bluuebunny/crossref_metadata_2025 huggingface dataset:
New Approaches in the Classification and Prognosis of Sign Clusters on Pulmonary CT Images in Patients With Multidrug-Resistant Tuberculosis
Authors: Song Qisheng , Guo Xiaohong , Zhang Liling , Yang Lianjun , Lu Xiwei
Published: October 2021

Background: To date, radiographic sign clusters of multidrug-resistant pulmonary tuberculosis (MDR-TB) patients have not been reported. We conducted a study to investigate the classification and prognosis of sign clusters in pulmonary Computed Tomography (CT) images from patients with MDR-TB for the first time by using principal component analysis (PCA).

Methods: The clinical data and pulmonary CT findings of 108 patients with MDR-TB in the Liupanshui Third Hospital were collected (from January 2018 to December 2020). PCA was used to analyze the sign clusters on pulmonary CT, and receiver operating characteristic (ROC) analysis was used to analyze the predictive value of the treatment outcome of MDR-TB patients.

Results: Six cluster signs of MDR-TB were determined by PCA: nodules, infiltration, consolidation, cavities, destroyed lung and non-active lesions. Nine months after treatment, the area under the ROC curve (AUC) of MDR-TB patients with a cavity sign cluster was 0.818 (95% CI: 0.733–0.886), and the positive predictive value (PPV) and negative predictive value (NPV) of the treatment outcome were 79.6% (95% CI: 65.7–89.8%) and 72.9% (95% CI: 59.7–83.6%), respectively.

Conclusion: PCA plays an important role in the classification of sign groups on pulmonary CT images of MDR-TB patients, and the sign clusters obtained from PCA are of great significance in predicting the treatment outcome.
The Macroevolutionary Consequences of Niche Construction in Microbial Metabolism
Authors: Bajić Djordje , Rebolleda-Gómez María , Muñoz Martha M. , Sánchez Álvaro
Published: October 2021

Microorganisms display a stunning metabolic diversity. Understanding the origin of this diversity requires understanding how macroevolutionary processes such as innovation and diversification play out in the microbial world. Metabolic networks, which govern microbial resource use, can evolve through different mechanisms, e.g., horizontal gene transfer orde novoevolution of enzymes and pathways. This process is governed by a combination of environmental factors, selective pressures, and the constraints imposed by the genetic architecture of metabolic networks. In addition, many independent results hint that the process of niche construction, by which organisms actively modify their own and each other’s niches and selective pressures, could play a major role in microbial innovation and diversification. Yet, the general principles by which niche construction shapes microbial macroevolutionary patterns remain largely unexplored. Here, we discuss several new hypotheses and directions, and suggest metabolic modeling methods that could allow us to explore large-scale empirical genotype-phenotype-(G-P)-environment spaces in order to study the macroevolutionary effects of niche construction. We hope that this short piece will further stimulate a systematic and quantitative characterization of macroevolutionary patterns and processes in microbial metabolism.
Tetrameric Neuraminidase of Influenza A Virus Is Required to Induce Protective Antibody Responses in Mice
Authors: Deng Xiren , Wang Qimin , Liu Mei , Zheng Qinwen , Wu Fan , Huang Jinghe
Published: October 2021

Influenza neuraminidase (NA) is able to induce cross-subtype immunity and is considered as a promising target for the development of universal influenza vaccines. However, commercial influenza vaccines only induced low NA-specific immune responses due to the low amounts and the denatured conformation of NA proteins in current inactivated or split influenza vaccines. Here we investigated the protective efficacy of recombinant tetrameric and monomeric NA proteins to determine whether the conformation contributed to induce protective immunity. We found that H1N1PR8NA tetramer (NAtet) could provide complete homologous protection against A/PR8 (H1N1) virus infection in mice, while the protection of H1N1PR8NA monomer (NAmono) was moderate. Higher levels of NA-reactive binding and inhibition antibodies and less weight loss were observed in the H1N1PR8NAtet-vaccinated group. Similarly, H5N1VNNAtet immunization exhibited a preferable heterologous protection than H5N1VNNAmono, but neither H7N9SHNAtet nor H7N9SHNAmono vaccination showed heterosubtypic protection. We also compared the effect of three adjuvants, aluminum, 3′3′-cGAMP (cGAMP), and Poly(I:C), on the humoral response and protective efficacy induced by H1N1PR8NAtet. H1N1PR8NAtet protein adjuvanted with aluminum was observed to exhibited better capacity in inducing NA-specific humoral immunity and preventing weight loss than with cGAMP or Poly(I:C). In conclusion, our data demonstrate that tetrameric NA with natural conformation is required to induce protective anti-NA immunity. The NA tetramer could provide homologous protection and subtype-specific cross-protection. In addition, the aluminum adjuvant is preferable in recombinant NA protein vaccination.
International High-Risk Clones Among Extended-Spectrum β-Lactamase–Producing Escherichia coli in Dhaka, Bangladesh
Authors: Mazumder Razib , Hussain Arif , Abdullah Ahmed , Islam Md. Nazrul , Sadique Md. Tuhin , Muniruzzaman S. M. , Tabassum Anika , Halim Farhana , Akter Nasrin , Ahmed Dilruba , Mondal Dinesh
Published: October 2021

Background:Escherichia coli is a major extended-spectrum β-lactamase (ESBL)–producing organism responsible for the rapid spread of antimicrobial resistance (AMR) that has compromised our ability to treat infections. Baseline data on population structure, virulence, and resistance mechanisms in E. coli lineages from developing countries such as Bangladesh are lacking.

Methods: Whole-genome sequencing was performed for 46 ESBL–E. coli isolates cultured from patient samples at the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)-Dhaka. Sequence data were analyzed to glean details of AMR, virulence, and phylogenetic and molecular markers of E. coli lineages.

Results: Genome comparison revealed presence of all major high-risk clones including sequence type 131 (ST131) (46%), ST405 (13%), ST648 (7%), ST410 (4.3%), ST38 (2%), ST73 (2%), and ST1193 (2%). The predominant ESBL gene and plasmid combination were blaCTX–M–15 and FII-FIA-FIB detected in diverse E. coli phylogroups and STs. The blaNDM–5 (9%) gene was present in prominent E. coli STs. One (2%) mcr-1–positive ST1011 E. coli, coharboring blaCTXM–55 gene, was detected. The extraintestinal pathogenic E. coli genotype was associated with specific E. coli lineages. The single nucleotide polymorphism (SNP)-based genome phylogeny largely showed correlation with phylogroups, serogroups, and fimH types. Majority of these isolates were susceptible to amikacin (93%), imipenem (93%), and nitrofurantoin (83%).

Conclusion: Our study reveals a high diversity of E. coli lineages among ESBL-producing E. coli from Dhaka. This study suggests ongoing circulation of ST131 and all major non-ST131 high-risk clones that are strongly associated with cephalosporin resistance and virulence genes. These findings warrant prospective monitoring of high-risk clones, which would otherwise worsen the AMR crises.
Nutrient Inputs Stimulate Mercury Methylation by Syntrophs in a Subarctic Peatland
Authors: Roth Spencer , Poulin Brett A. , Baumann Zofia , Liu Xiao , Zhang Lin , Krabbenhoft David P. , Hines Mark E. , Schaefer Jeffra K. , Barkay Tamar
Published: October 2021

Climate change dramatically impacts Arctic and subarctic regions, inducing shifts in wetland nutrient regimes as a consequence of thawing permafrost. Altered hydrological regimes may drive changes in the dynamics of microbial mercury (Hg) methylation and bioavailability. Important knowledge gaps remain on the contribution of specific microbial groups to methylmercury (MeHg) production in wetlands of various trophic status. Here, we measured aqueous chemistry, potential methylation rates (kmeth), volatile fatty acid (VFA) dynamics in peat-soil incubations, and genetic potential for Hg methylation across a groundwater-driven nutrient gradient in an interior Alaskan fen. We tested the hypotheses that (1) nutrient inputs will result in increased methylation potentials, and (2) syntrophic interactions contribute to methylation in subarctic wetlands. We observed that concentrations of nutrients, total Hg, and MeHg, abundance of hgcA genes, and rates of methylation in peat incubations (kmeth) were highest near the groundwater input and declined downgradient. hgcA sequences near the input were closely related to those from sulfate-reducing bacteria (SRB), methanogens, and syntrophs. Hg methylation in peat incubations collected near the input source (FPF2) were impacted by the addition of sulfate and some metabolic inhibitors while those down-gradient (FPF5) were not. Sulfate amendment to FPF2 incubations had higher kmeth relative to unamended controls despite no effect on kmeth from addition of the sulfate reduction inhibitor molybdate. The addition of the methanogenic inhibitor BES (25 mM) led to the accumulation of VFAs, but unlike molybdate, it did not affect Hg methylation rates. Rather, the concurrent additions of BES and molybdate significantly decreased kmeth, suggesting a role for interactions between SRB and methanogens in Hg methylation. The reduction in kmeth with combined addition of BES and molybdate, and accumulation of VFA in peat incubations containing BES, and a high abundance of syntroph-related hgcA sequences in peat metagenomes provide evidence for MeHg production by microorganisms growing in syntrophy. Collectively the results suggest that wetland nutrient regimes influence the activity of Hg methylating microorganisms and, consequently, Hg methylation rates. Our results provide key information about microbial Hg methylation and methylating communities under nutrient conditions that are expected to become more common as permafrost soils thaw.
The m6A RNA Demethylase ALKBH9B Plays a Critical Role for Vascular Movement of Alfalfa Mosaic Virus in Arabidopsis
Authors: Martínez-Pérez Mireya , Gómez-Mena Concepción , Alvarado-Marchena Luis , Nadi Riad , Micol José Luis , Pallas Vicente , Aparicio Frederic
Published: October 2021

The N6-methyladenosine (m6A) pathway has been widely described as a viral regulatory mechanism in animals. We previously reported that the capsid protein (CP) of alfalfa mosaic virus (AMV) interacts with the Arabidopsis m6A demethylase ALKBH9B regulating m6A abundance on viral RNAs (vRNAs) and systemic invasion of floral stems. Here, we analyze the involvement of other ALKBH9 proteins in AMV infection and we carry out a detailed evaluation of the infection restraint observed in alkbh9b mutant plants. Thus, via viral titer quantification experiments and in situ hybridization assays, we define the viral cycle steps that are altered by the absence of the m6A demethylase ALKBH9B in Arabidopsis. We found that ALKBH9A and ALKBH9C do not regulate the AMV cycle, so ALKBH9B activity seems to be highly specific. We also define that not only systemic movement is affected by the absence of the demethylase, but also early stages of viral infection. Moreover, our findings suggest that viral upload into the phloem could be blocked in alkbh9b plants. Overall, our results point to ALKBH9B as a possible new component of phloem transport, at least for AMV, and as a potential target to obtain virus resistance crops.
Nicotinamide Adenine Dinucleotide-Dependent Flavin Oxidoreductase of Mycoplasma hyopneumoniae Functions as a Potential Novel Virulence Factor and Not Only as a Metabolic Enzyme
Authors: Xie Xing , Hao Fei , Chen Rong , Wang Jingjing , Wei Yanna , Liu Jin , Wang Haiyan , Zhang Zhenzhen , Bai Yun , Shao Guoqing , Xiong Qiyan , Feng Zhixin
Published: October 2021

Mycoplasma hyopneumoniae (Mhp) is the main pathogen that causes enzootic pneumonia, a disease that has a significant impact on the pig industry worldwide. The pathogenesis of enzootic pneumonia, especially possible virulence factors of Mhp, has still not been fully elucidated. The transcriptomic and proteomic analyses of different Mhp strains reported in the literature have revealed differences in virulence, and differences in RNA transcription levels between high- and low-virulence strains initially indicated that nicotinamide adenine dinucleotide (NADH)-dependent flavin oxidoreductase (NFOR) was related to Mhp pathogenicity. Prokaryotic expression and purification of the NFOR protein from Mhp were performed, a rabbit-derived polyclonal antibody against NFOR was prepared, and multiple sequence alignment and evolutionary analyses of Mhp NFOR were performed. For the first time, it was found that the NFOR protein was conserved among all Mhp strains, and NFOR was localized to the cell surface and could adhere to immortalized porcine bronchial epithelial cells (hTERT-PBECs). Adhesion to hTERT-PBECs could be specifically inhibited by an anti-NFOR polyclonal antibody, and the rates of adhesion to both high- and low-virulence strains, 168 and 168L, significantly decreased by more than 40%. Moreover, Mhp NFOR not only recognized and interacted with host fibronectin and plasminogen but also induced cellular oxidative stress and apoptosis in hTERT-PBECs. The release of lactate dehydrogenase by hTERT-PBECs incubated with Mhp NFOR was significantly positively correlated with the virulence of Mhp. Overall, in addition to being a metabolic enzyme related to oxidative stress, NFOR may also function as a potential novel virulence factor of Mhp, thus contributing to the pathogenesis of Mhp; these findings provide new ideas and theoretical support for studying the pathogenic mechanisms of other mycoplasmas.
Monitoring Bacterial Conjugation by Optical Microscopy
Authors: Carranza Gerardo , Menguiano Tamara , Valenzuela-Gómez Fernando , García-Cazorla Yolanda , Cabezón Elena , Arechaga Ignacio
Published: October 2021

Bacterial conjugation is the main mechanism for horizontal gene transfer, conferring plasticity to the genome repertoire. This process is also the major instrument for the dissemination of antibiotic resistance genes. Hence, gathering primary information of the mechanism underlying this genetic transaction is of a capital interest. By using fluorescent protein fusions to the ATPases that power conjugation, we have been able to track the localization of these proteins in the presence and absence of recipient cells. Moreover, we have found that more than one copy of the conjugative plasmid is transferred during mating. Altogether, these findings provide new insights into the mechanism of such an important gene transfer device.
Longitudinal Multi-Omics Study of a Mother-Infant Dyad from Breastfeeding to Weaning: An Individualized Approach to Understand the Interactions Among Diet, Fecal Metabolome and Microbiota Composition
Authors: Conta Giorgia , Del Chierico Federica , Reddel Sofia , Marini Federico , Sciubba Fabio , Capuani Giorgio , Tomassini Alberta , Di Cocco Maria Enrica , Laforgia Nicola , Baldassarre Maria Elisabetta , Putignani Lorenza , Miccheli Alfredo
Published: October 2021

The development of the human gut microbiota is characterized by a dynamic sequence of events from birth to adulthood, which make the gut microbiota unique for everyone. Its composition and metabolism may play a critical role in the intestinal homeostasis and health. We propose a study on a single mother-infant dyad to follow the dynamics of an infant fecal microbiota and metabolome changes in relation to breast milk composition during the lactation period and evaluate the changes induced by introduction of complementary food during the weaning period. Nuclear Magnetic Resonance (NMR)-based metabolomics was performed on breast milk and, together with 16S RNA targeted-metagenomics analysis, also on infant stool samples of a mother-infant dyad collected over a period running from the exclusive breastfeeding diet to weaning. Breast milk samples and neonatal stool samples were collected from the 4th to the 10th month of life. Both specimens were collected from day 103 to day 175, while from day 219–268 only stool samples were examined. An exploratory and a predictive analysis were carried out by means of Common component and specific weight analysis and multi-block partial least squares discriminant analysis, respectively. Stools collected during breastfeeding and during a mixed fruit/breastfeeding diet were characterized by high levels of fucosyl-oligosaccharides and glycolysis intermediates, including succinate and formate. The transition to a semi-solid food diet was characterized by several changes in fecal parameters: increase in short-chain fatty acids (SCFAs) levels, including acetate, propionate and butyrate, dissapearance of HMOs and the shift in the community composition, mainly occurring within the Firmicutes phylum. The variations in the fecal metabolome reflected the infant’s diet transition, while the composition of the microbiota followed a more complex and still unstable behavior.
Functional Analysis of Rare Genetic Variants in the Negative Regulator of Intracellular Calcium Signaling RCAS/SLC10A7
Authors: Wannowius Marie , Karakus Emre , Geyer Joachim
Published: October 2021

The solute carrier family 10 member SLC10A7 is a negative regulator of intracellular calcium signaling (RCAS). In cell culture, SLC10A7 expression is negatively correlated with store-operated calcium entry (SOCE) via the plasma membrane. SLC10A7-deficient cells have significantly increased calcium influx after treatment with thapsigargin for depletion of ER calcium stores, whereas SLC10A7/RCAS overexpression limits calcium influx. Genetic variants in the human SLC10A7 gene are associated with skeletal dysplasia and amelogenesis imperfecta and reveal loss of function on cellular calcium influx. More recently, an additional disease-related genetic variant (P303L) as well as some novel genetic variants (V235F, T221M, I136M, L210F, P285L, and G146S) have been identified. In the present study, these variants were expressed in HEK293 cells to study their subcellular localization and their effect on cellular calcium influx. All variants were properly sorted to the ER compartment and closely co-localized with the STIM protein, a functional component of SOCE. The variants P303L and L210F showed significantly reduced effects on cellular calcium influx compared to the wild type but still maintained some degree of residual activity. This might explain the milder phenotype of patients bearing the P303L variant and might indicate disease potential for the newly identified L210F variant. In contrast, all other variants behaved like the wild type. In conclusion, the occurrence of variants in the SLC10A7 gene should be considered in patients with skeletal dysplasia and amelogenesis imperfecta. In addition to the already established variants, the present study identifies another potential disease-related SLC10A7/RCAS variant, namely, L210F, which seems to be most frequent in South Asian populations.
The Serendipity of Viral Trans-Neuronal Specificity: More Than Meets the Eye
Authors: Beier Kevin Thomas
Published: October 2021

Trans-neuronal viruses are frequently used as neuroanatomical tools for mapping neuronal circuits. Specifically, recombinant one-step rabies viruses (RABV) have been instrumental in the widespread application of viral circuit mapping, as these viruses have enabled labs to map the direct inputs onto defined cell populations. Within the neuroscience community, it is widely believed that RABV spreads directly between neurons via synaptic connections, a hypothesis based principally on two observations. First, the virus labels neurons in a pattern consistent with known anatomical connectivity. Second, few glial cells appear to be infected following RABV injections, despite the fact that glial cells are abundant in the brain. However, there is no direct evidence that RABV can actually be transmitted through synaptic connections. Here we review the immunosubversive mechanisms that are critical to RABV’s success for infiltration of the central nervous system (CNS). These include interfering with and ultimately killing migratory T cells while maintaining levels of interferon (IFN) signaling in the brain parenchyma. Finally, we critically evaluate studies that support or are against synaptically-restricted RABV transmission and the implications of viral-host immune responses for RABV transmission in the brain.
Changes of Health-Related Quality of Life Within the 1st Year After Stroke–Results From a Prospective Stroke Cohort Study
Authors: Kainz Anabelle , Meisinger Christa , Linseisen Jakob , Kirchberger Inge , Zickler Philipp , Naumann Markus , Ertl Michael
Published: October 2021

Introduction: As prospective data on long-term patient-reported outcome measures (PROMs) to assess Health related Quality of Life (HRQoL) after stroke are still scarce, this study examined the long-term course of PROMs and investigated influential factors such as recanalization therapies.

Materials and Methods: A total of 945 (mean age 69 years; 56% male) stroke patients were enrolled with a personal interview and chart review performed at index event. One hundred forty (15%) patients received thrombolysis (IVT) and 53 (5%) patients received endovascular therapy (ET) or both treatments as bridging therapy (BT). After 3 and 12 months, a follow-up was conducted using a postal questionnaire including subjective quality of life EQ-5D-5L (European Quality of Life 5 Dimensions). At all time-points, Modified Rankin Scale (mRS) was additionally used to quantify functional stroke severity. Differences between therapy groups were identified using post-hoc-tests. Linear and logistic regression analyses were used to identify predictors of outcomes.

Results: Recanalization therapies were associated with significant improvements of NIHSS (National Institutes of Health Stroke Scale [regression coefficient IVT 1.21 (p = 0.01) and ET/BT 7.6; p = 0.001] and mRS (modified Rankin Scale) [regression coefficient IVT 0.83; p = 0.001 and ET/BT 2.0; p = 0.001] between admission and discharge compared to patients with stroke unit therapy only, with a trend toward improvement of EQ-5D after 12 months [regression coefficient 4.67 (p = 0.17)] with IVT. HRQoL was considerably impaired by stroke and increased steadily in 3- and 12-months follow-up in patients with (mean EQ-5D from 56 to 68) and without recanalization therapy (mean EQ-5D from 62 to 68). In severe strokes a major and significant improvement was only detected during period of 3 to 12 months (p = 0.03 in patients with and p = 0.005 in patients without recanalization therapy).

Conclusions: Despite significant and continuous improvements after stroke the HRQoL after 12 months remained below the age-matched general population, but was still unexpectedly high in view of the accumulation of permanent disabilities in up to 30% of the patients. Especially in severe strokes, it is important to evaluate HRQoL beyond a 3-months follow-up as improvements became significant only between 3 months and 1 year.
GABAergic Gene Regulatory Elements Used in Adeno-Associated Viral Vectors
Authors: Duba-Kiss Robert , Niibori Yosuke , Hampson David R.
Published: October 2021

Several neurological and psychiatric disorders have been associated with impairments in GABAergic inhibitory neurons in the brain. Thus, in the current era of accelerated development of molecular medicine and biologically-based drugs, there is a need to identify gene regulatory sequences that can be utilized for selectively manipulating the expression of nucleic acids and proteins in GABAergic neurons. This is particularly important for the use of viral vectors in gene therapy. In this Mini Review, we discuss the use of various gene regulatory elements for targeting GABAergic neurons, with an emphasis on adeno-associated viral vectors, the most widely used class of viral vectors for treating brain diseases.
Can a Single Representational Object Account for Different Number-Space Mappings?
Authors: Viarouge Arnaud , de Hevia Maria Dolores
Published: October 2021

Numbers are mapped onto space from birth on, as evidenced by a variety of interactions between the processing of numerical and spatial information. In particular, larger numbers are associated to larger spatial extents (number/spatial extent mapping) and to rightward spatial locations (number/location mapping), and smaller numbers are associated to smaller spatial extents and leftward spatial locations. These two main types of number/space mappings (number/spatial extent and number/location mappings) are usually assumed to reflect the fact that numbers are represented on an internal continuum: the mental number line. However, to date there is very little evidence that these two mappings actually reflect a single representational object. Across two experiments in adults, we investigated the interaction between number/location and number/spatial extent congruency effects, both when numbers were presented in a non-symbolic and in a symbolic format. We observed a significant interaction between the two mappings, but only in the context of an implicit numerical task. The results were unaffected by the format of presentation of numbers. We conclude that the number/location and the number/spatial extent mappings can stem from the activation of a single representational object, but only in specific experimental contexts.
Analysis of the Distribution of Urine Color and Its Relationship With Urine Dry Chemical Parameters Among College Students in Beijing, China – A Cross-Sectional Study
Authors: Liu Jingnan , Zhang Zijuan , Pang Xiaohan , Cheng Yaxing , Man Da , He Xinyi , Zhao Huihui , Zhao Ruizhen , Wang Wei
Published: October 2021

Objectives: The objective of this study was to provide a new classification method by analyzing the relationship between urine color (Ucol) distribution and urine dry chemical parameters based on image digital processing. Furthermore, this study aimed to assess the reliability of Ucol to evaluate the states of body hydration and health.

Methods: A cross-sectional study among 525 college students, aged 17–23 years old, of which 59 were men and 466 were women, was conducted. Urine samples were obtained during physical examinations and 524 of them were considered valid, including 87 normal samples and 437 abnormal dry chemistry parameters samples. The urinalysis included both micro- and macro-levels, in which the CIE L*a*b* values and routine urine chemical examination were performed through digital imaging colorimetry and a urine chemical analyzer, respectively.

Results: The results showed that L* (53.49 vs. 56.69) in the abnormal urine dry chemistry group was lower than the normal group, while b* (37.39 vs. 33.80) was greater. Urine color can be initially classified based on shade by grouping b*. Abnormal urine dry chemical parameter samples were distributed more in the dark-colored group. Urine dry chemical parameters were closely related to Ucol. Urine specific gravity (USG), protein, urobilinogen, bilirubin, occult blood, ketone body, pH, and the number of abnormal dry chemical parameters were all correlated with Ucol CIE L*a*b*; according to a stepwise regression analysis, it was determined that more than 50% of the variation in the three-color space values came from the urine dry chemical parameters, and the b* value was most affected by USG (standardized coefficient β = 0.734, p < 0.05). Based on a receiver operating characteristic curve (ROC) analysis, Ucol ≥ 4 provided moderate sensitivity and good specificity (AUC = 0.892) for the detection of USG ≥ 1.020.

Conclusions: Our findings on the Ucol analysis showed that grouping Ucol based on b* value is an objective, simple, and practical method. At the same time, the results suggested that digital imaging colorimetry for Ucol quantification is a potential method for evaluating body hydration and, potentially, health.
Older Adults’ Knowledge and Perceptions of Whole Foods as an Exercise Recovery Strategy
Authors: Hayes Eleanor Jayne , Granic Antoneta , Hurst Christopher , Dismore Lorelle , Sayer Avan A. , Stevenson Emma
Published: October 2021

Resistance exercise is a widely advocated treatment for improving muscle strength and performance in older adults. Maximizing the benefit of resistance exercise by ensuring optimal recovery is an important aim and studies are now seeking interventions to expedite exercise recovery in older people. A recovery strategy that has acquired considerable interest is the consumption of protein, and more recently, the consumption of protein-rich whole foods. This study aimed to understand the perspectives of community-dwelling older adults, and determine their knowledge of exercise recovery strategies, their preferences for recovery strategies, and their attitudes toward using whole foods, such as milk as a post-exercise recovery aid. Two hundred ninety-one older adults (74 ± 4 years) were recruited to complete a self-administered online survey. A mixed methods approach was used to gather in-depth data from the cohort. Participants were asked to complete a combination of free-text (open-ended) and multiple-choice questions. Content analysis was conducted on responses to open-ended questions through a systematic classification process of coding. The most common recovery strategies reported were heat treatment, rest, and massage. Nutrition was rarely cited as a recovery strategy. Less than 2% of respondents mentioned nutrition, of these, only half mentioned a protein source. Forty-nine percent expressed negative opinions toward recovery supplements (e.g., “waste of money”) compared to 7% expressing positive opinions. Whole foods such as milk, meat, fish, and fruit, were deemed to be a more acceptable recovery strategy than supplements by 80% of respondents. Those that found whole foods to be equally as acceptable (18%), cited efficacy as their main concern, and those that declared whole foods less acceptable (2%) had no common reason. Despite the high acceptability of whole foods, only 35% were aware that these foods could aid recovery. When asked about milk specifically, the majority of older adults (73%) said this would, or might, be an acceptable exercise recovery strategy. Those that found milk an unacceptable recovery strategy (27%) often cited disliking milk or an allergy/intolerance. In conclusion, whilst whole foods represented an acceptable recovery intervention for older adults, the majority were unaware of the potential benefits of nutrition for post-exercise recovery.
Unique Genomic Alterations of Cerebrospinal Fluid Cell-Free DNA Are Critical for Targeted Therapy of Non-Small Cell Lung Cancer With Leptomeningeal Metastasis
Authors: Wang Yongsheng , Jiang Feng , Xia Ruixue , Li Ming , Yao Chengyun , Li Yan , Li Hui , Zhao Qi , Shi Mingke , Yu Yanzhe , Shao Yang W. , Zhou Guoren , Xia Hongping , Miao Liyun , Cai Hourong
Published: October 2021

We reported unique molecular features of cerebrospinal fluid (CSF) of nonsmall cell lung cancer (NSCLC) patients with leptomeningeal metastasis (LM), suggesting establishing CSF as a better liquid biopsy in clinical practices. We performed next-generation panel sequencing of primary tumor tissue, plasma, and CSF from 131 NSCLC patients with LM and observed high somatic copy number variations (CNV) in CSF of NSCLC patients with LM. The status of EGFR-activating mutations was highly concordant between CSF, plasma, and primary tumors. ALK translocation was detected in 8.3% of tumor tissues but only 2.4% in CSF and 2.7% in plasma. Others such as ROS1 rearrangement, RET fusion, HER2 mutation, NTRK1 fusion, and BRAF V600E mutation were detected in 7.9% of CSF and 11.1% of tumor tissues but only 4% in plasma. Our study has shed light on the unique genomic variations of CSF and demonstrated that CSF might represent better liquid biopsy for NSCLC patients with LM.
CCL23 in Balancing the Act of Endoplasmic Reticulum Stress and Antitumor Immunity in Hepatocellular Carcinoma
Authors: Karan Dev
Published: October 2021

Endoplasmic reticulum (ER) stress is a cellular process in response to stress stimuli in protecting functional activities. However, sustained hyperactive ER stress influences tumor growth and development. Hepatocytes are enriched with ER and highly susceptible to ER perturbations and stress, which contribute to immunosuppression and the development of aggressive and drug-resistant hepatocellular carcinoma (HCC). ER stress-induced inflammation and tumor-derived chemokines influence the immune cell composition at the tumor site. Consequently, a decrease in the CCL23 chemokine in hepatic tumors is associated with poor survival of HCC patients and could be a mechanism hepatic tumor cells use to evade the immune system. This article describes the prospective role of CCL23 in alleviating ER stress and its impact on the HCC tumor microenvironment in promoting antitumor immunity. Moreover, approaches to reactivate CCL23 combined with immune checkpoint blockade or chemotherapy drugs may provide novel opportunities to target hepatocellular carcinoma.
Honokiol Suppresses Perineural Invasion of Pancreatic Cancer by Inhibiting SMAD2/3 Signaling
Authors: Qin Tao , Li Jie , Xiao Ying , Wang Xueni , Gong Mengyuan , Wang Qiqi , Zhu Zeen , Zhang Simei , Zhang Wunai , Cao Fang , Han Liang , Wang Zheng , Ma Qingyong , Sha Huanchen
Published: October 2021

Background

Perineural invasion (PNI) is an important pathologic feature of pancreatic cancer, and the incidence of PNI in pancreatic cancer is 70%-100%. PNI is associated with poor outcome, metastasis, and recurrence in pancreatic cancer patients. There are very few treatments for PNI in pancreatic cancer. Honokiol (HNK) is a natural product that is mainly obtained from Magnolia species and has been indicated to have anticancer activity. HNK also has potent neurotrophic activity and may be effective for suppressing PNI. However, the potential role of HNK in the treatment of PNI in pancreatic cancer has not been elucidated.

Methods

In our study, pancreatic cancer cells were treated with vehicle or HNK, and the invasion and migration capacities were assessed by wound scratch assays and Transwell assays. A cancer cell-dorsal root ganglion coculture model was established to evaluate the effect of HNK on the PNI of pancreatic cancer. Western blotting was used to detect markers of EMT and neurotrophic factors in pancreatic tissue. Recombinant TGF-β1 was used to activate SMAD2/3 to verify the effect of HNK on SMAD2/3 and neurotrophic factors. The subcutaneous tumor model and the sciatic nerve invasion model, which were established in transgenic engineered mice harboring spontaneous pancreatic cancer, were used to investigate the mechanism by which HNK inhibits EMT and PNI in vivo.

Results

We found that HNK can inhibit the invasion and migration of pancreatic cancer cells. More importantly, HNK can inhibit the PNI of pancreatic cancer. The HNK-mediated suppression of pancreatic cancer PNI was partially mediated by inhibition of SMAD2/3 phosphorylation. In addition, the inhibitory effect of HNK on PNI can be reversed by activating SMAD2/3. In vivo, we found that HNK can suppress EMT in pancreatic cancer. HNK can also inhibit cancer cell migration along the nerve, reduce the damage to the sciatic nerve caused by tumor cells and protect the function of the sciatic nerve.

Conclusion

Our results demonstrate that HNK can inhibit the invasion, migration, and PNI of pancreatic cancer by blocking SMAD2/3 phosphorylation, and we conclude that HNK may be a new strategy for suppressing PNI in pancreatic cancer.
Comparison of PET/CT and MRI in the Diagnosis of Bone Metastasis in Prostate Cancer Patients: A Network Analysis of Diagnostic Studies
Authors: Liu Fanxiao , Dong Jinlei , Shen Yelong , Yun Canhua , Wang Ruixiao , Wang Ganggang , Tan Jiyang , Wang Tao , Yao Qun , Wang Bomin , Li Lianxin , Mi Jingyi , Zhou Dongsheng , Xiong Fei
Published: October 2021

Background

Accurate diagnosis of bone metastasis status of prostate cancer (PCa) is becoming increasingly more important in guiding local and systemic treatment. Positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) have increasingly been utilized globally to assess the bone metastases in PCa. Our meta-analysis was a high-volume series in which the utility of PET/CT with different radioligands was compared to MRI with different parameters in this setting.

Materials and Methods

Three databases, including Medline, Embase, and Cochrane Library, were searched to retrieve original trials from their inception to August 31, 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The methodological quality of the included studies was assessed by two independent investigators utilizing Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). A Bayesian network meta-analysis was performed using an arm-based model. Absolute sensitivity and specificity, relative sensitivity and specificity, diagnostic odds ratio (DOR), and superiority index, and their associated 95% confidence intervals (CI) were used to assess the diagnostic value.

Results

Forty-five studies with 2,843 patients and 4,263 lesions were identified. Network meta-analysis reveals that 68Ga-labeled prostate membrane antigen (68Ga-PSMA) PET/CT has the highest superiority index (7.30) with the sensitivity of 0.91 and specificity of 0.99, followed by 18F-NaF, 11C-choline, 18F-choline, 18F-fludeoxyglucose (FDG), and 18F-fluciclovine PET/CT. The use of high magnetic field strength, multisequence, diffusion-weighted imaging (DWI), and more imaging planes will increase the diagnostic value of MRI for the detection of bone metastasis in prostate cancer patients. Where available, 3.0-T high-quality MRI approaches 68Ga-PSMA PET/CT was performed in the detection of bone metastasis on patient-based level (sensitivity, 0.94 vs. 0.91; specificity, 0.94 vs. 0.96; superiority index, 4.43 vs. 4.56).

Conclusions

68Ga-PSMA PET/CT is recommended for the diagnosis of bone metastasis in prostate cancer patients. Where available, 3.0-T high-quality MRI approaches 68Ga-PSMA PET/CT should be performed in the detection of bone metastasis.
High Expression of PAMR1 Predicts Favorable Prognosis and Inhibits Proliferation, Invasion, and Migration in Cervical Cancer
Authors: Yang Rui , Ma Mingjun , Yu Sihui , Li Xi , Zhang Jiawen , Wu Sufang
Published: October 2021

Peptidase domain containing associated with muscle regeneration 1 (PAMR1) is frequently lost in breast cancer samples and is considered as a tumor suppressor. The roles and mechanisms of PAMR1 in other types of cancers are still unclear. In our present study, we identified PAMR1 as an invasion-related regulator in cervical cancer. Public database and immunohistochemical (IHC) analysis showed that the expression level of PAMR1 in cervical cancer tissues was lower than that in normal cervix tissues and was negatively related to clinicopathologic features. The high expression of PAMR1 also predicted a better prognosis of cervical cancer patients. CCK8, Transwell, and wound-healing assays demonstrated that knockdown of PAMR1 facilitated the proliferation, migration, and invasion of cervical cancer cells. Additionally, gene set enrichment analysis (GSEA) showed a variety of cancer-related pathways potentially activated or suppressed by PAMR1. Moreover, we verified that PAMR1 inhibited MYC target and mTORC1 signaling pathways. In conclusion, our study revealed the suppressor role of PAMR1 in cervical cancer, providing a new insight into the molecular mechanism of cervical cancer progression.
The Clinical Implications and Molecular Mechanism of CX3CL1 Expression in Urothelial Bladder Cancer
Authors: Jiang Guangliang , Wang Hui , Huang Da , Wu Yishuo , Ding Weihong , Zhou Qidong , Ding Qiang , Zhang Ning , Na Rong , Xu Ke
Published: October 2021

Background

CX3CL1 is a chemokine that may play important roles in cancer immune regulation. Its mechanism in bladder cancer (BCa) is poorly understood. The objective of the current study was to evaluate the association between CX3CL1 and BCa and the related biological mechanisms.

Methods

A total of 277 patients with BCa were enrolled in the present study. The association between CX3CL1 expression and disease outcome was evaluated. In vitro and in vivo experiments were performed using the TCCSUP cell line to investigate the function of CX3CL1 in BCa.

Results

Compared with low expression, high expression of CX3CL1 was significantly associated with poorer progression-free survival (hazard ratio [HR]=2.03, 95% confidence interval [95% CI]: 1.26-3.27, P=0.006), cancer-specific survival (HR=2.16, 95% CI: 1.59-2.93, P<0.001), and overall survival (HR=1.55, 95% CI: 1.08-2.24, P=0.039). Multivariable Cox regression analysis suggested that CX3CL1 was an independent prognostic factor for BCa outcomes. In vitro and in vivo experiments indicated that high expression of CX3CL1 was significantly associated with cell proliferation (P<0.001) and invasion (P<0.001). Gene expression profiling results showed that after CX3CL1 knockdown, CDH1 was significantly upregulated, while ETS1, RAF1, and EIF4E were significantly downregulated. Pathway enrichment analysis suggested that the ERK/MAPK signaling pathway was significantly inhibited (P<0.001).

Conclusions

CX3CL1 is an independent predictor of a poor prognosis in BCa and can promote the proliferation and invasion of BCa cells.
The Association of Real-World CA 19-9 Level Monitoring Patterns and Clinical Outcomes Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma
Authors: George Ben , Kent Matthew , Surinach Andy , Lamarre Neil , Cockrum Paul
Published: October 2021

Background

Pancreatic cancer is expected to be the third deadliest cancer in the US in 2021. Evaluation of treatment response in patients with mPDAC necessitates scheduled clinical and radiographic assessments along with monitoring serum CA 19-9 levels. Currently available single-institution data examining the importance of CA 19-9 monitoring cannot be generalized to real-world settings. We investigated the impact of serum CA 19-9 monitoring and its association with clinical outcomes in patients with mPDAC in a population-based setting.

Methods

Data were extracted from the Flatiron Health electronic health record (EHR)-derived de-identified database for patients diagnosed with mPDAC between January 1, 2015, and June 30, 2020. Serum CA 19-9 levels at baseline – defined as the values obtained ≤ 60 days prior to treatment initiation - and during treatment were extracted. CA 19-9 levels > 40 IU/mL were considered elevated. Survival outcomes were compared based on testing frequency, baseline CA 19-9 levels, and change in CA 19-9.

Results

6,118 patients with mPDAC who received treatment were included in the analysis. The median age at diagnosis was 68 years (IQR: 61-75). Patients with normal baseline CA 19-9 experienced longer median survival than patients with elevated levels [1L: 8.8 months (95% CI: 7.9 - 10) vs. 7.2 months (6.8 – 7.5), p < 0.001; 2L: 7.2 months (6.1 – 9.2) vs. 5.2 months (4.9 – 5.6), p < 0.001; 3L: 6.1 months (5.4 – 9.1) vs. 3.9 months (3.4 – 4.3), p < 0.001]. Patients with decreasing/stable CA 19-9 during treatment experienced longer survival than patients who experienced an increase in CA 19-9 levels [1L: 10.9 months (10.5 – 11.3) vs. 5.4 months (5.1 – 5.9), p < 0.0001; 2L: 8.2 months (7.7 – 8.5) vs. 4.3 months (4.1 – 4.7), p < 0.001; 3L: 7.5 months (6.6 – 9.2) vs. 3.7 months (3.4 – 4.3), p < 0.001].

Conclusions

In one of the largest, contemporary, real-world studies of patients with mPDAC, elevated CA 19-9 level at treatment initiation demonstrated a prognostic impact. Routine serial monitoring of CA 19-9 levels during treatment may be warranted, in addition to clinical and radiographic assessment, and may translate into better patient outcomes. Further validation studies are needed to understand the generalizability of these results.
SPRY4-AS1, A Novel Enhancer RNA, Is a Potential Novel Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma
Authors: Ye Mu , Wang Sheng , Qie Jing-bo , Sun Pei-long
Published: October 2021

A growing number of evidence have demonstrated the involvement of enhancer RNAs (eRNAs) in tumor progression. However, the possible functions of eRNAs in hepatocellular carcinoma (HCC) remain largely unclear. Our present research aimed to screen critical eRNAs and to further delve into the clinical significance of eRNAs in HCC patients. In this study, we identified 124 prognosis-related eRNAs by analyzing The Cancer Genome Atlas (TCGA) datasets. Among them, SPRY4 antisense RNA 1 (SPRY4-AS1) may be a key eRNA involved in HCC progression. SPRY4 was a regulatory target of SPRY4-AS1. High SPRY4-AS1 expression was associated with poor prognosis of HCC patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) assays revealed that the mainly enriched biological process included Human papillomavirus infection, Hippo signaling pathway, and Proteoglycans in cancer. Besides, RT-PCR and immunohistochemical staining confirmed SPRY4-AS1 as an overexpressed eRNA in HCC specimens. The pan-cancer assays revealed that SPRY4-AS1 was associated with glioblastoma multiforme (GBM), adrenocortical carcinoma (ACC), brain lower grade glioma (LGG) and mesothelioma(MESO). Positive associations were observed between SPRY4-AS1 and SPRY4 (its target gene) in 16 tumor types. Collectively, our findings reveal a novel eRNA SPRY4-AS1 for HCC progression and suggest that SPRY4-AS1 may be a potential biomarker and therapeutic target for HCC.
Feasibility and Challenges of Performing Magnetoencephalography Experiments in Children With Arthrogryposis Multiplex Congenita
Authors: Golosheykin Semyon A. , Blagoveschenskiy Evgueni D. , Agranovich Olga E. , Nazarova Maria A. , Nikulin Vadim V. , Moiseenko Olesya E. , Chan Russell W. , Shestakova Anna N.
Published: October 2021

Arthrogryposis multiplex congenita (AMC) has recently drawn substantial attention from researchers and clinicians. New effective surgical and physiotherapeutic methods have been developed to improve the quality of life of patients with AMC. While it is clear that all these interventions should strongly rely on the plastic reorganization of the central nervous system, almost no studies have investigated this topic. The present study demonstrates the feasibility of using magnetoencephalography (MEG) to investigate brain activity in young AMC patients. We also outlined the general challenges and limitations of electrophysiological investigations on patients with arthrogryposis. We conducted MEG recordings using a 306-channel Elekta Neuromag VectorView system during a cued motor task performance in four patients with arthrogryposis, five normally developed children, and five control adults. Following the voice command of the experimenter, each subject was asked to bring their hand toward their mouth to imitate the self-feeding process. Two patients had latissimus dorsi transferred to the biceps brachii position, one patient had a pectoralis major transferred to the biceps brachii position, and one patient had no elbow flexion restoration surgery before the MEG investigation. Three patients who had undergone autotransplantation prior to the MEG investigation demonstrated activation in the sensorimotor area contralateral to the elbow flexion movement similar to the healthy controls. One patient who was recorded before the surgery demonstrated subjectively weak distributed bilateral activation during both left and right elbow flexion. Visual inspection of MEG data suggested that neural activity associated with motor performance was less pronounced and more widely distributed across the cortical areas of patients than of healthy control subjects. In general, our results could serve as a proof of principle in terms of the application of MEG in studies on cortical activity in patients with AMC. Reported trends might be consistent with the idea that prolonged motor deficits are associated with more difficult neuronal recruitment and the spatial heterogeneity of neuronal sources, most likely reflecting compensatory neuronal mechanisms. On the practical side, MEG could be a valuable technique for investigating the neurodynamics of patients with AMC as a function of postoperative abilitation.