bluuebunny/crossref_metadata_2025 huggingface dataset:
Case report: Significant relief of linezolid-induced peripheral neuropathy in a pre-XDR-TB case after acupuncture treatment
Authors: Mo Yuping , Zhu Zhu , Tan Jie , Liang Zhilin , Wu Jiahui , Chen Xingcheng , Hu Ming , Zhang Peize , Deng Guofang , Fu Liang
Published: September 2022

The revised WHO guidelines on multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) include linezolid in the core drug group. Common adverse events of prolonged linezolid use are bone marrow suppression and peripheral neuropathy (PN). Available measures against linezolid-induced PN (LIPN) often have insignificant effects, leading to linezolid discontinuation and a decline in the success rate of MDR/RR-TB treatment. Acupuncture treatment is a symptomatic treatment measure from traditional Chinese medicine (TCM) to relieve pain with overall very low evidence and has never been reported in LIPN. The pilot use of acupuncture in a pre-extensively drug-resistant (XDR)-TB (a more severe form of MDR/RR-TB) patient exhibited significant improvements in LIPN and thus maintained linezolid in the regimen for a longer period.
m6A RNA methylation in brain injury and neurodegenerative disease
Authors: Deng Jianhui , Chen Xiaohui , Chen Andi , Zheng Xiaochun
Published: September 2022

N6-methyladenosine (m6A), the most prevalent post-transcriptional RNA modification throughout the eukaryotic transcriptome, participates in diverse biophysiological processes including cell fates, embryonic development and stress responses. Accumulating evidence suggests that m6A modification in neural development and differentiation are highly regulated processes. As RNA m6A is crucial to protein translation and various bioprocesses, its modification dysregulation may also be associated with brain injury. This review highlights the biological significance of m6A modification in neurodegenerative disease and brain injury, including cerebrovascular disorders, is highlighted. Emphasis is placed on recent findings that elucidate the relevant molecular functional mechanism of m6A modification after brain injury and neurodegenerative disease. Finally, a neurobiological basis for further investigation of potential treatments is described.
Early blindness modulates haptic object recognition
Authors: Leo Fabrizio , Gori Monica , Sciutti Alessandra
Published: September 2022

Haptic object recognition is usually an efficient process although slower and less accurate than its visual counterpart. The early loss of vision imposes a greater reliance on haptic perception for recognition compared to the sighted. Therefore, we may expect that congenitally blind persons could recognize objects through touch more quickly and accurately than late blind or sighted people. However, the literature provided mixed results. Furthermore, most of the studies on haptic object recognition focused on performance, devoting little attention to the exploration procedures that conducted to that performance. In this study, we used iCube, an instrumented cube recording its orientation in space as well as the location of the points of contact on its faces. Three groups of congenitally blind, late blind and age and gender-matched blindfolded sighted participants were asked to explore the cube faces where little pins were positioned in varying number. Participants were required to explore the cube twice, reporting whether the cube was the same or it differed in pins disposition. Results showed that recognition accuracy was not modulated by the level of visual ability. However, congenitally blind touched more cells simultaneously while exploring the faces and changed more the pattern of touched cells from one recording sample to the next than late blind and sighted. Furthermore, the number of simultaneously touched cells negatively correlated with exploration duration. These findings indicate that early blindness shapes haptic exploration of objects that can be held in hands.
Subthalamic high-beta oscillation informs the outcome of deep brain stimulation in patients with Parkinson's disease
Authors: Chen Po-Lin , Chen Yi-Chieh , Tu Po-Hsun , Liu Tzu-Chi , Chen Min-Chi , Wu Hau-Tieng , Yeap Mun-Chun , Yeh Chih-Hua , Lu Chin-Song , Chen Chiung-Chu
Published: September 2022

Background

The therapeutic effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) is related to the modulation of pathological neural activities, particularly the synchronization in the β band (13–35 Hz). However, whether the local β activity in the STN region can directly predict the stimulation outcome remains unclear.

Objective

We tested the hypothesis that low-β (13–20 Hz) and/or high-β (20–35 Hz) band activities recorded from the STN region can predict DBS efficacy.

Methods

Local field potentials (LFPs) were recorded in 26 patients undergoing deep brain stimulation surgery in the subthalamic nucleus area. Recordings were made after the implantation of the DBS electrode prior to its connection to a stimulator. The maximum normalized powers in the theta (4–7 Hz), alpha (7–13 Hz), low-β (13–20 Hz), high-β (20–35 Hz), and low-γ (40–55 Hz) subbands in the postoperatively recorded LFP were correlated with the stimulation-induced improvement in contralateral tremor or bradykinesia–rigidity. The distance between the contact selected for stimulation and the contact with the maximum subband power was correlated with the stimulation efficacy. Following the identification of the potential predictors by the significant correlations, a multiple regression analysis was performed to evaluate their effect on the outcome.

Results

The maximum high-β power was positively correlated with bradykinesia–rigidity improvement (rs = 0.549, p < 0.0001). The distance to the contact with maximum high-β power was negatively correlated with bradykinesia–rigidity improvement (rs = −0.452, p < 0.001). No significant correlation was observed with low-β power. The maximum high-β power and the distance to the contact with maximum high-β power were both significant predictors for bradykinesia–rigidity improvement in the multiple regression analysis, explaining 37.4% of the variance altogether. Tremor improvement was not significantly correlated with any frequency.

Conclusion

High-β oscillations, but not low-β oscillations, recorded from the STN region with the DBS lead can inform stimulation-induced improvement in contralateral bradykinesia–rigidity in patients with PD. High-β oscillations can help refine electrode targeting and inform contact selection for DBS therapy.
Modeling developmental changes in print tuning in a transparent alphabetic orthography
Authors: Verhoeven Ludo , Voeten Marinus , Keuning Jos
Published: September 2022

The development of print tuning involves the increased specificity and redundancy for orthographic representations. However, it is by no means clear how decoding accuracy and efficiency are related over the years and how it affects reading disability. In the present study, we monitored the development of accuracy and efficiency of decoding in Dutch as a relatively transparent orthography as a function of orthographic complexity and lexical status throughout the primary grades. There was clear evidence that development of decoding accuracy preceded development of decoding efficiency and that a certain threshold of accuracy is needed for decoding efficiency to evolve. Furthermore, it was shown that pseudoword decoding efficiency predicted growth in word decoding efficiency, especially for the higher levels of orthographic complexity. There was also evidence that accuracy precedes efficiency across different profiles of readers and that decoding strength can be defined as a function of orthographic complexity and lexicality.
Structural basis of retinal membrane guanylate cyclase regulation by GCAP1 and RD3
Authors: Ames James B.
Published: September 2022

Retinal membrane guanylate cyclases (RetGC1 and RetGC2) are expressed in photoreceptor rod and cone cells, where they promote the onset of visual recovery during phototransduction. The catalytic activity of RetGCs is regulated by their binding to regulatory proteins, guanylate cyclase activating proteins (GCAP1-5) and the retinal degeneration 3 protein (RD3). RetGC1 is activated by its binding to Ca2+-free/Mg2+-bound GCAP1 at low cytosolic Ca2+ levels in light-activated photoreceptors. By contrast, RetGC1 is inactivated by its binding to Ca2+-bound GCAP1 and/or RD3 at elevated Ca2+ levels in dark-adapted photoreceptors. The Ca2+ sensitive cyclase activation helps to replenish the cytosolic cGMP levels in photoreceptors during visual recovery. Mutations in RetGC1, GCAP1 or RD3 that disable the Ca2+-dependent regulation of cyclase activity are genetically linked to rod/cone dystrophies and other inherited forms of blindness. Here I review the structural interaction of RetGC1 with GCAP1 and RD3. I propose a two-state concerted model in which the dimeric RetGC1 allosterically switches between active and inactive conformational states with distinct quaternary structures that are oppositely stabilized by the binding of GCAP1 and RD3. The binding of Ca2+-free/Mg2+-bound GCAP1 is proposed to activate the cyclase by stabilizing RetGC1 in an active conformation (R-state), whereas Ca2+-bound GCAP1 and/or RD3 inhibit the cyclase by locking RetGC1 in an inactive conformation (T-state). Exposed hydrophobic residues in GCAP1 (residues H19, Y22, M26, F73, V77, W94) are essential for cyclase activation and could be targeted by rational drug design for the possible treatment of rod/cone dystrophies.
Myristic acid alleviates hippocampal aging correlated with GABAergic signaling
Authors: Shang Qi , Chen Guifeng , Zhang Peng , Zhao Wenhua , Chen Honglin , Yu Die , Yu Fuyong , Liu Huiwen , Zhang Xuelai , He Jiahui , Yu Xiang , Zhang Zhida , Tan Riwei , Wu Zixian , Tang Jingjing , Liang De , Shen Gengyang , Jiang Xiaobing , Ren Hui
Published: September 2022

Previous studies have shown that myristic acid (MA), a saturated fatty acid, could promote the proliferation and differentiation of neural stem cells in vitro. However, the effect of MA on hippocampal neurons aging has not been reported in vivo. Here we employed 22-month-old naturally aged C57BL/6 mice to evaluate the effect and mechanism of MA on hippocampal aging. First, we examined a decreased exploration and spatial memory ability in aging mice using the open field test and Morris water maze. Consistently, aging mice showed degenerative hippocampal histomorphology by H&E and Nissl staining. In terms of mechanism, imbalance of GABRB2 and GABRA2 expression in aging mice might be involved in hippocampus aging by mRNA high throughput sequencing (mRNA-seq) and immunohistochemistry (IHC) validation. Then, we revealed that MA alleviated the damage of exploration and spatial memory ability and ameliorated degeneration and aging of hippocampal neurons. Meanwhile, MA downregulated GABRB2 and upregulated GABRA2 expression, indicating MA might alleviate hippocampal aging correlated with GABAergic signaling. In conclusion, our findings revealed MA alleviated hippocampal aging correlated with GABAergic signaling, which might provide insight into the treatment of aging-associated diseases.
Iron metabolism mediates the relationship between Vitamin C and hepatic steatosis and fibrosis in NAFLD
Authors: Hu Zhengyu , Li Yan , Ma Bingwei , Lei Saifei , Wang Xingchun
Published: September 2022

Vitamin C (Vit C) and iron metabolism are closely related to metabolic disorders. However, the relation between iron storage protein ferritin and Vit C has not been elucidated. We aimed to investigate the crosstalk between Vit C and ferritin and its implications on non-alcoholic fatty liver disease (NAFLD). Clinical information of 3,614 subjects was obtained from the NHANES Public Data 2017–2018. FibroScan data, which estimates liver steatosis and fibrosis and Vit C, were selected to assess factors influencing NAFLD in this cross-sectional study. Ferritin and Vit C among different categories of liver steatosis and fibrosis were assessed by CAP and E value. Logistic regression and RCS models were used to analyze the correlations. In vitro study in hepG2 were conducted to validate the regulations. Ferritin increased while Vit C decreased with more severe hepatic steatosis and hepatic fibrosis (all P < 0.001). Logistic regression models indicated that increased serum ferritin was a risk factor for NAFLD while increased Vit C was a protective factor for NAFLD and hepatic fibrosis after adjusting the continuous and categorical variables. Vitamin C was negatively associated with ferritin. Further mediation analysis identified that ferritin mediates the impact of Vit C on NAFLD (P < 0.05) and cirrhosis (P < 0.001). The experiments on cellular level suggested Vit C alleviated PA/OA induced steatosis and maintains iron homeostasis through inhibiting PA/OA induced upregulation of iron bound protein ferritin and labile iron pool (LIP) induction in hepG2 cells. In conclusion, Vit C was a protective factor, whereas ferritin was a risk factor for hepatic steatosis and fibrosis. Vitamin C alleviated NAFLD and maintained iron homeostasis via ferritin suppression and LIP induction.
Plant-based diet for obesity treatment
Authors: Ahmad Siti Rohaiza
Published: September 2022

Obesity rates continue to rise, resulting in a global epidemic that shows no sign of slowing down. Our understanding of this complex disease is also constantly evolving, requiring healthcare providers to stay up to date with best practices. The application of plant-based diets (PBDs) may hold the key to a successful weight-control strategy. PBD refers to any dietary pattern that emphasizes the consumption of plant foods while excluding the consumption of most or all animal products. The purpose of this mini-review is to report on the application of PBDs as a potential treatment for obesity. PBDs have also been shown to be beneficial in the treatment of other non-communicable diseases, such as the prevention and treatment of type 2 diabetes. Many of the reported RCTs were of short duration. Longer-term studies, as well as studies focusing on strict adherence to the PBD regime, are needed. PBD is a beneficial approach to improving health, particularly in obese patients. Benefits include weight loss, improved cardiovascular health, lower blood pressure, and improved glucose metabolism.
Role of sympathetic pathway in light-phase time-restricted feeding-induced blood pressure circadian rhythm alteration
Authors: Hou Tianfei , Chacon Aaron N. , Su Wen , Katsumata Yuriko , Guo Zhenheng , Gong Ming C.
Published: September 2022

Disruption of blood pressure (BP) circadian rhythm, independent of hypertension, is emerging as an index for future target organ damage and is associated with a higher risk of cardiovascular events. Previous studies showed that changing food availability time alters BP rhythm in several mammalian species. However, the underlying mechanisms remain largely unknown. To address this, the current study specifically investigates (1) the relationship between rhythms of food intake and BP in wild-type mice; (2) effects of light-phase time-restricted feeding (TRF, food only available during light-phase) on BP circadian rhythm in wild-type and diabetic db/db mice; (3) the roles of the autonomic system and clock gene in light-phase TRF induced changes in BP circadian rhythm. Food intake and BP of C57BL/6J and db/db mice were simultaneously and continuously recorded using BioDAQ and telemetry systems under ad libitum or light-phase TRF. Per2 protein daily oscillation was recorded in vivo by IVIS spectrum in mPer2Luc mice. Autonomic nerve activity was evaluated by heart rate variability, baroreflex, urinary norepinephrine (NE) and epinephrine (Epi) excretion, and mRNA expressions of catecholamines biosynthetic and catabolic enzymes, and alpha-adrenergic receptors in mesenteric resistance arteries. We found that in wild-type mice, the BP level was correlated with the food intake temporally across the 24 h. Reversing the feeding time by imposing light-phase TRF resulted in reverse or inverted BP dipping. Interestingly, the net changes in food intake were correlated with the net alteration in BP temporally under light-phase TRF. In db/db mice, light-phase TRF worsened the existing non-dipping BP. The food intake and BP circadian rhythm changes were associated with alterations in Per2 protein daily oscillation and the time-of-day variations in heart rate variability, baroreflex, and urinary excretion of NE and Epi, and increased mRNA expression of Slc6a2 (encoding NE transporter) and Adra1d (encoding alpha-adrenergic receptor 1d) in the mesenteric resistance arteries, indicating the sympathetic nervous system (SNS) was modulated after light-phase TRF. Collectively, our results demonstrated that light-phase TRF results in reverse dipping of BP in wild-type and diabetic db/db mice and revealed the potential role of the sympathetic pathway in light-phase TRF-induced BP circadian rhythm alteration.
A matter of time: A systematic scoping review on a potential role of the circadian system in binge eating behavior
Authors: Romo-Nava Francisco , Guerdjikova Anna I. , Mori Nicole N. , Scheer Frank A. J. L. , Burgess Helen J. , McNamara Robert K. , Welge Jeffrey A. , Grilo Carlos M. , McElroy Susan L.
Published: September 2022

Background

Emerging research suggests that food intake timing, eating behavior and food preference are associated with aspects of the circadian system function but the role that the circadian system may play in binge eating (BE) behavior in humans remains unclear.

Objective

To systematically evaluate the evidence for circadian system involvement in BE behavior.

Methods

Systematic searches of PubMed, EMBASE, and Scopus were performed for reports published from inception until May 2020 (PROSPERO Registration CRD42020186325). Searches were conducted by combining Medical Subject Headings related to the circadian system, BE behavior, and/or interventions. Observational and interventional studies in humans with BE behavior published in peer-review journals in the English language were included. Studies were assessed using quality and risk of bias tools (AXIS, ROB 2.0, or ROBINS).

Results

The search produced 660 articles, 51 of which were included in this review. Of these articles, 46 were observational studies and 5 were interventional trials. Evidence from these studies suggests that individuals with BE behavior tend to have more food intake, more binge cravings, and more BE episodes later in the day. Hormonal and day/night locomotor activity rhythm disturbances may be associated with BE behavior. Furthermore, late diurnal preference (“eveningness”) was associated with BE behavior and chronobiological interventions that shift the circadian clock earlier (e.g., morning bright light therapy) were found to possibly decrease BE behavior. Substantive clinical overlap exists between BE and night eating behavior. However, there is a significant knowledge gap regarding their potential relationship with the circadian system. Limitations include the lack of studies that use best-established techniques to assess the chronobiology of BE behavior, heterogeneity of participants, diagnostic criteria, and study design, which preclude a meta-analytic approach.

Conclusion

Current evidence, although limited, suggests that the circadian system may play a role in the etiology of BE behavior. Further mechanistic studies are needed to fully characterize a potential role of the circadian system in BE behavior. A chronobiological approach to studying BE behavior may lead to identification of its neurobiological components and development of novel therapeutic interventions.

Systematic review registration

[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020186325], identifier [CRD42020186325].
Effect of inulin on the pasting and retrogradation characteristics of three different crystalline starches and their interaction mechanism
Authors: Ji Xiaolong , Wang Zhiwen , Jin Xueyuan , Qian Zhenpeng , Qin Le , Guo Xudan , Yin Mingsong , Liu Yanqi
Published: September 2022

At present, there are hardly any studies about the effect of inulin (IN) on the physicochemical properties and structures of different crystalline starches. In this study, three different crystalline starches (wheat, potato, and pea starch) were compounded with natural IN, and its pasting, retrogradation, and structural characteristics were investigated. Then, the potential mechanism of interaction between IN and starch was studied. The results showed that there were some differences in the effects of IN on the three different crystalline starch. Pasting experiments showed that the addition of IN not only increased pasting viscosity but also decreased the values of setback and breakdown. For wheat starch and pea starch, IN reduced their peak viscosity from 2,515 cP, 3,035 cP to 2,131 cP and 2,793 cP, respectively. Retrogradation experiment dates demonstrated that IN delayed gelatinization of all three starches. IN could reduce the enthalpy of gelatinization and retrogradation to varying degrees and inhibit the retrogradation of starch. Among them, it had a better inhibitory effect on potato starch. The addition of IN reduced the retrogradation rate of potato starch from 38.45 to 30.14%. Fourier-transform infrared spectroscopy and interaction force experiments results showed that IN interacted with amylose through hydrogen bonding and observed the presence of electrostatic force in the complexed system. Based on the above, experimental results speculate that the mechanism of interaction between IN and three crystalline starches was the same, and the difference in physicochemical properties was mainly related to the ratio of amylose to amylopectin in different crystalline starches. These findings could enrich the theoretical system of the IN with starch compound system and provide a solid theoretical basis for further applications.
Lessons learned from the “Goodie Box”: A message design study developed and evaluated in community settings for cervical cancer prevention
Authors: McFarlane Soroya Julian , Morgan Susan E. , Carcioppolo Nick
Published: September 2022

Despite the availability of free pap testing services, Jamaican women have low human papillomavirus (HPV) screening rates; 16% of women in the Kingston Metropolitan Area have been screened within the prior 3 years. This paper discusses the testing of theory-based messages to increase HPV screening uptake in a low-resource setting, using HPV self-test kits designed for this intervention. A total of 163 Jamaican women, aged 30–65 years, who had not had a pap test in at least 3 years, from two low socioeconomic status communities in Kingston, were enrolled and assigned to one of two versions of an HPV self-test kit, either with or without culturally targeted fear appeal messages. The uptake of screening was high across conditions; 95.6% of participants used the HPV self-test and returned their kits. However, surprising variations were observed in self-test acceptability, explained by differing attitudes toward the message conditions. Based on the results, we recommend four key components to increase HPV screening in low-resource settings: 1) focus on perceived threat in message design, 2) avoid written materials due to literacy concerns, 3) use culturally appropriate interpersonal or community-based channels, and 4) consider alternative solutions (such as a self-test) available at no or low cost to address structural barriers.
Exome sequencing link mutation in RGPD4 with systemic sclerosis-associated interstitial lung disease and the low level of testosterone—an exploration study
Authors: Wang Na , Zhang Qian , Sun Wei , Yang Xiaoyu , Huang Hui , Xu Zuojun
Published: September 2022

Background

Interstitial lung disease (ILD) is the most common and potentially most devastating manifestation of SSc in pulmonary involvement. However, the mechanism for systemic sclerosis-associated ILD (SSc-ILD) is unclear. This work aims to explore the potential candidates for SSc-ILD upon whole exome sequencing (WES) and attempts to analyze the possible pathogenesis of SSc-ILD from the perspective of the genetic level.

Materials

Variants were confirmed by whole exome sequencing (WES), and SKAT analysis was employed to explore the most differential variants. Targeted variants were performed in biological functions, associated with clinical manifestations, and the probable change of downstream.

Results

By WES and SKAT analysis of SSc with and without ILD, only the variants of RGPD4 achieved statistical power (P < 2.51 × 10-6, P-FDR = 0.025, OR = 15.95). A total of 20 rare functional variants (missense, truncating, splicing) were tested for the RGPD4 gene, and five truncating and damaging missense variants were identified. Carriers showed the older inclusion age (P = 0.02) and the higher frequency use of prednisone (P=0.02) compared to the non-carriers. Further analysis illustrated that carriers showed lower levels of TES in comparison to non-carriers but did not reach statistical difference (P = 0.08). In bivariate correlation analysis, we analyzed the relationship between the mutant status of RGPD4 and the levels of sex hormones after adjusting for age confounders. Only the level of TES showed a negative correlation with the mutant status (B = -0.509, P = 0.037).

Conclusion

The variants of RGPD4 might contribute to the ILD development of SSc and might also be a causative factor of lower TES among SSc-ILD, which provided insight to a better understanding of pathobiology of SSc-ILD, and androgen hormone supplement might be a therapeutic target in this debilitating disease.
A comprehensive role evaluation and mechanism exploration of POGLUT2 in pan-cancer
Authors: Xu Xianyun , Xie Guangming , Xie Mingfeng , Liu Qian
Published: September 2022

Objective

To evaluate the role of POGLUT2 in pan-cancer through bioinformatics analysis and experimental verification.

Methods

Expression, gene mutation and amplification, methylation, and copy number alteration (CNA) of POGLUT2 were evaluated using The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx) databases. Moreover, POGLUT2 on survival and disease progression in pan-cancer was performed using TCGA data. Immune infiltration and tumor microenvironment evaluations were assessed by ImmuneScore, ImmuCellAI, and TIMER databases. POGLUT2 correlated drug resistance analysis was performed using the GDSC2 database. Furthermore, POGLUT2 knockdown of breast cancer cells was established, followed by in vitro biological function assays and in vivo tumor growth study. The mechanisms of POGLUT2 in breast cancer were briefly evaluated via its connection with Notch signaling.

Results

Increased levels of POGLUT2 were found in multiple types of cancer tissues and cell lines. Moreover, increased gene mutation and amplification, methylation, and CNA of POGLUT2 were found in several types of cancers. POGLUT2 was mainly expressed in stromal cells as verified by StromalScore, ESTIMATEScore, ImmuneScore, and Tumor purity, and POGLUT2 was positively correlated with cancer-associated fibroblasts, macrophages, monocytes, and neutrophils in the tumor microenvironment. In vitro and in vivo results showed that POGLUT2 knockdown could delay tumor growth and progression. Notch signaling components were related to the function of POGLUT2.

Conclusions

Increased levels of POGLUT2 could result in the dysregulated immune cell infiltration and tumor microenvironment and showed a significant regulatory effect on the progression of breast cancer through Notch-related signaling.
Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma
Authors: Trudu Matteo , Oliva Laura , Orfanelli Ugo , Romano Alessandra , Di Raimondo Francesco , Sanvito Francesca , Ponzoni Maurilio , Cenci Simone
Published: September 2022

Multiple myeloma grows by establishing multiple interactions with bone marrow cells. These include expansion of myeloid-derived suppressor cells, which drive immunoevasion via mechanisms that include arginase-1-driven depletion of L-arginine, thus indirectly promoting myeloma cell survival and tumor progression. The peculiar biology of malignant plasma cells postulates that arginine depletion may benefit their fitness also directly, e.g., by engaging the integrated stress response, or by stimulating autophagy through mTORC1 inhibition. We thus investigated the direct impact of arginine deprivation on myeloma cells and challenged its pathophysiological relevance in vitro and in vivo. First, we found that partial arginine depletion spared proliferation of human multiple myeloma cells at concentrations that arrest human T cells. Next, we asked if arginine shortage activates putative adaptive pathways in myeloma cells. Low arginine failed to activate the integrated stress response, as indicated by unmodified phosphorylation of the eukaryotic initiation factor 2α, but sizably inhibited mTORC1, as revealed by reduced phosphorylation of ribosomal protein S6. Notably, depressed mTORC1 activity was not sufficient to increase autophagy, as assessed by the lysosomal digestion rate of the autophagosome-associated protein, LC3-II. Rather, it stimulated mTORC2, resulting in increased phosphatidylinositol-3 kinase-dependent AKT phosphorylation and activity, leading to heightened inhibitory phosphorylation of the pro-apoptotic BAD protein. We then tested whether arginine depletion-activated AKT may protect malignant plasma cells from cell death. Indeed, culturing myeloma cells in low arginine medium significantly reduced the apoptotic effect of the first-in-class proteasome inhibitor, bortezomib, an outcome prevented by pharmacological inhibition of AKT phosphorylation. Finally, we challenged the relevance of the identified circuit in vivo. To gauge the pathophysiologic relevance of low arginine to myeloma growth independently of immunoevasion, we xenotransplanted human myeloma cells subcutaneously into T cell-deficient Rag2–/–γc–/– recipient mice and treated palpable tumor-bearing mice with the clinical-grade arginase inhibitor CB1158. Arginase inhibition significantly raised serum arginine concentration, reduced tumor growth by caliper assessment, and decreased intra-tumor AKT phosphorylation in vivo. Altogether, our results reveal a novel direct pro-survival effect of arginine deprivation on myeloma cells, with potential therapeutic implications.
Identification of an amino acid metabolism-associated gene signature predicting the prognosis and immune therapy response of clear cell renal cell carcinoma
Authors: Zhang Fan , Lin Junyu , Zhu Daiwen , Tang Yongquan , Lu Yiping , Liu Zhihong , Wang Xianding
Published: September 2022

Background

The upregulation of amino acid metabolism is an essential form of metabolic reprogramming in cancer. Here, we developed an amino acid metabolism signature to predict prognosis and anti-PD-1 therapy response in clear cell renal cell carcinoma (ccRCC).

Methods

According to the amino acid metabolism-associated gene sets contained in the Molecular Signature Database, consensus clustering was performed to divide patients into two clusters. An amino acid metabolism-associated signature was identified and verified. Immune cell infiltrates and their corresponding signature risk scores were investigated. Two independent cohorts of clinical trials were analyzed to explore the correspondence between the signature risk score and the immune therapy response.

Results

Two clusters with different amino acid metabolic levels were identified by consensus clustering. The patients in the two clusters differed in overall survival, progression-free survival, amino acid metabolic status, and tumor microenvironment. We identified a signature containing eight amino acid metabolism-associated genes that could accurately predict the prognosis of patients with ccRCC. The signature risk score was positively correlated with infiltration of M1 macrophages, CD8+ T cells, and regulatory T cells, whereas it was negatively correlated with infiltration of neutrophils, NK cells, and CD4+ T cells. Patients with lower risk scores had better overall survival but worse responses to nivolumab.

Conclusion

Amino acid metabolic status is closely correlated with tumor microenvironment, response to checkpoint blockade therapy, and prognosis in patients with ccRCC. The established amino acid metabolism-associated gene signature can predict both survival and anti-PD-1 therapy response in patients with ccRCC.
Dual-layer dual-energy CT for improving differential diagnosis of squamous cell carcinoma from adenocarcinoma at gastroesophageal junction
Authors: Wu Meihong , Sheng Mao , Li Ruomei , Zhang Xinna , Chen Xingbiao , Liu Yin , Liu Bin , Yu Yongqiang , Li Xiaohu
Published: September 2022

Objective

To examine the clinical values of dual-energy CT parameters derived from dual-layer spectral detector CT (SDCT) in the differential diagnosis of squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the gastroesophageal junction (GEJ).

Methods

Totally 66 patients with SCC and AC of the GEJ confirmed by pathological analysis were retrospectively enrolled, and underwent dual-phase contrast-enhancement chest CT with SDCT. Plain CT value, CT attenuation enhancement (△CT), iodine concentration (IC), spectral slope (λHU), effective atomic number (Zeff) and 40keV CT value (CT40keV) of the lesion in the arterial phase (AP) and venous phase (VP) were assessed. Multivariate logistic regression analysis was performed to evaluate the diagnostic efficacies of different combinations of dual-energy CT parameters. Receiver operating characteristic (ROC) curves were used to analyze the accuracy of dual-energy CT parameters and Delong test was used to compare AUCs.

Results

IC, λHU, Zeff and CT40keV in AP and VP and △CT in VP were significantly higher in the AC group than those in the SCC group (all P<0.05). ROC curve analysis showed that IC, λHU, Zeff and CT40keV in VP had high diagnostic performances, with AUCs of 0.74, 0.74, 0.79 and 0.78, respectively. Logistic regression showed the combination of ICVP, λHU VP, CT40keV VP and Zeff VP had the highest AUC (0.84), with a threshold of 0.40, sensitivity and specificity in distinguishing SCC and AC were 93.1% and 73.0%, respectively. Delong test showed that the AUC of △CTVP was lower than other AUCs of dual-energy CT parameters.

Conclusion

Dual-energy CT parameters derived from SDCT provide added value in the differential diagnosis of SCC and AC of the GEJ, especially the combination of IC, λHU, CT40keV and Zeff in VP.

Advances in knowledge

Dual-energy CT parameters derived from dual-layer spectral detector CT provide added value to differentiate AC from SCC at the GEJ, especially the combination of effective atomic number, spectral slope, iodine concentration and 40keV CT value in VP.
Machine learning models predict lymph node metastasis in patients with stage T1-T2 esophageal squamous cell carcinoma
Authors: Li Dong-lin , Zhang Lin , Yan Hao-ji , Zheng Yin-bin , Guo Xiao-guang , Tang Sheng-jie , Hu Hai-yang , Yan Hang , Qin Chao , Zhang Jun , Guo Hai-yang , Zhou Hai-ning , Tian Dong
Published: September 2022

Background

For patients with stage T1-T2 esophageal squamous cell carcinoma (ESCC), accurately predicting lymph node metastasis (LNM) remains challenging. We aimed to investigate the performance of machine learning (ML) models for predicting LNM in patients with stage T1-T2 ESCC.

Methods

Patients with T1-T2 ESCC at three centers between January 2014 and December 2019 were included in this retrospective study and divided into training and external test sets. All patients underwent esophagectomy and were pathologically examined to determine the LNM status. Thirty-six ML models were developed using six modeling algorithms and six feature selection techniques. The optimal model was determined by the bootstrap method. An external test set was used to further assess the model’s generalizability and effectiveness. To evaluate prediction performance, the area under the receiver operating characteristic curve (AUC) was applied.

Results

Of the 1097 included patients, 294 (26.8%) had LNM. The ML models based on clinical features showed good predictive performance for LNM status, with a median bootstrapped AUC of 0.659 (range: 0.592, 0.715). The optimal model using the naive Bayes algorithm with feature selection by determination coefficient had the highest AUC of 0.715 (95% CI: 0.671, 0.763). In the external test set, the optimal ML model achieved an AUC of 0.752 (95% CI: 0.674, 0.829), which was superior to that of T stage (0.624, 95% CI: 0.547, 0.701).

Conclusions

ML models provide good LNM prediction value for stage T1-T2 ESCC patients, and the naive Bayes algorithm with feature selection by determination coefficient performed best.
Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in children with leukemia/lymphoma: A retrospective case series
Authors: Zhang Yucai , Zhou Yiping , Shi Jingyi , Shan Yijun , Sun Ting , Wang Chunxia , Shao Jingbo , Cui Yun
Published: September 2022

Objective

The cancer patients with severe acute respiratory distress syndrome (ARDS) benefit from extracorporeal membrane oxygenation (ECMO) remains unanswered. We analyzed clinical characteristics and outcomes of pediatric patients with leukemia/lymphoma who developed ARDS and treated with ECMO.

Methods

Pediatric leukemia or lymphoma patients with ARDS who underwent ECMO between August 2017 and December 2021 were retrospectively analyzed in a tertiary pediatric intensive care unit (PICU).

Results

Seven patients with median age 53 (IQR 42–117) months and 4 males were included. Six cases of leukemia [5 of acute lymphocytic leukemia (ALL) and 1 of acute myelogenous leukemia (AML, M5)] and 1 of non-Hodgkin lymphoma with severe ARDS received ECMO on chemotherapy period. The etiology of ARDS is community or chemotherapy-associated bacterial or/and fungal or viral infection. All the patients received chemotherapy in the 2 weeks prior to ECMO and five were neutropenic at initial ECMO. Six cases underwent veno-arterial ECMO (VA ECMO) and 1 for veno-venous ECMO (VV-ECMO). The median duration of ECMO support was 122 (IQR 56–166) hours. Overall, 42.9% (three of seven) survived to hospital discharge and 6 months survival rate was 28.6% (two of seven). Bleeding was the main ECMO-associated complication occurring in 7 patients, followed by nosocomial infection in 4 cases. All the patients required vasopressor support, and 6 received continuous renal replacement therapy (CRRT).

Conclusion

Our experiences suggest that rescue ECMO provides a selective treatment strategy in childhood hematologic malignancies with severe ARDS.
Acoustic conditioning of the neonatal incubator compartment: Improvement proposal
Authors: Rodríguez-Montaño Víctor M. , Beira-Jiménez Juan Luis , Puyana-Romero Virginia , Cueto-Ancela José Luis , Hernández-Molina Ricardo , Fernández-Zacarías Francisco
Published: September 2022

The objective of this work focuses on the study of the main sources of noise associated with incubators and the acoustic effects that derive from them. The method that has been established is based on tests carried out under different operating conditions of the incubators. Noise levels are analyzed under different boundary conditions (Neonatal ICU and “Controlled environment rooms”). Under normal operating conditions, the levels inside the incubator are around 56 dB (A), values that exceed the maximum limits recommended by the American Academy of Pediatrics. The scope of this study is to evaluate the existing noise levels in the incubator and analyze possible design improvements. The study was carried out in the hospitals of Cádiz, Huelva, and Malaga.
A mechanistic overview of approaches for the treatment of psychostimulant dependence
Authors: Jensen Kathrine Louise , Jensen Søren Brøgger , Madsen Kenneth Lindegaard
Published: September 2022

Psychostimulant use disorder is a major health issue around the world with enormous individual, family-related and societal consequences, yet there are no effective pharmacological treatments available. In this review, a target-based overview of pharmacological treatments toward psychostimulant addiction will be presented. We will go through therapeutic approaches targeting different aspects of psychostimulant addiction with focus on three major areas; 1) drugs targeting signalling, and metabolism of the dopamine system, 2) drugs targeting either AMPA receptors or metabotropic glutamate receptors of the glutamate system and 3) drugs targeting the severe side-effects of quitting long-term psychostimulant use. For each of these major modes of intervention, findings from pre-clinical studies in rodents to clinical trials in humans will be listed, and future perspectives of the different treatment strategies as well as their potential side-effects will be discussed. Pharmaceuticals modulating the dopamine system, such as antipsychotics, DAT-inhibitors, and disulfiram, have shown some promising results. Cognitive enhancers have been found to increase aspects of behavioural control, and drugs targeting the glutamate system such as modulators of metabotropic glutamate receptors and AMPA receptors have provided interesting changes in relapse behaviour. Furthermore, CRF-antagonists directed toward alleviating the symptoms of the withdrawal stage have been examined with interesting resulting changes in behaviour. There are promising results investigating therapeutics for psychostimulant addiction, but further preclinical work and additional human studies with a more stratified patient selection are needed to prove sufficient evidence of efficacy and tolerability.
Preventive effects of the Rehmannia glutinosa Libosch and Cornus officinalis Sieb herb couple on chronic kidney disease rats via modulating the intestinal microbiota and enhancing the intestinal barrier
Authors: Wang Ling , Zhu Jin-Hui , Jiang Xiao-Dan , Ma Zhen-Xiang , Tao Jin-Hua
Published: September 2022

CKD is a clinical syndrome with slow development and gradual deterioration of renal function. At present, modern medicine still lacks an ideal treatment method for this disease, while TCM has accumulated rich clinical experience in the treatment of CKD, which can effectively improve renal function and delay renal failure, and has unique advantages. RC is widely used in clinical practice to treat CKD, especially the “Kidney-Yin” deficiency syndrome. However, the compatibility mechanisms responsible for its effects in experimental studies, including preclinical and clinical research studies, are still not fully understood. Adenine-induced CKD rats were used to investigate the preventive effect of RC on CKD rats. Based on the high-throughput 16S rRNA gene sequencing results from Illumina, we discussed the intestinal flora abundance in rats in different treatment groups. According to a PCA and a PCoA based on a distance matrix, there was a clear separation of gut microbiome profiles between normal rats and model rats in terms of beta diversity. The abundance of Firmicutes in CKD rats was relatively increased, while that of Bacteroidetes was decreased. It is clear that the plot for the RC group was closer to that of the normal group, suggesting that the RC group had higher similarities among bacterial members with N rats. Ussing chamber, Western blot, and PCR assays were used to investigate the effects of RC on intestinal barrier function and its molecular mechanism in model animals. The results indicated that the protein expressions of ZO-1, claudin-1, and occludin-1 were decreased significantly in chronic kidney disease rats with the induction of adenine. With the treatment of RG, CO, and RC, the intestinal barrier was repaired due to the upregulated expressions of the aforementioned proteins in CKD rats. Based on our findings, RC appears to strengthen the intestinal barrier and modulate gut microbiota in adenine-induced CKD rats. This project revealed the compatibility mechanism of RC in regulating the intestinal microecology and barrier function to intervene in CKD and provided the basis and ideas for the clinical application of RC and the development of innovative drugs for CKD.
Cross-sectional study of the prevalence of prescription opioids misuse in French patients with chronic non-cancer pain: An update with the French version of the POMI scale
Authors: Kerckhove Nicolas , Delage Noémie , Bertin Célian , Kuhn Emmanuelle , Cantagrel Nathalie , Vigneau Caroline , Delorme Jessica , Lambert Céline , Pereira Bruno , Chenaf Chouki , Authier Nicolas ,   Poma Network
Published: September 2022

Public health issues related to chronic pain management and the risks of opioid misuse and abuse remain a challenge for practitioners. Data on the prevalence of disorders related to the use of prescribed opioids in patients suffering from chronic pain remains rather patchy, in particular because of the absence of a gold standard for their clinical assessment. We estimated the prevalence of prescription opioid misuse (POM), using a specific and validated opioid misuse scale (POMI-5F scale), in adults with chronic non-cancer pain. Nine-hundred-fifty-one (951) patients with opioids prescription and followed-up in pain clinics and addictology centers for chronic non-cancer pain (CNCP) completed the survey interview. The results suggest that 44.4% of participants have POM, accompanied by overuse (42.5%), use of opioids for effects other than analgesia (30.9%), withdrawal syndrome (65.7%), and craving (6.9%). The motivations cited for POM, apart from pain relief, were to calm down, relax and improve mood. POM was shown to be related to male sex (OR 1.52), young age (OR 2.21) and the presence of nociplastic pain (OR 1.62) of severe intensity (OR 2.31), codeine use (OR 1.72) and co-prescription of benzodiazepines (OR 1.59). Finally, despite the presence of three subgroups of misusers, no factor was associated with the intensity of misuse, reinforcing the view that distinguishing between strong and weak opioids is not appropriate in the context of use disorder. Almost half of patients with CNCP misuse their prescribed opioid. Practitioners should be attentive of profiles of patients at risk of POM, such as young, male patients suffering from severe nociplastic pain, receiving prescription for codeine and a co-prescription for benzodiazepine. We encourage French-speaking practitioners to use the POMI-5F scale to assess the presence of POM in their patients receiving opioid-based therapy.

Clinical Trial Registrationclinicaltrials.gov, identifier NCT03195374
A high throughput method for Monitoring of Sorafenib, regorafenib, cabozantinib and their metabolites with UPLC-MS/MS in rat plasma
Authors: Gu Er-Min , Liu Ya-Nan , Pan Lvjun , Hu Yingying , Ye Xuemei , Luo Pingping
Published: September 2022

As multi-targeted tyrosine kinase inhibitors, sorafenib, regorafenib and cabozantinib are widely used in hepatocellular carcinoma (HCC) for systemic therapies with anti-proliferative and anti-angiogenic effects. Nevertheless, adverse effects or insufficient efficacy appear frequently due to the plasma concentration with individual variability of these drugs. To ensure the curative effect and safety by therapeutic drug monitoring (TDM), this study developed a high throughput method to quantify sorafenib, regorafenib, cabozantinib and their active metabolites in plasma simultaneously. The chromatographic separation analysis achievement was performed on a Waters-ACQUITY UPLC BEH C18 column by UPLC-MS/MS system using a gradient elution of solvent A (acetonitrile) and solvent B (water with 0.1% formic acid) in 3.0 min. This method presented satisfactory results of specificity, precision (the intra-day coefficient of variation was between 2.5% and 6.6%, and the inter-day coefficient of variation was between 4.0% and 11.1%) and accuracy (within ±15% for intra-day and inter-day), as well as the stability under certain conditions, the matrix effect in plasma, and extraction recovery (75.6%–94.4%). The linearity of each analyte in the proper concentration scope indicated excellent. This study strictly complied with the performance rules of assay validation in biological medium proposed by FDA and was successfully applied to the pharmacokinetic study in rats. Thus, it would be an advantageous option to research the relationship between concentration-efficacy and concentration-toxic in HCC patients who were supposed to take these medications.