bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations Between Carotid Plaque Characteristics and Perioperative Cerebral Blood Flow Determined by Arterial Spin Labeling Imaging in Patients With Moderate-to-Severe Stenosis Undergoing Carotid Endarterectomy
Authors: Liu Ying , Huo Ran , Xu Huimin , Zhou Guangjin , Wang Tao , Yuan Huishu , Zhao Xihai
Published: July 2022

Purpose

To examine the associations between carotid plaque characteristics and perioperative cerebral blood flow (CBF) by arterial spin labeling (ASL) imaging.

Materials and Methods

Patients with unilateral moderate-to-severe carotid stenosis referred for carotid endarterectomy (CEA) were recruited and underwent carotid vessel wall and brain ASL magnetic resonance imaging. The following imaging features were measured: relative CBF (rCBF = CBFindex−hemisphere/CBFcontralateral−hemisphere) in the middle cerebral artery territory; plaque burden and the presence of lipid-rich necrotic core; intraplaque hemorrhage (IPH); calcification; ulcer and fibrous-cap rupture; and the volume and maximum plaque components' area percentages. The associations between plaque characteristics and perioperative CBF were analyzed.

Results

Sixty-one patients (mean age, 66.6 ± 7.8 years; 55 males) were included. Univariate linear regression showed that rCBFpre−CEA was associated with stenosis [β, −0.462; 95% confidence interval (CI), from −0.797 to −0.126; p = 0.008], calcification (β, 0.103; 95% CI, 0.005–0.201; p = 0.040), maximum IPH area percentage (β, −0.127; 95% CI, from −0.223 to −0.030; p = 0.012), and ulcer (β, 0.069; 95% CI, 0.025–0.113; p = 0.005); rCBFpost−CEA was associated with the IPH volume (β, −0.060; 95% CI, from −0.107 to −0.014; p = 0.013). After adjusting for the confounding factors, the associations of calcification with rCBFpre−CEA (β, 0.099; 95% CI, from 0.004 to −0.194; p = 0.042) and IPH volume with rCBFpost−CEA (β, −0.060; 95% CI, from −0.109 to −0.011; p = 0.020) remained statistically significant, while those of rCBFpre−CEA with maximum IPH area percentage (β, −0.089; 95% CI, from −0.188 to 0.011; p = 0.080) and ulcer (β, 0.050; 95% CI, from −0.012 to 0.112; p = 0.100) did not remain statistically significant.

Conclusion

The compositional characteristics of carotid atherosclerotic plaques, particularly IPH, were associated with perioperative CBF in patients with unilateral moderate-to-severe carotid stenosis undergoing CEA. Our findings indicated that the patients with larger carotid IPH could expect smaller improvement in CBF following CEA.
Responsive Thalamic Neurostimulation: A Systematic Review of a Promising Approach for Refractory Epilepsy
Authors: Feigen Chaim M. , Eskandar Emad N.
Published: July 2022

Introduction

Responsive neurostimulation is an evolving therapeutic option for patients with treatment-refractory epilepsy. Open-loop, continuous stimulation of the anterior thalamic nuclei is the only approved modality, yet chronic stimulation rarely induces complete seizure remission and is associated with neuropsychiatric adverse effects. Accounts of off-label responsive stimulation in thalamic nuclei describe significant improvements in patients who have failed multiple drug regimens, vagal nerve stimulation, and other invasive measures. This systematic review surveys the currently available data supporting the use of responsive thalamic neurostimulation in primary and secondary generalized, treatment-refractory epilepsy.

Materials and Methods

A systematic review was performed using the following combination of keywords and controlled vocabulary: (“Seizures”[Mesh] AND “Thalamus”[Mesh] AND “Deep Brain Stimulation”[Mesh]) OR (responsive neurostim* AND (thalamus[MeSH])) OR [responsive neurostimulation AND thalamus AND (epilepsy OR seizures)]. In addition, a search of the publications listed under the PubMed “cited by” tab was performed for all publications that passed title/abstract screening in addition to manually searching their reference lists.

Results

Ten publications were identified describing a total of 29 subjects with a broad range of epilepsy disorders treated with closed-loop thalamic neurostimulation. The median age of subjects was 31 years old (range 10–65 years). Of the 29 subjects, 15 were stimulated in the anterior, 11 in the centromedian, and 3 in the pulvinar nuclei. Excluding 5 subjects who were treated for 1 month or less, median time on stimulation was 19 months (range 2.4–54 months). Of these subjects, 17/24 experienced greater than or equal to 50%, 11/24 least 75%, and 9/24 at least 90% reduction in seizures. Although a minority of patients did not exhibit significant clinical improvement by follow-up, there was a general trend of increasing treatment efficacy with longer periods on closed-loop thalamic stimulation.

Conclusion

The data supporting off-label closed-loop thalamic stimulation for refractory epilepsy is limited to 29 adult and pediatric patients, many of whom experienced significant improvement in seizure duration and frequency. This encouraging progress must be verified in larger studies.
Ceftriaxone as a Novel Therapeutic Agent for Hyperglutamatergic States: Bridging the Gap Between Preclinical Results and Clinical Translation
Authors: Abulseoud Osama A. , Alasmari Fawaz , Hussein Abdelaziz M. , Sari Youssef
Published: July 2022

Dysregulation of glutamate homeostasis is a well-established core feature of neuropsychiatric disorders. Extracellular glutamate concentration is regulated by glutamate transporter 1 (GLT-1). The discovery of a beta-lactam antibiotic, ceftriaxone (CEF), as a safe compound with unique ability to upregulate GLT-1 sparked the interest in testing its efficacy as a novel therapeutic agent in animal models of neuropsychiatric disorders with hyperglutamatergic states. Indeed, more than 100 preclinical studies have shown the efficacy of CEF in attenuating the behavioral manifestations of various hyperglutamatergic brain disorders such as ischemic stroke, amyotrophic lateral sclerosis (ALS), seizure, Huntington’s disease, and various aspects of drug use disorders. However, despite rich and promising preclinical data, only one large-scale clinical trial testing the efficacy of CEF in patients with ALS is reported. Unfortunately, in that study, there was no significant difference in survival between placebo- and CEF-treated patients. In this review, we discussed the translational potential of preclinical efficacy of CEF based on four different parameters: (1) initiation of CEF treatment in relation to induction of the hyperglutamatergic state, (2) onset of response in preclinical models in relation to onset of GLT-1 upregulation, (3) mechanisms of action of CEF on GLT-1 expression and function, and (4) non-GLT-1-mediated mechanisms for CEF. Our detailed review of the literature brings new insights into underlying molecular mechanisms correlating the preclinical efficacy of CEF. We concluded here that CEF may be clinically effective in selected cases in acute and transient hyperglutamatergic states such as early drug withdrawal conditions.
Audiological and Other Factors Predicting the Presence of Misophonia Symptoms Among a Clinical Population Seeking Help for Tinnitus and/or Hyperacusis
Authors: Aazh Hashir , Erfanian Mercede , Danesh Ali A. , Moore Brian C. J.
Published: July 2022

This paper evaluates the proportion and the audiological and other characteristics of patients with symptoms of misophonia among a population seeking help for tinnitus and/or hyperacusis at an audiology clinic (n = 257). To assess such symptoms, patients were asked “over the last 2 weeks, how often have you been bothered by any of the following problems? Feeling angry or anxious when hearing certain sounds related to eating noises, lip-smacking, sniffling, breathing, clicking sounds, tapping?”. The results of routine audiological tests and self-report questionnaires were gathered retrospectively from the records of the patients. Measures included: pure tone audiometry, uncomfortable loudness levels (ULLs), and responses to the tinnitus impact questionnaire (TIQ), the hyperacusis impact questionnaire (HIQ), and the screening for anxiety and depression in tinnitus (SAD-T) questionnaire. The mean age of the patients was 53 years (SD = 16) (age range 17 to 97 years). Fifty four percent were female. Twenty-three percent of patients were classified as having misophonia. The presence and frequency of reporting misophonia symptoms were not related to audiometric thresholds, except that a steeply sloping audiogram reduced the likelihood of frequent misophonia symptoms. Those with more frequent misophonia symptoms had lower values of ULLmin (the across-frequency average of ULLs for the ear with lower average ULLs) than those with less frequent or no reported symptoms. The reported frequency of experiencing misophonia symptoms increased with increasing impact of tinnitus (TIQ score ≥9), increasing impact of hyperacusis (HIQ score >11), and symptoms of anxiety and depression (SAD-T score ≥4). It is concluded that, when assessing individuals with tinnitus and hyperacusis, it is important to screen for misophonia, particularly when ULLmin is abnormally low or the TIQ, HIQ or SAD-T score is high. This will help clinicians to distinguish patients with misophonia, guiding the choice of therapeutic strategies.
Frontal Alpha Asymmetry in Response to Stressor Moderates the Relation Between Parenting Hassles and Child Externalizing Problems
Authors: Mulligan Daniel J. , Palopoli Ava C. , van den Heuvel Marion I. , Thomason Moriah E. , Trentacosta Christopher J.
Published: July 2022

Inequitable urban environments are associated with toxic stress and altered neural social stress processing that threatens the development of self-regulation. Some children in these environments struggle with early onset externalizing problems that are associated with a variety of negative long-term outcomes. While previous research has linked parenting daily hassles to child externalizing problems, the role of frontal alpha asymmetry (FAA) as a potential modifier of this relationship has scarcely been explored. The present study examined mother-child dyads, most of whom were living in low socioeconomic status households in an urban environment and self-identified as members of racial minority groups. Analyses focused on frustration task electroencephalography (EEG) data from 67 children (mean age = 59.0 months, SD = 2.6). Mothers reported the frequency of their daily parenting hassles and their child’s externalizing problems. Frustration task FAA moderated the relationship between parenting daily hassles and child externalizing problems, but resting FAA did not. More specifically, children with left frontal asymmetry had more externalizing problems as their mothers perceived more hassles in their parenting role, but parenting hassles and externalizing problems were not associated among children with right frontal asymmetry. These findings lend support to the motivational direction hypothesis and capability model of FAA. More generally, this study reveals how individual differences in lateralization of cortical activity in response to a stressor may confer differential susceptibility to child behavioral problems with approach motivation (i.e., left frontal asymmetry) predicting externalizing problems under conditions of parental stress.
Free Fatty Acid and α-Lactalbumin-Oleic Acid Complexes in Preterm Human Milk Are Cytotoxic to Fetal Intestinal Cells in vitro
Authors: Chetta Katherine E. , Newton Danforth A. , Wagner Carol L. , Baatz John E.
Published: July 2022

Human milk, the best enteral selection for a preterm infant, becomes altered during freezing and soluble free fatty acid is generated over time. Free fatty acids may form complexes, such as the oleic acid-bound protein called HAMLET (human α-lactalbumin made lethal to tumor cells). We determined the in vitro biological activity of preterm human milk protein-oleic complexes (HAMLET-like complexes) and tested the hypothesis that laboratory-synthesized HAMLET exhibits cytotoxicity in human immature epithelial intestinal cell culture. Thirty-four milk samples from 15 mothers of hospitalized preterm infants were donated over time. Milk fractions were tested repeatedly for FHs 74 Int and HIEC-6 fetal cell cytotoxicity, using a sensitive viability assay. Protein and fatty acid identities were confirmed by Western blot, high performance liquid chromatography, and mass spectrometry. Cytotoxicity of intestinal cells exposed to milk increased respective to milk storage time (p < 0.001) and was associated with free oleic acid (p = 0.009). Synthesized HAMLET was cytotoxic in cultures of both lines. Preterm milk samples killed most cells in culture after an average 54 days in frozen storage (95% C.I. 34–72 days). After prolonged storage time, preterm milk and HAMLET showed a degree of cytotoxicity to immature intestinal cells in culture.
A Dietary Supplement Containing Micronutrients, Phosphatidylserine, and Docosahexaenoic Acid Counteracts Cognitive Impairment in D-Galactose-Induced Aged Rats
Authors: Ren Qian , Sun Jianqin , Xu Danfeng , Xie Hua , Ye Mengyao , Zhao Yanfang
Published: July 2022

At present, it is a trend to use dietary supplements to prevent age-related cognitive impairment. This study aimed to investigate the effects of a dietary supplement enriched with micronutrients, phosphatidylserine, and docosahexaenoic acid on cognitive performance using a D-galactose (D-gal) induced aging rat model. Seven-month-old male Sprague-Dawley rats were randomly divided into five groups, including the control group, D-gal model group, and low-dose (2 g/kg body weight), medium-dose (6 g/kg body weight), and high-dose (10 g/kg body weight) dietary supplement intervention groups, which were investigated for 13 weeks. The dietary supplement intervention was found to improve cognitive performance in Morris water maze test, increase superoxidase dismutase activity, reduce malondialdehyde activity, decrease tumor necrosis factor-α and interleukin-6 concentrations, inhibit the activation of astrocytes, and elevate brain-derived neurotrophic factor protein and mRNA expression in the brains of D-gal-induced aged rats. This dietary supplement customized for the aged can be applied to the restoration of cognitive performance by enhancing antioxidant and anti-neuroinflammatory abilities, up-regulating neurotrophic factors, and inhibiting the activation of astrocytes. These results will be useful for future studies focused on implementation in humans.
Fad Diets: Facts and Fiction
Authors: Tahreem Aaiza , Rakha Allah , Rabail Roshina , Nazir Aqsa , Socol Claudia Terezia , Maerescu Cristina Maria , Aadil Rana Muhammad
Published: July 2022

The global prevalence of obesity is alarmingly high and is impacting both developed and underdeveloped countries, beyond the borders of ethnicity, sex, and age. On the other hand, the global interest in dieting has increased, and people are obsessed with certain fad diets, assuming them as a magic bullet for their long-term problems. A fad diet is a popular dietary pattern known to be a quick fix for obesity. These diets are quite appealing due to the proposed claims, but the lack of scientific evidence is a big question mark. Such diets are often marketed with specific claims that defy the basic principles of biochemistry and nutritional adequacy. These diets may have protective effects against obesity and certain chronic diseases like cardiovascular diseases, metabolic syndrome, and certain cancers. Limited evidence exists to support the proposed claims; rather certain studies suggest the negative health consequences of long-term adherence to such dietary patterns. Many fad diets have emerged in the previous few decades. This review article will explore the current evidence related to the health impacts of some most popular diets: Atkins diet, ketogenic diet, Paleolithic diet, Mediterranean diet, vegetarian diet, intermittent fasting and detox diet.
Patient-Specific Assays Based on Whole-Genome Sequencing Data to Measure Residual Disease in Children With Acute Lymphoblastic Leukemia: A Proof of Concept Study
Authors: Arthur Cecilia , Rezayee Fatemah , Mogensen Nina , Saft Leonie , Rosenquist Richard , Nordenskjöld Magnus , Harila-Saari Arja , Tham Emma , Barbany Gisela
Published: July 2022

Risk-adapted treatment in acute lymphoblastic leukemia (ALL) relies on genetic information and measurable residual disease (MRD) monitoring. In this proof of concept study, DNA from diagnostic bone marrow (BM) of six children with ALL, without stratifying genetics or central nervous system (CNS) involvement, underwent whole-genome sequencing (WGS) to identify structural variants (SVs) in the leukemic blasts. Unique sequences generated by SVs were targeted with patient-specific droplet digital PCR (ddPCR) assays. Genomic DNA (gDNA) from BM and cell-free DNA (cfDNA) from plasma and cerebrospinal fluid (CSF) were analyzed longitudinally. WGS with 30× coverage enabled target identification in all cases. Limit of quantifiability (LoQ) and limit of detection (LoD) for the ddPCR assays (n = 15) were up to 10−5 and 10−6, respectively. All targets were readily detectable in a multiplexed ddPCR with minimal DNA input (1 ng of gDNA) at a 10−1 dilution, and targets for half of the patients were also detectable at a 10−2 dilution. The level of MRD in BM at end of induction and end of consolidation block 1 was in a comparable range between ddPCR and clinical routine methods for samples with detectable residual disease, although our approach consistently detected higher MRD values for patients with B-cell precursor ALL. Additionally, several samples with undetectable MRD by flow cytometry were MRD-positive by ddPCR. In plasma, the level of leukemic targets decreased in cfDNA over time following the MRD level detected in BM. cfDNA was successfully extracted from all diagnostic CSF samples (n = 6), and leukemic targets were detected in half of these. The results suggest that our approach to design molecular assays, together with ddPCR quantification, is a technically feasible option for accurate MRD quantification and that cfDNA may contribute valuable information regarding MRD and low-grade CNS involvement.
Addressing Health Disparities Across the Cancer Continuum—a Los Angeles Approach to Achieving Equity
Authors: Finster Laurel J. , Shirazipour Celina H. , Escobedo Loraine A. , Cockburn Myles , Surani Zul , Haile Robert W.
Published: July 2022

Introduction

Different models have been developed to address inequities across the cancer care continuum. However, there remains a scarcity of best practices on understanding and responding to the burden of cancer in a defined catchment area.As such, the National Cancer Institute (NCI) recently provided a framework to maximize the impact on cancer burden, including a greater focus on community outreach and engagement. In this paper, we describe how Cedars Sinai Cancer (CSC), a health system that serves one of the most diverse counties in the US, implemented the framework to define its catchment area, characterize its population, identify high risk priority groups, and make decisions to address health disparities.

Methods

We provide a review of the methods used to assess socio-ecological levels of influence. Data were reviewed from numerous national, statewide, and county sources and supplemented by locally administered questionnaires, heat maps, and community profile summaries to gain more localized snapshots of cancer disparities in Los Angeles County. Lastly, feedback was solicited from external peer groups, community stakeholders, and key decision-makers, and the proposed catchment area was aligned with the State’s Cancer Plan and the NCI Catchment Area and Community Outreach and Engagement Mandate.

Results

The selected CSC catchment area meets NCI criteria and has potential to demonstrate impact both at the population level and within specialty populations. As a result, strategies are being developed to organize community outreach and engagement, as well as research across basic, clinical, and population sciences to guide cancer control and prevention efforts.

Discussion

To maintain a high level of cultural inclusion and sensitivity, multiple layers of data are needed to understand localized pictures of cancer disparities and underlying causes. Community engagement remains essential to implementing policy, best practice, and translational science for broader impact.

Impact

The clinical and translation work conducted at any cancer center requires an understanding of the determinants of health that contribute to the differences in cancer incidence and mortality among different groups. The NCI-aligned approach that we highlight is critical to support the design of future cancer control strategies that address and possibly reduce local health inequities.
Transcriptome Profiling of N7-Methylguanosine Modification of Messenger RNA in Drug-Resistant Acute Myeloid Leukemia
Authors: Zhang Bing , Li Dong , Wang Ran
Published: July 2022

Acute myeloid leukemia (AML) is an aggressive hematological tumor caused by the malignant transformation of myeloid progenitor cells. Although intensive chemotherapy leads to an initial therapeutic response, relapse due to drug resistance remains a significant challenge. In recent years, accumulating evidence has suggested that post-transcriptional methylation modifications are strongly associated with tumorigenesis. However, the mRNA profile of m7G modification in AML and its role in drug-resistant AML are unknown. In this study, we used MeRIP-seq technology to establish the first transcriptome-wide m7G methylome profile for AML and drug-resistant AML cells, and differences in m7G between the two groups were analyzed. In addition, bioinformatics analysis was conducted to explore the function of m7G-specific methylated transcripts. We found significant differences in m7G mRNA modification between AML and drug-resistant AML cells. Furthermore, bioinformatics analysis revealed that differential m7G-modified mRNAs were associated with a wide range of cellular functions. Importantly, down-methylated m7G modification was significantly enriched in ABC transporter-related mRNAs, which are widely recognized to play a key role in multidrug resistance. Our results provide new insights into a novel function of m7G methylation in drug resistance progression of AML.
Implementation of HLA-B*15:02 Genotyping as Standard-of-Care for Reducing Carbamazepine/Oxcarbazepine Induced Cutaneous Adverse Drug Reactions in Thailand
Authors: Tiwattanon Kanyawan , John Shobana , Koomdee Napatrupron , Jinda Pimonpan , Rachanakul Jiratha , Jantararoungtong Thawinee , Nuntharadthanaphong Nutthan , Kloypan Chiraphat , Biswas Mohitosh , Boongird Apisit , Sukasem Chonlaphat
Published: July 2022

Objective: This study aimed to investigate the clinical impact of HLA-B*15:02 pharmacogenomics (PGx) testing before carbamazepine (CBZ)/oxcarbazepine (OXC) prescriptions and to determine whether this PGx testing was associated with the reduction of CBZ/OXC-induced cutaneous adverse drug reactions (CADRs) in Thailand.

Methods: This retrospective observational cohort study was conducted by obtaining relevant HLA-B*15:02 PGx-testing and clinical data from electronic medical records during 2011–2020. 384 patient data were included in this study to investigate the clinical decision on CBZ/OXC usage before and after the HLA-B*15:02 PGx testing, and 1,539 patient data were included in this study to demonstrate the incidence of CBZ/OXC-induced SCARs and SJS between HLA-B*15:02 tested and non-tested patients. To analyze and summarize the results, descriptive statistics were employed, and Fisher exact test was used to compare the clinical difference between the HLA-B*15:02 positive and negative groups and to compare the differences of SCARs incidence.

Results: 384 patients were included in this study as per the inclusion criteria. Of these, 70 patients carried HLA-B*15:02, of which 63 and 65 patients were not prescribed with CBZ/OXC before and after the availability of genotyping results, respectively. In the remaining HLA-B*15:02 non-carriers, 48, and 189 patients were prescribed CBZ/OXC before and after genotyping results were available, respectively. The findings of this study showed that the incidence of SCARs of CBZ/OXC was significantly lower (p < 0.001) in the HLA-B*15:02 screening arm than in the non-screening arm.

Conclusion:HLA-B pharmacogenetics testing influenced the selection of appropriate AEDs. The presence of mild rash in the HLA-B*15:02 negative group indicates that other genetic biomarker (HLA-A*31:01) and/or non-genetic variables are involved in CBZ/OXC-induced CADRs, emphasizing that CBZ/OXC prescriptions necessitate CADR monitoring. The hospital policy and clinical decision support (CDS) alert system is essential to overcome the barriers associated with the utilization of PGx guidelines into clinical practice.
Research Progress on the Anticancer Activities and Mechanisms of Polysaccharides From Ganoderma
Authors: Wang Man , Yu Fei
Published: July 2022

Cancer ranks as a primary reason for death worldwide. Conventional anticancer therapies can cause severe side effects, and thus natural products may be promising drug candidates for cancer therapy. Accumulating evidence has verified the prominent anticancer properties of Ganoderma polysaccharides, suggesting that Ganoderma polysaccharides may be effective chemopreventive agents of natural origin. Based on their abilities to prevent cancer development by regulating the DNA damage response, cancer cell proliferation, apoptosis, host immunity, gut microbiota and therapeutic sensitivity, there has been increasing interest in elucidating the clinical implication of Ganoderma polysaccharides in cancer therapy. In this review, we summarize recent findings pertaining to the roles of bioactive polysaccharides from Ganoderma in cancer pathogenesis, discuss the multifarious mechanisms involved and propose future directions for research. A more sophisticated understanding of the anticancer benefits of Ganoderma polysaccharides will be helpful for improving current treatments and developing novel therapeutic interventions for human malignancies.
Evaluation of the Effectiveness and Efficiency of the East African Community Joint Assessment Procedure by Member Countries: The Way Forward
Authors: Ngum Nancy , Mashingia Jane , Ndomondo-Sigonda Margareth , Walker Stuart , Salek Sam
Published: July 2022

Background: For almost a decade, the East African Community has implemented the Medicines Regulatory Harmonization (EAC-MRH) programme among its member states to harmonise technical requirements and standards for medical products regulation, jointly conduct scientific review of medical product dossiers to assess safety, efficacy and quality, inspect pharmaceutical manufacturing sites and streamline decision-making processes. This initiative enables the cost-effective use of limited resources and efficient and effective delivery of regulatory services to be determined, thus instilling transparency and accountability in all stakeholders, optimising the pharmaceutical market and economic development and improving access to safe, high-quality, effective medicines in the region. The aim of this study was to evaluate the effectiveness and efficiency of the current operating model of the EAC-MRH initiative, including challenges faced and to identify opportunities for improvement.

Methods: The Process Effectiveness and Efficiency Rating (PEER) questionnaire, which was used to identify the benefits, challenges, and suggestions for improving performance of EAC-MRH initiative, was completed by assessors representing seven EAC authorities in the joint assessment procedure. Semi-structured interviews were also carried out to validate the responses.

Results: This initiative has been of considerable value as it moves toward achieving its main objectives of shorter timelines for approval of medicines, information sharing among regulators and capacity building for assessments, resulting in quicker access and increased availability of medicines for patients in the region. However, the key challenges identified that have hindered effectiveness and efficiency were the lack of a centralised submission and tracking system; inadequate human resources, manufacturers’ failure to submit the exact same dossier to all countries of interest; lack of an integrated information management system; lack of information on national medical regulatory authority or EAC websites; and challenges in monitoring and tracking assessment reports.

Conclusion: The use of a robust information technology system for the central tracking of EAC products is essential to address the identified challenges and improve regulatory effectiveness and efficiency. One central point for payment is needed to expedite the process and to ensure transparency and the availability of information on decision making on national and regional websites. Other key strategies for enhancement include improving the capacity of assessors, work and information sharing and a coordination mechanism for the regional joint assessment, with the eventual establishment of a regional medicine agency.
Mechanism of Abnormal Coagulation Induced by Tigecycline in Cancer Patients
Authors: Sun Li-Hua , Bai Kun-Hao , Wu Guo-Yan , Tian Xiao-Peng , Zou Zhi-Qing , Wang Da-Wei , Dai Yu-Jun , Chen Si-Liang
Published: July 2022

Tigecycline is a broad-spectrum active intravenous antibiotic that is active against methicillin-resistant staphylococcus aureus. In Phase 3 and 4 clinical trials, increased all-cause mortality was observed in patients treated with tigecycline compared to patients in the control group. The reason for the increase is unclear. In this study, we found that tigecycline cause abnormal coagulation in tumor patients, especially in patients with hematological malignancies. The main manifestations were decreased fibrinogen and prolonged activated prothrombin time (APTT), thrombin time (TT), and D-dimer. In addition, through functional studies, we found that tigecycline inhibit platelet adhesion and aggregation, and the coagulation function of patients gradually recover after discontinuation. Gene sequencing results suggested that tigecycline significantly regulate the expression of genes related to platelet function pathways and increase the incidence of single nucleotide polymorphisms and the number of alternative splices in the Chinese hamster ovary (CHO) cells treated with tigecycline. An abnormal function and low numbers of platelets are common in patients with hematological malignancies. Our study can explain the mechanism of abnormal coagulation caused by tigecycline. Additionally, doctors who apply tigecycline to cure infections in tumor patients should be warned.
A ROCK1 Inhibitior Fasudil Alleviates Cardiomyocyte Apoptosis in Diabetic Cardiomyopathy by Inhibiting Mitochondrial Fission in a Type 2 Diabetes Mouse Model
Authors: Fan Xinhui , Li Xiaoxing , Liu Huiruo , Xu Feng , Ji Xiaoping , Chen Yuguo , Li Chuanbao
Published: July 2022

Diabetes mellitus (DM) often involves cardiovascular complications; however, treatment regimens are limited. ROCK1 (rho-associated coiled-coil containing protein kinase 1) serves as a pathological factor in several diabetic complications. Herein, we aimed to explore the effect of Fasudil (a ROCK1 inhibitor) on the progress of cardiac dysfunction in type 2 DM (T2DM), and to explore the possible mechanisms. Type II diabetic mice models were established by inducing insulin resistance through a high-fat diet combined with low-dose streptozotocin (STZ) injection. NMCMs (neonatal mouse ventricular cardiac myocytes) in the control group were treated with 5.5 mM glucose, while those in the High Glucose (HG) group were treated with 33 mM glucose and 10 nmol/L insulin. In vivo, we found that type 2 diabetes enhanced the expression and activation of ROCK1 (p < 0.05). The ROCK1 inhibitor, Fasudil, prevented cardiac dysfunction, fibrosis, oxidative stress and myocardial ultrastructural disorders (p < 0.05) in the diabetic mice. In vitro, ROCK1 was upregulated in HG-induced cardiomyocytes, and ROCK1 inhibition using Fasudil reversed the increased apoptosis, consistent with in vivo results. Mechanistically, ROCK1 inhibition abrogated apoptosis, relieved mitochondrial fission, and efficiently attenuated the escalated production of reactive oxygen species in vitro and in vivo. The content of Ser616-phosphorylated dynamin-related protein 1 (Drp1) increased while ROCK1 led to apoptosis in HG-treated cardiomyocytes, which could be partly neutralized by ROCK1 inhibition with Fasudil, consistent with the in vivo results. Fasudil attenuated the cardiac dysfunction in diabetes by decreasing excessive mitochondrial fission via inhibiting Drp1 phosphorylation at serine 616.
Therapeutic Strategies For Tay-Sachs Disease
Authors: Picache Jaqueline A. , Zheng Wei , Chen Catherine Z.
Published: July 2022

Tay-Sachs disease (TSD) is an autosomal recessive disease that features progressive neurodegenerative presentations. It affects one in 100,000 live births. Currently, there is no approved therapy or cure. This review summarizes multiple drug development strategies for TSD, including enzyme replacement therapy, pharmaceutical chaperone therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell replacement therapy. In vitro and in vivo systems are described to assess the efficacy of the aforementioned therapeutic strategies. Furthermore, we discuss using MALDI mass spectrometry to perform a high throughput screen of compound libraries. This enables discovery of compounds that reduce GM2 and can lead to further development of a TSD therapy.
Resveratrol Enhances the Anti-Cancer Effects of Cis-Platinum on Human Cervical Cancer Cell Lines by Activating the SIRT3 Relative Anti-Oxidative Pathway
Authors: Jiang Bin , Tian Qi , Shu Chuqiang , Zhao Jing , Xue Min , Zhu Shujuan
Published: July 2022

Background: Cervical cancer exerts considerable mortality in the world. The combinations of chemotherapy with cis-platinum were the first-line treatment in late-stage cervical cancer but may cause severe adverse effects. Resveratrol (RES, 3,5,4′-trihydroxy-trans-stilbene) is a phytoalexin, and it showed anti-cancer effects but with low toxicity and side effects. Herein, we examined the anti-cancer effects of cis-platinum combined with RES in human cervical cancer cell lines.

Methods: The antiproliferative effect was examined by cell counting and short-term MTT assay. Cell apoptosis was detected. The cell cycle distribution was determined by flow cytometry. Intracellular reactive oxygen species and mitochondrial transmembrane potential change were observed and calculated by confocal microscopy. The Si-RNA interference of SIRT3 in cancer cells was performed. Protein expression was checked by Western blotting.

Results: RES inhibited the growth of SiHa cell lines, and it significantly enhanced the cis-platinum-induced cell apoptosis and cell cycle arresting in 48 h. The activation of the SIRT3 relative anti-oxidative pathway was proved to be the reason for the enhanced anti-cancer effects of cis-platinum and RES combination. Si-RNA interference of SIRT3 compromised the anti-cancer effect of cis-platinum and RES combination. Furthermore, the silencing of SIRT3 RNA inhibited the expression of the anti-oxidant enzyme (MnSOD, GPx, SOD-1, and CAT) and decreased the generation of H2O2 in the cis-platinum and RES combination group.

Conclusion: RES enhances the anti-cancer effects of cis-platinum on SiHa cells by activating the SIRT3 relative anti-oxidative pathway. RES may act as a potential synergistic agent and be useful in the treatment of cervical cancer.
Jian-Pi-Yi-Shen Formula Improves Adenine-Induced Chronic Kidney Disease via Regulating Tryptophan Metabolism and Aryl Hydrocarbon Receptor Signaling
Authors: Liu Xinhui , Deng Ruyu , Chen Yulian , Huang Shiying , Lu Jiandong , Zheng Lin , Xiong Guoliang , Li Shunmin
Published: July 2022

Traditional Chinese medicine (TCM) is an important complementary and alternative branch of chronic kidney disease (CKD) therapy. Jian-Pi-Yi-Shen formula (JPYSF) is a TCM formula used for treating CKD with good efficacy. However, the underlying mechanisms of JPYSF in treating CKD remain to be elucidated. The purpose of the present study was to investigate the renoprotective effect and potential mechanism of JPYSF in treating CKD. CKD rat model was induced by feeding a diet containing 0.75% w/w adenine for 4 weeks. JPYSF was given by gavage every day, starting from the 3rd week of the adenine-containing diet and continuing for 4 weeks at the dose of 10.89 g/kg. Renal injury was evaluated by serum creatinine (Scr), blood urea nitrogen (BUN), histopathology, and fibrotic markers expression. Serum levels of tryptophan metabolites were detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Aryl hydrocarbon receptor (AHR) signaling was tested by Western blot analysis. The results found that JPYSF treatment significantly lowered Scr and BUN levels, improved renal pathological injury, and down-regulated fibrotic markers expression in CKD rats. Furthermore, JPYSF significantly reduced the levels of 10 tryptophan metabolites in the serum of CKD rats and restored the level of tryptophan. Additionally, the kidney expression of AHR signaling was enhanced in CKD rats and was further suppressed in JPYSF treated rats. These results suggested that JPYSF protected against adenine-induced CKD via modulating tryptophan metabolism and AHR activation.
Antibody-Targeted TNFRSF Activation for Cancer Immunotherapy: The Role of FcγRIIB Cross-Linking
Authors: Liu Luyan , Wu Yi , Ye Kaiyan , Cai Meichun , Zhuang Guanglei , Wang Jieyi
Published: July 2022

Co-stimulation signaling in various types of immune cells modulates immune responses in physiology and disease. Tumor necrosis factor receptor superfamily (TNFRSF) members such as CD40, OX40 and CD137/4-1BB are expressed on myeloid cells and/or lymphocytes, and they regulate antigen presentation and adaptive immune activities. TNFRSF agonistic antibodies have been evaluated extensively in preclinical models, and the robust antitumor immune responses and efficacy have encouraged continued clinical investigations for the last two decades. However, balancing the toxicities and efficacy of TNFRSF agonistic antibodies remains a major challenge in the clinical development. Insights into the co-stimulation signaling biology, antibody structural roles and their functionality in immuno-oncology are guiding new advancement of this field. Leveraging the interactions between antibodies and the inhibitory Fc receptor FcγRIIB to optimize co-stimulation agonistic activities dependent on FcγRIIB cross-linking selectively in tumor microenvironment represents the current frontier, which also includes cross-linking through tumor antigen binding with bispecific antibodies. In this review, we will summarize the immunological roles of TNFRSF members and current clinical studies of TNFRSF agonistic antibodies. We will also cover the contribution of different IgG structure domains to these agonistic activities, with a focus on the role of FcγRIIB in TNFRSF cross-linking and clustering bridged by agonistic antibodies. We will review and discuss several Fc-engineering approaches to optimize Fc binding ability to FcγRIIB in the context of proper Fab and the epitope, including a cross-linking antibody (xLinkAb) model and its application in developing TNFRSF agonistic antibodies with improved efficacy and safety for cancer immunotherapy.
Network-Based Pharmacological Study on the Mechanism of Guishao-Liujun Decoction in the Treatment of Gastric Cancer
Authors: Qian Xiaoqing , Zhang Lingle , Xie Feng , Cheng Yingsheng , Cui Daxiang
Published: July 2022

Objective: The aim of the study was to use a network pharmacological method to examine the mechanism of Guishao-Liujun decoction against gastric cancer (GC).

Methods: The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and the Traditional Chinese Medicine Integrated Database (TCMID) were used to obtain the chemical composition and targets of all the drugs of Guishao-Liujun decoction, and the targets of GC were screened using GeneCards and Online Mendelian Inheritance in Man (OMIM) databases. The obtained targets were imported into Cytoscape 3.7.2 software by using the R language to take the intersection for a Venn analysis to construct active ingredient target networks, and they were imported into the STRING database to construct protein–protein interaction (PPI) networks, with the BisoGenet plugin in Cytoscape 3.7.2 being used for analyzing network topology. On the potential target of Guishao-Liujun decoction for GC, gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using the R-language bioconductor platform, and the outcomes were imported into Cytoscape 3.7.2 software to obtain the KEGG network map. The core targets were docked with the active components by the macromolecular docking software application AutoDock Vina.

Results: A total of 243 chemical components and 1,448 disease targets including 127 intersecting targets were discovered. AKT1, TP53, and GO functional analysis were mainly associated with ubiquitination and oxidase reduction activity. In GC treatment, the KEGG analysis revealed that Guishao-Liujun decoction mainly acted through the tumor necrosis factor (TNF), interleukin 17 (IL-17), and cancer-related signaling pathways, with the best binding performance with TP53, as indicated by the outcomes of macromolecular docking.

Conclusion: In the treatment of GC, Guishao-Liujun decoction works with a variety of components and targets, establishing the groundwork for further research into its mechanism of action.
Rumex japonicus Houtt. Extract Suppresses Colitis-Associated Colorectal Cancer by Regulating Inflammation and Tight-Junction Integrity in Mice
Authors: Kim Hee-Young , Seo Ji Eun , Lee Hanul , Bae Chang-Hwan , Ha Ki-Tae , Kim Seungtae
Published: July 2022

Irritable bowel disease (IBD), which results in an elevated risk of colitis-associated colorectal cancer (CAC), is characterized by inflammation and barrier disruption of the gut. The genus Rumex has anti-oxidative and anti-inflammatory effects, and the roots of Rumex japonicus Houtt (RJ) have been traditionally used in East Asia to treat digestive problems. We investigated the protective effect of RJ against azoxymethane (AOM)-and dextran sulfate sodium (DSS)-induced CAC in C57BL/6N male mice. The mice were intraperitoneally injected with AOM on the first day and orally treated with 2% DSS for 2 weeks (on the third and sixth weeks). RJ extract (100 mg/kg) was administered to the mice in the RJ group for 4 weeks (from the third to sixth week), and all mice were sacrificed on the final day of the eighth week. Changes in morphology, tight junctions (TJs), inflammation-related factors in the colon and serum inflammatory cytokine levels were measured. The colons of AOM/DSS-treated mice were shorter and heavier than those of normal mice. The number of tumors in the colons of AOM/DSS-treated mice increased; however, RJ suppressed these changes. RJ also reduced the levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in the colon and serum, and it increased the level of IL-10 in the colon. Moreover, RJ inhibited the barrier disruption and apoptosis in the colons of AOM/DSS-treated mice. RJ effectively suppressed AOM/DSS-induced CAC by inhibiting tumor formation, inflammation, disruption of TJ, and apoptosis in the colon.
Salicylic Acid Priming Regulates Stomatal Conductance, Trichome Density and Improves Cadmium Stress Tolerance in Mentha arvensis L.
Authors: Zaid Abbu , Mohammad Firoz , Siddique Kadambot H. M.
Published: July 2022

The application of phytohormones through seed priming could enhance quality of important medicinal and aromatic plants (MAPs) under heavy metal stress. We evaluated the potential of salicylic acid (SA) priming for overcoming the adverse effects of cadmium stress in Mentha arvensis L. plants. Suckers of plants were primed with SA before transplanting them into soil. At 30 days after transplanting, two doses (50 and 100 μm) of CdCl2 were applied to the soil. Both Cd treatments altered plant growth, photosynthetic pigments, leaf gas exchange attributes, and mineral nutrient contents. The 50 and 100 μm Cd treatments increased endogenous Cd content by 97.95 and 98.03%, electrolyte leakage (EL) by 34.21 and 44.38%, hydrogen peroxide (H2O2) by 34.71 and 55.80%, malondialdehyde (MDA) by 53.08 and 63.15%, and superoxide content (O2–•) by 24.07 and 38.43%, respectively. Cd triggered the up-regulation of antioxidant enzyme activities (superoxide dismutase, SOD; catalase, CAT; ascorbate peroxidase, APX; and glutathione reductase GR) and increased osmolyte biosynthesis and, interestingly, secondary metabolite (SM) accumulation. The presence of SA and Cd had an additive effect on these parameters. Nevertheless, plants primed with SA regulated stomatal conductance under Cd stress. SA priming to menthol mint plants under Cd stress overcome the effects of Cd stress while increasing SMs.
Response of Source-Sink Characteristics and Rice Quality to High Natural Field Temperature During Reproductive Stage in Irrigated Rice System
Authors: Tu Debao , Jiang Yang , Salah Akram , Cai Mingli , Peng Wei , Zhang Lijuan , Li Chengfang , Cao Cougui
Published: July 2022

Global warming greatly affects the development of rice at different growth stages, thereby deteriorating rice quality. However, the effect of high natural field temperature during reproductive stages on rice quality is unclear. Thus, grain filling dynamics, source-sink characteristics and quality-related traits were compared between two contrasting natural field temperature conditions namely normal (low temperature) (LRT) and hot (high temperature) growth season (HRT) during reproductive stage. Compared with LRT, HRT significantly increased chalky grain rate (about 1.6–3.1%), chalkiness level (about 4.7–22.4%), protein content (about 0.93–1.07%), pasting temperature, setback, and consistence, and decreased total starch content (about 4.6–6.2%). Moreover, HRT significantly reduced the leaf area index (LAI, about 0.54–1.11 m2 m–2), specific leaf weight (SLW, about 1.27–1.44 mg cm–2) and source-sink ratio (leaf-sink ratio and/or stem-sink ratio), shortened the active grain filling period by 3.1–3.2 days, and reduced the rations of dry matter translocation to grain (RDMs). In conclusion, we suggested that significant reduction in assimilate translocation after flowering, resulting in the reduced active grain-filling duration and the poor rice quality (high chalkiness and the poor eating and cooking quality), modulated by source-sink characteristics in response to high natural field temperature during reproductive stage. These results enriched the study of high temperature-stressed rice and served as an important reference for selecting high-quality, heat-tolerant varieties and protecting rice quality under high-temperature conditions.