.99). No association was observed between each studied PCB congener and asthma symptoms or diagnosis. The same results were found also for other studied outcomes—allergic rhinitis and atopic dermatitis.

Conclusion: Our study joins a series of previous studies that attempt to shed light on environmental exposures in utero as influencing factors for atopic conditions in children. Our results reflect the complexity of the pathophysiology of these phenomena. No relationship between maternal serum PCBs levels was demonstrated for asthma, allergic rhinitis, or atopic dermatitis. However, additional multi-participant studies, with longer, spanning into later pediatric age follow up are needed.
Assessing the Consequences of External Reference Pricing for Global Access to Medicines and Innovation: Economic Analysis and Policy Implications
Authors: Incze András , Kaló Zoltán , Espín Jaime , Kiss Éva , Kessabi Sophia , Garrison Louis P.
Published: April 2022

Background: External reference pricing (ERP) is used to set pharmaceutical prices to improve affordability, but its application may have negative consequences on patient access—thus, equity—across countries and on global innovation. With the United States contemplating ERP, negative effects could be magnified. Our aim: identify and quantify some major consequences of ERP. Research design, methods: Besides relying on databases and ERP modelling, we developed a heart failure case study. 4-step approach: 1) review ERP policies; 2) establish worldwide “price corridor”; 3) quantify patient access and health outcomes impact by ERP; 4) estimate ERP impact on innovation.

Results: Our ERP referencing analysis highlights its perverse effects especially in lower-income countries. As counterstrategies to protect their revenues, manufacturers often implement tight list price corridors or launch avoidance/delays. Consequences include suboptimal patient access—hence, worse outcomes—illustrated by our case study: 500,000 + QALYs health loss. Additionally, the ensuing revenue reduction would likely cause innovation loss by one additional medicine that would have benefitted future patients.

Conclusion: This research provides key insights on potential unintentional consequences of medicine price setting by ERP worldwide and under a new proposal for the United States. Our results can inform stakeholder discussions to improve patient access to innovative medicines globally.
Efficacy and Safety of Subthreshold Micropulse Yellow Laser for Persistent Diabetic Macular Edema After Vitrectomy: A Pilot Study
Authors: Bonfiglio Vincenza , Rejdak Robert , Nowomiejska Katarzyna , Zweifel Sandrine Anne , Justus Wiest Maximilian Robert , Romano Giovanni Luca , Bucolo Claudio , Gozzo Lucia , Castellino Niccolò , Patane Clara , Pizzo Corrado , Reibaldi Michele , Russo Andrea , Longo Antonio , Fallico Matteo , Macchi Iacopo , Vadalà Maria , Avitabile Teresio , Costagliola Ciro , Jonak Kamil , Toro Mario Damiano
Published: April 2022

Aim: To examine the effect of subthreshold micropulse yellow laser (SMYL) on best-corrected visual acuity (BCVA), central macular thickness (CMT), and optical coherence tomography angiography (OCT-A) changes in eyes with persistent diabetic macular edema (DME) after pars plana vitrectomy (PPV) for tractional DME (TDME).

Patients and Methods: In a comparative study, 95 eyes of 95 consecutive patients with persistent DME were prospectively enrolled. The SMYL group (54 eyes) was treated with SMYL 6 months after PPV, while the control group (41 eyes) was followed up without treatment. BCVA and CMT by OCT were analyzed at baseline and 3 and 6 months. Additionally, parameters such as the vessel density (VD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), respectively, and the area of the foveal avascular zone (FAZ) were also evaluated on OCT-A.

Results: There were no significant differences between both groups in demographic data. In the SMYL group, mean BCVA was significantly increased [F(2,106) = 17.25; p < 0.001; ηp2 = 0.246] from 51.54 ± 13.81 ETDRS letters at baseline to 57.81 ± 12.82 ETDRS letters at 3 months (p < 0.001) and 57.83 ± 13.95 EDTRS letters at 6 months (p < 0.001), respectively. In comparison to the control group, BCVA values were statistically significantly higher in the SMYL group at 3 and 6 months, respectively. Mean CMT significantly decreased [F(2,106) = 30.98; p < 0.001; ηp2 = 0.368] from the baseline value 410.59 ± 129.91 μm to 323.50 ± 89.66 μm at 3 months (p < 0.001) and to 283.39 ± 73.45 μm at 6 months (p < 0.001). CMT values were significantly lower in the SMYL group (p < 0.001), especially at 6 months follow-up time (p < 0.001) compared with the control group. Parafoveal VD in the SCP and DCP was significantly higher in the SMYL group in comparison to the control group, respectively, at 3-month (SCP p < 0.001; DCP p < 0.001) and 6-month follow-up (SCP p < 0.001; DCP p < 0.001). FAZ area was also significantly smaller in the SMYL group at 6-month follow-up (p = 0.001). There were no adverse SMYL treatment effects.

Conclusion: SMYL therapy may be a safe and effective treatment option in eyes with persistent macular edema following PPV for TDME.
Huangqin Tang Interference With Colitis Associated Colorectal Cancer Through Regulation of Epithelial Mesenchymal Transition and Cell Cycle
Authors: Ma Xuran , Wang Dunfang , Feng Xue , Liu Yaqing , Li Jia , Yang Weipeng
Published: April 2022

Background: Although the exact molecular mechanisms of colitis-associated colorectal cancer are not fully understood, the chronic inflammation was positively correlated with tumorigenesis. The traditional Chinese medicine botanical formulation Huangqin Tang has significant anti-inflammatory effects. We investigated whether HQT can ameliorate the progression of inflammation to cancer through its anti-inflammatory effects by using relevant predictions and experiments.

Methods: We used the azoxymethane/dextran sodium sulfate method to induce the mice colitis-associated colorectal cancer model. After preventive administration of Huangqin Tang to the mice model, colonic tissues were taken for quantitative proteomic analysis of tandem mass tags, and the proteomic results were then experimentally validated using the molecular biology approach.

Results: Proteomic screening revealed that the effect of the mechanism of Huangqin-Tang on the colitis-associated colorectal cancer mice model may be related to infinite replication which demonstrated abnormal G1/S checkpoint and epithelial mesenchymal transition acceleration. The levels of inflammatory factors such as interleukin-1α, interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly reduced in colitis-associated colorectal cancer mice treated with Huangqin Tang; the aberrant expression of G1/S checkpoint-associated sites of cell cycle protein-dependent kinase 4, D1-type cyclins, and dysregulation of related sites of the WNT pathway which are most related to the acceleration of the epithelial mesenchymal transition process including WNT3A, β-catenin, E-cadherin, and glycogen synthase kinase 3β has been improved.

Conclusion: Reducing inflammation and thus inhibiting the progression of colitis-associated colorectal cancer by using Huangqin-Tang is effective, and the mechanism of action may be related to the inhibition of uncontrolled proliferation during tumorigenesis. In the follow-up, we will conduct a more in-depth study on the relevant mechanism of action.
Evaluating Osteogenic Differentiation of Osteoblastic Precursors Upon Intermittent Administration of PTH/IGFBP7
Authors: Xia Han , Tian Yueyang , Lin Yile , Huang Qia , Xue Yuan
Published: April 2022

Parathyroid hormone (PTH) 1–34 is the first anabolic agent approved for the treatment of osteoporosis. Preclinical evidence shows a potential association between PTH and osteosarcoma. The mechanisms mediating the bone- and neoplasm-forming effects of PTH remain incompleted understood, few studies on the role of Insulin-like growth factor-binding protein 7 (IGFBP7) in mediating the anabolic effects of PTH has been reported. Intermittent PTH administration was found to increase the expression of IGFBP7 in mesenchymal stem cells (MSCs) and pre-osteoblasts. The results indicated that the anabolic effects of PTH were interrupted when knockdown of IGFBP7, while supplementation with IGFBP7 protein could enhance the bone-forming efficacy of PTH and regulate the signaling pathways. Moreover, bone healing was accelerated by the administration of IGFBP7 along with PTH in a mouse model of fracture. The obtained results proved that IGFBP7 was necessary for the anabolic effects of PTH, and combined administration of PTH and IGFBP7 showed stronger bone-forming effects relative to administration of PTH alone.
OAT10/SLC22A13 Acts as a Renal Urate Re-Absorber: Clinico-Genetic and Functional Analyses With Pharmacological Impacts
Authors: Toyoda Yu , Kawamura Yusuke , Nakayama Akiyoshi , Morimoto Keito , Shimizu Seiko , Tanahashi Yuki , Tamura Takashi , Kondo Takaaki , Kato Yasufumi , Ichida Kimiyoshi , Suzuki Hiroshi , Shinomiya Nariyoshi , Kobayashi Yasushi , Takada Tappei , Matsuo Hirotaka
Published: April 2022

Dysfunctional missense variant of organic anion transporter 10 (OAT10/SLC22A13), rs117371763 (c.1129C>T; p.R377C), is associated with a lower susceptibility to gout. OAT10 is a urate transporter; however, its physiological role in urate handling remains unclear. We hypothesized that OAT10 could be a renal urate re-absorber that will be a new molecular target of urate-lowering therapy like urate transporter 1 (URAT1, a physiologically-important well-known renal urate re-absorber) and aimed to examine the effect of OAT10 dysfunction on renal urate handling. For this purpose, we conducted quantitative trait locus analyses of serum urate and fractional excretion of uric acid (FEUA) using samples obtained from 4,521 Japanese males. Moreover, we performed immunohistochemical and functional analyses to assess the molecular properties of OAT10 as a renal urate transporter and evaluated its potential interaction with urate-lowering drugs. Clinico-genetic analyses revealed that carriers with the dysfunctional OAT10 variant exhibited significantly lower serum urate levels and higher FEUA values than the non-carriers, indicating that dysfunction of OAT10 increases renal urate excretion. Given the results of functional assays and immunohistochemical analysis demonstrating the expression of human OAT10 in the apical side of renal proximal tubular cells, our data indicate that OAT10 is involved in the renal urate reabsorption in renal proximal tubules from urine. Additionally, we found that renal OAT10 inhibition might be involved in the urate-lowering effect of losartan and lesinurad which exhibit uricosuric effects; indeed, losartan, an approved drug, inhibits OAT10 more strongly than URAT1. Accordingly, OAT10 can be a novel potential molecular target for urate-lowering therapy.
Shuxie-1 Decoction Alleviated CUMS -Induced Liver Injury via IL-6/JAK2/STAT3 Signaling
Authors: Zhang Mengting , Wu Wanhong , Huang Caoxin , Cai Teng , Zhao Nengjiang , Liu Suhuan , Yang Shuyu
Published: April 2022

Introduction: Chronic stress has been shown to cause liver damage in addition to psychological depression. Besides, drug-induced liver injury is frequently caused by antidepressants. Shuxie-1 decoction (SX-1) is a formula of traditional Chinese medicine commonly used in nourishing liver blood, and relieving depression. However, the underlying molecular mechanism remains unclear. Therefore, this study was designed to explore the effects and mechanisms of SX-1 in treating chronic stress-induced depression as well as liver injury.

Methods: Chronic unpredictable mild stress (CUMS) was applied to male Wistar rats for 4 weeks, with or without administration of SX-1 at low-dose and high-dose for 6 weeks, using Fluoxetine (Flu) as a positive control. Body weight was monitored once every 2 weeks. In the sixth week, the sugar preference test and open field test were carried out to evaluate the depression status. After that, the serum and liver tissues were collected. The quality control of SX-1 decoctions and drug-containing serum was controlled by UHPLC-QE-MS. The cell viability was measured by Cell Counting Kit-8 (CCK8). Enzyme-linked immunosorbent assay (Elisa), Western Blot and immunohistochemistrical staining was obtained to detect the protein levels in the plasma and the hepatic tissues, respectively.

Results: CUMS led to decreased 1) body weight, 2) the preference for sugar water, 3) the desire to explore in open field, and increased serum levels of corticosterone. All these factors were completely reversed by SX-1 treatment. Hematoxylin-eosin staining (HE) showed that SX-1 improved the hepatocyte vacuolization in CUMS treated rats, decreased the serum levels of alanine aminotransferase (ALT) and the deposition of type I collagen (Col I) in hepatocytes as well. CUMS increased the levels of hepatic Interleukin-6 (IL-6), and provoked the activation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), which was abrogated by SX-1 treatment. Cobalt chloride (CoCl2) increased the protein expression of IL-6 and p-STAT3 in AML12 cells. Besides, nuclear pyknosis was observed under electron microscope, which were recovered after rat SX serum.

Conclusion: SX-1 effectively ameliorated CUMS-induced depression-like behaviors as well as hepatic injuries, probably by the blockade of hepatic IL-6/JAK2/STAT3 signaling.
Bushen Culuan Decoction Ameliorates Premature Ovarian Insufficiency by Acting on the Nrf2/ARE Signaling Pathway to Alleviate Oxidative Stress
Authors: Chen Yanxia , Fan Xiaodi , Ma Kun , Wang Kaili , Tian Caidie , Li Min , Gong Linjuan
Published: April 2022

Premature ovarian insufficiency (POI) can result in lower fertility and shorten the female reproductive span. Bushen-Culuan Decoction (BCD) is a traditional Chinese medication utilized for treating POI for many years. We previously observed that BCD protects against further deterioration of the ovarian reserve of POI patients, however, the underlying mechanism has not been well studied. Our investigation seeks to evaluate the effect of BCD on POI induced by Tripterygium wilfordii polyglycosidium (TWP) and the likely mechanistic pathways, which we hypothesize may involve the Nrf2/ARE pathway. The body weights, estrous cycle, serum hormone levels, histological follicular analysis and quantification, levels of oxidative stress biomarkers in the ovarian tissue of POI mice models were evaluated. Western blotting and RT-PCR enabled quantification of the components of the Nrf2/ARE pathway. Our results showed that BCD restored hormonal profiles and estrous cycles of POI mice similar to those observed in healthy controls. BCD reduced the numbers of atretic follicles while increasing the number of primordial follicles. BCD facilitated lower 8-OHdG and MDA levels while increasing levels of key antioxidant enzymes including GSH-Px, CAT, and SOD. Furthermore, TWP increased Bach 1, Nrf2, and Keap 1 expressions at the translational level, while decreased that of HO-1. BCD treatment also promoted nuclear translocation rates of Bach 1 and Nrf2, suppressed Keap 1 protein expression, as well as raised HO-1 protein expression. Taken together, BCD likely augments ovarian reserve by activating the Nrf2/ARE signaling pathway, which stimulated higher levels of antioxidants and suppressed oxidative stress. BCD may be an important therapeutic compound in POI.
mPEG-PDLLA Micelles Potentiate Docetaxel for Intraperitoneal Chemotherapy in Ovarian Cancer Peritoneal Metastasis
Authors: Zhang Yumei , Wang Shunli , Duan Xiaofan , Xu Xiaoxiao , Gao Yuan , Zhou Jiuli , Xu Xiaolin , Li Jin
Published: April 2022

Ovarian cancer is the second most common cause of gynecological cancer death in women. It is usually diagnosed late and accompanied by peritoneal metastasis. For ovarian cancer with peritoneal metastasis, intraperitoneal (IP) chemotherapy can maintain a high drug concentration in the abdominal cavity and reduce local and systemic toxicity. Recently, docetaxel (DTX) has shown broad-spectrum antitumor activity against various malignant tumors, including ovarian cancer with peritoneal metastasis. However, DTX has limited clinical applications due to its poor water solubility, predisposition to hypersensitivity, fluid retention, and varying degrees of neurotoxicity. In this study, we prepared methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) micelles loaded with DTX and developed an alternative, less toxic, more effective DTX formulation, without Tween 80, and evaluated its pharmacokinetics in the abdominal cavity and its efficacy in ovarian cancer with peritoneal metastasis. The mean diameter of DTX-mPEG-PDLLA was about 25 nm, and the pharmacokinetics of BALB/c mice via IP showed that the plasma exposure of DTX-mPEG-PDLLA was about four times lower than that of DTX. Importantly, DTX-mPEG-PDLLA was significantly more effective than DTX and prolonged the survival period in a SKOV-3 ovarian cancer peritoneal metastasis model. Moreover, the apoptosis rate was significantly increased in vitro. Based on these findings, it is expected that DTX-mPEG-PDLLA can enhance efficacy against ovarian cancer peritoneal metastasis, while reducing toxic side effects, and has the potential to be used in the clinical treatment of peritoneal metastatic cancer.