bluuebunny/crossref_metadata_2025 huggingface dataset:
Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis
Authors: Walker Rebecca V. , Maranto Anthony , Palicharla Vivek Reddy , Hwang Sun-Hee , Mukhopadhyay Saikat , Qian Feng
Published: June 2022

Primary cilia play counterregulatory roles in cystogenesis—they inhibit cyst formation in the normal renal tubule but promote cyst growth when the function of polycystins is impaired. Key upstream cilia-specific signals and components involved in driving cystogenesis have remained elusive. Recent studies of the tubby family protein, Tubby-like protein 3 (TULP3), have provided new insights into the cilia-localized mechanisms that determine cyst growth. TULP3 is a key adapter of the intraflagellar transport complex A (IFT-A) in the trafficking of multiple proteins specifically into the ciliary membrane. Loss of TULP3 results in the selective exclusion of its cargoes from cilia without affecting their extraciliary pools and without disrupting cilia or IFT-A complex integrity. Epistasis analyses have indicated that TULP3 inhibits cystogenesis independently of the polycystins during kidney development but promotes cystogenesis in adults when polycystins are lacking. In this review, we discuss the current model of the cilia-dependent cyst activation (CDCA) mechanism in autosomal dominant polycystic kidney disease (ADPKD) and consider the possible roles of ciliary and extraciliary polycystins in regulating CDCA. We then describe the limitations of this model in not fully accounting for how cilia single knockouts cause significant cystic changes either in the presence or absence of polycystins. Based on available data from TULP3/IFT-A-mediated differential regulation of cystogenesis in kidneys with deletion of polycystins either during development or in adulthood, we hypothesize the existence of cilia-localized components of CDCA (cCDCA) and cilia-localized cyst inhibition (CLCI) signals. We develop the criteria for cCDCA/CLCI signals and discuss potential TULP3 cargoes as possible cilia-localized components that determine cystogenesis in kidneys during development and in adult mice.
New Trends in Aviation and Medical Technology Enabled by Additive Manufacturing
Authors: Wegner Marie , Hartwich Tobias S. , Heyden Emil , Schwan Lukas , Schwenke Johann , Wortmann Nadine , Krause Dieter
Published: June 2022

In this publication, the potentials of additive manufacturing in the field of sustainability and individualization for aviation and medical technology are presented. Design approaches for each application field as well as examples in the fields are shown. In the field of aviation, structures can be manufactured so that they are load path optimized. This has a great lightweight potential and results in a low resource consumption. The examples contain the design of an aircraft cabin partition using the Direct Energy Deposition process and the optimization of load introduction points directly integrated into the sandwich core. Furthermore, in medical technology, additive manufacturing can be used to produce patient-specific models based on original medical imaging data, which can be used for training of medical treatments, quality assurance or for the validation of new developed medical devices. As examples a stroke simulation model containing a modular aortic model as well as functional stenose models are shown. Furthermore, the use of AM molds to generate a deformable bladder shell and a prostate phantom are described.
The Relative and Combined Effects of Noise Exposure and Aging on Auditory Peripheral Neural Deafferentation: A Narrative Review
Authors: Shehabi Adnan M. , Prendergast Garreth , Plack Christopher J.
Published: June 2022

Animal studies have shown that noise exposure and aging cause a reduction in the number of synapses between low and medium spontaneous rate auditory nerve fibers and inner hair cells before outer hair cell deterioration. This noise-induced and age-related cochlear synaptopathy (CS) is hypothesized to compromise speech recognition at moderate-to-high suprathreshold levels in humans. This paper evaluates the evidence on the relative and combined effects of noise exposure and aging on CS, in both animals and humans, using histopathological and proxy measures. In animal studies, noise exposure seems to result in a higher proportion of CS (up to 70% synapse loss) compared to aging (up to 48% synapse loss). Following noise exposure, older animals, depending on their species, seem to either exhibit significant or little further synapse loss compared to their younger counterparts. In humans, temporal bone studies suggest a possible age- and noise-related auditory nerve fiber loss. Based on the animal data obtained from different species, we predict that noise exposure may accelerate age-related CS to at least some extent in humans. In animals, noise-induced and age-related CS in separation have been consistently associated with a decreased amplitude of wave 1 of the auditory brainstem response, reduced middle ear muscle reflex strength, and degraded temporal processing as demonstrated by lower amplitudes of the envelope following response. In humans, the individual effects of noise exposure and aging do not seem to translate clearly into deficits in electrophysiological, middle ear muscle reflex, and behavioral measures of CS. Moreover, the evidence on the combined effects of noise exposure and aging on peripheral neural deafferentation in humans using electrophysiological and behavioral measures is even more sparse and inconclusive. Further research is necessary to establish the individual and combined effects of CS in humans using temporal bone, objective, and behavioral measures.
Selective Serotonin Reuptake Inhibitor-Treatment Does Not Show Beneficial Effects on Cognition or Amyloid Burden in Cognitively Impaired and Cognitively Normal Subjects
Authors: Bouter Yvonne , Bouter Caroline
Published: June 2022

Preclinical studies indicate that selective serotonin reuptake inhibitors (SSRI) have beneficial effects on Alzheimer-related pathologies. Therefore, the aim of this study was to evaluate the influence of SSRI-treatment on amyloid burden in 18F-Florbetapir-positron emission tomography (PET) and on cognition in cognitively normal and cognitively impaired subjects. We included n = 755 cognitively impaired and n = 394 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that underwent at least one 18F-Florbetapir-PET. Standardized uptake ratios (SUVR) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS) scores as well as follow-up results were compared between subgroups with a history of SSRI-treatment (SSRI+) and without SSRI-treatment (SSRI-) as well as in subgroups of SSRI+/Depression+ and SSRI+/Depression- and SSRI-/Depression+ and SSRI-/Depression-. 18F-Florbetapir-PET did not show significant differences of SUVR between the SSRI+ and SSRI- groups in both, cognitively impaired and cognitively normal participants. There were no differences in subgroups of SSRI+/Depression+ and SSRI+/Depression- and SSRI-/Depression+ and SSRI-/Depression-. However, SUVR showed a dose-dependent inverse correlation to the duration of medication in cognitively normal and in cognitively impaired patients. SRRI-treatment did not show an effect on ADAS scores. Furthermore, there was no effect on follow-up SUVR or on follow-up ADAS scores. Overall, SSRI-treatment did not show beneficial effects on amyloid load nor on cognition.
Application of Intelligent Inspection Robot in Coal Mine Industrial Heritage Landscape: Taking Wangshiwa Coal Mine as an Example
Authors: Shen Yan , Li Yu , Li Zengping
Published: June 2022

This study is developed to explore the role of intelligent inspection robot in the protection and utilization of coal mine industrial heritage. Based on the actual situation of the coal mine, the underground planning protection scope is analyzed. Aiming at the problems of imperfect fire early warning detection technology, management mechanism, high labor cost and low work efficiency in underground protection, the intelligent inspection robot technology is proposed to realize safety tour, underground intelligent management and early warning of underground security, fire protection facilities construction, and intelligent early warning system. This paper analyzes the key technology of intelligent inspection robot in coal mine industrial heritage protection, introduces the composition, structure and implementation method, and proposes its construction path and method. Besides, the path planning, motion obstacle avoidance and sensing detection of the robot are studied. The research shows that the intelligent inspection robot has comprehensive functions and stable performance, and can realize the scientific, intelligent and refined management of industrial heritage protection, which provides a guiding basis for the intelligent protection of coal mine industrial heritage.
Altered Long- and Short-Range Functional Connectivity Density in Patients With Thyroid-Associated Ophthalmopathy: A Resting-State fMRI Study
Authors: Jiang Wen-Hao , Chen Huan-Huan , Chen Wen , Wu Qian , Chen Lu , Zhou Jiang , Xu Xiao-Quan , Hu Hao , Wu Fei-Yun
Published: June 2022

Background and Purpose

Although previous neuroimaging studies have demonstrated emotion- and psychology-associated brain abnormalities in patients with thyroid-associated ophthalmopathy (TAO), the changes of brain functional connectivity in TAO were seldom focused. We aimed to investigate interregional and intraregional functional interactions in patients with TAO by using resting-state functional MRI (rs-fMRI) with long- and short-range functional connectivity density (FCD) analysis.

Methods

Thirty patients with TAO and 30 well-matched healthy controls (HCs) were recruited in our study. Long- and short-range FCD values were calculated and compared between the two groups. Correlations between long- and short-range FCD values and clinical indicators were analyzed.

Results

Compared with HCs, patients with showed both increased long- and short-range FCDs in the left middle frontal gyrus (MFG), orbital part of superior frontal gyrus (ORBsup), and dorsolateral part of superior frontal gyrus (SFGdor); meanwhile, both decreased long- and short-range FCDs in bilateral postcentral gyrus (PoCG), left superior parietal gyrus (SPG), and inferior parietal (IPL). In addition, patients with TAO showed increased short-range FCD in the right SFGdor, bilateral medial part of superior frontal gyrus (SFGmed), left orbital part of middle frontal gyrus (ORBmid), and orbital part of inferior frontal gyrus (ORBinf), as well as decreased short-range FCD in the right supplementary motor area (SMA) and the left paracentral lobule (PCL) than HCs. Moreover, the short-range value in the left SFGdor showed a negative correlation with Montreal Cognitive Assessment (MoCA) score (r = −0.501, p = 0.005).

Conclusion

Our findings complemented the functional neural mechanism of TAO, and provided potential neuroimaging markers for assessing the psychiatric, visual, and emotional disturbances in patients with TAO.
Arousal-Mediated Sleep Disturbance Persists During Cocaine Abstinence in Male Mice
Authors: Bjorness Theresa E. , Greene Robert W.
Published: June 2022

Acute cocaine disturbs sleep on a dose-dependent basis; however, the consequences of chronic cocaine remain unclear. While the arousal promotion following cocaine has been well-established, effects of cocaine on sleep after termination of chronic cocaine exposure appear variable in human subjects with few studies in non-human subjects. Here, a within-subjects design (outcomes normalized to baseline, undisturbed behavior) and between-subjects design (repeated experimenter-administered cocaine vs. experimenter-administered saline) was used to investigate sleep homeostasis and sleep/waking under repeated cocaine/saline exposure and prolonged forced abstinence conditions in mice. Overall, during the forced abstinence period increases in arousal, as determined by sleep latency and gamma energy, persisted for 2 weeks. However, the sleep response to externally enforced sleep deprivation was unchanged suggesting that sleep disruptions during the forced abstinence period were driven by enhancement of arousal in the absence of changes in sleep homeostatic responses.
Stanniocalcin2, but Not Stanniocalcin1, Responds to Hypoxia in a HIF1-Dependent Manner in the Retina
Authors: Ail Divya , Samardzija Marijana , Chang Andy C. M. , Keck Jadwiga , Reddel Roger R. , Grimm Christian
Published: June 2022

The quest for neuroprotective factors that can prevent or slow down the progression of retinal degeneration is still ongoing. Acute hypoxic stress has been shown to provide transient protection against subsequent damage in the retina. Stanniocalcins – STC1 and STC2 – are secreted glycoproteins that are hypoxia-regulated and were shown to be cytoprotective in various in vitro studies. Hence, we investigated the expression of stanniocalcins in the normal, degenerating and hypoxic retina. We show that the expression of Stc1 and Stc2 in the retina was detectable as early as postnatal day 10 and persisted during aging. Retinal expression of Stc2, but not Stc1, was induced in mice in an in vivo model of acute hypoxia and a genetic model of chronic hypoxia. Furthermore, we show that HIF1, not HIF2, is responsible for regulating Stc2 in cells with the molecular response to hypoxia activated due to the absence of von Hippel Lindau protein. Surprisingly, Stc2 was not normally expressed in photoreceptors but in the inner retina, as shown by laser capture microdissection and immunofluorescence data. The expression of both Stc1 and Stc2 remained unchanged in the degenerative retina with an almost complete loss of photoreceptors, confirming their expression in the inner retina. However, the absence of either Stc1 or Stc2 had no effect on retinal architecture, as was evident from retinal morphology of the respective knockout mice. Taken together our data provides evidence for the differential regulation of STC1 and STC2 in the retina and the prospect of investigating STC2 as a retinal neuroprotective factor.
The Rise and Fall of Slow Wave Tides: Vacillations in Coupled Slow Wave/Spindle Pairing Shift the Composition of Slow Wave Activity in Accordance With Depth of Sleep
Authors: McConnell Brice V. , Kronberg Eugene , Medenblik Lindsey M. , Kheyfets Vitaly O. , Ramos Alberto R. , Sillau Stefan H. , Pulver Rachelle L. , Bettcher Brianne M.
Published: June 2022

Slow wave activity (SWA) during sleep is associated with synaptic regulation and memory processing functions. Each cycle of non-rapid-eye-movement (NREM) sleep demonstrates a waxing and waning amount of SWA during the transitions between stages N2 and N3 sleep, and the deeper N3 sleep is associated with an increased density of SWA. Further, SWA is an amalgam of different types of slow waves, each identifiable by their temporal coupling to spindle subtypes with distinct physiological features. The objectives of this study were to better understand the neurobiological properties that distinguish different slow wave and spindle subtypes, and to examine the composition of SWA across cycles of NREM sleep. We further sought to explore changes in the composition of NREM cycles that occur among aging adults. To address these goals, we analyzed subsets of data from two well-characterized cohorts of healthy adults: (1) The DREAMS Subjects Database (n = 20), and (2) The Cleveland Family Study (n = 60). Our analyses indicate that slow wave/spindle coupled events can be characterized as frontal vs. central in their relative distribution between electroencephalography (EEG) channels. The frontal predominant slow waves are identifiable by their coupling to late-fast spindles and occur more frequently during stage N3 sleep. Conversely, the central-associated slow waves are identified by coupling to early-fast spindles and favor occurrence during stage N2 sleep. Together, both types of slow wave/spindle coupled events form the composite of SWA, and their relative contribution to the SWA rises and falls across cycles of NREM sleep in accordance with depth of sleep. Exploratory analyses indicated that older adults produce a different composition of SWA, with a shift toward the N3, frontal subtype, which becomes increasingly predominant during cycles of NREM sleep. Overall, these data demonstrate that subtypes of slow wave/spindle events have distinct cortical propagation patterns and differ in their distribution across lighter vs. deeper NREM sleep. Future efforts to understand how slow wave sleep and slow wave/spindle coupling impact memory performance and neurological disease may benefit from examining the composition of SWA to avoid potential confounds that may occur when comparing dissimilar neurophysiological events.
Fatty Acids as a Tool to Boost Cancer Immunotherapy Efficacy
Authors: Westheim Annemarie J. F. , Stoffels Lara M. , Dubois Ludwig J. , van Bergenhenegouwen Jeroen , van Helvoort Ardy , Langen Ramon C. J. , Shiri-Sverdlov Ronit , Theys Jan
Published: June 2022

Although immunotherapy represents one of the most potent therapeutic anti-cancer approaches, only a limited number of patients shows clinical benefit. Recent evidence suggests that patients' nutritional status plays a major role in immunotherapy outcome. Fatty acids are essential in a balanced diet and well-known to influence the immune response. Moreover, short-chain fatty acids (SCFAs) show beneficial effects in metabolic disorders as well as in cancer and polyunsaturated fatty acids (PUFAs) contribute to body weight and fat free mass preservation in cancer patients. In line with these data, several studies imply a role for SCFAs and PUFAs in boosting the outcome of immunotherapy. In this review, we specifically focus on mechanistic data showing that SCFAs modulate the immunogenicity of tumor cells and we discuss the direct effects of SCFAs and PUFAs on the immune system in the context of cancer. We provide preclinical and clinical evidence indicating that SCFAs and PUFAs may have the potential to boost immunotherapy efficacy. Finally, we describe the challenges and address opportunities for successful application of nutritional interventions focusing on SCFAs and PUFAs to increase the therapeutic potential of immunotherapeutic approaches for cancer.
Linking Mitochondrial Function to Insulin Resistance: Focusing on Comparing the Old and the Young
Authors: Wang Jingxuan , Wu Junnan , Li Wenjing , Wang Xinyu , Liu Ruifang , Liu Tao , Xiao Jianhua
Published: June 2022

Long-term intake of high-energy diet can lead to decreased insulin sensitivity and even insulin resistance, eventually leading to diabetes. Diabetes often occurs in middle-aged and elderly people. However, there is growing evidence that the incidence rate of young body is increasing over the years. This means that insulin resistance can be caused by excessive energy intake in both young and old people. In this study, high-fat diet (HFD) and normal diet were fed to rats of elderly experimental group (EE), elderly control group (EC), young experimental group (YE), and young control group (YC), respectively, for 8 weeks, by which insulin resistance model was obtained. Insulin sensitivity was measured, histopathology changes in liver and skeletal muscle tissues were observed, and mitochondrial fusion and division and cell senescence were detected in four groups of rats. The results showed that both young and elderly rats developed significant insulin resistance, fat deposition, decline of mitochondrial function and mitochondrial biosynthesis in liver and skeletal muscle, and cell aging after HFD feeding. In addition, the degree of mitochondrial dysfunction and aging in young rats was similar to that of aged rats fed a normal diet after HFD. This experiment provides a reference for an in-depth study of the regulatory mechanisms of cellular energy metabolism in this state.
Interaction of Hydration Status and Physical Activity Level on Early Renal Damage in Children: A Longitudinal Study
Authors: Li Menglong , Shu Wen , Amaerjiang Nubiya , Xiao Huidi , Zunong Jiawulan , Vermund Sten H. , Huang Dayong , Hu Yifei
Published: June 2022

Background

Optimal water intake positively affects various aspects of human physiology, especially renal function. Physical activity (PA) may have an impact on hydration status and renal health, but the interaction of hydration status and PA level on renal function is not well-studied in children.

Methods

We conducted four waves of urine assays in our child cohort (PROC) study from October 2018 to November 2019 in Beijing, China. We measured urinary specific gravity, β2-microglobulin (β2-MG), and microalbumin (MA) excretion to assess hydration status and renal damage in the context of PA level and other covariates among 1,914 primary school children. We determined the associations of renal damage with the interaction of hydration status and PA level using generalized linear mixed-effects models.

Results

The prevalence of dehydration was 35.0%, 62.1%, 63.9%, and 63.3%, and the prevalence of insufficient PA was 86.2%, 44.9%, 90.4%, and 90.2% from wave 1 to wave 4 among 1,914 primary school children. From wave 1 to wave 4, the prevalence of renal tubular damage had a significant increasing trend of 8.8%, 15.9%, 25.7%, and 29.0% (Z = 16.9, P < 0.001), while the prevalence of glomerular damage revealed a declining trend of 5.6%, 5.5%, 4.4%, and 4.1% (Z = −2.4, P = 0.016). There were stable longitudinal associations of renal tubular and glomerular damage with hydration status (euhydration: OR = 0.50 and 0.33, respectively) but not with PA level. In multivariate analysis, significant interactions of hydration status and PA level were noted with renal tubular damage (β = 0.43, P = 0.014) and glomerular damage (β = 0.60, P = 0.047). Children with euhydration and insufficient PA were less likely to have renal tubular damage (OR = 0.46, 95% CI: 0.39, 0.53) or glomerular damage (OR = 0.28, 95% CI: 0.20, 0.39); children with euhydration and sufficient PA were also less likely to have renal tubular damage (OR = 0.57, 95% CI: 0.44, 0.75) or glomerular damage (OR = 0.47, 95% CI: 0.30, 0.74), adjusting for age, sex, BMI z-score, standardized SBP, sleep duration, computer/cell phone screen time, and fruit and vegetable intake.

Conclusion

Children with euhydration and either sufficient or insufficient PA were less likely to have early renal damage. Adequate daily water intake for children is important, especially after PA.
Impact of Eating Speed on Muscle Mass in Older Patients With Type 2 Diabetes: A Prospective Study of KAMOGAWA–DM Cohort
Authors: Kobayashi Genki , Hashimoto Yoshitaka , Takahashi Fuyuko , Kaji Ayumi , Sakai Ryosuke , Okamura Takuro , Okada Hiroshi , Kitagawa Noriyuki , Nakanishi Naoko , Majima Saori , Osaka Takafumi , Senmaru Takafumi , Ushigome Emi , Asano Mai , Hamaguchi Masahide , Yamazaki Masahiro , Fukui Michiaki
Published: June 2022

Background and Aims

Maintenance of muscle mass is important for sarcopenia prevention. However, the effect of eating speed, especially fast, normal, or slow speed, on muscle mass changes remains unclear. Therefore, the purpose of this prospective study was to investigate the effect of eating speed on muscle mass changes in patients with type 2 diabetes (T2DM).

Methods

This study included 284 patients with T2DM. Based on a self–reported questionnaire, participants were classified into three groups: fast–, normal–, and slow–speed eating. Muscle mass was assessed using a multifrequency impedance body composition analyzer, and skeletal muscle mass (SMI) decrease (kg/m2/year) was defined as [baseline SMI (kg/m2)–follow–up SMI (kg/m2)] ÷ follow–up duration (year). The rate of SMI decrease (%) was defined as [SMI decrease (kg/m2/year) ÷ baseline SMI (kg/m2)] × 100.

Results

The proportions of patients with fast–, normal–, and slow–speed eating were, respectively, 50.5%, 42.9%, and 6.6% among those aged <65 years and 40.4%, 38.3%, and 21.3% among those aged ≥65 years. In patients aged ≥65 years, the rate of SMI decrease in the normal (0.85 [95% confidence interval, CI: −0.66 to 2.35]) and slow (0.93 [95% CI −0.61 to 2.46]) speed eating groups was higher than that in the fast speed eating group (−1.08 [95% CI −2.52 to 0.36]). On the contrary, there was no difference in the rate of SMI decrease among the groups in patients aged <65 years. Compared with slow speed eating, the adjusted odds ratios of incident muscle loss [defined as rate of SMI decrease (%) ≥0.5%] due to fast– and normal–speed eating were 0.42 (95% CI 0.18 to 0.98) and 0.82 (95% CI 0.36 to 2.03), respectively.

Conclusion

Slow–speed eating is associated with a higher risk of muscle mass loss in older patients with T2DM.
KDELR1 Is an Independent Prognostic Predictor and Correlates With Immunity in Glioma
Authors: Yuan Yifan , Yang Biao , Qi Zengxin , Han Zhenyuan , Cai Jiajun , Song Jianping
Published: June 2022

Background

Gliomas are the most malignant central nervous system tumors. With the development of sequencing technology, more potential biomarkers related to the treatment, prognosis, and molecular classification of glioma have been identified. Here, we intend to investigate the potential biological function and clinical value of a new biomarker in glioma.

Methods

KDELR1 expression data and the corresponding clinical information were downloaded from public databases and then preprocessed using R language. Correlation, Kaplan–Meier survival, and Cox regression analyses were performed to explore the clinical significance of KDELR1 in glioma patients. Furthermore, the immune infiltration and microenvironment parameters were evaluated via TIMER and CIBERSORT. Immunohistochemistry was conducted to confirm the KDELR1 expression and its correlation with immunity infiltration and prognosis.

Results

KDELR1 was upregulated in glioma samples compared with normal brain tissues, and its expression was significantly correlated with age, the World Health Organization (WHO) grade, recurrence, necrosis, microvascular proliferation, molecular classification, isocitrate dehydrogenase (IDH) mutation, and 1p/19q codeletion status. In addition, survival analysis showed that glioma patients with KDELR1 overexpression had shorter overall survival (OS) and disease-free survival times, and Cox regression analysis revealed that KDELR1 acted as an independent prognostic factor of OS in glioma patients. Gene set enrichment analysis indicated a significant enrichment of metabolism-associated pathways. KDELR1 expression was positively associated with immune infiltration (including infiltration by CD8+ T cells, CD4+ T cells, macrophages, and so on) and microenvironment parameters (including stromal, immune, and ESTIMATE scores) in gliomas. The expression of KDELR1 and its correlation with the tumor grade and prognosis were confirmed by immunohistochemistry in clinical samples (n = 119, P < 0.05).

Conclusions

Taken together, these findings suggest that KDELR1 is correlated with the tumor grade, molecular classifications, and immune infiltration; highlighting that KDELR1 is a novel and promising biomarker for molecular classification, treatment, and prognostic assessment may further indicate the treating effect of immune therapy.
Risk of Adverse Events in Cancer Patients Receiving Nivolumab With Ipilimumab: A Meta-Analysis
Authors: Zhao Xin , Gao Fengwei , Yang Jie , Fan Hua , Xie Qingyun , Jiang Kangyi , Gong Jie , Gao Benjian , Yang Qian , Lei Zehua
Published: June 2022

Background

Combining two immune checkpoint inhibitors (ICIs) instead of using one can effectively improve the prognosis of advanced malignant tumors. At present, ipilimumab alongside nivolumab is the most widely used combinatorial regimen of ICIs. However, the risk of treatment-related adverse events is higher in combinatorial regimens than in single-drug regimens. Thus, this study aimed to evaluate the risks of common adverse events associated with the combinatorial regimen of ipilimumab and nivolumab by using meta-analysis.

Methods

We searched Pubmed, Medline, EMBASE, and Cochrane Library for reports published by 30 September 2021. A randomized controlled study was developed and analyzed using the statistical software R to determine the efficacy of the combinatorial treatment. Risk estimates (hazard ratios, RR) and 95% confidence intervals for various common serious adverse events were used.

Results

A total of 23 randomized control trials (n = 3970 patients) were included. Our meta-analysis indicated the risks of adverse events of any grade and grade ≥ 3 as 90.42% (95%CI: 85.91% ~ 94.18%) and 46.46% (95%CI: 39.37% ~ 53.69%), respectively; the risks of treatment-related death and adverse events leading to discontinuation were estimated at 0.42% (95% CI, 0.18% ~ 0.72%) and 19.11% (95% CI, 14.99% ~ 24.38%), respectively. Classification of 19 common adverse events. The top 5 grade 1-2 adverse events were found to be fatigue (30.92%, 95% CI: 24.59% ~ 37.62%), pruritus (26.05%, 95%CI: 22.29%~29.99%), diarrhea (23.58%, 95% CI: 20.62% ~ 26.96%), rash (19.90%, 95%CI: 15.75% ~ 25.15%), and nausea (17.19%, 95% CI:13.7% ~ 21.57%). The top 5 grade ≥ 3 adverse events were identified as increased alanine aminotransferase(8.12%, 95% CI: 5.90%~10.65%), increased lipase(7.62%, 95% CI: 4.88% ~ 10.89%), and colitis (6.39%, 95%CI: 3.98% ~ 10.25%), increased aspartate aminotransferase (6.30%, 95% CI: 4.61% ~ 8.22%), and diarrhea(5.72%, 95%CI: 3.50% ~ 8.44%). Subgroup analysis revealed some differences in the adverse events between the N1-I3 and N3-I1 subgroups and between subgroups of different cancer types.

Conclusion

This study summarized the risks of common adverse events in the co-treatment of malignant-tumor patients with ipilimumab and nivolumab and identified the impacts of various initial administration schemes on the risks of such events, thereby providing an important reference for the toxicity of co-treatment with ipilimumab and nivolumab.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/, identifier: CRD42020181350.
Pulsatilla chinensis (Bge.) Regel: A Systematic Review on Anticancer of Its Pharmacological Properties, Clinical Researches and Pharmacokinetic Studies
Authors: Li Hang , Wang Lilan , Zhang Xiaojing , Xia Wenxin , Zhou Xirong , Sui Hong , Fu Xueyan
Published: June 2022

Pulsatilla chinensis (Bge.) Regel (PC) is one of the most commonly used Chinese medicines and has a history of thousands of years. This article reviews the research results of anti-cancer activity and its mechanism of action obtained from experimental, clinical, pharmacokinetic and bioinformatic studies in recent years. A large number of studies have shown that PC exerts had anti-cancer effects on different types of tumor cells by inhibiting cell proliferation, inducing apoptosis, inhibiting cell cycle and energy metabolism, inducing autophagy, and inhibiting angiogenesis. The literature has shown that PC can trigger the expression of autophagy-related molecules, activate the mitochondrial apoptotic pathway, inhibit the phosphorylation of PI3K downstream factors, down-regulate the expression of glycolysis-related proteins, and regulate a series of cancer-related signal pathways and proteins. The molecular mechanisms involved in PC include signal pathways such as Notch, PI3K/AKT/m TOR, AKT/mTOR, and MEK/ERK. The article also discusses the derivatives of the active ingredients in PC, which greatly improved the anti-cancer effect. In conclusion, this review provides a comprehensive overview of the biological effects and mechanisms of PC against cancer. The analysis of the literature shows that PC can be used as a potential drug candidate for the treatment of cancer.
Case Report: An Adolescent Soft Tissue Sarcoma With YWHAE-NUTM2B Fusion Is Effectively Treated With Combined Therapy of Epirubicin and Anlotinib
Authors: He Jiajia , Xu Yanjie , Ni Xuefeng , Zhang Dachuan , Zhao Jiemin
Published: June 2022

Soft tissue sarcoma is a relatively rare entity that comprises heterogeneous types of tumors. Here we report the case of a 14-year-old girl with pelvic sarcoma with a YWHAE-NUTM2B fusion gene. This fusion transcript has been reported in endometrial stromal sarcomas and clear cell renal sarcomas, but its description in pelvic sarcomas is recent. To our knowledge, this is the first case report describing this translocation in an adolescent patient with soft tissue sarcoma. The patient underwent cytoreductive surgery, followed by systemic chemotherapy and targeted drug treatment. Surprisingly, the treatment was effective, and the young patient is being followed up in our department.
Lysophosphatidic Acid Signaling and microRNAs: New Roles in Various Cancers
Authors: Rafiyan Mahdi , Abadi Mohammad Hassan Jafari Najaf , Zadeh Seyed Saeed Tamehri , Hamblin Michael R. , Mousavi Mahboubeh , Mirzaei Hamed
Published: June 2022

A wide range of microRNAs (miRNAs) are coded for in the human genome and contribute to the regulation of gene expression. MiRNAs are able to degrade mRNAs and/or prevent the RNA transcript from being translated through complementary binding of the miRNA seed region (nucleotide 2-8) to the 3’-untranslated regions of many mRNAs. Although miRNAs are involved in almost all processes of normal human cells, they are also involved in the abnormal functions of cancer cells. MiRNAs can play dual regulatory roles in cancer, acting either as tumor suppressors or as tumor promoters, depending on the target, tumor type, and stage. In the current review, we discuss the present status of miRNA modulation in the setting of lysophosphatidic acid (LPA) signaling. LPA is produced from lysophosphatidylcholine by the enzyme autotaxin and signals via a range of G protein-coupled receptors to affect cellular processes, which ultimately causes changes in cell morphology, survival, proliferation, differentiation, migration, and adhesion. Several studies have identified miRNAs that are over-expressed in response to stimulation by LPA, but their functional roles have not yet been fully clarified. Since RNA-based treatments hold tremendous promise in the area of personalized medicne, many efforts have been made to bring miRNAs into clinical trials, and this field is evolving at an increasing pace.
ILP-2: A New Bane and Therapeutic Target for Human Cancers
Authors: Zhang Zhiliang , Xiang Siqi , Cui Ruxia , Peng Hang , Mridul Roy , Xiang Mingjun
Published: June 2022

Inhibitor of apoptosis protein-related-like protein-2 (ILP-2), also known as BIRC-8, is a member of the inhibitor of apoptosis protein (IAPs) family, which mainly encodes the negative regulator of apoptosis. It is selectively overexpressed in a variety of human tumors and can help tumor cells evade apoptosis, promote tumor cell growth, increase tumor cell aggressiveness, and appears to be involved in tumor cell resistance to chemotherapeutic drugs. Several studies have shown that downregulation of ILP-2 expression increases apoptosis, inhibits metastasis, reduces cell growth potential, and sensitizes tumor cells to chemotherapeutic drugs. In addition, ILP-2 inhibits apoptosis in a unique manner; it does not directly inhibit the activity of caspases but induces apoptosis by cooperating with other apoptosis-related proteins. Here, we review the current understanding of the various roles of ILP-2 in the apoptotic cascade and explore the use of interfering ILP-2, and the combination of related anti-tumor agents, as a novel strategy for cancer therapy.
Responsive Caregiving and Opportunities for Early Learning Associated With Infant Development: Results From a Prospective Birth Cohort in China
Authors: Wang Ke , Qi Yue , Wei Qian , Shi Yuyang , Zhang Yunhui , Shi Huijing
Published: June 2022

Background

Infant development shapes children’s health into adulthood. Although providing responsive caregiving and opportunities regarding early learning for infants have received increasing attention from the international community, few studies have been published on these topics thus far. The purpose of the present study, then, was to explore the influences of responsive caregiving and the opportunities for early learning on infant development.

Methods

Mother-child dyads (3,714 pairs) were recruited from the Shanghai Maternal-Child Pairs Cohort (Shanghai MCPC) for the present study, and the development of infants, responsive caregiving and opportunities for early learning were collected from three waves of follow-up (2-, 6-, and 12-month old) We used the cross-lagged model to analyze the longitudinal correlation between responsive caregiving or opportunities for early learning and development of infants. We used the generalized estimation equation (GEE) to evaluate the effect of responsive caregiving and opportunities for early learning on suspected developmental delay; we also conducted a hierarchical analysis to investigate the interaction between responsive caregiving or opportunities for early learning and annual family income.

Results

There was a mutual prediction between responsive caregiving or opportunities for early learning and some developmental domains of the Ages and Stages Questionnaires, third edition (ASQ-3). Sustained high-exposure to responsive caregiving or opportunities for early learning significantly decreased the risk of suspected developmental delay in most domains of the ASQ-3. And For infants whose annual family income was < ¥200,000, sustained high-exposure (Adjusted Odds Ratio = 0.456, 95% CI, 0.325–0.638) and fluctuating-exposure (Adjusted Odds Ratio = 0.510, 95% CI, 0.414–0.627) to responsive caregiving significantly reduced the risk for suspected developmental delay.

Conclusion

Responsive caregiving or opportunities for early learning interacted with infant development. Infants’ early access to adequate responsive caregiving and opportunities for early learning exerted a sustained and positive impact on infant development, and this effect is more pronounced in relative low-income families.
The Potential Mechanisms of Cinobufotalin Treating Colon Adenocarcinoma by Network Pharmacology
Authors: Wang Jiyan , Chang Hongkai , Su Meng , Zhao Huifang , Qiao Yaya , Wang Yu , Shang Luqing , Shan Changliang , Zhang Shuai
Published: June 2022

Network pharmacology, as a novel way using bioinformatics to explore drug targets and interactions in cancer, broadens our understanding of drug action, thereby facilitating drug discovery. Here, we utilized network pharmacology to explore the role and mechanism by which cinobufotalin functions in colon adenocarcinoma (COAD). We found that cinobufotalin represses the growth and proliferation of colon cancer cells, and integrated public databases for targets reported to be associated with COAD, together with those predicted to be targets of cinobufotalin. Targets overlapped between COAD-associated proteins and cinobufotalin target proteins were used to filter candidate targets of cinobufotalin in COAD. The following proteins were thought to occupy a key position in COAD-cinobufotalin target networks: SRC, PIK3R1, MAPK1, PIK3CA, HSP90AA1, CTNNB1, GRB2, RHO1, PTPN11, and EGFR. The networks regulated by cinobufotalin were involved mainly in extracellular signal stimulation and transduction, including MAPK signaling pathway, PI3K-AKT signaling pathway, and JAK-STAT signaling pathway. Besides, transcriptome sequencing results also indicated that cinobufotalin inhibits the response of colon cancer cells to extracellular stimulation and promotes cell apoptosis. Molecular docking results showed that cinobufotalin matches in the pocket of the top candidate cinobufotalin target proteins (SRC, PIK3R1, MAPK1 and PIK3CA). These findings demonstrate cinobufotalin can be developed as potential anti-cancer therapeutics.
Growth Performance, Immune-Related and Antioxidant Genes Expression, and Gut Bacterial Abundance of Pacific White Leg Shrimp, Litopenaeus vannamei, Dietary Supplemented With Natural Astaxanthin
Authors: Mansour Abdallah Tageldein , Ashour Mohamed , Abbas Eman M. , Alsaqufi Ahmed Saud , Kelany Mahmoud S. , El-Sawy Mohamed A. , Sharawy Zaki Z.
Published: June 2022

The current study examines the effect of dietary supplementation of ethanolic extract of Arthrospira platensis NIOF17/003, which is mainly natural astaxanthins (97.50%), on the growth performance, feed utilization, bacterial abundance, and immune-related and antioxidant gene expressions of the Pacific white leg shrimp, Litopenaeus vannamei. A total of 360 healthy L. vannamei postlarvae (0.19 ± 0.003 g) were divided into four groups (0, 2, 4, and 6 g natural astaxanthins/kg diet) each in three replicates, at an initial density of 30 PLs per tank (40 L capacity). The shrimp were fed the tested diets three times a day at a rate of 10% of their total body weight for 90 days. Diets supplemented with different astaxanthin levels significantly improved shrimp growth performance and feed conversion ratio compared to the control diet. No significant differences were observed in survival rates among all experimental groups. The immune-related genes (prophenoloxidase, lysozyme, beta-glucan binding protein, transglutaminase, and crustin) mRNA levels were significantly upregulated in groups fed with different concentrations of the natural astaxanthins in a dose-dependent manner. The prophenoloxidase gene is the highest immune-upregulated gene (14.71-fold change) in response to astaxanthin supplementation. The superoxide dismutase mRNA level was significantly increased with increasing dietary astaxanthin supplementation. In addition, increasing astaxanthin supplementation levels significantly reduced the count of heterotrophic bacteria and Vibrio spp. in the culture water and shrimp intestine. Overall, the current results concluded that diet supplementation with natural astaxanthin, extracted from Arthrospira platensis, enhanced the growth performance, immune response, and antioxidant status of L. vannamei.
Myostatin and its Regulation: A Comprehensive Review of Myostatin Inhibiting Strategies
Authors: Baig Mohammad Hassan , Ahmad Khurshid , Moon Jun Sung , Park So-Young , Ho Lim Jeong , Chun Hee Jin , Qadri Afsha Fatima , Hwang Ye Chan , Jan Arif Tasleem , Ahmad Syed Sayeed , Ali Shahid , Shaikh Sibhghatulla , Lee Eun Ju , Choi Inho
Published: June 2022

Myostatin (MSTN) is a well-reported negative regulator of muscle growth and a member of the transforming growth factor (TGF) family. MSTN has important functions in skeletal muscle (SM), and its crucial involvement in several disorders has made it an important therapeutic target. Several strategies based on the use of natural compounds to inhibitory peptides are being used to inhibit the activity of MSTN. This review delivers an overview of the current state of knowledge about SM and myogenesis with particular emphasis on the structural characteristics and regulatory functions of MSTN during myogenesis and its involvements in various muscle related disorders. In addition, we review the diverse approaches used to inhibit the activity of MSTN, especially in silico approaches to the screening of natural compounds and the design of novel short peptides derived from proteins that typically interact with MSTN.
ESRRG, ATP4A, and ATP4B as Diagnostic Biomarkers for Gastric Cancer: A Bioinformatic Analysis Based on Machine Learning
Authors: Chen Qiu , Wang Yu , Liu Yongjun , Xi Bin
Published: June 2022

Based on multiple bioinformatics methods and machine learning techniques, this study was designed to explore potential hub genes of gastric cancer with a diagnostic value. The novel biomarkers were detected through multiple databases of gastric cancer–related genes. The NCBI Gene Expression Omnibus (GEO) database was used to obtain gene expression files. Three hub genes (ESRRG, ATP4A, and ATP4B) were detected through a combination of weighted gene co-expression network analysis (WGCNA), gene–gene interaction network analysis, and supervised feature selection method. GEPIA2 was used to verify the differences in the expression levels of the hub genes in normal and cancer tissues in the RNA-seq levels of Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. The objectivity of potential hub genes was also verified by immunohistochemistry in the Human Protein Atlas (HPA) database and transcription factor–hub gene regulatory network. Machine learning (ML) methods including data pre-processing, model selection and cross-validation, and performance evaluation were examined on the hub-gene expression profiles in five Gene Expression Omnibus datasets and verified on a GEO external validation (EV) dataset. Six supervised learning models (support vector machine, random forest, k-nearest neighbors, neural network, decision tree, and eXtreme Gradient Boosting) and one semi-supervised learning model (label spreading) were established to evaluate the diagnostic value of biomarkers. Among the six supervised models, the support vector machine (SVM) algorithm was the most effective one according to calculated performance metrics, including 0.93 and 0.99 area under the curve (AUC) scores on the test and external validation datasets, respectively. Furthermore, the semi-supervised model could also successfully learn and predict sample types, achieving a 0.986 AUC score on the EV dataset, even when 10% samples in the five GEO datasets were labeled. In conclusion, three hub genes (ATP4A, ATP4B, and ESRRG) closely related to gastric cancer were mined, based on which the ML diagnostic model of gastric cancer was conducted.
Decoding RNA Editing Sites Through Transcriptome Analysis in Rice Under Alkaline Stress
Authors: Rehman Obaid , Uzair Muhammad , Chao Haoyu , Khan Muhammad Ramzan , Chen Ming
Published: June 2022

Ribonucleic acid editing (RE) is a post-transcriptional process that altered the genetics of RNA which provide the extra level of gene expression through insertion, deletions, and substitutions. In animals, it converts nucleotide residues C-U. Similarly in plants, the role of RNA editing sites (RES) in rice under alkaline stress is not fully studied. Rice is a staple food for most of the world population. Alkaline stress cause reduction in yield. Here, we explored the effect of alkaline stress on RES in the whole mRNA from rice chloroplast and mitochondria. Ribonucleic acid editing sites in both genomes (3336 RESs) including chloroplast (345 RESs) and mitochondria (2991 RESs) with average RES efficiency ∼55% were predicted. Our findings showed that majority of editing events found in non-synonymous codon changes and change trend in amino acids was hydrophobic. Four types of RNA editing A-G (A-I), C-T (C-U), G-A, and T-C were identified in treated and untreated samples. Overall, RNA editing efficiency was increased in the treated samples. Analysis of Gene Ontology revealed that mapped genes were engaged in many biological functions and molecular processes. We also checked the expression of pentatricopeptide repeat (PPR), organelle zinc-finger (OZI), and multiple organellar RNA editing factors/RNA editing factor interacting proteins genes in control and treatment, results revealed upregulation ofPPRandOZ1genes in treated samples. This induction showed the role of these genes in RNA editing. The current findings report that RNA editing increased under alkaline stress which may contribute in adaptation for rice by changing amino acids in edited genes (88 genes). These findings will provide basis for identification of RES in other crops and also will be useful in alkaline tolerance development in rice.