bluuebunny/crossref_metadata_2025 huggingface dataset:
Service-Learning, Movies, and Infectious Diseases: Implementation of an Active Educational Program in Microbiology as a Tool for Engagement in Social Justice
Authors: Linares M. , López-Ejeda N. , Álvarez P. , Culebras E. , Díaz E. , García M.T. , Majano C. , Morales M. L. , Rodríguez-García A. , Rodríguez-Avial I. , Utrilla C. L. , Valenzuela M.V. , Valderrama M. J.
Published: June 2021

Service-Learning is an educational methodology that allows student learning while addressing community needs. A program in microbiology and infectious diseases was implemented in Universidad Complutense de Madrid, Spain. University lecturers, clinical microbiologists, doctorate students, and undergraduates from several Bachelor Degrees and courses worked in an interdisciplinary team along with social institutions that attend disadvantaged persons. Using commercial movies that deal with infectious diseases, the students learn clinical microbiology, prepare divulgation materials, visit social centers to accompany, and help others to know about illnesses and prevention. The program was developed through two academic years and involved 58 voluntary students, 13 teachers and tutors, and 4 social entities as community partners. Postsurvey evaluation of the program revealed a highly satisfactory achievement of goals: acquiring scientific and personal competencies by university students, including critical analysis and science diffusion, solving problems or collaborative team working, and contributing, together with the tutors, to the social responsibility of the university.
Evaluation of Virulence Determinants Using Whole-Genome Sequencing and Phenotypic Biofilm Analysis of Outbreak-Linked Staphylococcus aureus Isolates
Authors: Hait Jennifer M. , Cao Guojie , Kastanis George , Yin Lanlan , Pettengill James B. , Tallent Sandra M.
Published: June 2021

Biofilms are a frequent cause of food contamination of potentially pathogenic bacteria, such as Staphylococcus aureus. Given its vast role in human disease, the possible impact of biofilm-producing S. aureus isolates in a food processing environment is evident. Sixty-nine S. aureus isolates collected from one firm following multiple staphylococcal food poisoning outbreak investigations were utilized for this analysis. Strain evaluations were performed to establish virulence determinants and the evolutionary relationships using data generated by shotgun whole-genome sequencing (WGS), along with end point polymerase chain reaction (PCR) and in vitro phenotypic assessments. S. aureus isolates were grouped into six well-supported clades in the phylogenetic tree, with the relationships within the clades indicating a strong degree of clonal structure. Our analysis identified four major sequence types 47.8% ST1, 31.9% ST45, 7.2% ST5, and 7.2% ST30 and two major spa types 47.8% t127 and 29.0% t3783. Extrapolated staphylococcal enterotoxin (SE) analysis found that all isolates were positive for at least 1 of the 23 SEs and/or SE-like toxin genes. Enterotoxigenic assessments found that 93% of the isolates expressed a classical SE(A–E). SE gene concurrence was observed at 96.2%, based on PCR and WGS results. In total, 46 gene targets were distinguished. This included genes that encode for adhesion and biofilm synthesis such as clfA, clfB, bbp, ebpS, ica, bap and agr. Our evaluation found agr group III to be the most prevalent at 55%, followed by 35% for agr group I. All isolates harbored the complete intercellular adhesion operon that is recognized to contain genes responsible for the adhesion step of biofilm formation by encoding proteins involved in the syntheses of the biofilm matrix. Phenotypic characterization of biofilm formation was evaluated three times, with each test completed in triplicate and accomplished utilizing the microtiter plate method and Congo red agar (CRA). The microtiter plate results indicated moderate to high biofilm formation for 96% of the isolates, with 4% exhibiting weak to no biofilm development. CRA results yielded all positive to intermediate results. The potential to inadvertently transfer pathogenic bacteria from the environment into food products creates challenges to any firm and may result in adulterated food.
Identification of LuxR Family Regulators That Integrate Into Quorum Sensing Circuit in Vibrio parahaemolyticus
Authors: Zhong Xiaojun , Lu Ranran , Liu Fuwen , Ye Jinjie , Zhao Junyang , Wang Fei , Yang Menghua
Published: June 2021

Vibrio parahaemolyticus is one of the most important food-borne pathogens that cause economic and public health problems worldwide. Quorum sensing (QS) is a way for the cell-cell communication between bacteria that controls a wide spectrum of processes and phenotypic behaviors. In this study, we performed a systematic research of LuxR family regulators in V. parahaemolyticus and found that they influence the bacterial growth and biofilm formation. We then established a QS reporter plasmid based on bioluminescence luxCDABE operon of Vibrio harveyi and demonstrated that several LuxR family regulators integrated into QS circuit in V. parahaemolyticus. Thereinto, a novel LuxR family regulator, named RobA, was identified as a global regulator by RNA-sequencing analyses, which affected the transcription of 515 genes in V. parahaemolyticus. Subsequent studies confirmed that RobA regulated the expression of the exopolysaccharides (EPS) synthesis cluster and thus controlled the biofilm formation. In addition, bioluminescence reporter assays showed that RobA plays a key role in the QS circuit by regulating the expression of opaR, aphA, cpsQ-mfpABC, cpsS, and scrO. We further demonstrated that the regulation of RobA to EPS and MfpABC depended on OpaR and CpsQ, which combined the QS signal with bis-(3′-5′)-cyclic dimeric GMP to construct a complex regulatory network of biofilm formation. Our data provided new insights into the bacterial QS mechanisms and biofilm formation in V. parahaemolyticus.
Network Modeling Sex Differences in Brain Integrity and Metabolic Health
Authors: Foret Janelle T. , Dekhtyar Maria , Cole James H. , Gourley Drew D. , Caillaud Marie , Tanaka Hirofumi , Haley Andreana P.
Published: June 2021

Hypothesis-driven studies have demonstrated that sex moderates many of the relationships between brain health and cardiometabolic disease, which impacts risk for later-life cognitive decline. In the present study, we sought to further our understanding of the associations between multiple markers of brain integrity and cardiovascular risk in a midlife sample of 266 individuals by using network analysis, a technique specifically designed to examine complex associations among multiple systems at once. Separate network models were constructed for male and female participants to investigate sex differences in the biomarkers of interest, selected based on evidence linking them with risk for late-life cognitive decline: all components of metabolic syndrome (obesity, hypertension, dyslipidemia, and hyperglycemia); neuroimaging-derived brain-predicted age minus chronological age; ratio of white matter hyperintensities to whole brain volume; seed-based resting state functional connectivity in the Default Mode Network, and ratios of N-acetyl aspartate, glutamate and myo-inositol to creatine, measured through proton magnetic resonance spectroscopy. Males had a sparse network (87.2% edges = 0) relative to females (69.2% edges = 0), indicating fewer relationships between measures of cardiometabolic risk and brain integrity. The edges in the female network provide meaningful information about potential mechanisms between brain integrity and cardiometabolic health. Additionally, Apolipoprotein ϵ4 (ApoE ϵ4) status and waist circumference emerged as central nodes in the female model. Our study demonstrates that network analysis is a promising technique for examining relationships between risk factors for cognitive decline in a midlife population and that investigating sex differences may help optimize risk prediction and tailor individualized treatments in the future.
Precision Repetitive Transcranial Magnetic Stimulation Over the Left Parietal Cortex Improves Memory in Alzheimer’s Disease: A Randomized, Double-Blind, Sham-Controlled Study
Authors: Jia Yanli , Xu Luoyi , Yang Kehua , Zhang Yingchun , Lv Xinghui , Zhu Zhenwei , Chen Zheli , Zhu Yunlong , Wei Lili , Li Xia , Qian Mincai , Shen Yuedi , Hu Weiming , Chen Wei
Published: June 2021

Objective

We aim to study the effect of precision repetitive transcranial magnetic stimulation (rTMS) over the left parietal cortex on the memory and cognitive function in Alzheimer’s disease (AD).

Methods

Based on the resting-state functional magnetic resonance imaging, the left parietal cortex site with the highest functional connectivity to the hippocampus was selected as the target of rTMS treatment. Sixty-nine AD patients were randomized to either rTMS or sham treatment (five sessions/week for a total of 10 sessions). The Mini-Mental State Examination (MMSE), 12-Word Philadelphia Verbal Learning Test (PVLT), and Clinical Dementia Rating (CDR) were assessed at baseline and after the last session.

Results

After a 2-week treatment, compared to patients in the sham group, those in the rTMS group scored significantly higher on PVLT total score and its immediate recall subscale score. Moreover, in the rTMS group, there were significant improvements after the 2-week treatment, which were manifested in MMSE total score and its time orientation and recall subscale scores, as well as PVLT total score and its immediate recall and short delay recall subscale scores. In the sham group, the PVLT total score was significantly improved.

Conclusion

The target site of the left parietal cortex can improve AD patients’ cognitive function, especially memory, providing a potential therapy.
Stroke Severity and Outcomes in Patients With Newly Diagnosed Atrial Fibrillation
Authors: Watanabe Kotaro , Okazaki Shuhei , Kitano Takaya , Sugiyama Shintaro , Ohara Mariko , Kanki Hideaki , Sasaki Tsutomu , Sakaguchi Manabu , Mochizuki Hideki , Todo Kenichi
Published: June 2021

Background and Purpose: Once a stroke occurs in a patient with atrial fibrillation (AF), it is likely to be severe. Patients with newly diagnosed AF after stroke and those with known AF before stroke have different background characteristics, yet the difference in stroke severity has not been sufficiently evaluated. In the current study, we compared the stroke severity and in-hospital outcomes between these patient groups.

Methods: We retrospectively analyzed a database of 196 patients with acute ischemic stroke and AF between January 2010 and October 2019. We divided the patients into two groups: patients with “newly diagnosed AF” and those with “known AF.” We assessed the stroke severity using the National Institutes of Health Stroke Scale (NIHSS) score on admission and in-hospital outcomes using the modified Rankin Scale (mRS) score at discharge.

Results: The proportion of newly diagnosed AF was 33% (64/196). There were no differences in age, hypertension, diabetes mellitus, and past history of heart failure between patients with newly diagnosed AF and those with known AF. Patients with newly diagnosed AF were associated with a lower proportion of male sex (male; 50 vs. 67%, p < 0.05), a lower proportion of past history of stroke (12 vs. 35%, p < 0.01), a lower CHA2DS2-VASc score (median [interquartile range]; 3 [2–4] vs. 3.5 [3–5], p < 0.01), and a lower proportion of pre-stroke oral anticoagulation (5 vs. 59%, p < 0.01). There were no differences in the NIHSS score on admission (12 [4–19] vs. 9 [3–19]) or the mRS score at discharge (3 [1–5] vs. 3 [1–5]). After adjustment for relevant covariates, newly diagnosed AF was not associated with the NIHSS score on admission [adjusted common odds ratio (OR), 0.85; 95% confidence interval (CI), 0.45–1.60] or the mRS score at discharge (adjusted common OR, 1.67; 95% CI, 0.88–3.18). After propensity score matching, newly diagnosed AF was not associated with the NIHSS score on admission (adjusted common OR, 0.91; 95% CI, 0.48–1.73) and the mRS score at discharge (adjusted common OR, 1.77; 95% CI, 0.92–3.43).

Conclusion: Stroke severity and in-hospital outcomes in patients with newly diagnosed AF did not differ from those in patients with known AF after adjustment for clinically relevant factors. The importance of detection of latent AF and subsequent anticoagulation in preventing severe stroke should be further emphasized.
Frequency of Non-motor Symptoms in Parkinson's Patients With Motor Fluctuations
Authors: Fernandes Mariana , Pierantozzi Mariangela , Stefani Alessandro , Cattaneo Carlo , Bonizzoni Erminio A. , Cerroni Rocco , Mercuri Nicola Biagio , Liguori Claudio
Published: June 2021

Background: Non-motor symptoms (NMS), including neuropsychiatric, sleep, autonomic, and sensory domains, are an integral aspect of the clinical presentation of Parkinson disease (PD) and affect neurocognitive functioning as well as patients' and caregivers' well-being.

Objective: To describe the occurrence of NMS in PD patients with motor fluctuations in real-life condition.

Methods: The present study is a secondary analysis of a previous multinational, multicenter, retrospective-prospective cohort observational study (SYNAPSES). Patients with PD diagnosis and motor fluctuations aged ≥18 years were included. Data collected at the baseline visit were used for this study, and descriptive analyzes were conducted to describe the distribution of NMS in motor-fluctuating PD patients distributed according to different clinical characteristics.

Results: Of the 1,610 patients enrolled, 1,589 were included for the analysis (978 males and 611 females), with a mean age of 68.4 (SD = 9.6). Most patients had at least one NMS (88.5%). Sleep problems and psychiatric symptoms were the most prevalent NMS in motor fluctuating PD patients in all H and Y stages. Psychiatric disorders were more frequent in older patients and in patients with a larger number of years of PD diagnosis, while sleep problems were more preeminent in younger patients and with inferior disease duration.

Conclusions: The present findings further support the high prevalence of NMS in PD patients with motor fluctuations, thus reinforcing the need for assessing them for diagnostic accuracy and for delivering holistic care.
Absence Seizure Detection Algorithm for Portable EEG Devices
Authors: Glaba Pawel , Latka Miroslaw , Krause Małgorzata J. , Kroczka Sławomir , Kuryło Marta , Kaczorowska-Frontczak Magdalena , Walas Wojciech , Jernajczyk Wojciech , Sebzda Tadeusz , West Bruce J.
Published: June 2021

Absence seizures are generalized nonmotor epileptic seizures with abrupt onset and termination. Transient impairment of consciousness and spike-slow wave discharges (SWDs) in EEG are their characteristic manifestations. This type of seizure is severe in two common pediatric syndromes: childhood (CAE) and juvenile (JAE) absence epilepsy. The appearance of low-cost, portable EEG devices has paved the way for long-term, remote monitoring of CAE and JAE patients. The potential benefits of this kind of monitoring include facilitating diagnosis, personalized drug titration, and determining the duration of pharmacotherapy. Herein, we present a novel absence detection algorithm based on the properties of the complex Morlet continuous wavelet transform of SWDs. We used a dataset containing EEGs from 64 patients (37 h of recordings with almost 400 seizures) and 30 age and sex-matched controls (9 h of recordings) for development and testing. For seizures lasting longer than 2 s, the detector, which analyzed two bipolar EEG channels (Fp1-T3 and Fp2-T4), achieved a sensitivity of 97.6% with 0.7/h detection rate. In the patients, all false detections were associated with epileptiform discharges, which did not yield clinical manifestations. When the duration threshold was raised to 3 s, the false detection rate fell to 0.5/h. The overlap of automatically detected seizures with the actual seizures was equal to ~96%. For EEG recordings sampled at 250 Hz, the one-channel processing speed for midrange smartphones running Android 10 (about 0.2 s per 1 min of EEG) was high enough for real-time seizure detection.
Zinc and Copper Brain Levels and Expression of Neurotransmitter Receptors in Two Rat ASD Models
Authors: Zieminska Elzbieta , Ruszczynska Anna , Augustyniak Justyna , Toczylowska Beata , Lazarewicz Jerzy W.
Published: June 2021

Zinc and copper are important trace elements necessary for the proper functioning of neurons. Impaired zinc and/or copper metabolism and signaling are implicated in many brain diseases, including autism (ASD). In our studies, autistic-like behavior in rat offsprings was induced by application to pregnant mothers valproic acid or thalidomide. Zinc and copper contents were measured in serum and brain structures: hippocampus, cerebral cortex, and cerebellum. Our research shows no interconnections in the particular metal concentrations measured in autistic animal brains and their sera. Based on patient researches, we studied 26 genes belonging to disturbed neurotransmitter pathways. In the same brain regions, we examined the expression of genes encoding proteins of cholinergic, adrenergic, serotonin, and dopamine receptors. In both rats’ ASD models, 17 out of the tested gene expression were decreased. In the cerebellum and cerebral cortex, expression of genes encoding cholinergic, adrenergic, and dopaminergic receptors decreased, whereas in the hippocampus only expression of serotoninergic receptors genes was downregulated. The changes in metals content observed in the rat brain can be secondary phenomena, perhaps elements of mechanisms that compensate for neurotransmission dysfunctions.
Association Between Low Handgrip Strength and 90-Day Mortality Among Older Chinese Inpatients: A National Multicenter Prospective Cohort Study
Authors: Zhang Xiao-Ming , Jiao Jing , Zhu Chen , Guo Na , Liu Ying , Lv Dongmei , Wang Hui , Jin Jingfen , Wen Xianxiu , Zhao Shengxiu , Wu Xinjuan , Xu Tao
Published: June 2021

Background: The knowledge of the association between low handgrip strength and mortality among older Chinese inpatients is limited. Given China's aging society, a great number of older adults require hospital admission.

Objective: To explore the association between low handgrip strength and 90-day mortality, providing evidence for clinicians to predict the risk of mortality and improve clinical outcomes for older inpatients.

Materials and Methods: We conducted a national multicenter cohort study with a baseline survey from October 2018 to February 2019 and followed up for 90 days to record mortality outcomes. The assessment of handgrip strength was conducted using a hand dynamometer with the cutoff (handgrip strength < 28 kg for men and < 18 kg for women) to define low handgrip strength. Multivariable logistic regression analysis was applied to explore the association between low handgrip strength and 90-day mortality.

Results: A total of 8,910 older Chinese inpatients [mean (SD) age, 72.39 (5.68) years; 3,750 women (42.09%)], with a prevalence of low handgrip strength, at 49.57%, were included. Compared to inpatients with normal handgrip strength, inpatients with low handgrip strength were older, had less education, more were female, had lower activities of daily living (ADL) score, had lower BMI, higher frailty, higher rates of depression, and poorer cognitive function (all p < 0.05). At 90 days, after adjusting for gender, age, education, frailty, depression, ADL score, malnutrition, and diagnosis, low handgrip strength was independently associated with 90-day mortality, compared to normal handgrip strength (OR = 1.64, 95% CI:1.14–2.37; P = 0.008). Additionally, subgroup and interaction analysis showed a significant interaction effect (P = 0.031) between two age groups (65–74 years older vs. ≥ 75 years old), with the OR being 3.19 (95%CI:2.07–4.93) and 1.49 (95%CI:0.87–2.55), respectively.

Conclusion: Older Chinese inpatients with low handgrip strength had a 1.64-fold risk of 90-day mortality, compared to those with normal handgrip strength, indicating that clinicians need to screen early for handgrip strength and recommend corresponding interventions, such as resistance training and nutrition, as a priority for older inpatients.

Clinical Trial Registration: Chinese Clinical Trial Registry, Identifier: ChiCTR1800017682.
Carotenoid-Rich Brain Nutrient Pattern Is Positively Correlated With Higher Cognition and Lower Depression in the Oldest Old With No Dementia
Authors: Tanprasertsuk Jirayu , Scott Tammy M. , Barbey Aron K. , Barger Kathryn , Wang Xiang-Dong , Johnson Mary Ann , Poon Leonard W. , Vishwanathan Rohini , Matthan Nirupa R. , Lichtenstein Alice H. , Ferland Guylaine , Johnson Elizabeth J.
Published: June 2021

Background: Healthy dietary patterns are related to better cognitive health in aging populations. While levels of individual nutrients in neural tissues are individually associated with cognitive function, the investigation of nutrient patterns in human brain tissue has not been conducted.

Methods: Brain tissues were acquired from frontal and temporal cortices of 47 centenarians from the Georgia Centenarian Study. Fat-soluble nutrients (carotenoids, vitamins A, E, K, and fatty acids [FA]) were measured and averaged from the two brain regions. Nutrient patterns were constructed using principal component analysis. Cognitive composite scores were constructed from cognitive assessment from the time point closest to death. Dementia status was rated by Global Deterioration Scale (GDS). Pearson's correlation coefficients between NP scores and cognitive composite scores were calculated controlling for sex, education, hypertension, diabetes, and APOE ε4 allele.

Result: Among non-demented subjects (GDS = 1–3, n = 23), a nutrient pattern higher in carotenoids was consistently associated with better performance on global cognition (r = 0.38, p = 0.070), memory (r = 0.38, p = 0.073), language (r = 0.42, p = 0.046), and lower depression (r = −0.40, p = 0.090). The findings were confirmed with univariate analysis.

Conclusion: Both multivariate and univariate analyses demonstrate that brain nutrient pattern explained mainly by carotenoid concentrations is correlated with cognitive function among subjects who had no dementia. Investigation of their synergistic roles on the prevention of age-related cognitive impairment remains to be performed.
The Preoperative Diagnostic Value of MRI and Otoneural Tests in Acoustic Neuroma
Authors: Dai Qingqing , Zheng Meijun , Chen Qiurong , Zheng Hong , Li Bilan
Published: June 2021

Objectives

To determine the preoperative diagnostic accuracy of MRI and otoneural tests (ONT) for acoustic neuroma (AN) in a cohort of unselected patients with pontocerebellar angle tumors. To find a convenient way to screening out the potential asymptomatic AN patient earlier.

Design

This diagnostic accuracy study was performed in a central hospital and included a consecutive sample of unilateral incipient pontocerebellar angle tumor patients referred for MRI and ONT before surgery. Different AN features of MRI and ONT were collected and concluded into preoperative diagnostic variables or variable combinations. Those of MRI and ONT are analyzed and compared with biopsy results by multivariable receiver operating characteristic (ROC) analysis. The early-stage group, the course of which is 1 year or less, was separately computed and compared.

Results

Eighty-three subjects were collected from June 2013 to June 2019; 62 were confirmed AN postoperatively by biopsy, whereas others are not AN. The area under the curve (AUC) of MRI was 0.611, whereas the AUC of ONT was 0.708. In the early-stage group, the AUC of MRI was 0.539, and the AUC of ONT was 0.744.

Conclusions

ONT was able to identify more subjects affected by unilateral incipient AN than MRI preoperatively. Given that ONT is a functional test for internal auditory canal nerves, it is an optimal screening test for AN patients because it provides more information than MRI for the further clinical plan. It is particularly noteworthy for identifying asymptomatic AN patients and for early stage. Therefore, it may help more patients from unnessesary surgery. Furthermore, an MRI follow-up is suggested if the patient was found alert in ONT.
Development and Validation of Novel Biomarkers Related to M2 Macrophages Infiltration by Weighted Gene Co-Expression Network Analysis in Prostate Cancer
Authors: Xu Ning , Dong Ru-Nan , Lin Ting-Ting , Lin Tian , Lin Yun-Zhi , Chen Shao-Hao , Zhu Jun-Ming , Ke Zhi-Bin , Huang Fei , Chen Ye-Hui , Xue Xue-Yi
Published: June 2021

M2-tumor-associated macrophages (TAMs) work as a promoter in the processes of bone metastases, chemotherapy resistance, and castration resistance in prostate cancer (PCa), but how M2-TAMs affect PCa has not been fully understood. In this study, we analyzed the proportion of tumor-infiltrating immune cells using the CIBERSORT algorithm, based on samples from the Cancer Genome Atlas database. Then we performed weighted gene co-expression network analysis to examine the modules concerning infiltrated M2-TAMs. Gene Ontology analysis and pathway enrichment analysis were performed for functional annotation and a protein–protein interaction network was constructed. The International Cancer Genomics Consortium cohort was used as a validation cohort. The red module showed the most correlation with M2-TAMs in PCa. Biological processes and pathways were mainly associated with the immune-related processes, as revealed by functional annotation. Four hub genes were screened: ACSL1, DLGAP5, KIF23 and NCAPG. Further validation showed that the four hub genes had a higher expression level in tumor tissues than that in normal tissues, and they were good prognosis biomarkers for PCa. In conclusion, these findings contribute to understanding the underlying molecular mechanisms of how M2-TAMs affect PCa, and looking for the potential biomarkers and therapeutic targets for PCa patients.
PI3K Promotes Basal Cell Carcinoma Growth Through Kinase-Induced p21 Degradation
Authors: Chow Rachel Y. , Jeon Ung Seop , Levee Taylor M. , Kaur Gurleen , Cedeno Daniel P. , Doan Linda T. , Atwood Scott X.
Published: June 2021

Basal cell carcinoma (BCC) is a locally invasive epithelial cancer that is primarily driven by the Hedgehog (HH) pathway. Advanced BCCs are a critical subset of BCCs that frequently acquire resistance to Smoothened (SMO) inhibitors and identifying pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify a PI3K pathway expression signature in BCC. Pharmacological inhibition of PI3K activity in BCC cells significantly reduces cell proliferation and HH signaling. However, treatment of Ptch1fl/fl; Gli1-CreERT2 mouse BCCs with the PI3K inhibitor BKM120 results in a reduction of tumor cell growth with no significant effect on HH signaling. Downstream PI3K components aPKC and Akt1 showed a reduction in active protein, whereas their substrate, cyclin-dependent kinase inhibitor p21, showed a concomitant increase in protein stability. Our results suggest that PI3K promotes BCC tumor growth by kinase-induced p21 degradation without altering HH signaling.
A Mechanistic DNA Repair and Survival Model (Medras): Applications to Intrinsic Radiosensitivity, Relative Biological Effectiveness and Dose-Rate
Authors: McMahon Stephen Joseph , Prise Kevin M.
Published: June 2021

Variations in the intrinsic radiosensitivity of different cells to ionizing radiation is now widely believed to be a significant driver in differences in response to radiotherapy. While the mechanisms of radiosensitivity have been extensively studied in the laboratory, there are a lack of models which integrate this knowledge into a predictive framework. This paper presents an overview of the Medras model, which has been developed to provide a mechanistic framework in which different radiation responses can be modelled and individual responses predicted. This model simulates the repair of radiation-induced DNA damage, incorporating the overall kinetics of repair and its fidelity, to predict a range of biological endpoints including residual DNA damage, mutation, chromosome aberration, and cell death. Validation of this model against a range of exposure types is presented, including considerations of varying radiation qualities and dose-rates. This approach has the potential to inform new tools to deliver mechanistic predictions of radiation sensitivity, and support future developments in treatment personalization.
P2X Receptors: Potential Therapeutic Targets for Symptoms Associated With Lung Cancer — A Mini Review
Authors: Mai Yonglin , Guo Zhihua , Yin Weiqiang , Zhong Nanshan , Dicpinigaitis Peter V. , Chen Ruchong
Published: June 2021

Symptoms associated with lung cancer mainly consist of cancer-associated pain, cough, fatigue, and dyspnea. However, underlying mechanisms of lung cancer symptom clusters remain unclear. There remains a paucity of effective treatment to ameliorate debilitating symptoms and improve the quality of life of lung cancer survivors. Recently, extracellular ATP and its receptors have attracted increasing attention among researchers in the field of oncology. Extracellular ATP in the tumor microenvironment is associated with tumor cell metabolism, proliferation, and metastasis by driving inflammation and neurotransmission via P2 purinergic signaling. Accordingly, ATP gated P2X receptors expressed on tumor cells, immune cells, and neurons play a vital role in modulating tumor development, invasion, progression, and related symptoms. P2 purinergic signaling is involved in the development of different lung cancer-related symptoms. In this review, we summarize recent findings to illustrate the role of P2X receptors in tumor proliferation, progression, metastasis, and lung cancer- related symptoms, providing an outline of potential anti-neoplastic activity of P2X receptor antagonists. Furthermore, compared with opioids, P2X receptor antagonists appear to be innovative therapeutic interventions for managing cancer symptom clusters with fewer side effects.
Development and Validation of a Prognostic Nomogram Based on the Systemic Immune-Inflammation Index for Resectable Gallbladder Cancer to Predict Survival and Chemotherapy Benefit
Authors: Li Lin , Ren Tai , Liu Ke , Li Mao-Lan , Geng Ya-Jun , Yang Yang , Li Huai-Feng , Li Xue-Chuan , Bao Run-Fa , Shu Yi-Jun , Weng Hao , Gong Wei , Lau Wan Yee , Wu Xiang-Song , Liu Ying-Bin
Published: June 2021

Objectives

To investigate the prognostic significance of the systemic immune-inflammation index (SII) in patients after radical cholecystectomy for gallbladder cancer (GBC) using overall survival (OS) as the primary outcome measure.

Methods

Based on data from a multi-institutional registry of patients with GBC, significant prognostic factors after radical cholecystectomy were identified by multivariate Cox proportional hazards model. A novel staging system was established, visualized as a nomogram. The response to adjuvant chemotherapy was compared between patients in different subgroups according to the novel staging system.

Results

Of the 1072 GBC patients enrolled, 691 was randomly selected in the discovery cohort and 381 in the validation cohort. SII>510 was found to be an independent predictor of OS (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.42-2.54). Carbohydrate antigen 199(CA19-9), tumor differentiation, T stage, N stage, margin status and SII were involved in the nomogram. The nomogram showed a superior prediction compared with models without SII (1-, 3-, 5-year integrated discrimination improvement (IDI):2.4%, 4.1%, 5.4%, P<0.001), and compared to TNM staging system (1-, 3-, 5-year integrated discrimination improvement (IDI):5.9%, 10.4%, 12.2%, P<0.001). The C-index of the nomogram in predicting OS was 0.735 (95% CI 0.683-0.766). The novel staging system based on the nomogram showed good discriminative ability for patients with T2 or T3 staging and with negative lymph nodes after R0 resection. Adjuvant chemotherapy offered significant survival benefits to these patients with poor prognosis.

Conclusions

SII was an independent predictor of OS in patients after radical cholecystectomy for GBC. The new staging system identified subgroups of patients with T2 or T3 GBC with negative lymph nodes who benefited from adjuvant chemotherapy.

Clinical Trial Registration

ClinicalTrials.gov, identifier (NCT04140552).
Intratumor Heterogeneity of MIF Expression Correlates With Extramedullary Involvement of Multiple Myeloma
Authors: Xu Juan , Yu Nanhui , Zhao Pan , Wang Fangfang , Huang Jingcao , Cui Yushan , Ding Hong , Yang Yan , Gao Yuhan , Pan Ling , Chang Hong , Wu Yu , Xiang Bing , Gong Yuping , Shuai Xiao , Hou Li , Xie Liping , Niu Ting , Liu Ting , Zhang Li , Liu Weiping , Zhang Wenyan , Qu Ying , Lin Wei , Zhu Yimin , Zhao Sha , Zheng Yuhuan
Published: June 2021

Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIFLow) in vivo. Of note, IMM had dominantly MIFHigh cells, while EMM showed a significantly increased ratio of MIFLow cells. Furthermore, we harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIFHigh to MIFLow state were indicated. The MIFHigh cells featured higher proliferation. The MIFLow ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.
Pim1 Kinase Inhibitors Exert Anti-Cancer Activity Against HER2-Positive Breast Cancer Cells Through Downregulation of HER2
Authors: Wang Bo-Wei , Huang Chih-Hao , Liu Liang-Chih , Cheng Fang-Ju , Wei Ya-Ling , Lin Yueh-Ming , Wang Yu-Fei , Wei Ching-Ting , Chen Yeh , Chen Yun-Ju , Huang Wei-Chien
Published: June 2021

The proviral integration site for moloney murine leukemia virus 1 (Pim1) is a serine/threonine kinase and able to promote cell proliferation, survival and drug resistance. Overexpression of Pim1 has been observed in many cancer types and is associated with the poor prognosis of breast cancer. However, it remains unclear whether Pim1 kinase is a potential therapeutic target for breast cancer patients. In this study, we found that Pim1 expression was strongly associated with HER2 expression and that HER2-overexpressing breast cancer cells were more sensitive to Pim1 inhibitor-induced inhibitions of cell viability and metastatic ability. Mechanistically, Pim1 inhibitor suppressed the expression of HER2 at least in part through transcriptional level. More importantly, Pim1 inhibitor overcame the resistance of breast cancer cells to HER2 tyrosine kinase inhibitor lapatinib. In summary, downregulation of HER2 by targeting Pim1 may be a promising and effective therapeutic approach not only for anti-cancer growth but also for circumventing lapatinib resistance in HER2-positive breast cancer patients.
Efficacy and Safety of Anti-PD-1/ PD-L1 Monotherapy for Metastatic Breast Cancer: Clinical Evidence
Authors: Qi Yihang , Zhang Lin , Wang Zhongzhao , Kong Xiangyi , Zhai Jie , Fang Yi , Wang Jing
Published: June 2021

Background: Success has been reported in PD-1/PD-L1 blockade via pembrolizumab, atezolizumab, or avelumab monotherapy in manifold malignancies including metastatic breast cancer. Due to lack of large-scale study, here we present interim analyses to evaluate the safety and efficacy of these promising strategies in patients with advanced breast cancer.

Methods: Six studies including 586 advanced breast cancer patients treated with anti-PD-1/PD-L1 monotherapy agents before July 1, 2020, were included. The anti-PD-1/PD-L1 agents include pembrolizumab, atezolizumab, land avelumab. Statistics was analyzed by R software and IBM SPSS Statistics 22.

Results: Global analysis showed that for this monotherapy, the complete response was 1.26%, partial response was 7.65%, objective response rate (ORR) was 9.85%, and disease control rate (DCR) was 18.33%. 1-year overall survival rate and 6-month progression-free survival rate were 43.34 and 17.24%. Overall incidence of adverse events (AEs) was 64.18% in any grade and 12.94% in severe grade, while the incidence of immune-related AEs (irAEs) was approximately 14.75%: the most common treatment-related AEs of any grade that occurred in at least 5% of patients were arthralgia and asthenia; the most common severe treatment-related AEs occurred in at least 1% of patients were anemia and autoimmune hepatitis; the most common irAEs were hypothyroidism. Besides, the incidence of discontinue and death due to treatment-related AEs was about 3.06 and 0.31%, respectively. Additionally, by comparing efficacy indicators between PD-L1–positive and PD-L1–negative groups, an implicated correspondence between efficacy and the expression of PD-L1 biomarker was found: the PR was 9.93 vs 2.69%; the ORR was 10.62 vs. 3.07%; the DCR was 17.95 vs. 4.71%.

Conclusion: Anti–PD-1/PD-L1 monotherapy showed a manageable safety profile and had a promising and durable anti-tumor efficacy in metastatic breast cancer patients. Higher PD-L1 expression may be closely correlated to a better clinical efficacy.
Real-World Effectiveness of Adjuvant Oxaliplatin Chemotherapy in Stage III Colon Cancer: A Controlled Interrupted Time Series Analysis
Authors: Huang Wen-Kuan , Hsu Hung-Chih , Chang Shu-Hao , Chou Wen-Chi , Chang Pei-Hung , Chiang Sum-Fu , Chang John Wen-Cheng , Chen Jen-Shi , Yang Tsai-Sheng , See Lai-Chu
Published: June 2021

Background: The real-world effectiveness of oxaliplatin in stage III colon cancer has not been determined in a large-scale population. We aimed to assess the real-world impact of adjuvant oxaliplatin treatment on the survival of these patients.

Methods: Based on Taiwan cancer registry, we evaluated 17,801 patients with resected stage III colon cancer, including 14,168 patients receiving adjuvant chemotherapy and 3,633 not receiving adjuvant chemotherapy as the control group between 2004 and 2014. We used the controlled interrupted time-series analysis to assess the three-year disease-free survival and five-year overall survival rates before (2004–2008) and after (2009–2014) the addition of oxaliplatin.

Results: The introduction of oxaliplatin was associated with no significant improvement in the slopes (per half-year) of the three-year disease-free survival rate (0.2%, 95% CI: −1.7∼2.2%) and five-year overall survival rate (0.6%, 95% CI: −1.8∼3%). The patients receiving oxaliplatin-based chemotherapy also showed no significant increase in the slopes (per half-year) of the three-year disease-free survival rate (0.6%, 95% CI: −1.4∼2.6%) and five-year overall survival rate (1%, 95% CI: −1.5∼3.5%). The nonsignificant results were consistent across subgroup analyses of age (<70 vs. ≥70 years), recurrence risk (T1-3 or N1 vs. T4 or N2), and cycle of oxaliplatin use (≤6 vs. >6). However, oxaliplatin-based chemotherapy significantly increased the slope (per half-year) of the five-year OS (2%, 95% CI: 0.2∼3.8%) for patients in the high-risk group (T4 or N2). The present results were robust in several sensitivity analyses.

Conclusion: Among real-world patients with stage III colon cancer, the introduction of oxaliplatin does not yield a significant improvement in survival. Future work should identify the subpopulation(s) of patients who benefit significantly from the addition of oxaliplatin.
The Role of Pulmonary Surfactants in the Treatment of Acute Respiratory Distress Syndrome in COVID-19
Authors: Wang Shengguang , Li Zhen , Wang Xinyu , Zhang Shiming , Gao Peng , Shi Zuorong
Published: June 2021

Lung alveolar type-II (AT-II) cells produce pulmonary surfactant (PS), consisting of proteins and lipids. The lipids in PS are primarily responsible for reducing the air-fluid surface tension inside the alveoli of the lungs and to prevent atelectasis. The proteins are of two types: hydrophilic and hydrophobic. Hydrophilic surfactants are primarily responsible for opsonisation, thereby protecting the lungs from microbial and environmental contaminants. Hydrophobic surfactants are primarily responsible for respiratory function. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters the lungs through ACE-2 receptors on lungs and replicates in AT-II cells leading to the etiology of Coronavirus disease – 2019 (COVID-19). The SARS-CoV-2 virus damages the AT-II cells and results in decreased production of PS. The clinical symptoms of acute respiratory distress syndrome (ARDS) in COVID-19 patients are like those of neonatal respiratory distress syndrome (NRDS). The PS treatment is first-line treatment option for NRDS and found to be well tolerated in ARDS patients with inconclusive efficacy. Over the past 70°years, a lot of research is underway to produce natural/synthetic PS and developing systems for delivering PS directly to the lungs, in addition to finding the association between PS levels and respiratory illnesses. In the present COVID-19 pandemic situation, the scientific community all over the world is searching for the effective therapeutic options to improve the clinical outcomes. With a strong scientific and evidence-based background on role of PS in lung homeostasis and infection, few clinical trials were initiated to evaluate the functions of PS in COVID-19. Here, we connect the data on PS with reference to pulmonary physiology and infection with its possible therapeutic benefit in COVID-19 patients.
Peak-Inspiratory-Flow-Rate Guided Inhalation Therapy Reduce Severe Exacerbation of COPD
Authors: Chen Shih-Yu , Huang Chun-Kai , Peng Hui-Chuan , Tsai Hsing-Chen , Huang Szu-Ying , Yu Chong-Jen , Chien Jung-Yien
Published: June 2021

Optimal peak inspiratory flow rate (PIFR) is crucial for inhalation therapy in patients with chronic obstructive pulmonary disease (COPD). However, little is known about the impact of PIFR-guided inhalation therapy on the clinical outcomes among patients with varying severities of COPD. A PIFR-guided inhalation therapy, including PIFR assessment and PIFR-guided inhaler education, was introduced in a pay-for-performance COPD management program in National Taiwan University Hospital. Among 383 COPD patients, there was significant reduction in incidence of severe acute exacerbation in the PIFR-guided inhalation therapy (PIFR group) than conventional inhaler education (control group) (11.9 vs. 21.1%, p = 0.019) during one-year follow-up. A multivariable Cox’s proportional-hazards analysis revealed that the PIFR-guided inhalation therapy was a significant, independent factor associated with the reduced risk of severe exacerbation (adjusted hazard ratio = 0.49, 95% confidence interval, 0.28–0.84, p = 0.011). Subgroup analysis found PIFR-guided inhalation therapy was more beneficial to patients with older age, short body stature, COPD stage 1&2, group C&D (frequent exacerbation phenotype), and using multiple inhalers. This study showed the PIFR-guided inhalation therapy significantly reduced the incidence of severe acute exacerbation than conventional inhaler education in patients with COPD. Careful PIFR-assessment and education would be crucial in the management of COPD.
Comparative Transcriptome and DNA Methylation Analysis of Phenotypic Plasticity in the Pacific Abalone (Haliotis discus hannai)
Authors: Huang Zekun , Xiao Qizhen , Yu Feng , Gan Yang , Lu Chengkuan , Peng Wenzhu , Zhang Yifang , Luo Xuan , Chen Nan , You Weiwei , Ke Caihuan
Published: June 2021

Phenotypic plasticity is an adaptive mechanism used by organisms to cope with environmental fluctuations. Pacific abalone (Haliotis discus hannai) are large-scale farmed in the temperate area of northern China and in the warmer waters of southern China. RNA-seq and comparative transcriptomic analysis here were performed to determine if the northern and southern populations have evolved divergent plasticity and if functional differences are associated with protein synthesis and growth-related biological progress. The DNA methylation (5mC) landscape of H. discus hannai from the two populations using whole genomic bisulfite sequencing (WGBS), exhibited different epigenetic patterns. The southern population had significant genomic hypo-methylation that may have resulted from long-term acclimation to heat stress. Combining 790 differentially expressed genes (DEGs) and 7635 differentially methylated genes (DMGs), we found that methylation within the gene body might be important in predicting abalone gene expression. Genes related to growth, development, transduction, and apoptosis may be regulated by methylation and could explain the phenotypic divergence of H. discus hannai. Our findings not only emphasize the significant roles of adaptive plasticity in the acclimation of H. discus hannai to high temperatures but also provide a new understanding of the epigenetic mechanism underlying the phenotypic plasticity in adaptation to climate change for marine organisms.
Smooth Muscle Hypocontractility and Airway Normoresponsiveness in a Mouse Model of Pulmonary Allergic Inflammation
Authors: Boucher Magali , Henry Cyndi , Dufour-Mailhot Alexis , Khadangi Fatemeh , Bossé Ynuk
Published: June 2021

The contractility of airway smooth muscle (ASM) is labile. Although this feature can greatly modulate the degree of airway responsiveness in vivo, the extent by which ASM’s contractility is affected by pulmonary allergic inflammation has never been compared between strains of mice exhibiting a different susceptibility to develop airway hyperresponsiveness (AHR). Herein, female C57BL/6 and BALB/c mice were treated intranasally with either saline or house dust mite (HDM) once daily for 10 consecutive days to induce pulmonary allergic inflammation. The doses of HDM were twice greater in the less susceptible C57BL/6 strain. All outcomes, including ASM contractility, were measured 24 h after the last HDM exposure. As expected, while BALB/c mice exposed to HDM became hyperresponsive to a nebulized challenge with methacholine in vivo, C57BL/6 mice remained normoresponsive. The lack of AHR in C57BL/6 mice occurred despite exhibiting more than twice as much inflammation than BALB/c mice in bronchoalveolar lavages, as well as similar degrees of inflammatory cell infiltrates within the lung tissue, goblet cell hyperplasia and thickening of the epithelium. There was no enlargement of ASM caused by HDM exposure in either strain. Unexpectedly, however, excised tracheas derived from C57BL/6 mice exposed to HDM demonstrated a decreased contractility in response to both methacholine and potassium chloride, while tracheas from BALB/c mice remained normocontractile following HDM exposure. These results suggest that the lack of AHR in C57BL/6 mice, at least in an acute model of HDM-induced pulmonary allergic inflammation, is due to an acquired ASM hypocontractility.