bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic Signatures of Type 2 Diabetes Mellitus and Hypertension in COVID-19 Patients With Different Disease Severity
Authors: Elrayess Mohamed A. , Cyprian Farhan S. , Abdallah Abdallah M. , Emara Mohamed M. , Diboun Ilhame , Anwardeen Najeha , Schuchardt Sven , Yassine Hadi M.
Published: January 2022

Introduction: Increased COVID-19 disease severity is higher among patients with type 2 diabetes mellitus and hypertension. However, the metabolic pathways underlying this association are not fully characterized. This study aims to identify the metabolic signature associated with increased COVID-19 severity in patients with diabetes mellitus and hypertension.

Methods: One hundred and fifteen COVID-19 patients were divided based on disease severity, diabetes status, and hypertension status. Targeted metabolomics of serum samples from all patients was performed using tandem mass spectrometry followed by multivariate and univariate models.

Results: Reduced levels of various triacylglycerols were observed with increased disease severity in the diabetic patients, including those containing palmitic (C16:0), docosapentaenoic (C22:5, DPA), and docosahexaenoic (C22:6, DHA) acids (FDR < 0.01). Functional enrichment analysis revealed triacylglycerols as the pathway exhibiting the most significant changes in severe COVID-19 in diabetic patients (FDR = 7.1 × 10−27). Similarly, reduced levels of various triacylglycerols were also observed in hypertensive patients corresponding with increased disease severity, including those containing palmitic, oleic (C18:1), and docosahexaenoic acids. Functional enrichment analysis revealed long-chain polyunsaturated fatty acids (n-3 and n-6) as the pathway exhibiting the most significant changes with increased disease severity in hypertensive patients (FDR = 0.07).

Conclusions: Reduced levels of triacylglycerols containing specific long-chain unsaturated, monounsaturated, and polyunsaturated fatty acids are associated with increased COVID-19 severity in diabetic and hypertensive patients, offering potential novel diagnostic and therapeutic targets.
Antimicrobial Resistance and Molecular Epidemiology of Escherichia coli From Bloodstream Infection in Shanghai, China, 2016–2019
Authors: Xiao Shuzhen , Tang Chenyue , Zeng Qian , Xue Yilun , Chen Qing , Chen Erzhen , Han Lizhong
Published: January 2022

Background: Bloodstream infections are recognized as important nosocomial infections. Escherichia coli (E. coli) is the most prevalent Gram-negative bacillary pathogen causing bloodstream infections (BSIs). This retrospective study investigated drug susceptibility and molecular epidemiology of E. coli isolated from patients with BSI in Shanghai, China.

Methods: We collected E. coli isolated from the blood cultures of patients with BSI between January 2016 and December 2019. We randomly selected 20 strains each year to investigate antimicrobial resistance, resistance genes, and molecular epidemiological characteristics. Antimicrobial susceptibility testing was performed by the disk diffusion method. PCR was performed to detect extended-spectrum β-lactamases (ESBLs), carbapenemase genes, and housekeeping genes, and phyloviz was applied to analyze multilocus sequence typing (MLST).

Results: Penicillins, first- and second-generation cephalosporins and fluoroquinolones have high resistance rates (>60%). Among the 80 randomly selected strains, 47 (58.8%) produced ESBLs, and one produced carbapenemase. Sequencing of resistance genes identified blaCTX−M−14 (34%, 16/47), blaCTX−M−15 (23.4%, 11/47) and blaCTX−M−27 (14.8%, 7/47) as the most prevalent genotypes of ESBLs. ST131 (14/80) was the most prevalent sequence type (ST), followed by ST1193 (10/80), ST648 (7/80).

Conclusions: Our findings suggest that amikacin, carbapenems, and piperacillin-tazobactam have relatively low resistance rates and may be the preferred antibiotic regimens for empiric therapy. ST131 and blaCTX−M−14 are still the main prevalent in Shanghai with a rapid increase in the occurrence of ST1193 is rapidly increasing and more diverse blaCTX genes.
The Impact of Age and BMI on the VWF/ADAMTS13 Axis and Simultaneous Thrombin and Plasmin Generation in Hospitalized COVID-19 Patients
Authors: Thangaraju Kiruphagaran , Katneni Upendra , Akpan Imo J. , Tanaka Kenichi , Thomas Tiffany , Setua Saini , Reisz Julie A. , Cendali Francesca , Gamboni Fabia , Nemkov Travis , Kahn Stacie , Wei Alexander Z. , Valk Jacob E. , Hudson Krystalyn E. , Roh David J. , Moriconi Chiara , Zimring James C. , D'Alessandro Angelo , Spitalnik Steven L. , Francis Richard O. , Buehler Paul W.
Published: January 2022

Aging and obesity independently contribute toward an endothelial dysfunction that results in an imbalanced VWF to ADAMTS13 ratio. In addition, plasma thrombin and plasmin generation are elevated and reduced, respectively, with increasing age and also with increasing body mass index (BMI). The severity risk of Corona Virus Disease 2019 (COVID-19) increases in adults older than 65 and in individuals with certain pre-existing health conditions, including obesity (>30 kg/m2). The present cross-sectional study focused on an analysis of the VWF/ADAMTS13 axis, including measurements of von Willebrand factor (VWF) antigen (VWF:AG), VWF collagen binding activity (VWF:CBA), Factor VIII antigen, ADAMTS13 antigen, and ADAMTS13 activity, in addition to thrombin and plasmin generation potential, in a demographically diverse population of COVID-19 negative (−) (n = 288) and COVID-19 positive (+) (n = 543) patient plasmas collected at the time of hospital presentation. Data were analyzed as a whole, and then after dividing patients by age (<65 and ≥65) and independently by BMI [<18.5, 18.5–24.9, 25–29.9, >30 (kg/m2)]. These analyses suggest that VWF parameters (i.e., the VWF/ADAMTS13 activity ratio) and thrombin and plasmin generation differed in COVID-19 (+), as compared to COVID-19 (−) patient plasma. Further, age (≥65) more than BMI contributed to aberrant plasma indicators of endothelial coagulopathy. Based on these findings, evaluating both the VWF/ADAMTS13 axis, along with thrombin and plasmin generation, could provide insight into the extent of endothelial dysfunction as well as the plasmatic imbalance in coagulation and fibrinolysis potential, particularly for at-risk patient populations.
Advances in Diagnostic Imaging of Hepatopulmonary Syndrome
Authors: Luo Bi-Wei , Du Zhi-Yong
Published: January 2022

Hepatopulmonary syndrome (HPS) is a serious pulmonary complication of progressive liver disease that leads to a poor clinical prognosis. Patients with HPS may develop acute respiratory failure, which requires intensive care and therapy. At present, the only effective treatment is liver transplantation; therefore, early diagnosis and timely treatment are of considerable significance. The three main features of HPS are liver disease, oxygenation disorder, and intrapulmonary vascular dilatation (IPVD). Diagnosing HPS is challenging due to the difficulty in detecting the presence or absence of IPVD. As such, imaging examination is very important for detecting IPVD. This paper reviews the imaging methods for diagnosing HPS such as ultrasound, dynamic pulmonary perfusion imaging, pulmonary angiography, and computed tomography.
Adaptation to a Commercial Quaternary Ammonium Compound Sanitizer Leads to Cross-Resistance to Select Antibiotics in Listeria monocytogenes Isolated From Fresh Produce Environments
Authors: Bland Rebecca , Waite-Cusic Joy , Weisberg Alexandra J. , Riutta Elizabeth R. , Chang Jeff H. , Kovacevic Jovana
Published: January 2022

The effective elimination of Listeria monocytogenes through cleaning and sanitation is of great importance to the food processing industry. Specifically in fresh produce operations, the lack of a kill step requires effective cleaning and sanitation to mitigate the risk of cross-contamination from the environment. As facilities rely on sanitizers to control L. monocytogenes, reports of the development of tolerance to sanitizers and other antimicrobials through cross-resistance is of particular concern. We investigated the potential for six L. monocytogenes isolates from fresh produce handling and processing facilities and packinghouses to develop cross-resistance between a commercial sanitizer and antibiotics. Experimental adaptation of isolates belonging to hypervirulent clonal complexes (CC2, CC4, and CC6) to a commercial quaternary ammonium compound sanitizer (cQAC) resulted in elevated minimum inhibitory concentrations (2–3 ppm) and minimum bactericidal concentrations (3–4 ppm). Susceptibility to cQAC was restored for all adapted (qAD) isolates in the presence of reserpine, a known efflux pump inhibitor. Reduced sensitivity to 7/17 tested antibiotics (chloramphenicol, ciprofloxacin, clindamycin, kanamycin, novobiocin, penicillin, and streptomycin) was observed in all tested isolates. qAD isolates remained susceptible to antibiotics commonly used in the treatment of listeriosis (i.e., ampicillin and gentamicin). The whole genome sequencing of qAD strains, followed by comparative genomic analysis, revealed several mutations in fepR, the regulator for FepA fluoroquinolone efflux pump. The results suggest that mutations in fepR play a role in the reduction in antibiotic susceptibility following low level adaptation to cQAC. Further investigation into the cross-resistance mechanisms and pressures leading to the development of this phenomenon among L. monocytogenes isolates recovered from different sources is needed to better understand the likelihood of cross-resistance development in food chain isolates and the implications for the food industry.
Biogeochemical Niche of Magnetotactic Cocci Capable of Sequestering Large Polyphosphate Inclusions in the Anoxic Layer of the Lake Pavin Water Column
Authors: Bidaud Cécile C. , Monteil Caroline L. , Menguy Nicolas , Busigny Vincent , Jézéquel Didier , Viollier Éric , Travert Cynthia , Skouri-Panet Fériel , Benzerara Karim , Lefevre Christopher T. , Duprat Élodie
Published: January 2022

Magnetotactic bacteria (MTB) are microorganisms thriving mostly at oxic–anoxic boundaries of aquatic habitats. MTB are efficient in biomineralising or sequestering diverse elements intracellularly, which makes them potentially important actors in biogeochemical cycles. Lake Pavin is a unique aqueous system populated by a wide diversity of MTB with two communities harbouring the capability to sequester not only iron under the form of magnetosomes but also phosphorus and magnesium under the form of polyphosphates, or calcium carbonates, respectively. MTB thrive in the water column of Lake Pavin over a few metres along strong redox and chemical gradients representing a series of different microenvironments. In this study, we investigate the relative abundance and the vertical stratification of the diverse populations of MTB in relation to environmental parameters, by using a new method coupling a precise sampling for geochemical analyses, MTB morphotype description, and in situ measurement of the physicochemical parameters. We assess the ultrastructure of MTB as a function of depth using light and electron microscopy. We evidence the biogeochemical niche of magnetotactic cocci, capable of sequestering large PolyP inclusions below the oxic–anoxic transition zone. Our results suggest a tight link between the S and P metabolisms of these bacteria and pave the way to better understand the implication of MTB for the P cycle in stratified environmental conditions.
Corynebacterium Species Inhibit Streptococcus pneumoniae Colonization and Infection of the Mouse Airway
Authors: Horn Kadi J. , Jaberi Vivar Alexander C. , Arenas Vera , Andani Sameer , Janoff Edward N. , Clark Sarah E.
Published: January 2022

The stability and composition of the airway microbiome is an important determinant of respiratory health. Some airway bacteria are considered to be beneficial due to their potential to impede the acquisition and persistence of opportunistic bacterial pathogens such as Streptococcus pneumoniae. Among such organisms, the presence of Corynebacterium species correlates with reduced S. pneumoniae in both adults and children, in whom Corynebacterium abundance is predictive of S. pneumoniae infection risk. Previously, Corynebacterium accolens was shown to express a lipase which cleaves host lipids, resulting in the production of fatty acids that inhibit growth of S. pneumoniae in vitro. However, it was unclear whether this mechanism contributes to Corynebacterium-S. pneumoniae interactions in vivo. To address this question, we developed a mouse model for Corynebacterium colonization in which colonization with either C. accolens or another species, Corynebacterium amycolatum, significantly reduced S. pneumoniae acquisition in the upper airway and infection in the lung. Moreover, the lungs of co-infected mice had reduced pro-inflammatory cytokines and inflammatory myeloid cells, indicating resolution of infection-associated inflammation. The inhibitory effect of C. accolens on S. pneumoniae in vivo was mediated by lipase-dependent and independent effects, indicating that both this and other bacterial factors contribute to Corynebacterium-mediated protection in the airway. We also identified a previously uncharacterized bacterial lipase in C. amycolatum that is required for inhibition of S. pneumoniae growth in vitro. Together, these findings demonstrate the protective potential of airway Corynebacterium species and establish a new model for investigating the impact of commensal microbiota, such as Corynebacterium, on maintaining respiratory health.
Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation
Authors: Del Giovane Alice , Russo Mariagiovanna , Tirou Linda , Faure Hélène , Ruat Martial , Balestri Sonia , Sposato Carola , Basoli Francesco , Rainer Alberto , Kassoussi Abdelmoumen , Traiffort Elisabeth , Ragnini-Wilson Antonella
Published: January 2022

The regeneration of myelin is known to restore axonal conduction velocity after a demyelinating event. Remyelination failure in the central nervous system contributes to the severity and progression of demyelinating diseases such as multiple sclerosis. Remyelination is controlled by many signaling pathways, such as the Sonic hedgehog (Shh) pathway, as shown by the canonical activation of its key effector Smoothened (Smo), which increases the proliferation of oligodendrocyte precursor cells via the upregulation of the transcription factor Gli1. On the other hand, the inhibition of Gli1 was also found to promote the recruitment of a subset of adult neural stem cells and their subsequent differentiation into oligodendrocytes. Since Smo is also able to transduce Shh signals via various non-canonical pathways such as the blockade of Gli1, we addressed the potential of non-canonical Smo signaling to contribute to oligodendroglial cell maturation in myelinating cells using the non-canonical Smo agonist GSA-10, which downregulates Gli1. Using the Oli-neuM cell line, we show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMP-activated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. Moreover, GSA-10 promotes the recruitment and differentiation of oligodendroglial progenitors into the demyelinated corpus callosum in vivo. Altogether, our data indicate that non-canonical signaling involving Smo/AMPK modulation and Gli1 downregulation promotes oligodendroglia maturation until axon engagement. Thus, GSA-10, by activation of this signaling pathway, represents a novel potential remyelinating agent.
Reducing the Risk of Cognitive Decline and Dementia: WHO Recommendations
Authors: Chowdhary Neerja , Barbui Corrado , Anstey Kaarin J. , Kivipelto Miia , Barbera Mariagnese , Peters Ruth , Zheng Lidan , Kulmala Jenni , Stephen Ruth , Ferri Cleusa P. , Joanette Yves , Wang Huali , Comas-Herrera Adelina , Alessi Charles , Suharya (Dy) Kusumadewi , Mwangi Kibachio J. , Petersen Ronald C. , Motala Ayesha A. , Mendis Shanthi , Prabhakaran Dorairaj , Bibi Mia Sorefan Ameenah , Dias Amit , Gouider Riadh , Shahar Suzana , Ashby-Mitchell Kimberly , Prince Martin , Dua Tarun
Published: January 2022

With population ageing worldwide, dementia poses one of the greatest global challenges for health and social care in the 21st century. In 2019, around 55 million people were affected by dementia, with the majority living in low- and middle-income countries. Dementia leads to increased costs for governments, communities, families and individuals. Dementia is overwhelming for the family and caregivers of the person with dementia, who are the cornerstone of care and support systems throughout the world. To assist countries in addressing the global burden of dementia, the World Health Organisation (WHO) developed the Global Action Plan on the Public Health Response to Dementia 2017–2025. It proposes actions to be taken by governments, civil society, and other global and regional partners across seven action areas, one of which is dementia risk reduction. This paper is based on WHO Guidelines on risk reduction of cognitive decline and dementia and presents recommendations on evidence-based, multisectoral interventions for reducing dementia risks, considerations for their implementation and policy actions. These global evidence-informed recommendations were developed by WHO, following a rigorous guideline development methodology and involved a panel of academicians and clinicians with multidisciplinary expertise and representing geographical diversity. The recommendations are considered under three broad headings: lifestyle and behaviour interventions, interventions for physical health conditions and specific interventions. By supporting health and social care professionals, particularly by improving their capacity to provide gender and culturally appropriate interventions to the general population, the risk of developing dementia can be potentially reduced, or its progression delayed.
Critical Role of E1623 Residue in S3-S4 Loop of Nav1.1 Channel and Correlation Between Nature of Substitution and Functional Alteration
Authors: Su Tao , Chen Meng-Long , Liu Li-Hong , Meng Hen , Tang Bin , Liu Xiao-Rong , Liao Wei-Ping
Published: January 2022

Objective: An overwhelming majority of the genetic variants associated with genetic disorders are missense. The association between the nature of substitution and the functional alteration, which is critical in determining the pathogenicity of variants, remains largely unknown. With a novel missense variant (E1623A) identified from two epileptic cases, which occurs in the extracellular S3-S4 loop of Nav1.1, we studied functional changes of all latent mutations at residue E1623, aiming to understand the relationship between substitution nature and functional alteration.

Methods: Six latent mutants with amino acid substitutions at E1623 were generated, followed by measurements of their electrophysiological alterations. Different computational analyses were used to parameterize the residue alterations.

Results: Structural modeling indicated that the E1623 was located in the peripheral region far from the central pore, and contributed to the tight turn of the S3-S4 loop. The E1623 residue exhibited low functional tolerance to the substitutions with the most remarkable loss-of-function found in E1623A, including reduced current density, less steady-state availability of activation and inactivation, and slower recovery from fast inactivation. Correlation analysis between electrophysiological parameters and the parameterized physicochemical properties of different residues suggested that hydrophilicity of side-chain at E1623 might be a crucial contributor for voltage-dependent kinetics. However, none of the established algorithms on the physicochemical variations of residues could well predict changes in the channel conductance property indicated by peak current density.

Significance: The results established the important role of the extracellular S3-S4 loop in Nav1.1 channel gating and proposed a possible effect of local conformational loop flexibility on channel conductance and kinetics. Site-specific knowledge of protein will be a fundamental task for future bioinformatics.
Circulating Cell-Free Tumor DNA in Advanced Pancreatic Adenocarcinoma Identifies Patients With Worse Overall Survival
Authors: Botrus Gehan , Uson Junior Pedro Luiz Serrano , Raman Puneet , Kaufman Adrienne E. , Kosiorek Heidi , Yin Jun , Fu Yu , Majeed Umair , Sonbol Mohamad Bassam , Ahn Daniel H. , Chang Isabela W. , Drusbosky Leylah M. , Dada Hiba , Starr Jason , Borad Mitesh , Mody Kabir , Bekaii-Saab Tanios S.
Published: January 2022

Background

Plasma-based circulating cell-free tumor DNA (ctDNA) genomic profiling by next-generation sequencing (NGS)is an emerging diagnostic tool for pancreatic cancer (PC). The impact of detected genomic alterations and variant allele fraction (VAF) in tumor response to systemic treatments and outcomes is under investigation.

Methods

Patients with advanced PC who had ctDNA profiled at time of initial diagnosis were retrospectively evaluated. We considered the somatic alteration with the highest VAF as the dominant clone allele frequency (DCAF). ctDNA NGS results were related to clinical demographics, progression-free survival (PFS) and overall survival (OS).

Results

A total of 104 patients were evaluated. Somatic alterations were detected in 84.6% of the patients. Patients with ≥ 2 detectable genomic alterations had worse median PFS (p < 0.001) and worse median OS (p = 0.001). KRAS was associated with disease progression to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (p < 0.001) and worse median OS (p = 0.002). TP53 was associated with worse median PFS (p = 0.02) and worse median OS (p = 0.001). The median DCAF was 0.45% (range 0-55%). DCAF >0.45% was associated with worse median PFS (p<0.0001) and median OS (p=0.0003). Patients that achieved clearance of KRAS had better PFS (p=0.047), while patients that achieved clearance of TP53 had better PFS (p=0.0056) and OS (p=0.037).

Conclusions

Initial detection of ctDNA in advanced PC can identify somatic alterations that may help predict clinical outcomes. The dynamics of ctDNA are prognostic of outcomes and should be evaluated in prospective studies.
Comparative Efficacy of Chinese Herbal Injections for Treating Severe Pneumonia: A Systematic Review and Bayesian Network Meta-Analysis of Randomized Controlled Trials
Authors: Niu Liqing , Xiao Lu , Zhang Xuemin , Liu Xuezheng , Liu Xinqiao , Huang Xianglong , Zhang Mingzhu
Published: January 2022

Background: Severe pneumonia (SP) has a high mortality rate and is responsible for significant healthcare costs. Chinese herbal injections (CHIs) have been widely used in China as a novel and promising treatment option for SP. Therefore, this study assessed and ranked the effectiveness of CHIs to provide more sights for the selection of SP treatment.

Method: Seven databases were searched from their inception up to April 1, 2021. The methodological quality of included study was evaluated by the Cochrane risk-of-bias tool. Then, a Bayesian network meta-analysis (NMA) was performed by OpenBUGS 3.2.3 and STATA 14.0 software. The surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the examined treatments. A clustering analysis was utilized to compare the effect of CHIs between two different outcomes.

Results: A total of 64 eligible randomized controlled trials (RCTs) involving 5,904 participants were identified for this analysis. Six CHIs including Xuebijing injection (XBJ), Tanreqing injection (TRQ), Reduning injection (RDN), Xiyanping injection (XYP), Shenfu injection (SF), and Shenmai injection (SM) were included. The results of the NMA showed that XBJ [odds ratio (OR) = 0.24, 95% credible interval (CI): 0.19, 0.30], TRQ (OR = 0.22, 95% CI: 0.12, 0.37), RDN (OR = 0.29, 95% CI: 0.04, 0.94), and SM (OR = 0.27, 95% CI: 0.08, 0.63) combined with conventional Western medicine (WM) improved the clinical effective rate more significantly than WM alone. Based on SUCRA values, TRQ + WM (SUCRA: 66.4%) ranked the highest in improving the clinical effective rate, second in four different outcomes, and third in only one. According to the cluster analysis, TRQ + WM exerted a positive effect on improving the efficacy of SP. As for safety, less than 30% (18 RCTs) of the included studies reported adverse drug reactions/adverse drug events (ADRs/ADEs), including 14 RCTs of XBJ, 3 RCTs of TRQ, and 1 RCT of RDN.

Conclusion: In conclusion, the study found that the CHIs as co-adjuvant therapy could be beneficial for patients with SP. TRQ + WM showed an outstanding improvement in patients with SP considering both the clinical effective rate and other outcomes.

Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021244587].
Application of Nanoparticles in the Treatment of Lung Cancer With Emphasis on Receptors
Authors: Wang Jingyue , Zhou Tong , Liu Ying , Chen Shuangmin , Yu Zhenxiang
Published: January 2022

Lung cancer is one of the malignant tumors that has seen the most rapid growth in terms of morbidity and mortality in recent years, posing the biggest threat to people’s health and lives. In recent years, the nano-drug loading system has made significant progress in the detection, diagnosis, and treatment of lung cancer. Nanomaterials are used to specifically target tumor tissue to minimize therapeutic adverse effects and increase bioavailability. It is achieved primarily through two mechanisms: passive targeting, which entails the use of enhanced penetration and retention (EPR) effect, and active targeting, which entails the loading recognition ligands for tumor marker molecules onto nanomaterials. However, it has been demonstrated that the EPR effect is effective in rodents but not in humans. Taking this into consideration, researchers paid significant attention to the active targeting nano-drug loading system. Additionally, it has been demonstrated to have a higher affinity and specificity for tumor cells. In this review, it describes the development of research into active targeted nano-drug delivery systems for lung cancer treatment from the receptors’ or targets’ perspective. We anticipate that this study will help biomedical researchers use nanoparticles (NPs) to treat lung cancer by providing more and novel drug delivery strategies or solid ligands.
Cost-Effectiveness of Pembrolizumab Plus Chemotherapy Versus Pembrolizumab Monotherapy in Metastatic Non-Squamous and Squamous NSCLC Patients With PD-L1 Expression ≥ 50%
Authors: Liu Qiao , Zhou Zhen , Luo Xia , Yi Lidan , Peng Liubao , Wan Xiaomin , Tan Chongqing , Zeng Xiaohui
Published: January 2022

Objective To compare the cost-effectiveness of the combination of pembrolizumab and chemotherapy (Pembro+Chemo) versus pembrolizumab monotherapy (Pembro) as the first-line treatment for metastatic non-squamous and squamous non-small-cell lung cancer (NSCLC) with PD-L1expression ≥50%, respectively, from a US health care perspective.

Material and Methods A comprehensive Makrov model were designed to compare the health costs and outcomes associated with first-line Pembro+Chemo and first-line Pembro over a 20-years time horizon. Health states consisted of three main states: progression-free survival (PFS), progressive disease (PD) and death, among which the PFS health state was divided into two substates: PFS while receiving first-line therapy and PFS with discontinued first-line therapy. Two scenario analyses were performed to explore satisfactory long-term survival modeling.

Results In base case analysis, for non-squamous NSCLC patients, Pembro+Chemo was associated with a significantly longer life expectancy [3.24 vs 2.16 quality-adjusted life-years (QALYs)] and a substantially greater healthcare cost ($341,237 vs $159,055) compared with Pembro, resulting in an ICER of $169,335/QALY; for squamous NSCLC patients, Pembro+Chemo was associated with a slightly extended life expectancy of 0.22 QALYs and a marginal incremental cost of $3,449 compared with Pembro, resulting in an ICER of $15,613/QALY. Our results were particularly sensitive to parameters that determine QALYs. The first scenario analysis yielded lower ICERs than our base case results. The second scenario analysis founded Pembro+Chemo was dominated by Pembro.

Conclusion For metastatic non-squamous NSCLC patients with PD-L1 expression ≥50%, first-line Pembro+Chemo was not cost-effective when compared with first-line Pembro. In contrast, for the squamous NSCLC patient population, our results supported the first-line Pembro+Chemo as a cost-effective treatment. Although there are multiple approaches that are used for extrapolating long-term survival, the optimal method has yet to be determined.
Tannins in the Treatment of Diabetic Neuropathic Pain: Research Progress and Future Challenges
Authors: Omar Norsuhana , Ismail Che Aishah Nazariah , Long Idris
Published: January 2022

Diabetes mellitus and its consequences continue to put a significant demand on medical resources across the world. Diabetic neuropathic pain (DNP) is a frequent diabetes mellitus chronic microvascular outcome. Allodynia, hyperalgesia, and aberrant or lack of nerve fibre sensation are all symptoms of DNP. These clinical characteristics will lead to worse quality of life, sleep disruption, depression, and increased mortality. Although the availability of numerous medications that alleviate the symptoms of DNP, the lack of long-term efficacy and unfavourable side effects highlight the urgent need for novel treatment strategies. This review paper systematically analysed the preclinical research on the treatment of DNP using plant phytochemicals that contain only tannins. A total of 10 original articles involved in in-vivo and in-vitro experiments addressing the promising benefits of phytochemical tannins on DNP were examined between 2008 and 2021. The information given implies that these phytochemicals may have relevant pharmacological effects on DNP symptoms through their antihyperalgesic, anti-inflammatory, and antioxidant properties; however, because of the limited sample size and limitations of the studies conducted so far, we were unable to make definitive conclusions. Before tannins may be employed as therapeutic agents for DNP, more study is needed to establish the specific molecular mechanism for all of these activities along the pain pathway and examine the side effects of tannins in the treatment of DNP.
Computational Modeling of Drug Dissolution in the Human Stomach
Authors: Seo Jung Hee , Mittal Rajat
Published: January 2022

A computational model of drug dissolution in the human stomach is developed to investigate the interaction between gastric flow and orally administrated drug in the form of a solid tablet. The stomach model is derived from the anatomical imaging data and the motion and dissolution of the drug in the stomach are modeled via fluid-structure interaction combined with mass transport simulations. The effects of gastric motility and the associated fluid dynamics on the dissolution characteristics are investigated. Two different pill densities are considered to study the effects of the gastric flow as well as the gravitational force on the motion of the pill. The average mass transfer coefficient and the spatial distributions of the dissolved drug concentration are analyzed in detail. The results show that the retropulsive jet and recirculating flow in the antrum generated by the antral contraction wave play an important role in the motion of the pill as well as the transport and mixing of the dissolved drug concentration. It is also found that the gastric flow can increase the dissolution mass flux, especially when there is substantial relative motion between the gastric flow and the pill.
Voltage-Dependent Anion Selective Channel 3: Unraveling Structural and Functional Features of the Least Known Porin Isoform
Authors: Reina Simona , Checchetto Vanessa
Published: January 2022

Voltage-dependent anion-selective channels (VDAC) are pore-forming proteins located in the outer mitochondrial membrane. Three isoforms are encoded by separate genes in mammals (VDAC1-3). These proteins play a crucial role in the cell, forming the primary interface between mitochondrial and cellular metabolisms. Research on the role of VDACs in the cell is a rapidly growing field, but the function of VDAC3 remains elusive. The high-sequence similarity between isoforms suggests a similar pore-forming structure. Electrophysiological analyzes revealed that VDAC3 works as a channel; however, its gating and regulation remain debated. A comparison between VDAC3 and VDAC1-2 underlines the presence of a higher number of cysteines in both isoforms 2 and 3. Recent mass spectrometry data demonstrated that the redox state of VDAC3 cysteines is evolutionarily conserved. Accordingly, these residues were always detected as totally reduced or partially oxidized, thus susceptible to disulfide exchange. The deletion of selected cysteines significantly influences the function of the channel. Some cysteine mutants of VDAC3 exhibited distinct kinetic behavior, conductance values and voltage dependence, suggesting that channel activity can be modulated by cysteine reduction/oxidation. These properties point to VDAC3 as a possible marker of redox signaling in the mitochondrial intermembrane space. Here, we summarize our current knowledge about VDAC3 predicted structure, physiological role and regulation, and possible future directions in this research field.
Ultrasound-Derived Diaphragm Contractile Reserve as a Marker of Clinical Status in Patients With Cystic Fibrosis
Authors: Gabrysz-Forget Fanny , Maynard-Paquette Anne-Catherine , Kharat Aileen , Tremblay François , Silviet-Carricart Maité , Lavoie Annick , Girard Martin , Dubé Bruno-Pierre
Published: January 2022

Introduction: In patients with cystic fibrosis (CF), the monitoring of respiratory muscle activity using electromyography can provide information on the demand-to-capacity ratio of the respiratory system and act as a clinical marker of disease activity, but this technique is not adapted to routine clinical care. Ultrasonography of the diaphragm could provide an alternative, simpler and more widely available alternative allowing the real-time assessment of the diaphragm contractile reserve (DCR), but its relationship with recognized markers of disease severity and clinical outcomes are currently unknown.

Methods: Stable patients with CF were prospectively recruited. Diaphragm ultrasound was performed and compared to forced expiratory volume in 1 s (FEV1), residual volume (RV), handgrip strength, fat-free mass index (FFMI), serum vitamin levels, dyspnea levels and rate of acute exacerbation (AE). Diaphragm activity was reported as DCR (the ratio of tidal-to-maximal thickening fractions, representing the remaining diaphragm contractility available after tidal inspiration) and TFmax (representing maximal diaphragm contractile strength). Inter-observer reliability of the measurement of DCR was evaluated using intra-class correlation analysis.

Results: 110 patients were included [61 males, median (interquartile range), age 31 (27–38) years, FEV1 66 (46–82)% predicted]. DCR was significantly correlated to FEV1 (rho = 0.46, p < 0.001), RV (rho = −0.46, p < 0.001), FFMI (rho = 0.41, p < 0.001), and handgrip strength (rho = 0.22, p = 0.02), but TFmax was not. In a multiple linear regression analysis, both RV and FFMI were independent predictors of DCR. DCR, but not TFmax, was statistically lower in patients with > 2 exacerbations/year (56 ± 25 vs. 71 ± 17%, p = 0.001) and significantly lower with higher dyspnea levels. A ROC analysis showed that DCR performed better than FEV1 (mean difference in AUROC 0.09, p = 0.04), RV (mean difference in AUROC 0.11, p = 0.03), and TFmax at identifying patients with an mMRC score > 2. Inter-observer reliability of DCR was high (ICC = 0.89, 95% CI 0.84–0.92, p < 0.001).

Conclusion: In patients with CF, DCR is a reliable and non-invasive marker of disease severity that is related to respiratory and extra-pulmonary manifestations of the disease and to clinical outcomes. Future studies investigating the use of DCR as a longitudinal marker of disease progression, response to interventions or target for therapy would further validate its translation into clinical practice.
State of the Art of Genetic Engineering in Potato: From the First Report to Its Future Potential
Authors: Nahirñak Vanesa , Almasia Natalia I. , González Matías N. , Massa Gabriela A. , Décima Oneto Cecilia A. , Feingold Sergio E. , Hopp Horacio E. , Vazquez Rovere Cecilia
Published: January 2022

Potato (Solanum tuberosum L.) is a crop of world importance that produces tubers of high nutritional quality. It is considered one of the promising crops to overcome the challenges of poverty and hunger worldwide. However, it is exposed to different biotic and abiotic stresses that can cause significant losses in production. Thus, potato is a candidate of special relevance for improvements through conventional breeding and biotechnology. Since conventional breeding is time-consuming and challenging, genetic engineering provides the opportunity to introduce/switch-off genes of interest without altering the allelic combination that characterize successful commercial cultivars or to induce targeted sequence modifications by New Breeding Techniques. There is a variety of methods for potato improvement via genetic transformation. Most of them incorporate genes of interest into the nuclear genome; nevertheless, the development of plastid transformation protocols broadened the available approaches for potato breeding. Although all methods have their advantages and disadvantages, Agrobacterium-mediated transformation is the most used approach. Alternative methods such as particle bombardment, protoplast transfection with polyethylene glycol and microinjection are also effective. Independently of the DNA delivery approach, critical steps for a successful transformation are a rapid and efficient regeneration protocol and a selection system. Several critical factors affect the transformation efficiency: vector type, insert size, Agrobacterium strain, explant type, composition of the subculture media, selective agent, among others. Moreover, transient or stable transformation, constitutive or inducible promoters, antibiotic/herbicide resistance or marker-free strategies can be considered. Although great efforts have been made to optimize all the parameters, potato transformation protocols are highly genotype-dependent. Genome editing technologies provide promising tools in genetic engineering allowing precise modification of targeted sequences. Interestingly, transient expression of genome editing components in potato protoplasts was reported to generate edited plants without the integration of any foreign DNA, which is a valuable aspect from both a scientific and a regulatory perspective. In this review, current challenges and opportunities concerning potato genetic engineering strategies developed to date are discussed. We describe their critical parameters and constrains, and the potential application of the available tools for functional analyses or biotechnological purposes. Public concerns and safety issues are also addressed.
Chloroplast Genome Evolution in Four Montane Zingiberaceae Taxa in China
Authors: Yang Qian , Fu Gao-Fei , Wu Zhi-Qiang , Li Li , Zhao Jian-Li , Li Qing-Jun
Published: January 2022

Chloroplasts are critical to plant survival and adaptive evolution. The comparison of chloroplast genomes could provide insight into the adaptive evolution of closely related species. To identify potential adaptive evolution in the chloroplast genomes of four montane Zingiberaceae taxa (Cautleya, Roscoea, Rhynchanthus, and Pommereschea) that inhabit distinct habitats in the mountains of Yunnan, China, the nucleotide sequences of 13 complete chloroplast genomes, including five newly sequenced species, were characterized and compared. The five newly sequenced chloroplast genomes (162,878–163,831 bp) possessed typical quadripartite structures, which included a large single copy (LSC) region, a small single copy (SSC) region, and a pair of inverted repeat regions (IRa and IRb), and even though the structure was highly conserved among the 13 taxa, one of the rps19 genes was absent in Cautleya, possibly due to expansion of the LSC region. Positive selection of rpoA and ycf2 suggests that these montane species have experienced adaptive evolution to habitats with different sunlight intensities and that adaptation related to the chloroplast genome has played an important role in the evolution of Zingiberaceae taxa.
Effective Use of Water in Crop Plants in Dryland Agriculture: Implications of Reactive Oxygen Species and Antioxidative System
Authors: Rane Jagadish , Singh Ajay Kumar , Tiwari Manish , Prasad P. V. Vara , Jagadish S. V. Krishna
Published: January 2022

Under dryland conditions, annual and perennial food crops are exposed to dry spells, severely affecting crop productivity by limiting available soil moisture at critical and sensitive growth stages. Climate variability continues to be the primary cause of uncertainty, often making timing rather than quantity of precipitation the foremost concern. Therefore, mitigation and management of stress experienced by plants due to limited soil moisture are crucial for sustaining crop productivity under current and future harsher environments. Hence, the information generated so far through multiple investigations on mechanisms inducing drought tolerance in plants needs to be translated into tools and techniques for stress management. Scope to accomplish this exists in the inherent capacity of plants to manage stress at the cellular level through various mechanisms. One of the most extensively studied but not conclusive physiological phenomena is the balance between reactive oxygen species (ROS) production and scavenging them through an antioxidative system (AOS), which determines a wide range of damage to the cell, organ, and the plant. In this context, this review aims to examine the possible roles of the ROS-AOS balance in enhancing the effective use of water (EUW) by crops under water-limited dryland conditions. We refer to EUW as biomass produced by plants with available water under soil moisture stress rather than per unit of water (WUE). We hypothesize that EUW can be enhanced by an appropriate balance between water-saving and growth promotion at the whole-plant level during stress and post-stress recovery periods. The ROS-AOS interactions play a crucial role in water-saving mechanisms and biomass accumulation, resulting from growth processes that include cell division, cell expansion, photosynthesis, and translocation of assimilates. Hence, appropriate strategies for manipulating these processes through genetic improvement and/or application of exogenous compounds can provide practical solutions for improving EUW through the optimized ROS-AOS balance under water-limited dryland conditions. This review deals with the role of ROS-AOS in two major EUW determining processes, namely water use and plant growth. It describes implications of the ROS level or content, ROS-producing, and ROS-scavenging enzymes based on plant water status, which ultimately affects photosynthetic efficiency and growth of plants.
Optimizing Photoperiod Switch to Maximize Floral Biomass and Cannabinoid Yield in Cannabis sativa L.: A Meta-Analytic Quantile Regression Approach
Authors: Dang Michelle , Arachchige Nishara Muthu , Campbell Lesley G.
Published: January 2022

Cannabis sativa L. is an annual, short-day plant, such that long-day lighting promotes vegetative growth while short-day lighting induces flowering. To date, there has been no substantial investigation on how the switch between these photoperiods influences yield of C. sativa despite the tight correlation that plant size and floral biomass have with the timing of photoperiod switches in indoor growing facilities worldwide. Moreover, there are only casual predictions around how the timing of the photoperiodic switch may affect the production of secondary metabolites, like cannabinoids. Here we use a meta-analytic approach to determine when growers should switch photoperiods to optimize C. sativa floral biomass and cannabinoid content. To this end, we searched through ISI Web of Science for peer-reviewed publications of C. sativa that reported experimental photoperiod durations and results containing cannabinoid concentrations and/or floral biomass, then from 26 studies, we estimated the relationship between photoperiod and yield using quantile regression. Floral biomass was maximized when the long daylength photoperiod was minimized (i.e., 14 days), while THC and CBD potency was maximized under long day length photoperiod for ~42 and 49–50 days, respectively. Our work reveals a yield trade-off in C. sativa between cannabinoid concentration and floral biomass where more time spent under long-day lighting maximizes cannabinoid content and less time spent under long-day lighting maximizes floral biomass. Growers should carefully consider the length of long-day lighting exposure as it can be used as a tool to maximize desired yield outcomes.
Generating Novel Male Sterile Tomatoes by Editing Respiratory Burst Oxidase Homolog Genes
Authors: Dai Xiaojuan , Han Huanan , Huang Wei , Zhao Lianghui , Song Minglei , Cao Xuesong , Liu Chenglan , Niu Xiaomu , Lang Zhaobo , Ma Changle , Xie Hongtao
Published: January 2022

Hybrid breeding of tomatoes (Solanum lycopersicum), an important vegetable crop, is an effective way to improve yield and enhance disease and stress resistance. However, the efficiency of tomato hybridization is hindered by self-fertilization, which can be overcome using male sterile lines. It has been reported that reactive oxygen species (ROS) act as a key regulator for anther development, mediated by RBOH (Respiratory Burst Oxidase Homolog) genes. Here, two tomato anther-expressed genes, LeRBOH (Solyc01g099620) and LeRBOHE (Solyc07g042460), were selected to cultivate novel tomato male sterile strains. By using a CRISPR/Cas9 system with a two-sgRNA module, the lerboh, lerbohe, and lerboh lerbohe mutant lines were generated, among which the lerbohe and lerboh lerbohe mutants displayed complete male sterility but could accept wild-type pollens and produce fruits normally. Further analysis uncovered significantly decreased ROS levels and abnormal programmed cell death in lerboh lerbohe anthers, indicating a key role of ROS metabolism in tomato pollen development. Taken together, our work demonstrates a successful application of gene editing via CRISPR/Cas9 in generating male sterile tomatoes and afforded helpful information for understanding how RBOH genes regulating tomato reproduction process.