bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced Neutrophil Extracellular Trap Formation During Ischemia Reperfusion Injury in C3 KO Mice: C3 Requirement for NETs Release
Authors: Wu Xiaoting , You Danyu , Cui Jiong , Yang Liyan , Lin Liyu , Chen Yi , Xu Changsheng , Lian Guili , Wan Jianxin
Published: February 2022

Complement C3 plays a prominent role in inflammatory processes, and its increase exacerbates ischemia reperfusion injury (IRI)-induced acute kidney injury (AKI). Infiltrated neutrophils can be stimulated to form neutrophil extracellular traps (NETs), leading to renal injury. However, the relationship between the increase of C3 and the release of NETs in AKI was not clear. Here we found that IRI in the mouse kidney leads to increased neutrophils infiltration and NET formation. Furthermore, neutrophils depletion by anti-Ly6G IgG (1A8) did not reduce C3 activation but reduced kidney injury and inflammation, indicating a link between neutrophils infiltration and renal tissue damage. Pretreatment with 1A8 suppressed ischemia-induced NET formation, proving that extracellular traps (ETs) in renal tissue were mainly derived from neutrophils. Renal ischemia injury also leads to increased expression of C3. Moreover, C3 KO mice (C3 KO) with IRI exhibited attenuated kidney damage and decreased neutrophils and NETs. In vitro, C3a primed neutrophils to form NETs, reflected by amorphous extracellular DNA structures that colocalized with CitH3 and MPO. These data reveal that C3 deficiency can ameliorate AKI by reducing the infiltration of neutrophils and the formation of NETs. Targeting C3 activation may be a new therapeutic strategy for alleviating the necroinflammation of NETs in AKI.
Comparative Magnitude and Persistence of Humoral SARS-CoV-2 Vaccination Responses in the Adult Population in Germany
Authors: Dulovic Alex , Kessel Barbora , Harries Manuela , Becker Matthias , Ortmann Julia , Griesbaum Johanna , Jüngling Jennifer , Junker Daniel , Hernandez Pilar , Gornyk Daniela , Glöckner Stephan , Melhorn Vanessa , Castell Stefanie , Heise Jana-Kristin , Kemmling Yvonne , Tonn Torsten , Frank Kerstin , Illig Thomas , Klopp Norman , Warikoo Neha , Rath Angelika , Suckel Christina , Marzian Anne Ulrike , Grupe Nicole , Kaiser Philipp D. , Traenkle Bjoern , Rothbauer Ulrich , Kerrinnes Tobias , Krause Gérard , Lange Berit , Schneiderhan-Marra Nicole , Strengert Monika
Published: February 2022

Recent increases in SARS-CoV-2 infections have led to questions about duration and quality of vaccine-induced immune protection. While numerous studies have been published on immune responses triggered by vaccination, these often focus on studying the impact of one or two immunisation schemes within subpopulations such as immunocompromised individuals or healthcare workers. To provide information on the duration and quality of vaccine-induced immune responses against SARS-CoV-2, we analyzed antibody titres against various SARS-CoV-2 antigens and ACE2 binding inhibition against SARS-CoV-2 wild-type and variants of concern in samples from a large German population-based seroprevalence study (MuSPAD) who had received all currently available immunisation schemes. We found that homologous mRNA-based or heterologous prime-boost vaccination produced significantly higher antibody responses than vector-based homologous vaccination. Ad26.CoV2S.2 performance was particularly concerning with reduced titres and 91.7% of samples classified as non-responsive for ACE2 binding inhibition, suggesting that recipients require a booster mRNA vaccination. While mRNA vaccination induced a higher ratio of RBD- and S1-targeting antibodies, vector-based vaccines resulted in an increased proportion of S2-targeting antibodies. Given the role of RBD- and S1-specific antibodies in neutralizing SARS-CoV-2, their relative over-representation after mRNA vaccination may explain why these vaccines have increased efficacy compared to vector-based formulations. Previously infected individuals had a robust immune response once vaccinated, regardless of which vaccine they received, which could aid future dose allocation should shortages arise for certain manufacturers. Overall, both titres and ACE2 binding inhibition peaked approximately 28 days post-second vaccination and then decreased.
B-Cell Homeostasis Is Maintained During Two Months of Head-Down Tilt Bed Rest With or Without Antioxidant Supplementation
Authors: Bonnefoy Julie , Baselet Bjorn , Moser Dominique , Ghislin Stéphanie , Miranda Silvana , Riant Elodie , Vermeesen Randy , Keiler Annekathrin M. , Baatout Sarah , Choukér Alexander , Frippiat Jean-Pol
Published: February 2022

Alterations of the immune system could seriously impair the ability to combat infections during future long-duration space missions. However, little is known about the effects of spaceflight on the B-cell compartment. Given the limited access to astronaut samples, we addressed this question using blood samples collected from 20 healthy male volunteers subjected to long-duration bed rest, an Earth-based analog of spaceflight. Hematopoietic progenitors, white blood cells, total lymphocytes and B-cells, four B-cell subsets, immunoglobulin isotypes, six cytokines involved in inflammation, cortisone and cortisol were quantified at five time points. Tibia microarchitecture was also studied. Moreover, we investigated the efficiency of antioxidant supplementation with a cocktail including polyphenols, omega 3, vitamin E and selenium. Our results show that circulating hematopoietic progenitors, white blood cells, total lymphocytes and B-cells, and B-cell subsets were not affected by bed rest. Cytokine quantification suggested a lower systemic inflammatory status, supported by an increase in serum cortisone, during bed rest. These data confirm the in vivo hormonal dysregulation of immunity observed in astronauts and show that bed rest does not alter B-cell homeostasis. This lack of an impact of long-term bed rest on B-cell homeostasis can, at least partially, be explained by limited bone remodeling. None of the evaluated parameters were affected by the administration of the antioxidant supplement. The non-effectiveness of the supplement may be because the diet provided to the non-supplemented and supplemented volunteers already contained sufficient antioxidants. Given the limitations of this model, further studies will be required to determine whether B-cell homeostasis is affected, especially during future deep-space exploration missions that will be of unprecedented durations.
Brain Abscess Caused by Nocardia farcinica and Diagnosed by Metagenomic Next-Generation Sequencing: A Case Report
Authors: Yang Jianhua , Xie Shuhua , Li Junda , Xia Han , Liu Xianghong
Published: February 2022

Background

Brain abscesses caused by Nocardia farcinica are rare and difficult to diagnose. Conventional methods for diagnosing Nocardia species include blood culture, microscopy, and tissue slice, but the performance is not satisfied. We report a case of brain abscess due to N. farcinica diagnosed by metagenomic next-generation sequencing (mNGS).

Case Presentation

We report a case of a 58-year-old man with brain abscess caused by N. farcinica. The patient had a history of pemphigus and required long-term methylprednisolone administration. No pathogen was detected in blood culture, cerebrospinal fluid (CSF) culture, and fast-acid staining. mNGS identified N. farcinica in the CSF. The symptoms and signs of the patient were significantly improved after changing the antibiotics accordingly to sensitive antibiotics.

Conclusion

Metagenomic next-generation sequencing (mNGS) is helpful for early diagnosis and subsequent treatment of Nocardia-associated meningitis and encephalitis, avoiding brain surgery. Early and accurate diagnosis and prompt antibiotic treatment reduced its mortality.
Impact of Pals1 on Expression and Localization of Transporters Belonging to the Solute Carrier Family
Authors: Berghaus Carmen , Groh Ann-Christin , Breljak Davorka , Ciarimboli Giuliano , Sabolić Ivan , Pavenstädt Hermann , Weide Thomas
Published: February 2022

Pals1 is part of the evolutionary conserved Crumbs polarity complex and plays a key role in two processes, the formation of apicobasal polarity and the establishment of cell-cell contacts. In the human kidney, up to 1.5 million nephrons control blood filtration, as well as resorption and recycling of inorganic and organic ions, sugars, amino acids, peptides, vitamins, water and further metabolites of endogenous and exogenous origin. All nephron segments consist of polarized cells and express high levels of Pals1. Mice that are functionally haploid for Pals1 develop a lethal phenotype, accompanied by heavy proteinuria and the formation of renal cysts. However, on a cellular level, it is still unclear if reduced cell polarization, incomplete cell-cell contact formation, or an altered Pals1-dependent gene expression accounts for the renal phenotype. To address this, we analyzed the transcriptomes of Pals1-haploinsufficient kidneys and the littermate controls by gene set enrichment analysis. Our data elucidated a direct correlation between TGFβ pathway activation and the downregulation of more than 100 members of the solute carrier (SLC) gene family. Surprisingly, Pals1-depleted nephrons keep the SLC’s segment-specific expression and subcellular distribution, demonstrating that the phenotype is not mainly due to dysfunctional apicobasal cell polarization of renal epithelia. Our data may provide first hints that SLCs may act as modulating factors for renal cyst formation.
Role of ATP-Small Heat Shock Protein Interaction in Human Diseases
Authors: Nandi Sandip K. , Panda Alok Kumar , Chakraborty Ayon , Rathee Shivani , Roy Ipsita , Barik Subhashree , Mohapatra Saswati Soumya , Biswas Ashis
Published: February 2022

Adenosine triphosphate (ATP) is an important fuel of life for humans and Mycobacterium species. Its potential role in modulating cellular functions and implications in systemic, pulmonary, and ocular diseases is well studied. Plasma ATP has been used as a diagnostic and prognostic biomarker owing to its close association with disease’s progression. Several stresses induce altered ATP generation, causing disorders and illnesses. Small heat shock proteins (sHSPs) are dynamic oligomers that are dominantly β-sheet in nature. Some important functions that they exhibit include preventing protein aggregation, enabling protein refolding, conferring thermotolerance to cells, and exhibiting anti-apoptotic functions. Expression and functions of sHSPs in humans are closely associated with several diseases like cataracts, cardiovascular diseases, renal diseases, cancer, etc. Additionally, there are some mycobacterial sHSPs like Mycobacterium leprae HSP18 and Mycobacterium tuberculosis HSP16.3, whose molecular chaperone functions are implicated in the growth and survival of pathogens in host species. As both ATP and sHSPs, remain closely associated with several human diseases and survival of bacterial pathogens in the host, therefore substantial research has been conducted to elucidate ATP-sHSP interaction. In this mini review, the impact of ATP on the structure and function of human and mycobacterial sHSPs is discussed. Additionally, how such interactions can influence the onset of several human diseases is also discussed.
The Neural Signature of Visual Learning Under Restrictive Virtual-Reality Conditions
Authors: Lafon Gregory , Geng Haiyang , Avarguès-Weber Aurore , Buatois Alexis , Massou Isabelle , Giurfa Martin
Published: February 2022

Honey bees are reputed for their remarkable visual learning and navigation capabilities. These capacities can be studied in virtual reality (VR) environments, which allow studying performances of tethered animals in stationary flight or walk under full control of the sensory environment. Here, we used a 2D VR setup in which a tethered bee walking stationary under restrictive closed-loop conditions learned to discriminate vertical rectangles differing in color and reinforcing outcome. Closed-loop conditions restricted stimulus control to lateral displacements. Consistently with prior VR analyses, bees learned to discriminate the trained stimuli. Ex vivo analyses on the brains of learners and non-learners showed that successful learning led to a downregulation of three immediate early genes in the main regions of the visual circuit, the optic lobes (OLs) and the calyces of the mushroom bodies (MBs). While Egr1 was downregulated in the OLs, Hr38 and kakusei were coincidently downregulated in the calyces of the MBs. Our work thus reveals that color discrimination learning induced a neural signature distributed along the sequential pathway of color processing that is consistent with an inhibitory trace. This trace may relate to the motor patterns required to solve the discrimination task, which are different from those underlying pathfinding in 3D VR scenarios allowing for navigation and exploratory learning and which lead to IEG upregulation.
APOE-ε4 Is Associated With Reduced Verbal Memory Performance and Higher Emotional, Cognitive, and Everyday Executive Function Symptoms Two Months After Mild Traumatic Brain Injury
Authors: Hellstrøm Torgeir , Andelic Nada , Holthe Øyvor Øistensen , Helseth Eirik , Server Andres , Eiklid Kristin , Sigurdardottir Solrun
Published: February 2022

Background

Substantial variance exists in outcomes after mild traumatic brain injury (MTBI), and these differences are not fully explained by injury characteristics or severity. Genetic factors are likely to play a role in this variance.

Objectives

The aim of this study was to examine associations between the apolipoprotein (APOE)-ε4 allele and memory measures at two months post-MTBI and to evaluate whether subjective cognitive and affective symptoms were associated with APOE-ε4 status. Based on previous research, it was hypothesized that APOE-ε4 carriers would show poorer verbal memory performance compared to APOE-ε4 non-carriers.

Methods

Neuropsychological data at two months post-injury and blood samples that could be used to assess APOE genotype were available for 134 patients with MTBI (mean age 39.2 years, 62% males, 37% APOE-ε4 carriers). All patients underwent computed tomography at hospital admission and magnetic resonance imaging four weeks post-injury.

Results

The APOE-ε4 + status was associated with decreased immediate memory recall (p = 0.036; β = −0.10, 95% CI [−0.19, −0.01]). Emotional, cognitive, and everyday executive function symptoms at two months post-injury were significantly higher in APOE-ε4 carriers compared to non-carriers.

Conclusion

The APOE-ε4+ allele has a negative effect on verbal memory and symptom burden two months after MTBI.
Vision and Visuomotor Performance Following Acute Ischemic Stroke
Authors: Wijesundera Chamini , Crewther Sheila G. , Wijeratne Tissa , Vingrys Algis J.
Published: February 2022

Background

As measurable sensory and motor deficits are key to the diagnosis of stroke, we investigated the value of objective tablet based vision and visuomotor capacity assessment in acute mild-moderate ischemic stroke (AIS) patients.

Methods

Sixty AIS patients (65 ± 14 years, 33 males) without pre-existing visual/neurological disorders and acuity better than 6/12 were tested at their bedside during the first week post-stroke and were compared to 40 controls (64 ± 11 years, 15 males). Visual field sensitivity, quantified as mean deviation (dB) and visual acuity (with and without luminance noise), were tested on MRFn (Melbourne Rapid Field-Neural) iPad application. Visuomotor capacity was assessed with the Lee-Ryan Eye-Hand Coordination (EHC) iPad application using a capacitive stylus for iPad held in the preferred hand.Time to trace 3 shapes and displacement errors (deviations of >3.5 mm from the shape) were recorded. Diagnostic capacity was considered with Receiver Operating Characteristics. Vision test outcomes were correlated with National Institutes of Health Stroke Scale (NIHSS) score at the admission.

Results

Of the 60 AIS patients, 58 grasped the iPad stylus in their preferred right hand even though 31 had left hemisphere lesions. Forty-one patients (68%) with better than 6/12 visual acuity (19 right, 19 left hemisphere and 3 multi-territorial lesions) returned significantly abnormal visual fields. The stroke group took significantly longer (AIS: 93.4 ± 60.1 s; Controls: 33.1 ± 11.5 s, p < 0.01) to complete EHC tracing and made larger displacements (AIS: 16,388 ± 36,367 mm; Controls: 2,620 ± 1,359 mm, p < 0.01) although both control and stroke groups made similar numbers of errors. EHC time was not significantly different between participants with R (n = 26, 84.3 ± 55.3 s) and L (n = 31, 101.3 ± 64.7 s) hemisphere lesions. NIHSS scores and EHC measures showed low correlations (Spearman R: −0.15, L: 0.17). ROC analysis of EHC and vision tests found high diagnostic specificity and sensitivity for a fail at EHC time, or visual field, or Acuity-in-noise (sensivity: 93%, specificity: 83%) that shows little relationship to NIHSS scores.

Conclusions

EHC time and vision test outcomes provide an easy and rapid bedside measure that complements existing clinical assessments in AIS. The low correlation between visual function, NIHSS scores and lesion site offers an expanded clinical view of changes following stroke.
Effects of Exercise on Parkinson’s Disease: A Meta-Analysis of Brain Imaging Studies
Authors: Li Jingwen , Guo Jian , Sun Weijuan , Mei Jinjin , Wang Yiying , Zhang Lihong , Zhang Jianyun , Gao Jing , Su Kaiqi , Lv Zhuan , Feng Xiaodong , Li Ruiqing
Published: February 2022

Background

Exercise is increasingly recognized as a key component of Parkinson’s disease (PD) treatment strategies, but the underlying mechanism of how exercise affects PD is not yet fully understood.

Objective

The activation likelihood estimation (ALE) method is used to study the mechanism of exercise affecting PD, providing a theoretical basis for studying exercise and PD, and promoting the health of patients with PD.

Methods

Relevant keywords were searched on the PubMed, Cochrane Library, and Web of Science databases. Seven articles were finally included according to the screening criteria, with a total sample size of 97 individuals. Using the GingerALE 3.0.2 software, an ALE meta-analysis was performed using seven studies that met the requirements, and the probability of the cross-experiment activation of each voxel was calculated.

Results

The meta-analysis produced seven clusters, and major activations were found in the cerebellum, occipital lobe, parietal lobe, and frontal lobe brain regions.

Conclusion

Exercise for PD mainly results in the enhanced activation of the cerebellum, occipital lobe, parietal lobe, and frontal lobe. Exercise for PD does not cause a change in the activation of a single brain area, and the observed improvement may result from coordinated changes in multiple brain areas.
Decreased Functional Connectivities of Low-Degree Level Rich Club Organization and Caudate in Post-stroke Cognitive Impairment Based on Resting-State fMRI and Radiomics Features
Authors: Miao Guofu , Rao Bo , Wang Sirui , Fang Pinyan , Chen Zhuo , Chen Linglong , Zhang Xin , Zheng Jun , Xu Haibo , Liao Weijing
Published: February 2022

Background

Stroke is an important cause of cognitive impairment. Rich club organization, a highly interconnected network brain core region, is closely related to cognition. We hypothesized that the disturbance of rich club organization exists in patients with post-stroke cognitive impairment (PSCI).

Methods

We collected data on resting-state functional magnetic resonance imaging (rs-fMRI) with 21 healthy controls (HC), 16 hemorrhagic stroke (hPSCI), and 21 infarct stroke (iPSCI). 3D shape features and first-order statistics of stroke lesions were extracted using 3D slicer software. Additionally, we assessed cognitive function using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE).

Results

Normalized rich club coefficients were higher in hPSCI and iPSCI than HC at low-degree k-levels (k = 1–8 in iPSCI, k = 2–8 in hPSCI). Feeder and local connections were significantly decreased in PSCI patients versus HC, mainly distributed in salience network (SN), default-mode network (DMN), cerebellum network (CN), and orbitofrontal cortex (ORB), especially involving the right and left caudate with changed nodal efficiency. The feeder and local connections of significantly between-group difference were positively related to MMSE and MoCA scores, primarily distributed in the sensorimotor network (SMN) and visual network (VN) in hPSCI, SN, and DMN in iPSCI. Additionally, decreased local connections and low-degree ϕnorm(k) were correlated to 3D shape features and first-order statistics of stroke lesions.

Conclusion

This study reveals the disrupted low-degree level rich club organization and relatively preserved functional core network in PSCI patients. Decreased feeder and local connections in cognition-related networks (DMN, SN, CN, and ORB), particularly involving the caudate nucleus, may offer insight into pathological mechanism of PSCI patients. The shape and signal features of stroke lesions may provide an essential clue for the damage of functional connectivity and the whole brain networks.
Impaired Glucose Homeostasis in a Tau Knock-In Mouse Model
Authors: Benderradji Hamza , Kraiem Sarra , Courty Emilie , Eddarkaoui Sabiha , Bourouh Cyril , Faivre Emilie , Rolland Laure , Caron Emilie , Besegher Mélanie , Oger Frederik , Boschetti Theo , Carvalho Kévin , Thiroux Bryan , Gauvrit Thibaut , Nicolas Emilie , Gomez-Murcia Victoria , Bogdanova Anna , Bongiovanni Antonino , Muhr-Tailleux Anne , Lancel Steve , Bantubungi Kadiombo , Sergeant Nicolas , Annicotte Jean-Sebastien , Buée Luc , Vieau Didier , Blum David , Buée-Scherrer Valérie
Published: February 2022

Alzheimer’s disease (AD) is the leading cause of dementia. While impaired glucose homeostasis has been shown to increase AD risk and pathological loss of tau function, the latter has been suggested to contribute to the emergence of the glucose homeostasis alterations observed in AD patients. However, the links between tau impairments and glucose homeostasis, remain unclear. In this context, the present study aimed at investigating the metabolic phenotype of a new tau knock-in (KI) mouse model, expressing, at a physiological level, a human tau protein bearing the P301L mutation under the control of the endogenous mouse Mapt promoter. Metabolic investigations revealed that, while under chow diet tau KI mice do not exhibit significant metabolic impairments, male but not female tau KI animals under High-Fat Diet (HFD) exhibited higher insulinemia as well as glucose intolerance as compared to control littermates. Using immunofluorescence, tau protein was found colocalized with insulin in the β cells of pancreatic islets in both mouse (WT, KI) and human pancreas. Isolated islets from tau KI and tau knock-out mice exhibited impaired glucose-stimulated insulin secretion (GSIS), an effect recapitulated in the mouse pancreatic β-cell line (MIN6) following tau knock-down. Altogether, our data indicate that loss of tau function in tau KI mice and, particularly, dysfunction of pancreatic β cells might promote glucose homeostasis impairments and contribute to metabolic changes observed in AD.
Targeting Epithelial-to-Mesenchymal Transition in Radioresistance: Crosslinked Mechanisms and Strategies
Authors: Qiao Lili , Chen Yanfei , Liang Ning , Xie Jian , Deng Guodong , Chen Fangjie , Wang Xiaojuan , Liu Fengjun , Li Yupeng , Zhang Jiandong
Published: February 2022

Radiotherapy exerts a crucial role in curing cancer, however, its treatment efficiency is mostly limited due to the presence of radioresistance. Epithelial-to-mesenchymal transition (EMT) is a biological process that endows the cancer cells with invasive and metastatic properties, as well as radioresistance. Many potential mechanisms of EMT-related radioresistance being reported have broaden our cognition, and hint us the importance of an overall understanding of the relationship between EMT and radioresistance. This review focuses on the recent progresses involved in EMT-related mechanisms in regulating radioresistance, irradiation-mediated EMT program, and the intervention strategies to increase tumor radiosensitivity, in order to improve radiotherapy efficiency and clinical outcomes of cancer patients.
Oscillations and Dynamic Symbiosis in Cellular Metabolism in Cancer
Authors: Amemiya Takashi , Yamaguchi Tomohiko
Published: February 2022

The grade of malignancy differs among cancer cell types, yet it remains the burden of genetic studies to understand the reasons behind this observation. Metabolic studies of cancer, based on the Warburg effect or aerobic glycolysis, have also not provided any clarity. Instead, the significance of oxidative phosphorylation (OXPHOS) has been found to play critical roles in aggressive cancer cells. In this perspective, metabolic symbiosis is addressed as one of the ultimate causes of the grade of cancer malignancy. Metabolic symbiosis gives rise to metabolic heterogeneities which enable cancer cells to acquire greater opportunities for proliferation and metastasis in tumor microenvironments. This study introduces a real-time new imaging technique to visualize metabolic symbiosis between cancer-associated fibroblasts (CAFs) and cancer cells based on the metabolic oscillations in these cells. The causality of cellular oscillations in cancer cells and CAFs, connected through lactate transport, is a key point for the development of this novel technique.
Complete Response With Cetuximab-Based Treatment of Metastatic Colorectal Cancers: Two Case Reports and Literature Review
Authors: Wei Li , Lin Zexiao , Xie Sidong , Ruan Danyun , Jiang Wen , Cui Yueli , Liu Sisi , Wang Tiantian , Chen Zhanhong , Lin Qu
Published: February 2022

Metastases typically develop before diagnosis and during the treatment of colorectal cancers, while patients with metastatic colorectal cancers (mCRCs) currently have a poor prognosis. In terms of surgical approaches, adjuvant therapies, and targeted therapies, the treatment of mCRCs has had numerous recent advances. As a targeted agent widely used in mCRCs, cetuximab-based treatment is still under dispute due to its side effects and unstable effect. We present two mCRC cases treated with cetuximab-based therapy, of which two patients achieved complete response and without recurrence for over 22 and 84 months, respectively. To better understand the drug usage, we also reviewed the recent achievements and usage precautions of cetuximab in mCRCs. Present and many previous observations support that cetuximab might be a referred drug in the first-line chemotherapy of mCRCs with wild-type RAS and BRAF and proficient mismatch repair.
Involvement of LDL and ox-LDL in Cancer Development and Its Therapeutical Potential
Authors: Deng Chang-Feng , Zhu Neng , Zhao Tan-Jun , Li Hong-Fang , Gu Jia , Liao Duan-Fang , Qin Li
Published: February 2022

Lipid metabolism disorder is related to an increased risk of tumorigenesis and is involved in the rapid growth of cancer cells as well as the formation of metastatic lesions. Epidemiological studies have demonstrated that low-density lipoprotein (LDL) and oxidized low-density lipoprotein (ox-LDL) are closely associated with breast cancer, colorectal cancer, pancreatic cancer, and other malignancies, suggesting that LDL and ox-LDL play important roles during the occurrence and development of cancers. LDL can deliver cholesterol into cancer cells after binding to LDL receptor (LDLR). Activation of PI3K/Akt/mTOR signaling pathway induces transcription of the sterol regulatory element-binding proteins (SREBPs), which subsequently promotes cholesterol uptake and synthesis to meet the demand of cancer cells. Ox-LDL binds to the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 36 (CD36) to induce mutations, resulting in inflammation, cell proliferation, and metastasis of cancer. Classic lipid-lowering drugs, statins, have been shown to reduce LDL levels in certain types of cancer. As LDL and ox-LDL play complicated roles in cancers, the potential therapeutic effect of targeting lipid metabolism in cancer therapy warrants more investigation.
Predictive and Prognostic Assessment Models for Tumor Deposit in Colorectal Cancer Patients With No Distant Metastasis
Authors: Chen Jingyu , Zhang Zizhen , Ni Jiaojiao , Sun Jiawei , Ren Wenhao , Shen Yan , Shi Liuhong , Xue Meng
Published: February 2022

Background

More and more evidence indicated that tumor deposit (TD) was significantly associated with local recurrence, distant metastasis (DM), and poor prognosis for patients with colorectal cancer (CRC). This study aims to explore the main clinical risk factors for the presence of TD in CRC patients with no DM (CRC-NDM) and the prognostic factors for TD-positive patients after surgery.

Methods

The data of patients with CRC-NDM between 2010 and 2017 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. A logistic regression model was used to identify risk factors for TD presence. Fine and Gray’s competing-risk model was performed to analyze prognostic factors for TD-positive CRC-NDM patients. A predictive nomogram was constructed using the multivariate logistic regression model. The concordance index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), and the calibration were used to evaluate the predictive nomogram. Also, a prognostic nomogram was built based on multivariate competing-risk regression. C-index, the calibration, and decision-curve analysis (DCA) were performed to validate the prognostic model.

Results

The predictive nomogram to predict the presence of TD had a C-index of 0.785 and AUC of 0.787 and 0.782 in the training and validation sets, respectively. From the competing-risk analysis, chemotherapy (subdistribution hazard ratio (SHR) = 0.542, p < 0.001) can significantly reduce CRC-specific death (CCSD). The prognostic nomogram for the outcome prediction in postoperative CRC-NDM patients with TD had a C-index of 0.727. The 5-year survival of CCSD was 17.16%, 36.20%, and 63.19% in low-, medium-, and high-risk subgroups, respectively (Gray’s test, p < 0.001).

Conclusions

We constructed an easily predictive nomogram in identifying the high-risk TD-positive CRC-NDM patients. Besides, a prognostic nomogram was built to help clinicians identify poor-outcome individuals in postoperative CRC-NDM patients with TD. For the high-risk or medium-risk subgroup, additional chemotherapy may be more advantageous for the TD-positive patients rather than radiotherapy.
KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer
Authors: Osterlund Emerik , Ristimäki Ari , Kytölä Soili , Kuopio Teijo , Heervä Eetu , Muhonen Timo , Halonen Päivi , Kallio Raija , Soveri Leena-Maija , Sundström Jari , Keinänen Mauri , Ålgars Annika , Ristamäki Raija , Sorbye Halfdan , Pfeiffer Per , Nunes Luís , Salminen Tapio , Lamminmäki Annamarja , Mäkinen Markus J. , Sjöblom Tobias , Isoniemi Helena , Glimelius Bengt , Osterlund Pia
Published: February 2022

Background

KRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting.

Methods

Patients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan–Meier, and differences were compared using Cox regression, adjusted for baseline factors.

Results

The KRAS-G12C frequency was 2%–4% of all tested in the seven cohorts (mean 3%) and 4%–8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74–1.42, reference KRAS-G12C) nor within treatment groups defined as “systemic chemotherapy, alone or with biologics”, “metastasectomy and/or ablations”, or “best supportive care”, RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors.

Conclusions

In these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.
Case Report: Metastatic Signet-Ring-Cell Carcinoma of the Bladder From Breast Invasive Lobular Carcinoma Detected by Computed Tomography
Authors: Jin Xiaoxiang , Tang Haibin , Chen Hualin , Chen Gang
Published: February 2022

Secondary bladder tumors are relatively rare among all bladder tumors, while bladder metastases from breast cancer have been rarely reported. Furthermore, signet-ring differentiation may appear in the metastases from a breast invasive lobular carcinoma regardless of whether the primary breast tumor had signet-ring cells, which may cause diagnostic uncertainty. We report a case of a 55-year-old female patient with diffuse bladder thickening as the chief complaint and no specific clinical manifestations. While the cystoscopy showed multiple scattered red protuberances, the biopsy suggested signet-ring-cell carcinoma. The gastroscopy results suggested poorly differentiated adenocarcinoma with signet-ring cells. Considering the patient’s history of invasive lobular carcinoma of the breast, chronic myeloid leukemia, and metastatic endometrial carcinoma from the breast, we performed an immunohistochemical analysis and the results indicated that signet-ring-cell carcinomas of the stomach and bladder originated from the invasive lobular carcinoma of the breast. We performed positron emission tomography/computed tomography and the results showed that there were multiple bone metastases already present. This was the first English case report of invasive lobular carcinoma of the breast metastasizing to the uterus, stomach, bladder, and bones with multiple signet-ring-cell variations. This study shares our reasons for misdiagnosing and opinions on diagnosing and treating for this kind of cases.
Decreasing Shortest Path Length of the Sensorimotor Network Induces Frontal Glioma-Related Epilepsy
Authors: Fang Shengyu , Li Lianwang , Weng Shimeng , Guo Yuhao , Zhang Zhong , Wang Lei , Fan Xing , Wang Yinyan , Jiang Tao
Published: February 2022

Background

Glioma-related epilepsy (GRE) is a common symptom in patients with prefrontal glioma. Epilepsy onset is associated with functional network alterations. This study investigated alterations of functional networks in patients with prefrontal glioma and GRE.

Methods

Sixty-five patients with prefrontal lobe gliomas were retrospectively assessed and classified into GRE and non-GRE groups. Additionally, 25 healthy participants were enrolled after matching for general information. Imaging data were acquired within 72 h in pre-operation. The sensorimotor network was used to delineate alterations in functional connectivity (FC) and topological properties. One-way analysis of variance and post-hoc analysis with Bonferroni correction were used to calculate differences of FC and topological properties.

Results

All significant alterations were solely found in the sensorimotor network. Irrespective of gliomas located in the left or right prefrontal lobes, the edge between medial Brodmann area 6 and caudal ventrolateral Brodmann area 6 decreased FC in the GRE group compared with the non-GRE group [p < 0.0001 (left glioma), p = 0.0002 (right glioma)]. Moreover, the shortest path length decrease was found in the GRE group compared with the non-GRE group [p = 0.0292 (left glioma) and p = 0.0129 (right glioma)].

Conclusions

The reduction of FC between the medial BA 6 (supplementary motor area) and caudal ventrolateral BA 6 in the ipsilateral hemisphere and the shortening of the path length of the sensorimotor network were characteristics alterations in patients with GRE onset. These findings fill in the gap which is the relationship between GRE onset and the alterations of functional networks in patients with prefrontal glioma.

Significance Statement

Glioma related epilepsy is the most common symptom of prefrontal glioma. It is important to identify characteristic alterations in functional networks in patients with GRE. We found that all significant alterations occurred in the sensorimotor network. Moreover, a decreased FC in the supplementary motor area and a shortening of the path’s length are additional characteristics of glioma-related epilepsy. We believe that our findings indicate new directions of research that will contribute to future investigations of glioma-related epilepsy onset.
Gut Microbiota: A Promising Milestone in Enhancing the Efficacy of PD1/PD-L1 Blockade Therapy
Authors: Zhou Yuqing , Liu Zhaoxia , Chen Tingtao
Published: February 2022

In the past few decades, immunotherapy has emerged as one of the most promising strategies among current treatments of cancer. In particular, the field of PD1/PD-L1 inhibitors has been boosted, widely applied into clinical practice with potent therapeutic efficacy and remarkable survival benefits on various cancers such as melanoma, non-small cell lung cancer (NSCLC), and urothelial carcinoma (UC). However, the application of PD1/PD-L1 blockade therapy is still quite restricted because of unexpected toxicities, limited response rate, as well as associated resistance. In consequence, searching for potential strategies that possibly resolve the existing limitations and enhance the therapeutic responsiveness of PD1/PD-L1 blockade is of great significance. Fortunately, the gut microbiome has been demonstrated to serve as a pivotal regulator in anti-PD1/PD-L1 therapy, providing an applicable tool to improve anti-PD1/PD-L1 clinical efficacy. In this review, we summarized published advancements about how microbiota modulated in anti-PD1/PD-L1 therapy and illustrated its underlying mechanisms, giving insights into putative manipulation of gut microbiota to facilitate PD1/PD-L1 blockade.
Trends in Staging, Treatment, and Survival in Colorectal Cancer Between 1990 and 2014 in the Rotterdam Study
Authors: Lavrijssen Birgit D. A. , Ruiter Rikje , Fest Jesse , Ikram Mohammad A. , Stricker Bruno H. , van Eijck Casper H. J.
Published: February 2022

Background

This study aims to assess trends in patient-related factors and treatment strategies in Dutch colorectal cancer (CRC) patients and their effect on survival.

Methods

Data were obtained from the Rotterdam study, an ongoing population-based study of individuals aged ≥45 years. Between 1990 and 2014, incident, pathology-confirmed CRC cases were divided into two groups based on date of diagnosis (either before or after January 1, 2003). Patient characteristics, initial treatment, and date of mortality were collected. Analyses were performed using Kaplan–Meier and Cox proportional hazard models.

Results

Of 14,928 individuals, 272 developed colon cancer and 124 rectal cancer. Median follow-up was 13.2 years. Patients diagnosed after January 1, 2003 were treated chemotherapeutically more often than those diagnosed prior to this date in colon cancer (28.6% vs. 9.1%, p = 0.02) and treated more often with chemotherapy (38.6% vs. 12.3%, p = 0.02) and radiotherapy (41.3% vs. 10.2%, p = 0.001) in rectal cancer. Overall survival, adjusted for patient, tumor characteristics, and treatment, improved in rectal cancer (HR, 0.31; 95% CI, 0.13–0.74) but remained stable in colon cancer (HR, 1.28; 95% CI, 0.84–1.95).

Conclusion

Chemotherapeutic agents and radiotherapy are increasingly used in CRC patients. Survival in rectal cancer improved, whereas in colon cancer this was not observed.
Probiotics and Functional Gastrointestinal Disorders in Pediatric Age: A Narrative Review
Authors: Capozza Manuela , Laforgia Nicola , Rizzo Valentina , Salvatore Silvia , Guandalini Stefano , Baldassarre Mariella
Published: February 2022

Assessment and management of pain are essential components of pediatric care. Pain in pediatric age is characterized by relevant health and socio-economic consequences due to parental concern, medicalization, and long-term physical and psychological impact in children. Pathophysiological mechanisms of nociception include several pathways in which also individual perception and gut-brain axis seem to be involved. In this narrative review, we analyze the rational and the current clinical findings of probiotic use in the management of functional gastrointestinal disorders (FGID) in pediatric age, with special focus on infantile colic, irritable bowel syndrome, constipation, and gastroesophageal reflux. Some specific probiotics showed a significant reduction in crying and fussing compared to placebo in breastfed infants with colic, although their exact mechanism of action in this disorder remains poorly understood. In irritable bowel syndrome, a limited number of studies showed that specific strains of probiotics can improve abdominal pain/discomfort and bloating/gassiness, although data are still scarce. As for constipation, whilst some strains appear to reduce the number of hard stools in constipated children, the evidence is not adequate to support the use of probiotics in the management of functional constipation. Similarly, although some probiotic strains could promote gastric emptying with a potential improvement of functional symptoms related to gastroesophageal reflux, current evidence is insufficient to provide any specific recommendation for the prevention or treatment of gastroesophageal reflux. In conclusion, probiotics have been proposed as part of management of pain in functional gastrointestinal disorders in pediatric age, but mechanisms are still poorly understood and evidence to guide clinical practice is currently inadequate.
Salvia miltiorrhiza-Containing Chinese Herbal Medicine Combined With GnRH Agonist for Postoperative Treatment of Endometriosis: A Systematic Review and meta-Analysis
Authors: Gao Qiang , Shen Lei , Jiang Bei , Luan Yi-feng , Lin Li-na , Meng Fan-ci , Wang Chao-ying , Cong Hui-fang
Published: February 2022

Background: Endometriosis is an estrogen-dependent gynecological inflammatory condition that may lead to infertility and recurrent pelvic pain. The purpose of this research was to determine the efficacy and safety of Salvia miltiorrhiza-containing Chinese herbal medicine (CHM) combined with gonadotropin-releasing hormone agonist (GnRH-a) for postoperative endometriosis management.

Methods:Eight databases were systematically searched before October 2021, including PubMed, Embase, Cochrane Library, Scopus, Web of Sceince, CNKI, VIP, and Wanfang. Finally, all randomized controlled studies comparing Salvia miltiorrhiza-containing CHM paired with GnRH-a to GnRH-a alone for postoperative endometriosis management were included.

Results: A total of 10 trials involving 836 patients were reported and analyzed. Compared with the control group, the Salvia miltiorrhiza-containing CHM combined with GnRH-a group showed significant superiority in decreasing endometriosis recurrence (risk ratio [RR] = 0.26; 95% confidence intervals [CI]: 0.16–0.41) and increasing the pregnancy rate ([RR] = 1.96; 95% CI: 1.58–2.44). Similarly, the effect of the Salvia miltiorrhiza-containing CHM combined with GnRH-a on CA-125 serum levels was positive (standardized mean difference [SMD] = -0.79; 95% CI: −1.11 to −0.47). Furthermore, this group showed a significant reduction in adverse effects.

Conclusion: The results indicate that Salvia miltiorrhiza-containing CHM may be a viable choice for postoperative endometriosis therapy, with the potential to enhance pregnancy while decreasing recurrence and adverse effects.
Auxin-Glucose Conjugation Protects the Rice (Oryza sativa L.) Seedlings Against Hydroxyurea-Induced Phytotoxicity by Activating UDP-Glucosyltransferase Enzyme
Authors: Kantharaj Vimalraj , Ramasamy Nirmal Kumar , Yoon Young-Eun , Cheong Mi Sun , Kim Young-Nam , Lee Keum-Ah , Kumar Vikranth , Choe Hyeonji , Kim Song Yeob , Chohra Hadjer , Lee Yong Bok
Published: February 2022

Hydroxyurea (HU) is the replication stress known to carry out cell cycle arrest by inhibiting ribonucleotide reductase (RNR) enzyme upon generating excess hydrogen peroxide (H2O2) in plants. Phytohormones undergo synergistic and antagonistic interactions with reactive oxygen species (ROS) and redox signaling to protect plants against biotic and abiotic stress. Therefore, in this study, we investigated the protective role of Indole-3-acetic acid (IAA) in mitigating HU-induced toxicity in rice seedlings. The results showed that IAA augmentation improved the growth of the seedlings and biomass production by maintaining photosynthesis metabolism under HU stress. This was associated with reduced H2O2 and malondialdehyde (MDA) contents and improved antioxidant enzyme [superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT), and peroxidase (POD)] activity that was significantly affected under HU stress. Furthermore, we showed that the HU stress-induced DNA damage leads to the activation of uridine 5′-diphosphate-glucosyltransferase (UGT), which mediates auxin homeostasis by catalyzing IAA-glucose conjugation in rice. This IAA-glucose conjugation upregulates the RNR, transcription factor 2 (E2F2), cyclin-dependent kinase (CDK), and cyclin (CYC) genes that are vital for DNA replication and cell division. As a result, perturbed IAA homeostasis significantly enhanced the key phytohormones, such as abscisic acid (ABA), salicylic acid (SA), cytokinin (CTK), and gibberellic acid (GA), that alter plant architecture by improving growth and development. Collectively, our results contribute to a better understanding of the physiological and molecular mechanisms underpinning improved growth following the HU + IAA combination, activated by phytohormone and ROS crosstalk upon hormone conjugation via UGT.