bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the ability of fatty acid metabolism signature to predict response to neoadjuvant chemoradiotherapy and prognosis of patients with locally advanced rectal cancer
Authors: Zhou Han , Chen Yanping , Xiao Yu , Wu Qian , Li Hui , Li Yi , Su Guangjian , Ke Longfeng , Wu Junxin , Li Jinluan
Published: November 2022

Neoadjuvant chemoradiotherapy (nCRT) is widely used to treat patients with locally advanced rectal cancer (LARC), and treatment responses vary. Fatty acid metabolism (FAM) is closely associated with carcinogenesis and cancer progression. In this study, we investigated the vital role of FAM on the gut microbiome and metabolism in the context of cancer. We screened 34 disease-free survival (DFS)-related, FAM-related, and radiosensitivity-related genes based on the Gene Expression Omnibus database. Subsequently, we developed a five-gene FAM-related signature using the least absolute shrinkage and selection operator Cox regression model. The FAM-related signature was also validated in external validation from Fujian Cancer Hospital for predicting nCRT response, DFS, and overall survival (OS). Notably, patients with a low-risk score were associated with pathological complete response and better DFS and OS outcomes. A comprehensive evaluation of the tumor microenvironment based on the FAM-related signature revealed that patients with high-risk scores were closely associated with activating type I interferon response and inflammation-promoting functions. In conclusion, our findings indicate the potential ability of FAM to predict nCRT response and the prognosis of DFS and OS in patients with LARC.
Pro-resolving and anti-arthritic properties of the MC1 selective agonist PL8177
Authors: Garrido-Mesa Jose , Thomas Bethan Lynne , Dodd John , Spana Carl , Perretti Mauro , Montero-Melendez Trinidad
Published: November 2022

Background

Melanocortins are peptides endowed with anti-inflammatory and pro-resolving activities. Many of these effects are mediated by the Melanocortin receptor 1 (MC1) as reported in several experimental settings. As such, MC1 can be a viable target for the development of new therapies that mimic endogenous pro-resolving mediators. The aim of this study was to assess the immunopharmacology of a selective MC1 agonist (PL8177) in vitro and in a mouse model of inflammatory arthritis.

Methods

PL8177 and the natural agonist αMSH were tested for activation of mouse and human Melanocortin receptors (MC1,3,4,5), monitoring cAMP accumulation and ERK1/2 phosphorylation, using transiently transfected HEK293A cells. The anti-inflammatory and pro-resolving effects of PL8177 and αMSH were evaluated using mouse peritoneal Macrophages. Finally, a model of K/BxN serum transfer induced arthritis was used to determine the in vivo potential of PL8177.

Results

PL8177 activates mouse and human MC1 with apparent EC50 values of 0.01 and 1.49 nM, respectively, using the cAMP accumulation assay. Similar profiles were observed for the induction of ERK phosphorylation (EC50: 0.05 and 1.39 nM). PL8177 displays pro-resolving activity (enhanced Macrophage efferocytosis) and counteracts the inflammatory profile of zymosan-stimulated macrophages, reducing the release of IL-1β, IL-6, TNF-α and CCL-2. In the context of joint inflammation, PL8177 (3mg/kg i.p.) reduces clinical score, paw swelling and incidence of severe disease as well as the recruitment of immune cells into the arthritic joint.

Conclusion

These results demonstrate that the MC1 agonism with PL8177 affords therapeutic effects in inflammatory conditions including arthritis.

Significance

Drugs targeting the Melanocortin system have emerged as promising therapeutics for several conditions including inflammation or obesity. Multiple candidates are under clinical development, and some have already reached approval. Here we present the characterization of a novel drug candidate, PL8177, selective for the Melanocortin 1 receptor (MC1), demonstrating its selectivity profile on cAMP and ERK1/2 phosphorylation signaling pathways, of relevance as selective drugs will translate into lesser off-target effect. PL8177 also demonstrated, not only anti-inflammatory activity, but pro-resolving actions due to its ability to enhance efferocytosis (i.e. the phagocytosis of apoptotic cells), endowing this molecule with therapeutic advantages compared to classical anti-inflammatory drugs. Using a mouse model of inflammatory arthritis, the compound demonstrated in vivo efficacy by reducing clinical score, paw swelling and overall disease severity. Taken together, these results present Melanocortin-based therapies, and specifically targeting MC1 receptor, as a promising strategy to manage chronic inflammatory diseases.
Connectivity patterns of Brazilian coral reefs associated with potential variation on thermal stress tolerance
Authors: Silva Gabriel Lucas Xavier da , Kampel Milton
Published: November 2022

The rising trend in sea surface temperature presents a threat to tropical coral reefs, causing increased mass bleaching and mortality events. Brazilian reefs have been characterized as less susceptible to thermal stress, where the assessment of bleaching events based on temperature anomalies often overpredicts its actual occurrences in comparison with other regions of the global ocean. With coral reefs acclimatized to local environmental conditions, larval connectivity presents a potential role in introducing organisms adapted to different temperature conditions. In the present study, we evaluated the connectivity patterns of Brazilian coral reefs, verifying its potential influence on the variation of thermal stress tolerance supported by these communities. Connectivity was estimated based on 27-year larval dispersion simulations, from 1993 to 2019, among 180 reef sites distributed in seven ecoregions on the Brazilian continental margin. Simulations were performed using a biophysical model coupling ocean currents data and life history traits of Mussismilia hispida, a widespread stony-coral type species and one of the major endemic reef builders in the South Atlantic. The potential influence of larval connectivity on thermal stress tolerance was evaluated considering the probability of connections between each reef site, their respective bleaching thresholds, and the accumulation of sea surface temperature anomalies over 12-week periods. The results indicated that connectivity-influenced bleaching estimations were significantly closer to observations reported in the literature when compared to estimations without connectivity (p-value < 0.05). These findings present an evidence that larval connectivity may display a relevant role in the adaptation of Brazilian corals to changes in seawater temperature, leading to a potential variation of ± 0.3°C in local thermal stress thresholds. Different connectivity patterns assessed during the occurrence of El Niño–Southern Oscillation events were also observed in association with the migrations of the South Equatorial Current bifurcation. These conditions led to the disruption of connections between the Eastern and Northeastern reef sites during El Niño, and between the Northeastern and Amazon reef sites during La Niña. Ultimately, it is expected that those findings may contribute to the management of Brazilian coral reefs regarding changes in dispersal pathways and thermal stress tolerance given future climate change scenarios.
Modified kinetic energy feature-based graph convolutional network for fish appetite grading using time-limited data in aquaculture
Authors: Wei Dan , Ji Baimin , Li Haijun , Zhu Songming , Ye Zhangying , Zhao Jian
Published: November 2022

Feed has the greatest impact on the carbon footprint of the aquaculture, and also determines the water quality in aquaculture to a great extent. Making appropriate feeding control strategies is one of the most effective ways to promote cleaner production as well as fish welfare in aquaculture. Reliable and accurate fish appetite grading especially based on time-limited data is a prerequisite for achieving high-precision and reasonable feeding control in practical production. To date, however, few efforts have been done on this challenge. For these, regarding Micropterus salmoides as the experimental fish, a novel and practical method, based on a modified kinetic energy feature-based graph convolutional network (GCN), was developed in this study. First, graphs were constructed based on the extracted modified kinetic energy features and their temporal correlation. Then, with the help of a series of the convolution and global pooling operations, a GCN model was customized based on the constructed graphs. Following this, the customized GCN model was enriched by the self-attention pooling mechanism and customized network structure. Results show that the proposed GCN-based approach outperforms other typical state-of-the-art methods in fish appetite grading, and the grading accuracy obtained here could be 98.60% using only the first 4.2 seconds as well as the first 8.3 seconds of input data, which is not much different from that (98.89%) using full-length (25 second-long) input data. What’s more, compared to the recurrent neural network (RNN)-based method which performance is closest to our method, the space complexity of the proposed approach here can better satisfy the requirements of real aquaculture, in which the quantity of the trainable parameters here is only 6.4% ~ 31.8% of the RNN-based method. In summary, the proposed modified kinetic energy feature-based GCN approach is favorable for the appetite grading of fish like Micropterus salmoides with time-limited data, which is a promising approach in dealing with feeding control tasks and alleviating the water environmental burden in aquaculture.
Observing the spread of Agulhas Leakage into the Western South Atlantic by tracking mode waters within ocean rings
Authors: Guerra Luiz Alexandre A. , Mill Guilherme N. , Paiva Afonso M.
Published: November 2022

The Agulhas rings transport warm and salty waters that feed the surface limb of the Atlantic Meridional Overturning Circulation. Some studies have focused on the conveying capacity of ocean eddies, and recently, the role of the Agulhas rings in advecting water masses and organisms has been explored. Here we show evidence that the Agulhas rings are responsible for the advection of mode waters from the Cape Basin to the western side of the Atlantic. We analyzed more than 3,200 temperature profiles and 2,400 salinity profiles from historical databases collocated with 52 long-lived Agulhas rings tracked from 1993 through 2016. An automated algorithm was used to identify thermostads in the profiles acquired within the rings. The data revealed mode water layers trapped inside 88% of the rings. The joint distribution of temperature and salinity indicated two types of mode waters in the range 16.2 ± 0.6°C, 35.6 ± 0.1 (Type I) and 12.9 ± 0.7°C, 35.2 ± 0.1 (Type II). The majority (67%) of the rings carrying mode waters had both types detected inside. Moreover, considering only those rings sampled west of the Mid-Atlantic Ridge, we found that 45% of them advected mode waters to the western basin. Therefore, our results demonstrate that, despite the long journey, interaction with the bottom topography and other vortices, ocean-atmosphere exchanges, and decay, the Agulhas rings are responsible for spreading mode waters initially available at the Cape Basin throughout the South Atlantic, contributing to a positive anomaly in temperature and salinity along the eddy corridor joining the Cape Basin to the Brazil Basin.
Carbon fiber-reinforced epoxy with 100% fiber recycling by transesterification reactions
Authors: Wu Jianqiao , Pan Ying , Ruan Ziyi , Zhao Ziji , Ai Jing , Ban Jinghai , Jing Xianghai
Published: November 2022

Carbon fiber (CF)-reinforced epoxy is the most commonly used advanced composite with high performance. However, these composites usually face intractable disposal problems in their lifecycles, due to the stable cross-linked network structures of epoxy. To address this dilemma, this work proposes a facile yet efficient strategy for recycling carbon fibers from traditional carbon fiber-reinforced epoxy composites using epoxy–anhydride systems as a matrix. Diglycidyl ester of aliphatic cyclo (DGEAC) and methylhexahydrophthalic anhydride (MHHPA) were used as matrix, while T300 woven carbon fiber was used as reinforcement, to construct the composites CF/DGEAC/MHHPA. The epoxy matrix exhibited a high glass transition temperature (Tg = 126°C), high decomposition temperature (Td5 = 300°C), and good solvent resistance. By using 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as a catalyst, the DGEAC/MHHPA networks could be degraded completely in ethylene glycol (EG) at 180°C within 6 h because of transesterification reactions between EG and the networks. Taking advantage of this result, a fiber recycling process was developed for carbon fiber composites, where the cross-linked networks of epoxy could be degraded with 100% carbon fiber recycling. Furthermore, the recycled carbon fiber maintained nearly 100% similarity in surface microscopic morphology and chemical structure compared with virgin carbon fiber. This work proposes a simple and efficient strategy for recycling carbon fiber from traditional high-performance composites, offering a convenient concept for the cyclic utilization of advanced composites.
Tigecycline in the treatment of severe pneumonia caused by Chlamydia psittaci: A case report and literature review
Authors: Liu Jiaming , Gao Yuan
Published: November 2022

Psittacosis is a zoonotic disease caused by Chlamydia psittaci. Systemic infections are mainly transmitted through the respiratory tract. The most common related disease is human atypical pneumonia, which is a rare pathogen of community-acquired pneumonia. Due to the difficulty of diagnosis, there have been few reports of C. psittaci pneumonia in the past. In recent years, with the widespread application of metagenomic next-generation sequencing (mNGS), the number of reported cases of C. psittaci has increased year by year. However, at present, most hospitals have little understanding of C. psittaci, especially for severe patients, and lack experience in diagnosis and treatment. Herein, we report the case of a 71-year-old woman with severe pneumonia that caused by C. psittaci. This patient was diagnosed through mNGS and was treated with tigecycline successfully. The level of IL-6 in the BALF was significantly increased. We discontinued tigecycline after mNGS of the blood was negative. In this review, we analyzed 53 cases to summarize the etiology, clinical manifestations, diagnosis and treatment strategies of severe C. psittaci pneumonia and hope to raise clinicians’ awareness of this disease.
Clinicopathologic and genomic characterizations of brain metastases using a comprehensive genomic panel
Authors: Barakeh Duna H. , Alsolme Ebtehal , Alqubaishi Fatimah , Almutairi Amal , Alhabeeb Lamees , Al Abdulmohsen Sally , Almohsen Shahd S. , Alayed Doaa , AlAnazi Sara Rashid , AlZahrani Malak , Binowayn Albandari Mohammed , AlOtaibi Sarah S. , Alkhureeb Fahad A. , Al Shakweer Wafa , Al-Hindi Hindi , Alassiri Ali , Robinson Heather A. , Abedalthagafi Malak
Published: November 2022

Central nervous system (CNS) metastasis is the most common brain tumor type in adults. Compared to their primary tumors, these metastases undergo a variety of genetic changes to be able to survive and thrive in the complex tissue microenvironment of the brain. In clinical settings, the majority of traditional chemotherapies have shown limited efficacy against CNS metastases. However, the discovery of potential driver mutations, and the development of drugs specifically targeting affected signaling pathways, could change the treatment landscape of CNS metastasis. Genetic studies of brain tumors have so far focused mainly on common cancers in western populations. In this study, we performed Next Generation Sequencing (NGS) on 50 pairs of primary tumors, including but not limited to colorectal, breast, renal and thyroid tumors, along with their brain metastatic tumor tissue counterparts, from three different local tertiary centers in Saudi Arabia. We identified potentially clinically relevant mutations in brain metastases that were not detected in corresponding primary tumors, including mutations in the PI3K, CDK, and MAPK pathways. These data highlight the differences between primary cancers and brain metastases and the importance of acquiring and analyzing brain metastatic samples for further clinical management.
Efficacy of finafloxacin in a murine model of inhalational glanders
Authors: Barnes Kay B. , Bayliss Marc , Davies Carwyn , Richards Mark I. , Laws Thomas R. , Vente Andreas , Harding Sarah V.
Published: November 2022

Burkholderia mallei, the causative agent of glanders, is principally a disease of equines, although it can also infect humans and is categorized by the U.S. Centers for Disease Control and Prevention as a category B biological agent. Human cases of glanders are rare and thus there is limited information on treatment. It is therefore recommended that cases are treated with the same therapies as used for melioidosis, which for prophylaxis, is co-trimoxazole (trimethoprim/sulfamethoxazole) or co-amoxiclav (amoxicillin/clavulanic acid). In this study, the fluoroquinolone finafloxacin was compared to co-trimoxazole as a post-exposure prophylactic in a murine model of inhalational glanders. BALB/c mice were exposed to an aerosol of B. mallei followed by treatment with co-trimoxazole or finafloxacin initiated at 24 h post-challenge and continued for 14 days. Survival at the end of the study was 55% or 70% for mice treated with finafloxacin or co-trimoxazole, respectively, however, this difference was not significant. However, finafloxacin was more effective than co-trimoxazole in controlling bacterial load within tissues and demonstrating clearance in the liver, lung and spleen following 14 days of therapy. In summary, finafloxacin should be considered as a promising alternative treatment following exposure to B. mallei.
Tracking the phage trends: A comprehensive review of applications in therapy and food production
Authors: Jaglan Anu Bala , Anand Taruna , Verma Ravikant , Vashisth Medhavi , Virmani Nitin , Bera B. C. , Vaid R. K. , Tripathi B. N.
Published: November 2022

In the present scenario, the challenge of emerging antimicrobial resistance is affecting human health globally. The increasing incidences of multidrug-resistant infections have become harder to treat, causing high morbidity, and mortality, and are posing extensive financial loss. Limited discovery of new antibiotic molecules has further complicated the situation and has forced researchers to think and explore alternatives to antibiotics. This has led to the resurgence of the bacteriophages as an effective alternative as they have a proven history in the Eastern world where lytic bacteriophages have been used since their first implementation over a century ago. To help researchers and clinicians towards strengthening bacteriophages as a more effective, safe, and economical therapeutic alternative, the present review provides an elaborate narrative about the important aspects of bacteriophages. It abridges the prerequisite essential requirements of phage therapy, the role of phage biobank, and the details of immune responses reported while using bacteriophages in the clinical trials/compassionate grounds by examining the up-to-date case reports and their effects on the human gut microbiome. This review also discusses the potential of bacteriophages as a biocontrol agent against food-borne diseases in the food industry and aquaculture, in addition to clinical therapy. It finishes with a discussion of the major challenges, as well as phage therapy and phage-mediated biocontrols future prospects.
Latency-associated upregulation of SERBP1 is important for the recruitment of transcriptional repressors to the viral major immediate early promoter of human cytomegalovirus during latent carriage
Authors: Poole Emma , Sinclair John
Published: November 2022

Suppression of human cytomegalovirus (HCMV) major immediate early gene (IE) expression from the viral major immediate early promoter (MIEP) is known to be crucial for the establishment and maintenance of HCMV latency in myeloid progenitor cells and their undifferentiated derivatives. This suppression of the MIEP during latent infection is known to result from epigenetic histone modification imparting a repressive chromatin structure around the MIEP in undifferentiated myeloid cells. In contrast, reactivation, resulting from, e.g., myeloid cell differentiation, is associated with activatory chromatin marks around the MIEP. Recently, recruitment of the transcriptional repressor SETDB1, via KAP1, to latent HCMV genomes was shown to be involved in latency-associated MIEP suppression in CD34+ progenitor cells. KAP1 is also known to associate with Chromodomain-helicase-DNA-binding protein 3 (CHD3) as part of the NuRD complex which can aid transcriptional silencing. We now show that the cellular protein Plasminogen activator inhibitor 1 RNA-binding protein (SERBP1), a known interactor of CHD3, is significantly upregulated during HCMV latency and that this protein is required for MIEP suppression during latent infection of myeloid cells. We further show that SERBP1 mediates CHD3 association with the MIEP as well as KAP1 association with viral genomic DNA. We suggest that SERBP1 functions as a scaffold protein to recruit transcriptional repressors to the latent viral genome and to mediate transcriptional silencing of the MIEP during latent carriage.
Beneficial effects of bempedoic acid treatment in polycystic kidney disease cells and mice
Authors: Hallows Kenneth R. , Li Hui , Saitta Biagio , Sepehr Saman , Huang Polly , Pham Jessica , Wang Jonathan , Mancino Valeria , Chung Eun Ji , Pinkosky Stephen L. , Pastor-Soler Núria M.
Published: November 2022

ADPKD has few therapeutic options. Tolvaptan slows disease but has side effects limiting its tolerability. Bempedoic acid (BA), an ATP citrate-lyase (ACLY) inhibitor FDA-approved for hypercholesterolemia, catalyzes a key step in fatty acid/sterol synthesis important for cell proliferation. BA is activated by very long-chain acyl-CoA synthetase (FATP2) expressed primarily in kidney and liver. BA also activates AMPK. We hypothesized that BA could be a novel ADPKD therapy by inhibiting cyst growth, proliferation, injury, and metabolic dysregulation via ACLY inhibition and AMPK activation. Pkd1-null kidney cell lines derived from mouse proximal tubule (PT) and collecting duct (IMCD) were grown in 2D or 3D Matrigel cultures and treated ± BA, ± SB-204990 (another ACLY inhibitor) or with Acly shRNA before cyst analysis, immunoblotting or mitochondrial assays using MitoSox and MitoTracker staining. Pkd1fl/fl; Pax8-rtTA; Tet-O-Cre C57BL/6J mice were induced with doxycycline injection on postnatal days 10 and 11 (P10-P11) and then treated ± BA (30 mg/kg/d) ± tolvaptan (30–100 mg/kg/d) by gavage from P12-21. Disease severity was determined by % total-kidney-weight-to-bodyweight (%TKW/BW) and BUN levels at euthanasia (P22). Kidney and liver homogenates were immunoblotted for expression of key biomarkers. ACLY expression and activity were upregulated in Pkd1-null PT and IMCD-derived cells vs. controls. Relative to controls, both BA and SB-204990 inhibited cystic growth in Pkd1-null kidney cells, as did Acly knockdown. BA inhibited mitochondrial superoxide production and promoted mitochondrial elongation, suggesting improved mitochondrial function. In ADPKD mice, BA reduced %TKW/BW and BUN to a similar extent as tolvaptan vs. untreated controls. Addition of BA to tolvaptan caused a further reduction in %TKW/BW and BUN vs. tolvaptan alone. BA generally reduced ACLY and stimulated AMPK activity in kidneys and livers vs. controls. BA also inhibited mTOR and ERK signaling and reduced kidney injury markers. In liver, BA treatment, both alone and together with tolvaptan, increased mitochondrial biogenesis while inhibiting apoptosis. We conclude that BA and ACLY inhibition inhibited cyst growth in vitro, and BA decreased ADPKD severity in vivo. Combining BA with tolvaptan further improved various ADPKD disease parameters. Repurposing BA may be a promising new ADPKD therapy, having beneficial effects alone and along with tolvaptan.
Water-soluble trehalose glycolipids show superior Mincle binding and signaling but impaired phagocytosis and IL-1β production
Authors: Manthrirathna M. A. Thathsaranie P. , Dangerfield Emma M. , Ishizuka Shigenari , Woods Aodhamair , Luong Brenda S. , Yamasaki Sho , Timmer Mattie S. M. , Stocker Bridget L.
Published: November 2022

The tremendous potential of trehalose glycolipids as vaccine adjuvants has incentivized the study of how the structures of these ligands relate to their Mincle-mediated agonist activities. Despite this, structure-activity work in the field has been largely empirical, and less is known about how Mincle-independent pathways might be affected by different trehalose glycolipids, and whether Mincle binding by itself can serve as a proxy for adjuvanticity. There is also much demand for more water-soluble Mincle ligands. To address this need, we prepared polyethylene glycol modified trehalose glycolipids (PEG-TGLs) with enhanced water solubility and strong murine Mincle (mMincle) binding and signaling. However, only modest cytokine and chemokine responses were observed upon the treatment of GM-CSF treated bone-marrow cells with the PEG-TGLs. Notability, no IL-1β was observed. Using RNA-Seq analysis and a representative PEG-TGL, we determined that the more water-soluble adducts were less able to activate phagocytic pathways, and hence, failed to induce IL-1β production. Taken together, our data suggests that in addition to strong Mincle binding, which is a pre-requisite for Mincle-mediated cellular responses, the physical presentation of trehalose glycolipids in colloidal form is required for inflammasome activation, and hence, a strong inflammatory immune response.
The amygdala–insula–medial prefrontal cortex–lateral prefrontal cortex pathway and its disorders
Authors: Ben Shalom Dorit
Published: November 2022

Smith and Lane have suggested a model of emotion processing with at least three stations: areas like the amygdala, which process discrete body features areas like the anterior insula, which process whole-body patterns and areas like the medial prefrontal cortex, which process emotion concepts. Ben Shalom and Bonneh have suggested a model of the prefrontal cortex, in which medial BA 9 integrates emotional states, and lateral BA 9 performs selection/inhibition on these states. Taken together, the current paper suggests a pathway for emotion processing with at least four stations: areas like the amygdala, which process discrete body features areas like the anterior insula, which process whole-body patterns, medial BA 9 which integrates emotion concepts, and lateral BA 9, which performs selection/inhibition on these concepts. Following the existing literature, it then suggest that there is a significant involvement of the amygdala in psychopathy (Blair), of the anterior insula in alexithymia (Bird), of the medial BA 9 in deficits in somatosensory discrimination (Ben Shalom), and of lateral BA 9 in emotional impulsivity (Ronel).
Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice
Authors: Sun Xiuping , Li Xianglei , Zhang Ling , Zhang Yu , Qi Xiaolong , Wang Siyuan , Qin Chuan
Published: November 2022

Introduction

Despite the widespread use of the unilateral striatal 6-hydroxydopamine (6-OHDA) lesion model in mice in recent years, the stability of behavioral deficits in the 6-OHDA striatal mouse model over time is not yet clear, raising concerns about using this model to evaluate a compound’s long-term therapeutic effects.

Materials and methods

In the current study, mice were tested at regular intervals in the cylinder test and gait analysis beginning 3 days after 6-OHDA injection of 4 and 8 μg and lasting until 56 days post-lesion. Apomorphine-induced rotational test and rotarod test were also performed on Day 23 and 43 post-lesion, respectively. Immunohistochemistry for dopaminergic neurons stained by tyrosine hydroxylase (TH) was also performed.

Results

Our results showed that both the 4 and 8 μg 6-OHDA lesion groups exhibited forelimb use asymmetry with a preference for the ipsilateral (injection) side on Day 3 and until Day 21 post-lesion, but did not show forelimb asymmetry on Day 28 to 56 post-lesion. The 8 μg 6-OHDA lesion group still exhibited forelimb asymmetry on Day 28 and 42 post-lesion, but not on Day 56. The gait analysis showed that the contralateral front and hind step cycles increased from Day 3 to 42 post-lesion and recovered on Day 56 post-lesion. In addition, our results displayed a dose-dependent reduction in TH+ cells and TH+ fibers, as well as dose-dependent apomorphine-induced rotations. In the rotarod test, the 8 μg 6-OHDA lesion group, but not the 4 μg group, decreased the latency to fall on the rotarod on Day 43 post-lesion.

Conclusion

In summary, unilateral striatal 6-OHDA injections of 4 and 8 μg induced spontaneous motor impairment in mice, which partially recovered starting on Day 28 post-lesion. Forced motor deficits were observed in the 8 g 6-OHDA lesion group, which remained stable on Day 43 post-lesion. In addition, the rotarod test and apomorphine-induced rotational test can distinguish between lesions of different extents and are useful tools for the assessment of functional recovery in studies screening novel potential therapies.
Structure and activity alteration in adult highland residents' cerebrum: Voxel-based morphometry and amplitude of low-frequency fluctuation study
Authors: Zhong Minzhi , Zeng Huaqu , Wang Dongye , Li Jiesheng , Duan Xuguang , Li Yong
Published: November 2022

Introduction

People living in highland areas may have factors that allow them to adapt to chronic hypoxia, but these physiological mechanisms remain unclear. This study aimed to investigate the brain mechanism in a cohort of adult residents of Tibet, a well-known plateau section in China, by observing differences in brain structure and function in non-plateau populations.

Methods

The study included 27 Tibetan and 27 non-plateau region residents who were matched in age, sex, and education. All participants underwent high-resolution three-dimensional T1 weighted imaging (3D-T1WI) and resting-state functional magnetic resonance imaging (rs-fMRI) scans on a 1.5 Tesla MR. Gray matter volumes and regional spontaneous neuronal activity (SNA) were calculated and compared between the two groups.

Results

When comparing gray matter in people living in high altitudes to those living in the flatlands, the results showed positive activation of gray matter in local brain regions (p < 0.05, false discovery rate (FDR) corrected), in the right postcentral [automated atomic labeling (aal)], left postcentral (aal), and right lingual (aal) regions. Comparing the people of high altitude vs. flat land in the brain function study (p < 0.05, FDR corrected), positive activation was found in the right superior motor area (aal) and left superior frontal (aal), and negative activation was found in the right precuneus (aal).

Conclusion

In high-altitude individuals, larger regional gray matter volumes and higher SNA may represent a compensatory mechanism to adapt to chronic hypoxia.
Spinal cord dorsal horn sensory gate in preclinical models of chemotherapy-induced painful neuropathy and contact dermatitis chronic itch becomes less leaky with Kcc2 gene expression-enhancing treatments
Authors: Yeo Michele , Zhang Qiaojuan , Ding LeAnne , Shen Xiangjun , Chen Yong , Liedtke Wolfgang
Published: November 2022

Low intraneuronal chloride in spinal cord dorsal horn (SCDH) pain relay neurons is of critical relevance for physiological transmission of primary sensory afferents because low intraneuronal chloride dictates GABA-ergic and glycin-ergic neurotransmission to be inhibitory. If neuronal chloride rises to unphysiological levels, the primary sensory gate in the spinal cord dorsal horn becomes corrupted, with resulting behavioral hallmarks of hypersensitivity and allodynia, for example in pathological pain. Low chloride in spinal cord dorsal horn neurons relies on the robust gene expression of Kcc2 and sustained transporter function of the KCC2 chloride-extruding electroneutral transporter. Based on a recent report where we characterized the GSK3-inhibitory small molecule, kenpaullone, as a Kcc2 gene expression-enhancer that potently repaired diminished Kcc2 expression and KCC2 transporter function in SCDH pain relay neurons, we extend our recent findings by reporting (i) effective pain control in a preclinical model of taxol-induced painful peripheral neuropathy that was accomplished by topical application of a TRPV4/TRPA1 dual-inhibitory compound (compound 16-8), and was associated with the repair of diminished Kcc2 gene expression in the SCDH; and (ii) potent functioning of kenpaullone as an antipruritic in a DNFB contact dermatitis preclinical model. These observations suggest that effective peripheral treatment of chemotherapy-induced painful peripheral neuropathy impacts the pain-transmitting neural circuit in the SCDH in a beneficial manner by enhancing Kcc2 gene expression, and that chronic pruritus might be relayed in the primary sensory gate of the spinal cord, following similar principles as pathological pain, specifically relating to the critical functioning of Kcc2 gene expression and the KCC2 transporter function.
Association between tea consumption and prevention of coronary artery disease: A systematic review and dose-response meta-analysis
Authors: Yang Xin , Dai Haiyun , Deng Ruihang , Zhang Ziang , Quan Yiwen , Giri Mohan , Shen Jian
Published: November 2022

Background

Evidence from previous studies reporting on the relationship between tea consumption and its preventive effect on coronary artery disease (CAD) has conflicting outcomes. With the accumulation of new clinical evidence, we conducted this meta-analysis to assess tea consumption and CAD risk.

Methods

We searched PubMed, EMBASE, Cochrane Library, and Medline databases for published observational studies from their inception to May 2022. A random-effects model was used to calculate risk ratios with 95% confidence intervals. We also conducted linear and non-linear dose-response meta-analyses to analyze the association. We regarded that one cup equals 237 mL. Subgroup analyses and univariate meta-regression were conducted to explore the source of heterogeneity.

Results

A total of 35 studies, including 24 on green tea and 11 on black tea consumption, were included in this meta-analysis. An inverse association for the risk of CAD was observed for black tea (RR: 0.85; 95% CI: 0.76, 0.96) and green tea (RR: 0.93; 95% CI: 0.88, 0.99). The dose-response meta-analysis showed that drinking less than four cups of black tea daily may effectively prevent CAD, while more than 4–6 cups/d will promote disease risk. Furthermore, the dose-response relationship between green tea consumption and the prevention of CAD showed that the risk of CAD gradually decreased as green tea consumption increased. We also demonstrated that the more cups of green tea consumed, the lower the risk of CAD. In the subgroup analysis by continent, a significant negative correlation between CAD risk and green tea consumption was observed in the Asian population (RR: 0.92; 95% CI: 0.85, 0.99) but not in the western population [North America (RR: 0.97; 95% CI: 0.92, 1.03), Europe/Oceana (RR: 0.91; 95% CI: 0.78, 1.07)].

Conclusions

Higher green tea consumption was associated with reduced CAD risk, but drinking more than 4–6 cups of black tea per day may increase the risk. This study offers new insight into the relationship between tea consumption and its preventive effect on CAD. However, further large prospective cohort studies are needed to validate these findings.

Systematic review registration

The protocol of this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) system (CRD42022348069).
Association between triglyceride-glucose index and worsening renal function in the elderly
Authors: Lei Li , Liang Hongbin , Qu Yali , Zhong Qianhong , Zhang Qiuxia , Dai Lei , Lu Junyan , Xiao Min , Zhao Zhimeng , Zhou Fengyun , Li Yun , Hu Guifang , Xiu Jiancheng , Zhang Xinlu
Published: November 2022

Background

Triglyceride-glucose (TyG) index is a simple marker of insulin resistance. However, insufficient data is available on whether the TyG index is associated with worsening renal function (WRF) in the elderly. Therefore, this study was designed to explore the association between the TyG index and WRF based on a community elderly cohort.

Methods

In this study, 7,822 elderly (aged ≥ 65 years) adults from southern China were enrolled and divided into four groups according to the TyG index quartiles. The primary endpoint was incident chronic kidney disease (CKD), defined as incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Additional endpoints included a decline in eGFR of 30% and 40% during the follow-up period.

Results

During the median 2.04 year follow-up period, 1,541 (19.7%) participants developed CKD. After adjusting for confounding factors, multivariable Cox regression models revealed significant associations between TyG index and incident CKD (HR per SD increase, 1.21; 95% CI: 1.14–1.29), a decline in eGFR of 30% (HR per SD increase, 1.38; 95% CI: 1.26–1.50), and decline in eGFR of 40% (HR per SD increase, 1.42; 95% CI: 1.24–1.63). Furthermore, compared with those in Q1, participants in Q4 demonstrated a higher risk of developing CKD (HR, 1.59; 95% CI: 1.35–1.88). These positive associations remained consistent across different subgroup populations.

Conclusion

Our study suggests a positive and independent association between the TyG index and WRF in the elderly.
Skin cancer outcomes and risk factors in renal transplant recipients: Analysis of organ procurement and transplantation network data from 2000 to 2021
Authors: Hao Xiaowei , Lai Wenhui , Xia Xinze , Xu Junnan , Wu Yangyang , Lv Chao , Meng Qingyang , Lv Kaikai , Huang Shuai , Luo Zhenjun , Dong Jun , Yuan Qing
Published: November 2022

Purpose

Posttransplant skin cancer is the most common malignancy after patients have undergone renal transplantation. Through comprehensive observation with a large sample size nationwide, understanding the risk factors and outcome of posttransplant skin cancer will help to develop appropriate patient surveillance and disease prevention strategies.

Materials and methods

This retrospective population-based cohort study was based on Organ Procurement and Transplantation Network data released in March 2021. Characteristics and outcomes, including patient survival and graft survival of recipients, were compared. Risk factors for posttransplant skin cancer, cancer onset momentum, and mortality were determined.

Results

A total of 199,564 renal transplant recipients were included. After renal transplantation, 7,334 (3.68%), 6,093 (3.05%), and 936 (0.47%) were diagnosed with squamous cell carcinoma, basal cell carcinoma, and melanoma, respectively. Skin cancer was the major cause of death (squamous cell carcinoma: 23.8%, basal cell carcinoma: 18%, and melanoma: 41.6%). Five-year survival rates ranked from best to worst were as follows: basal cell carcinoma (96.7 [95% confidence interval: 96.3–97.2]%), squamous cell carcinoma (94.1 [93.5–94.6]%), melanoma (89.7 [87.7–91.6]%), and cancer-free (87.4 [87.2–87.5]%) (p < 0.001 for all except melanoma vs. cancer-free, p = 0.534). Regarding graft survival, death-censored graft survival, posttransplant skin cancer, and melanoma were significantly better than the cancer-free group (p < 0.001). Independent risk factors for developing posttransplant skin cancer included older age, male sex, Caucasian race, pretransplant malignancy, polycystic kidney disease-induced end-stage renal disease (ESRD), retransplantation, private health insurance, T-cell depletion induction, and tacrolimus/mycophenolic acid use. Caucasian race and pretransplant malignancy were independent risk factors for posttransplant skin cancer onset momentum. Male sex, Caucasian race, pretransplant malignancy, hypertension- or diabetes-induced ESRD, retransplantation, diabetes history, deceased donor, cyclosporin, and mTOR inhibitor use were independent risk factors for posttransplant skin cancer mortality.

Conclusion

Although posttransplant skin cancer is a major cause of recipient death, information regarding its impact on patient and graft survival is limited. Given the differences regarding risk factors for posttransplant skin cancer incidence, onset momentum, and mortality, personalized approaches to screening may be appropriate to address the complex issues encountered by kidney transplant recipients.
Zinc deficiency is associated with gynecologic cancer recurrence
Authors: Nakanishi Kazuho , Toyoshima Masafumi , Ichikawa Go , Suzuki Shunji
Published: November 2022

Zinc deficiency can cause various symptoms, including hair loss, anemia, and taste disorders. Recently, the association between cancer and zinc deficiency has received much attention with respect to its antioxidant properties. However, only a few studies have investigated the association between gynecologic cancers and zinc; to date, no studies have evaluated serum zinc status at the onset of gynecologic cancer or the relationship between zinc and cancer recurrence. The objectives of the present study were to determine whether serum zinc concentrations are associated with the development of gynecologic cancer, to clarify serum zinc dynamics between the onset and recurrence of gynecologic cancer, and to identify the associated factors. Accordingly, we retrospectively determined serum zinc concentrations before treatment in gynecologic patients with benign disease or cancer at the Nippon Medical School Chiba Hokusoh Hospital. We investigated anemia and hypoalbuminemia—the most common causes of zinc deficiency—as indicators of hyponutrition to determine the causal relationship of this deficiency with chemotherapy, radiation therapy, and recurrence, which may affect zinc concentration during cancer recurrence. The results indicated that there was no difference in zinc concentration between preoperative cancer patients and noncancer patients and that serum zinc concentrations were not associated with developing gynecologic cancers. However, patients with gynecologic cancer exhibited significantly lower serum zinc concentrations following treatment, and patients with recurrent cancer were 4.8 times more likely to develop zinc deficiency than those with nonrecurrent cancer. A serum zinc concentration of <61 μg/dL was an independent predictor of recurrence. Once zinc deficiency occurred, the recurrence rate of zinc deficiency reached as high as 69%. Overall, our study indicates that zinc deficiency is associated with recurrence in gynecological cancers and physicians should monitor zinc levels during disease management.
Advances in the understanding and treatment of Cutaneous T-cell Lymphoma
Authors: Bakr Farrah S. , Whittaker Sean J.
Published: November 2022

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin’s lymphomas (NHL) characterised by the clonal proliferation of malignant, skin homing T-cells. Recent advances have been made in understanding the molecular pathogenesis of CTCL. Multiple deep sequencing studies have revealed a complex genomic landscape with large numbers of novel single nucleotide variants (SNVs) and copy number variations (CNVs). Commonly perturbed genes include those involved in T-cell receptor signalling, T-cell proliferation, differentiation and survival, epigenetic regulators as well as genes involved in genome maintenance and DNA repair. In addition, studies in CTCL have identified a dominant UV mutational signature in contrast to systemic T-cell lymphomas and this likely contributes to the high tumour mutational burden. As current treatment options for advanced stages of CTCL are associated with short-lived responses, targeting these deregulated pathways could provide novel therapeutic approaches for patients. In this review article we summarise the key pathways disrupted in CTCL and discuss the potential therapeutic implications of these findings.
Prognostic analysis of pT1-T2aN0M0 cervical adenocarcinoma based on random survival forest analysis and the generation of a predictive nomogram
Authors: Ouyang Dong , Shi Mengting , Wang Yiman , Luo Limin , Huang Luzhong
Published: November 2022

Background

The efficacy of adjuvant radiotherapy for postoperative patients with early-stage cervical adenocarcinoma who are lymph node-negative is still inconclusive. Establishing a nomogram to predict the prognosis of such patients could facilitate clinical decision-making.

Methods

We recruited 4636 eligible patients with pT1-T2aN0M0 cervical adenocarcinoma between 2004 and 2016 from the Surveillance, Epidemiology and End Results (SEER) database. Random survival forest (RSF) and conditional survival forest (CSF) model was used to assess the prognostic importance of each clinical characteristic variable. We identified independent prognostic factors associated with overall survival (OS) by univariate and multivariate Cox regression risk methods and then constructed a nomogram. We stratified patients based on nomogram risk scores and evaluated the survival benefit of different adjuvant therapies. To reduce confounding bias, we also used propensity score matching (PSM) to match the cohorts before performing survival analyses.

Results

The RSF and CSF model identified several important variables that are associated with prognosis, including grade, age, radiotherapy and tumor size. Patients were randomly divided into training and validation groups at a ratio of 7:3. Multivariate cox analysis revealed that age, grade, tumor size, race, radiotherapy and histology were independent prognostic factors for overall survival. Using these variables, we then constructed a predictive nomogram. The C-index value for evaluating the prognostic nomogram fluctuated between 0.75 and 0.91. Patients were divided into three subgroups based on risk scores, and Kaplan-Meier (K-M) survival analysis revealed that in the low-risk group, postoperative chemotherapy alone was associated with a significantly worse OS than surgery alone. Following PSM, survival analysis showed that compared with surgery alone, radiotherapy was associated with a worse OS in the training group although there was no significant difference in the validation group.

Conclusions

For patients with pT1-T2aN0M0 cervical adenocarcinoma, adjuvant treatments such as postoperative radiotherapy or chemotherapy, compared with surgery alone, are of no benefit with regards to patient survival. Our prognostic nomogram exhibits high accuracy for predicting the survival of patients with early-stage postoperative cervical adenocarcinoma.