bluuebunny/crossref_metadata_2025 huggingface dataset:
A Mouse Model of Cancer Induced Bone Pain: From Pain to Movement
Authors: Ji Haiwang , Jin Xiang , Zhang Qing , Zhou Yuan , Zhu Chan , Yang Yan , Tang Zongxiang , Yu Guang , Wang Changming
Published: June 2022

Cancer induced bone pain (CIBP) occurs in patients with advanced osteosarcoma or metastasized bone tumors that can negatively affects the patient's quality of life. However, motor impairment in CIBP is still understudied. To improve the quality of life of patients with CIBP, the study of CIBP induced movement impairment is of particular importance. Here, we presented a model of metastatic cancer induced bone pain caused by an allograft of Lewis lung cancer cells. In this method, we injected Lewis lung cancer cells into the femoral medulla cavity and recorded the pain behavior and motor behavior after CIBP surgery. We observed enhanced pain after the initial surgery. Interestingly, we found the latency on rotarod was significantly reduced concomitant with tumor growth and pain. This result indicated that the motor coordination and balance were severely impaired in CIBP. We also found the pain and motor behavioral differences in models that severed the patellar ligament vs. maintaining the patellar ligament. These findings provide a novel clue for further investigating the mechanisms responsible for the generation and development of CIBP.
The Problem of Meaning: The Free Energy Principle and Artificial Agency
Authors: Kiverstein Julian , Kirchhoff Michael D. , Froese Tom
Published: June 2022

Biological agents can act in ways that express a sensitivity to context-dependent relevance. So far it has proven difficult to engineer this capacity for context-dependent sensitivity to relevance in artificial agents. We give this problem the label the “problem of meaning”. The problem of meaning could be circumvented if artificial intelligence researchers were to design agents based on the assumption of the continuity of life and mind. In this paper, we focus on the proposal made by enactive cognitive scientists to design artificial agents that possess sensorimotor autonomy—stable, self-sustaining patterns of sensorimotor interaction that can ground values, norms and goals necessary for encountering a meaningful environment. More specifically, we consider whether the Free Energy Principle (FEP) can provide formal tools for modeling sensorimotor autonomy. There is currently no consensus on how to understand the relationship between enactive cognitive science and the FEP. However, a number of recent papers have argued that the two frameworks are fundamentally incompatible. Some argue that biological systems exhibit historical path-dependent learning that is absent from systems that minimize free energy. Others have argued that a free energy minimizing system would fail to satisfy a key condition for sensorimotor agency referred to as “interactional asymmetry”. These critics question the claim we defend in this paper that the FEP can be used to formally model autonomy and adaptivity. We will argue it is too soon to conclude that the two frameworks are incompatible. There are undeniable conceptual differences between the two frameworks but in our view each has something important and necessary to offer. The FEP needs enactive cognitive science for the solution it provides to the problem of meaning. Enactive cognitive science needs the FEP to formally model the properties it argues to be constitutive of agency. Our conclusion will be that active inference models based on the FEP provides a way by which scientists can think about how to address the problems of engineering autonomy and adaptivity in artificial agents in formal terms. In the end engaging more closely with this formalism and its further developments will benefit those working within the enactive framework.
Ventrolateral Periaqueductal Gray Neurons Are Active During Urination
Authors: Rao Yu , Gao Ziyan , Li Xianping , Li Xing , Li Jun , Liang Shanshan , Li Daihan , Zhai Jinliang , Yan Junan , Yao Jiwei , Chen Xiaowei
Published: June 2022

The ventrolateral periaqueductal gray (VLPAG) is thought to be the main PAG column for bladder control. PAG neurons (especially VLPAG neurons) and neurons in the pontine micturition center (PMC) innervating the bladder detrusor have anatomical and functional synaptic connections. The prevailing viewpoint on neural control of the bladder is that PAG neurons receive information on the decision to void made by upstream brain regions, and consequently activate the PMC through their direct projections to initiate urination reflex. However, the exact location of the PMC-projecting VLPAG neurons, their activity in response to urination, and their whole-brain inputs remain unclear. Here, we identified the distribution of VLPAG neurons that may participate in control of the bladder or project to the PMC through retrograde neural tracing. Population Ca2+ signals of PMC-projecting VLPAG neurons highly correlated with bladder contractions and urination as shown by in vivo recording in freely moving animals. Using a RV-based retrograde trans-synaptic tracing strategy, morphological results showed that urination-related PMC-projecting VLPAG neurons received dense inputs from multiple urination-related higher brain areas, such as the medial preoptic area, medial prefrontal cortex, and lateral hypothalamus. Thus, our findings reveal a novel insight into the VLPAG for control of bladder function and provide a potential therapeutic midbrain node for neurogenic bladder dysfunction.
Effects of Acupuncture in Ischemic Stroke Rehabilitation: A Randomized Controlled Trial
Authors: Li Lixia , Zhu Weifeng , Lin Guohua , Chen Chuyun , Tang Donghui , Lin Shiyu , Weng Xiaorong , Xie Liqin , Lu Lihong , Li Weilin
Published: June 2022

Background

Acupuncture is a well-known treatment option for ischemic stroke recovery, but evidence of its effectiveness remains limited. This is a randomized controlled trial to evaluate the effectiveness of acupuncture treatment for ischemic stroke rehabilitation.

Methods

Rehabilitation training was provided to the control group. In acupuncture arm 1, these acupoints were derived from the ancient books, including GV20 (baihui), GV26 (shuigou), PC9 (zhongchong), ST6 (jiache), ST4 (dicang), LI15 (jianyu), LI11 (quchi), LI4 (hegu), GB30 (huantiao), GB31 (fengshi), GB34 (yanglingquan), and GB39 (xuanzhong). In acupuncture arm 2, the acupoints used were GV20 (baihui), PC6 (neiguan), LI11 (quchi), LI10 (shousanli), SJ5 (waiguan), LI4 (hegu), GB30 (huantiao), ST36 (zusanli), GB34 (yanglingquan), SP6 (sanyinjiao), ST41 (jiexi), and LR3 (taichong), which were extracted from Acupuncture and Moxibustion Science. After acupuncture, the needles were left in for 30 min and manually manipulated every 10 min. The three groups received treatment once a day, 5 times a week for 2 weeks. The primary outcome was the National Institutes of Health Stroke Scale (NIHSS), and the secondary outcomes were the Barthel Index (BI) and the Modified Ashworth Scale (MAS). Outcomes were measured in patients both before and after treatment.

Results

A total of 497 patients with ischemic stroke were randomized into either arm 1 (159 cases), arm 2 (173 cases), or the control group (165 cases). After 2 weeks of treatment, the NIHSS scores for arm 1 were lower than those of the control group (P = 0.017); the BI scores were higher in arm two than that in the control group at T2 (P = 0.016) and follow-up (P = 0.020). Additionally, there was no significant difference between arm one and the control group for either the BI scores or the MAS scores (P > 0.05) and no significant difference between arm two and the control group for the MAS scores or the NIHSS scores (P > 0.05).

Conclusion

The clinical efficacy of arm 1 and arm 2 (acupuncture groups) was superior to that of the control group, but there was no difference between the effects of the two acupuncture groups.

Clinical Trial Registration

http://www.chictr.org.cn/index.aspx, identifier: ChiCTR-IOR-16008627.
On the Comparison Between the Nc/CRN and the Ne/ERN
Authors: Vidal Franck , Burle Boris , Hasbroucq Thierry
Published: June 2022

After the Error Negativity (Ne or ERN) has been described on full-blown errors and on partial error, a smaller Error Negativity-like wave (CRN or Nc) has also been evidenced on correct trials, first in patients with schizophrenia and, later on, in healthy subjects. The functional significance of the Nc as compared to the Ne is of critical importance since most models accounting for the genesis of the Ne on errors and partial errors cannot account for the existence of the Nc if this Nc simply corresponds to a small Ne. On the contrary, if the Nc and the Ne are two completely distinct components, then the existence of a Nc poses no constraint to the existing models. To this end, we examine in the present review the similarities and the differences existing between the Ne and the Nc regarding their functional properties and their anatomical origin.
Electrophysiological Evidence of Enhanced Processing of Novel Pornographic Images in Individuals With Tendencies Toward Problematic Internet Pornography Use
Authors: Wang Jianfeng , Chen Yuanyuan , Zhang Hui
Published: June 2022

Novelty seeking is regarded as a core feature in substance use disorders. However, few studies thus far have investigated this feature in problematic Internet pornography use (PIPU). The main aim of the present study was to examine group differences in electrophysiological activity associated with novelty processing in participants with high tendencies toward PIPU vs. low tendencies using event-related potentials (ERPs). Twenty-seven participants with high tendencies toward PIPU and 25 with low tendencies toward PIPU completed a modified three-stimulus oddball task while electroencephalogram (EEG) was recorded. Participants were instructed to detect neutral target stimuli from distracting stimuli. The distracting stimuli contained a familiar sexual stimulus and a set of novel sexual stimuli. The novel-familiar difference waves were calculated to identify specific group difference in novelty effect. While both groups demonstrated a sustained novelty effect in the late positive potential (LPP) within the 500–800 ms time windows, the novelty effect was greater in the high tendencies toward PIPU group than in the low tendencies toward PIPU group. This result suggests that individuals with high tendencies toward PIPU allocate more attentional resources for novelty processing. Enhanced brain responding to novel sexual stimuli may facilitate pornographic consumption and play an essential role in the development and maintenance of PIPU.
Abnormal Functional Connectivity Between Cerebral Hemispheres in Patients With High Myopia: A Resting FMRI Study Based on Voxel-Mirrored Homotopic Connectivity
Authors: Cheng Yi , Chen Xiao-Lin , Shi Ling , Li Si-Yu , Huang Hui , Zhong Pei-Pei , Wu Xiao-Rong
Published: June 2022

Purpose

To study the changes in functional connections between the left and right hemispheres of patients with high myopia (HM) and healthy controls (HCs) by resting functional magnetic resonance imaging (fMRI) based on voxel-mirrored homotopic connectivity (VMHC). To study the changes in resting-state functional connectivity (rsFC) between the left and right hemispheres of patients with HM and healthy controls (HCS) at rest by using resting functional magnetic resonance imaging (fMRI) based on voxel-mirror homotopy connectivity (VMHC).

Patients and Methods

A total of 89 patients with HM (41 men and 48 women) and 59 HCs (24 men and 35 women) were collected and matched according to gender, age, and education level. The VMHC method was used to evaluate the changes in rsFC between cerebral hemispheres, and a correlation analysis was carried out to understand the differences in brain functional activities between the patients with HM and the HCs.

Results

Compared with the HCs, the VMHC values of the putamen and fusiform in the HM group were significantly lower (voxel-level p < 0.01, Gaussian random field correction cluster level p < 0.05).

Conclusion

This study preliminarily confirmed the destruction of interhemispheric functional connection in some brain regions of the patients with HM and provided effective information for clarifying the neural mechanism of patients with HM.
PyMVPD: A Toolbox for Multivariate Pattern Dependence
Authors: Fang Mengting , Poskanzer Craig , Anzellotti Stefano
Published: June 2022

Cognitive tasks engage multiple brain regions. Studying how these regions interact is key to understand the neural bases of cognition. Standard approaches to model the interactions between brain regions rely on univariate statistical dependence. However, newly developed methods can capture multivariate dependence. Multivariate pattern dependence (MVPD) is a powerful and flexible approach that trains and tests multivariate models of the interactions between brain regions using independent data. In this article, we introduce PyMVPD: an open source toolbox for multivariate pattern dependence. The toolbox includes linear regression models and artificial neural network models of the interactions between regions. It is designed to be easily customizable. We demonstrate example applications of PyMVPD using well-studied seed regions such as the fusiform face area (FFA) and the parahippocampal place area (PPA). Next, we compare the performance of different model architectures. Overall, artificial neural networks outperform linear regression. Importantly, the best performing architecture is region-dependent: MVPD subdivides cortex in distinct, contiguous regions whose interaction with FFA and PPA is best captured by different models.
State and Trait Anxiety Share Common Network Topological Mechanisms of Human Brain
Authors: Li Yubin , Jiang Lili
Published: June 2022

Anxiety is a future-oriented unpleasant and negative mental state induced by distant and potential threats. It could be subdivided into momentary state anxiety and stable trait anxiety, which play a complex and combined role in our mental and physical health. However, no studies have systematically investigated whether these two different dimensions of anxiety share a common or distinct topological mechanism of human brain network. In this study, we used macroscale human brain morphological similarity network and functional connectivity network as well as their spatial and temporal variations to explore the topological properties of state and trait anxiety. Our results showed that state and trait anxiety were both negatively correlated with the coefficient of variation of nodal efficiency in the left frontal eyes field of volume network; state and trait anxiety were both positively correlated with the median and mode of pagerank centrality distribution in the right insula for both static and dynamic functional networks. In summary, our study confirmed that state and trait anxiety shared common human brain network topological mechanisms in the insula and the frontal eyes field, which were involved in preliminary cognitive processing stage of anxiety. Our study also demonstrated that the common brain network topological mechanisms had high spatiotemporal robustness and would enhance our understanding of human brain temporal and spatial organization.
Impact of Intestinal Microbiota on Cognitive Flexibility by a Novel Touch Screen Operant System Task in Mice
Authors: Tamada Hazuki , Ikuta Kayo , Makino Yusuke , Joho Daisuke , Suzuki Takeru , Kakeyama Masaki , Matsumoto Mitsuharu
Published: June 2022

Cognitive flexibility is the ability to rapidly adapt to a constantly changing environment. It is impaired by aging as well as in various neurological diseases, including dementia and mild cognitive impairment. In rodents, although many behavioral test protocols have been reported to assess learning and memory dysfunction, few protocols address cognitive flexibility. In this study, we developed a novel cognitive flexibility test protocol using touch screen operant system. This test comprises a behavioral sequencing task, in which mice are required to discriminate between the “rewarded” and “never-rewarded” spots and shuttle between the two distantly positioned rewarded spots, and serial reversals, in which the diagonal spatial patterns of rewarded and never-rewarded spots were reversely changed repetitively. Using this test protocol, we demonstrated that dysbiosis treated using streptomycin induces a decline in cognitive flexibility, including perseveration and persistence. The relative abundances of Firmicutes and Bacteroides were lower and higher, respectively, in the streptomycin-treated mice with less cognitive flexibility than in the control mice. This is the first report to directly show that intestinal microbiota affects cognitive flexibility.
Comprehensive Spatial Profile of the Orphan G Protein Coupled Receptor GPRC5B Expression in Mouse Brain
Authors: Fu Wenqi , Franchini Luca , Orlandi Cesare
Published: June 2022

Orphan G Protein Coupled Receptors (GPCRs) are GPCRs whose endogenous ligands are unknown or still debated. Due to the lack of pharmacological modulators, the physiological function of orphan GPCRs is understudied. However, relevant physiological roles associated with orphan GPCRs have been revealed by analysis of animal models and genome wide association studies illuminating an untapped potential for drug discovery. G Protein Coupled Receptor class C Group 5 Member B (GPRC5B) is among the most expressed GPCRs in the central nervous system. Thus, the expression profiling of GPRC5B is an essential step toward understanding GPRC5B function in health and disease. In this study, we generated new GPRC5B polyclonal antibodies and investigated the expression levels of GPRC5B across different organs and brain regions. We identified high levels of GPRC5B glycosylation both in transfected cells and in mouse brain. Moreover, in situ hybridization imaging analysis indicated that Gprc5b was expressed at the highest level in olfactory bulb, hippocampus, cerebellum, and pons. To dissect expression within various neuronal populations, we conducted a comprehensive spatial profiling of Gprc5b across excitatory and inhibitory neuronal types in medial prefrontal cortex, motor cortex, hippocampal regions, hypothalamus, and cerebellum. Overall, we discovered that GABAergic neurons displayed higher Gprc5b expression levels than glutamatergic neurons in most of the analyzed regions with the important exception of the hippocampal dentate gyrus. Overall, the expression analysis of GPRC5B in mouse brain will guide functional studies ultimately positioning GPRC5B in pathophysiological mechanisms and drug discovery.
Dimethyl Fumarate Blocks Tumor Necrosis Factor-Alpha-Driven Inflammation and Metabolic Rewiring in the Retinal Pigment Epithelium
Authors: Shu Daisy Y. , Frank Scott I. , Fitch Tessa C. , Karg Margarete M. , Butcher Erik R. , Nnuji-John Emmanuella , Kim Leo A. , Saint-Geniez Magali
Published: June 2022

The retinal pigment epithelium (RPE) acts as a metabolic gatekeeper between photoreceptors and the choroidal vasculature to maintain retinal function. RPE dysfunction is a key feature of age-related macular degeneration (AMD), the leading cause of blindness in developed countries. Inflammation is a key pathogenic mechanism in AMD and tumor necrosis factor-alpha (TNFα) has been implicated as a pro-inflammatory cytokine involved in AMD. While mitochondrial dysfunction has been implicated in AMD pathogenesis, the interplay between inflammation and cellular metabolism remains elusive. The present study explores how the pro-inflammatory cytokine, TNFα, impacts mitochondrial morphology and metabolic function in RPE. Matured human primary RPE (H-RPE) were treated with TNFα (10 ng/ml) for up to 5 days. TNFα-induced upregulation of IL-6 secretion and inflammatory genes (IL-6, IL-8, MCP-1) was accompanied by increased oxidative phosphorylation (OXPHOS) and reduced glycolysis, leading to an increase in cellular adenosine triphosphate (ATP) content. Transmission electron microscopy (TEM) revealed defects in mitochondrial morphology with engorged mitochondria and loss of cristae integrity following TNFα treatment. Pre-treatment with the anti-inflammatory drug, 80 μM dimethyl fumarate (DMFu), blocked TNFα-induced inflammatory activation of RPE (IL-6, IL-8, MCP-1, CFH, CFB, C3) and normalized their bioenergetic profile to control levels by regulating PFKFB3 and PKM2 gene expression. Furthermore, DMFu prevented TNFα-induced mitochondrial dysfunction and morphological anomalies. Thus, our results indicate that DMFu serves as a novel therapeutic avenue for combating inflammatory activation and metabolic dysfunction of RPE in AMD.
SlimMe, a Chatbot With Artificial Empathy for Personal Weight Management: System Design and Finding
Authors: Rahmanti Annisa Ristya , Yang Hsuan-Chia , Bintoro Bagas Suryo , Nursetyo Aldilas Achmad , Muhtar Muhammad Solihuddin , Syed-Abdul Shabbir , Li Yu-Chuan Jack
Published: June 2022

As the obesity rate continues to increase persistently, there is an urgent need to develop an effective weight loss management strategy. Nowadays, the development of artificial intelligence (AI) and cognitive technologies coupled with the rapid spread of messaging platforms and mobile technology with easier access to internet technology offers professional dietitians an opportunity to provide extensive monitoring support to their clients through a chatbot with artificial empathy. This study aimed to design a chatbot with artificial empathic motivational support for weight loss called “SlimMe” and investigate how people react to a diet bot. The SlimMe infrastructure was built using Dialogflow as the natural language processing (NLP) platform and LINE mobile messenger as the messaging platform. We proposed a text-based emotion analysis to simulate artificial empathy responses to recognize the user's emotion. A preliminary evaluation was performed to investigate the early-stage user experience after a 7-day simulation trial. The result revealed that having an artificially empathic diet bot for weight loss management is a fun and exciting experience. The use of emoticons, stickers, and GIF images makes the chatbot response more interactive. Moreover, the motivational support and persuasive messaging features enable the bot to express more empathic and engaging responses to the user. In total, there were 1,007 bot responses from 892 user input messages. Of these, 67.38% (601/1,007) of the chatbot-generated responses were accurate to a relevant user request, 21.19% (189/1,007) inaccurate responses to a relevant request, and 10.31% (92/1,007) accurate responses to an irrelevant request. Only 1.12% (10/1,007) of the chatbot does not answer. We present the design of an artificially empathic diet bot as a friendly assistant to help users estimate their calorie intake and calories burned in a more interactive and engaging way. To our knowledge, this is the first chatbot designed with artificial empathy features, and it looks very promising in promoting long-term weight management. More user interactions and further data training and validation enhancement will improve the bot's in-built knowledge base and emotional intelligence base.
Associations Between Different Cortisol Measures and Adiposity in Children: A Systematic Review and Meta-Analysis
Authors: Ma Lu , Liu Xi , Yan Na , Gan Yiqun , Wu Yue , Li Ying , Chu Meng , Chiu Dorothy T. , Ma Le
Published: June 2022

This study examined associations between hair, salivary, serum, and urinary cortisol concentration with adiposity-related indicators in children, and explored their potential effects modification by age, sex, cortisol measurement method, and country developmental context. We systematically searched PubMed, Web of Science, and Embase for studies examining at least one of the four aforementioned cortisol with objectively measured adiposity-related outcomes in children. Meta-analyses of cross-sectional studies revealed that hair cortisol concentration was associated with fat mass index (FMI)-standard deviation score (SDS)/FMI z-score (pooled-β = 0.04, 95% CI: 0.01, 0.08) and BMI/BMI z-score (pooled-β = 0.15, 95% CI: 0.06, 0.25), and these associations were significant among children aged ≤ 12 years (pooled-β = 0.15, 95% CI: 0.05, 0.26) and >12 years (pooled-β = 0.13, 95% CI: 0.04, 0.22), children from developed countries (pooled β = 0.12, 95% CI: 0.03, 0.21) and developing countries (pooled-β = 0.193, 95% CI: 0.188, 0.198), and in studies extracting cortisol via LC-MS/MS (pooled-β = 0.18, 95% CI: 0.06, 0.29) but not ELISA (pooled-β = 0.08, 95% CI: −0.06, 0.22). Meta-analyses of both cohort and cross-sectional studies revealed non-significant associations of morning salivary cortisol concentration and total daily cortisol output with BMI/BMI z-score. Serum cortisol concentration was not associated with BMI or waist circumference. Meta-analysis of urinary cortisol concentration and adiposity was hindered by insufficient data. These findings further corroborate understanding of chronic stress’ physiological contribution to increased pediatric obesity risk.

Systematic Review Registration

[https://www.crd.york.ac.uk/prospero/#recordDetails], identifier [CRD42020215111].
A Heptaplex PCR Assay for Molecular Traceability of Species Origin With High Efficiency and Practicality in Both Raw and Heat Processing Meat Materials
Authors: Zhou Song , Zhong Guowei , Zhou Hanxiao , Zhang Xiaoxia , Zeng Xiaoqun , Wu Zhen , Pan Daodong , He Jun , Cai Zhendong , Liu Qianqian
Published: June 2022

Frequent meat frauds have become a global issue because adulteration risks the food safety, breaches market rules, and even threatens public health. Multiplex PCR is considered to be a simple, fast, and inexpensive technique that can be applied for the identification of meat products in food industries. However, relatively less is known about a multiplex PCR method authenticating seven animal species simultaneously in one reaction due to technological challenge. Through screening new species-specific primers and optimizing PCR system, a heptaplex PCR method was established, which could simultaneously detect seven meat ingredients of camel (128 bp), pigeon (157 bp), chicken (220 bp), duck (272 bp), horse (314 bp), beef (434 bp), and pork (502 bp) in a single-tube reaction. DNA sequencing solidly validated that each set of primers specifically amplified target species from total DNA mixtures of seven meat species. The developed multiplex assay was stable and sensitive enough to detect 0.01–0.025 ng DNA from various meat treatments including raw, boiled, and autoclaved meat samples or target meat content of 0.1% total meat weight, suggesting the suitability of the heptaplex PCR technique for tracing target meats with high accuracy and precision. Most importantly, a market survey validated the availability of this multiplex PCR technique in real-world meat products with a good application foreground.
Genkwanin Prevents Lipopolysaccharide-Induced Inflammatory Bone Destruction and Ovariectomy-Induced Bone Loss
Authors: Fu Xin , Sun Xiaochen , Zhang Chenxi , Lv Nanning , Guo Huan , Xing Chunlei , Lv Juan , Wu Jiwen , Zhu Xiaoli , Liu Mingming , Su Li
Published: June 2022

Objectives

The first objective of this study was to probe the effects of genkwanin (GKA) on osteoclast. The second goal of this study was to study whether GKA can protect lipopolysaccharide (LPS) and ovariectomized (OVX) induced bone loss.

Materials and Methods

Various concentrations of GKA (1 and 10 mg/kg) were injected into mice. Different concentrations of GKA (1 and 5 μM) were used to detect the effects of GKA on osteoclast and osteoblast.

Key Findings

GKA attenuated the osteoclast differentiation promoted by RANKL and expression of marker genes containing c-fos, ctsk as well as bone resorption related gene Trap and to the suppression of MAPK signaling pathway. In addition, GKA induced BMMs cell apoptosis in vitro. Moreover, GKA prevented LPS-induced and ovariectomized-induced bone loss in mice.

Conclusion

Our research revealed that GKA had a potential to be an effective therapeutic agent for osteoclast-mediated osteoporosis.
The Diuretic Effects of Coconut Water by Suppressing Aquaporin and Renin–Angiotensin–Aldosterone System in Saline-Loaded Rats
Authors: Wei Jing , Zhao Mantong , Meng Keke , Xia Guanghua , Pan Yonggui , Li Congfa , Zhang Weimin
Published: June 2022

The acute and prolonged diuretic effects of coconut water (CW) and the underlying mechanism were investigated with a saline-loaded rat model. In an acute diuretic experiment, CW could significantly increase urine excretion. In addition, the treatment of CW significantly increased urinary sodium and chloride ions, thereby considerably increasing the excretion of NaCl. However, the calcium concentration and pH value were not affected. In the prolonged diuretic experiment, CW dramatically increased the urine output and urine electrolyte concentrations (Na+, K+, and Cl–). Furthermore, CW could suppress the activation of renin–angiotensin–aldosterone system by decreasing serum antidiuretic hormone, angiotensin II, and aldosterone levels, and significantly increasing the serum atriopeptin level. CW treatment significantly reduced the mRNA expressions and protein levels of aquaporin 1 (AQP1), AQP2, and AQP 3. This report provided basic data for explaining the natural tropical beverage of CW as an alternative diuretic agent.
Defining the Magnetic Resonance Features of Renal Lesions and Their Response to Everolimus in a Transgenic Mouse Model of Tuberous Sclerosis Complex
Authors: Agarwal Shubhangi , Decavel-Bueff Emilie , Wang Yung-Hua , Qin Hecong , Santos Romelyn Delos , Evans Michael J. , Sriram Renuka
Published: June 2022

Tuberous sclerosis complex (TSC) is an inherited genetic disorder characterized by mutations in TSC1 or TSC2 class of tumor suppressers which impact several organs including the kidney. The renal manifestations are usually in the form of angiomyolipoma (AML, in 80% of the cases) and cystadenomas. mTOR inhibitors such as rapamycin and everolimus have shown efficacy in reducing the renal tumor burden. Early treatment prevents the progression of AML; however, the tumors regrow upon cessation of therapy implying a lifelong need for monitoring and management of this morbid disease. There is a critical need for development of imaging strategies to monitor response to therapy and progression of disease which will also facilitate development of newer targeted therapy. In this study we evaluated the potential of multiparametric 1H magnetic resonance imaging (mpMRI) to monitor tumor response to therapy in a preclinical model of TSC, the transgenic mouse A/J Tsc2+/-. We found 2-dimensional T2-weighted sequence with 0.5 mm slice thickness to be optimal for detecting renal lesions as small as 0.016 mm3. Baseline characterization of lesions with MRI to assess physiological parameters such as cellularity and perfusion is critical for distinguishing between cystic and solid lesions. Everolimus treatment for three weeks maintained tumor growth at 36% from baseline, while control tumors displayed steady growth and were 70% larger than baseline at the end of therapy. Apparent diffusion coefficient, T1 values and normalized T2 intensity changes were also indictive of response to treatment. Our results indicate that standardization and implementation of improved MR imaging protocols will significantly enhance the utility of mpMRI in determining the severity and composition of renal lesions for better treatment planning.
Pharmacological targets for the induction of ferroptosis: Focus on Neuroblastoma and Glioblastoma
Authors: Ferrada Luciano , Barahona María José , Salazar Katterine , Godoy Alejandro S. , Vera Matias , Nualart Francisco
Published: June 2022

Neuroblastomas are the main extracranial tumors that affect children, while glioblastomas are the most lethal brain tumors, with a median survival time of less than 12 months, and the prognosis of these tumors is poor due to multidrug resistance. Thus, the development of new therapies for the treatment of these types of tumors is urgently needed. In this context, a new type of cell death with strong antitumor potential, called ferroptosis, has recently been described. Ferroptosis is molecularly, morphologically and biochemically different from the other types of cell death described to date because it continues in the absence of classical effectors of apoptosis and does not require the necroptotic machinery. In contrast, ferroptosis has been defined as an iron-dependent form of cell death that is inhibited by glutathione peroxidase 4 (GPX4) activity. Interestingly, ferroptosis can be induced pharmacologically, with potential antitumor activity in vivo and eventual application prospects in translational medicine. Here, we summarize the main pathways of pharmacological ferroptosis induction in tumor cells known to date, along with the limitations of, perspectives on and possible applications of this in the treatment of these tumors.
An Integrated Analysis of Clinical, Genomic, and Imaging Features Reveals Predictors of Neurocognitive Outcomes in a Longitudinal Cohort of Pediatric Cancer Survivors, Enriched with CNS Tumors (Rad ART Pro)
Authors: Kline Cassie , Stoller Schuyler , Byer Lennox , Samuel David , Lupo Janine M. , Morrison Melanie A. , Rauschecker Andreas M. , Nedelec Pierre , Faig Walter , Dubal Dena B. , Fullerton Heather J. , Mueller Sabine
Published: June 2022

Background

Neurocognitive deficits in pediatric cancer survivors occur frequently; however, individual outcomes are unpredictable. We investigate clinical, genetic, and imaging predictors of neurocognition in pediatric cancer survivors, with a focus on survivors of central nervous system (CNS) tumors exposed to radiation.

Methods

One hundred eighteen patients with benign or malignant cancers (median diagnosis age: 7; 32% embryonal CNS tumors) were selected from an existing multi-institutional cohort (RadART Pro) if they had: 1) neurocognitive evaluation; 2) available DNA; 3) standard imaging. Utilizing RadART Pro, we collected clinical history, genomic sequencing, CNS imaging, and neurocognitive outcomes. We performed single nucleotide polymorphism (SNP) genotyping for candidate genes associated with neurocognition: COMT, BDNF, KIBRA, APOE, KLOTHO. Longitudinal neurocognitive testing were performed using validated computer-based CogState batteries. The imaging cohort was made of patients with available iron-sensitive (n = 28) and/or T2 FLAIR (n = 41) sequences. Cerebral microbleeds (CMB) were identified using a semi-automated algorithm. Volume of T2 FLAIR white matter lesions (WML) was measured using an automated method based on a convolutional neural network. Summary statistics were performed for patient characteristics, neurocognitive assessments, and imaging. Linear mixed effects and hierarchical models assessed patient characteristics and SNP relationship with neurocognition over time. Nested case-control analysis was performed to compare candidate gene carriers to non-carriers.

Results

CMB presence at baseline correlated with worse performance in 3 of 7 domains, including executive function. Higher baseline WML volumes correlated with worse performance in executive function and verbal learning. No candidate gene reliably predicted neurocognitive outcomes; however, APOE ϵ4 carriers trended toward worse neurocognitive function over time compared to other candidate genes and carried the highest odds of low neurocognitive performance across all domains (odds ratio 2.85, P=0.002). Hydrocephalus and seizures at diagnosis were the clinical characteristics most frequently associated with worse performance in neurocognitive domains (5 of 7 domains). Overall, executive function and verbal learning were the most frequently negatively impacted neurocognitive domains.

Conclusion

Presence of CMB, APOE ϵ4 carrier status, hydrocephalus, and seizures correlate with worse neurocognitive outcomes in pediatric cancer survivors, enriched with CNS tumors exposed to radiation. Ongoing research is underway to verify trends in larger cohorts.
Cross-Resistance Among Sequential Cancer Therapeutics: An Emerging Issue
Authors: Loria Rossella , Vici Patrizia , Di Lisa Francesca Sofia , Soddu Silvia , Maugeri-Saccà Marcello , Bon Giulia
Published: June 2022

Over the past two decades, cancer treatment has benefited from having a significant increase in the number of targeted drugs approved by the United States Food and Drug Administration. With the introduction of targeted therapy, a great shift towards a new era has taken place that is characterized by reduced cytotoxicity and improved clinical outcomes compared to traditional chemotherapeutic drugs. At present, targeted therapies and other systemic anti-cancer therapies available (immunotherapy, cytotoxic, endocrine therapies and others) are used alone or in combination in different settings (neoadjuvant, adjuvant, and metastatic). As a result, it is not uncommon for patients affected by an advanced malignancy to receive subsequent anti-cancer therapies. In this challenging complexity of cancer treatment, the clinical pathways of real-life patients are often not as direct as predicted by standard guidelines and clinical trials, and cross-resistance among sequential anti-cancer therapies represents an emerging issue. In this review, we summarize the main cross-resistance events described in the diverse tumor types and provide insight into the molecular mechanisms involved in this process. We also discuss the current challenges and provide perspectives for the research and development of strategies to overcome cross-resistance and proceed towards a personalized approach.
Associations of Pre-Diagnostic Serum Levels of Total Bilirubin and Albumin With Lung Cancer Risk: Results From the Southern Community Cohort Study
Authors: Yoon Hyung-Suk , Shu Xiao-Ou , Shidal Chris , Wu Jie , Blot William J. , Zheng Wei , Cai Qiuyin
Published: June 2022

Background

Previous studies conducted among European and Asian decedents reported inverse associations of serum total bilirubin and albumin with lung cancer risk. Yet, no study has been conducted among African Americans or low-income European Americans.

Methods

This study included 522 incident lung cancer cases and 979 matched controls nested in the Southern Community Cohort Study, a cohort of predominantly low-income African and European Americans. Serum levels of total bilirubin and albumin, collected up to 11 years prior to case diagnoses, were measured by a clinical chemistry analyzer. Conditional logistic regression models were applied to evaluate the associations of total bilirubin and albumin with lung cancer risk.

Results

Overall, serum levels of total bilirubin (ORT3 vs. T1= 0.96, 95% CI: 0.66-1.39) were not significantly associated with lung cancer risk. However, higher levels of serum total bilirubin were significantly associated with decreased risk of lung cancer among participants who were diagnosed within two years following sample collection (ORT3 vs. T1= 0.36, 95% CI: 0.15-0.87) and among former/never smokers (ORT3 vs. T1= 0.54, 95% CI: 0.32-0.93). Serum levels of albumin were significantly associated with decreased risk of lung cancer overall (ORT3 vs. T1= 0.70, 95% CI: 0.50-0.98) and among African Americans (ORT3 vs. T1= 0.62, 95% CI: 0.41-0.96), but not among European Americans.

Conclusion

Our results indicate that in a low-income African American and European American population, serum levels of total bilirubin may be related to lung cancer progression and differ by smoking status. Meanwhile, the association of serum albumin levels with lung cancer risk may differ by race. Further studies are warranted to confirm these results.
T.H.R.O.B.V.S. Score – A Comprehensive Model to Predict the Surgical Complexity of Renal Cell Carcinoma With Tumor Thrombus
Authors: Wang Kai , Liu Zhuo , Hong Peng , Qin Yan-chun , Zhao Xun , Zhang Hong-xian , Liu Cheng , Ge Li-yuan , Ma Lu-lin
Published: June 2022

Background

To propose a quantitative model for predicting the surgical complexity of patients with renal cell carcinoma (RCC) and venous tumor thrombus (VTT).

Method

The clinical data of 226 cases of RCC with VTT in Peking University Third Hospital from January 2014 to August 2020 were retrospectively analyzed. Seven indicators were selected to establish the T.H.R.O.B.V.S. system, including alkaline phosphatase, tumor thrombus height, maximum tumor diameter, obesity, bland thrombus, vascular wall invasion, and side. Each indicator was assigned with 0, (1), and 2 points, and the total scores of 0~2, 3~5, and ≥6 were set as the low-, middle-, and high-risk groups, respectively. The surgical complexity was compared and validated among groups.

Results

As the risk increased, the proportion of open surgery significantly increased (P<0.001). The operation time (P<0.001), intraoperative blood loss (P<0.001), blood or plasma transfusion (P<0.001), and hospitalization (P<0.001) increased significantly. The postoperative complications (P<0.001), including notable complications (≥Clavein-Dindo II, P<0.001), were significantly different, and similar trends were shown in the validation group.

Conclusion

The T.H.R.O.B.V.S. scoring system is a quantifiable and satisfactory model to predict the surgical complexity and perioperative management of RCC with VTT.
Oncological Safety of Diagnostic Hysteroscopy for Apparent Early-Stage Type II Endometrial Cancer: A Multicenter Retrospective Cohort Study
Authors: Zhou Hui , Lai Kai-Fa , Xiang Qian , Xu Yu , Zhang Qian-Wen , Hu Cui , Mao Xi-Guang , Chen Cheng , Huang Wu , Mi Gong-Sheng , Shen Juan , Tian Yong , Ke Feng-Mei
Published: June 2022

Objective

To study the oncological safety of diagnostic hysteroscopy for women with apparent early-stage type II endometrial cancer.

Patients and Methods

A total of 429 women with presumed early-stage type II endometrial cancer were included. The 5-year disease-free survival (DFS) and overall survival (OS) were estimated and compared using the Kaplan-Meier method and the log-rank test among patients diagnosed by Dilation & Curettage (D&C) or diagnostic hysteroscopy. The Cox proportional hazards regression model was employed to adjust for potential confounding factors.

Results

160 cases underwent D&C and 269 cases were diagnosed by diagnostic hysteroscopy. The 5-year DFS rate was 72.17% in the diagnostic hysteroscopy group and 76.16% in the D&C group, diagnostic hysteroscopy was not associated with deteriorated 5-year DFS rate (HR 1.25, 95% CI 0.84-1.86, P=0.281). The 5-year OS rate was 67.23% in the diagnostic hysteroscopy group and 70.71% in the D&C group, diagnostic hysteroscopy did not increase the risk of all-cause death (HR 1.11, 95% CI 0.78-1.57, P=0.573). Multivariable analysis showed that the method of endometrial sampling was not independently associated with DFS (aHR 1.38, 95% CI 0.92-2.07, P=0.122) and OS (aHR 1.23, 95% CI 0.85-1.77, P=0.272).

Conclusion

For apparent early-stage type II endometrial cancer, endometrial sampling by diagnostic hysteroscopy was as safe as D&C.
Conversion Therapy of Large Unresectable Hepatocellular Carcinoma With Ipsilateral Portal Vein Tumor Thrombus Using Portal Vein Embolization Plus Transcatheter Arterial Chemoembolization
Authors: He Chengjian , Ge Naijian , Wang Xiangdong , Li Hai , Chen Shiguang , Yang Yefa
Published: June 2022

Background

The study aimed to assess the safety and efficacy of conversion therapy with portal vein embolization (PVE) and transcatheter arterial chemoembolization (TACE) in patients with large unresectable hepatocellular carcinoma (HCC) and ipsilateral portal vein tumor thrombus (PVTT).

Methods

This retrospective study evaluated consecutive patients with initially large (≥5 cm) unresectable HCC with ipsilateral PVTT who underwent PVE + TACE at our center between June 2016 and September 2020 (Group A). Clinically equivalent patients from three centers who were receiving tyrosine kinase inhibitors (TKIs) + TACE (Group B) were included. The survival times were evaluated and compared between the two therapeutic groups.

Results

In Group A (n = 33), the median tumor diameter was 14 cm (range, 5–18 cm) and 19 (57.6%) patients underwent radical resection 18–95 days after PVE. Radical liver resection was not performed because of inadequate hypertrophy (n = 11), pulmonary metastasis (n = 1), lack of consent for surgery (n = 1), and the rupture of the HCC (n = 1). There were no patients who underwent radical resection in Group B (n = 64) (P = 0.000). The mean and median overall survival (OS) were 736.5 days and 425.0 days in Group A and 424.5 days and 344.0 days in Group B, respectively. Compared with TKIs + TACE, treatment with PVE + TACE prolonged OS (P = 0.023).

Conclusions

This study shows that conversion therapy was safe and effective in patients with initially large unresectable HCC with ipsilateral PVTT treated with PVE + TACE. Moreover, PVE + TACE conferred more favorable outcomes than treatment with TKIs + TACE.
Antibody Titers Against Human Cytomegalovirus gM/gN and gB Among Pregnant Women and Their Infants
Authors: Talavera-Barber Maria , Flint Kaitlyn , Graber Brianna , Dhital Ravi , Kaptsan Irina , Medoro Alexandra K. , Sánchez Pablo J. , Shimamura Masako
Published: June 2022

Congenital CMV (cCMV) infection can affect infants born to mothers with preconceptional seroimmunity. To prevent cCMV due to nonprimary maternal infection, vaccines eliciting responses exceeding natural immunity may be required. Anti-gM/gN antibodies have neutralizing capacity in-vitro and in animal models, but anti-gM/gN antibodies have not been characterized among seroimmune pregnant women. Paired maternal and infant cord sera from 92 CMV seropositive mothers and their full-term or preterm infants were tested for anti-gM/gN antibody titers in comparison with anti-gB titers and neutralizing activity. Anti-gM/gN titers were significantly lower than anti-gB titers for all groups and did not correlate with serum neutralizing capacity. Further study is needed to determine if higher anti-gM/gN antibody titers might enhance serum neutralizing capacity among seropositive adults.
Administration of α-Klotho Does Not Rescue Renal Anemia in Mice
Authors: Park Min Young , Le Henaff Carole , Sitara Despina
Published: June 2022

Renal anemia is a common complication in chronic kidney disease (CKD), associated with decreased production of erythropoietin (EPO) due to loss of kidney function, and subsequent decreased red blood cell (RBC) production. However, many other factors play a critical role in the development of renal anemia, such as iron deficiency, inflammation, and elevated fibroblast growth factor 23 (FGF23) levels. We previously reported that inhibition of FGF23 signaling rescues anemia in mice with CKD. In the present study we sought to investigate whether α-Klotho deficiency present in CKD also contributes to the development of renal anemia. To address this, we administered α-Klotho to mice with CKD induced by an adenine-rich diet. Mice were sacrificed 24 h after α-Klotho injection, and blood and organs were collected immediately post-mortem. Our data show that α-Klotho administration had no beneficial effect in mice with CKD-associated anemia as it did not increase RBC numbers and hemoglobin levels, and it did not stimulate EPO secretion. Moreover, α-Klotho did not improve iron deficiency and inflammation in CKD as it had no effect on iron levels or inflammatory markers. Interestingly, Klotho supplementation significantly reduced the number of erythroid progenitors in the bone marrow and downregulated renal Epo and Hif2α mRNA in mice fed control diet resulting in reduced circulating EPO levels in these mice. In addition, Klotho significantly decreased intestinal absorption of iron in control mice leading to reduced serum iron and transferrin saturation levels. Our findings demonstrate that α-Klotho does not have a direct role in renal anemia and that FGF23 suppresses erythropoiesis in CKD via a Klotho-independent mechanism. However, in physiological conditions α-Klotho appears to have an inhibitory effect on erythropoiesis and iron regulation.