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Background: Chronic psychological stress (PS) hinders the treatment of diabetes-associated cognitive decline (DACD). However, the impact of chronic PS on the risk of developing DACD remains unclear. There is growing evidence that gut flora interventions are promising targets for treating stress-related diseases. Objective: We examined whether chronic PS triggers or exacerbates the onset of DACD in rats and aimed to elucidate whether ZiBuPiYin recipe (ZBPYR) prevents and treats chronic PS-aggravated DACD by dynamically maintaining the components of the gut microbiota. Methods: We performed chronic PS (restraint, rotation, and congestion) on ZDF rats to establish a model. Cognitive function was evaluated by behavioral experiments, and activation of the hypothalamic-pituitary-adrenal axis was detected by ELISA. Weekly feces from rats were collected for 16 S RNA sequencing. Results: We found that chronic PS promoted cognitive abnormalities and exacerbated DACD phenotypes. Additionally, chronic PS altered intestinal flora diversity, dynamically elevating the abundance of Alistipes and Coprococcus; enriching Module 1 (Dorea, Blautia, Ruminococcus) and Module 48 (Blautia); and inhibiting Module 20 (Lactobacillus, SMB53), and Module 42 (Akkermansia). ZBPYR significantly alleviated hyperglycemia and cognitive impairment in chronic PS-aggravated DACD rats and dynamically reduced the abundance of Alistipes and Coprococcus; significantly enriched Module 3 (Ruminococcus) and Module 45 (Lactobacillus, Coprococcus, SMB53); and suppressed Module 2 (Lactobacillus), Module 16 (Turicibacter, Trichococcus, Lactobacillus, 02d06, Clostridium), Module 23 (Bifidobacterium), and Module 43 (Clostridium). Conclusion: ZBPYR might prevent and treat chronic PS-aggravated DACD by dynamically regulating Lactobacillus, Alistipes, and Coprococcus.

Cardiac inflammation is generally accompanied by hypoxia, while myocardial injury and an abnormal microenvironment caused by hypoxia tend to suppress the efficacy of common anti-inflammatory drugs. To improve the anti-inflammatory effect under hypoxia, a hypoxia-activated prodrug HAP1 consisting of a cyclooxygenase-2 (COX-2) inhibitor Ind and a carbonic anhydrase (CA) inhibitor Ace was synthesized. HAP1 was found to be activated by nitroreductase (NTR) under hypoxia to release two pharmacophores and achieve the combinatory medication intensively at the hypoxic site, better than Ind or Ace alone. When NTR activity was inhibited by Na

The purpose of this study was to comprehensively understand anal canal adenocarcinomas (AA) and develop a nomogram for prognostic prediction of AA.Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (the year 2004-2015). An external validation set was collected from West China Hospital (WCH) databases. Propensity-score matching (PSM) was performed to balance the demographic characteristic. A novel nomogram was developed to estimate individual survival probability and its performance was validated using the concordance index (C-index), calibration curves, and decision curve analyses (DCA).A total of 7901 patients were enrolled including 749 AA patients and 7152 squamous cell carcinomas of the anal canal (ASCC) patients. Before PSM, patients with AA had shorter cancer-specific survival (CSS) and OS than those with ASCC. However, after PSM, patients with AA were related to a favorable OS (p 0.001), but a comparable CSS (p = 0.140) to those with ASCC. Age, sex, grade, surgery, and M stage were the independent prognostic factors of CSS for AA and were included in the establishment of a novel nomogram. Patients from the WCH database (n = 112) were used as an external validation cohort. The C-index of the nomogram was 0.78 and 0.735 in internal and external validation, respectively, which suggested the good discrimination power of the model. Furthermore, calibration curves and DCA suggested good agreement between the predicted and actual survival. Lastly, a risk classification system based on a nomogram revealed the reliability of the novel model.AA and ASCC had distinct clinical features. AA was associated with a better prognosis than ASCC after PSM. The model of nomogram showed an accurate predictive ability for prognostic factors of AA patients.

The aim of the study was to comprehensively understand the combined hepatocellular and cholangiocarcinoma (CHC) and develop a nomogram for prognostic prediction of CHC.Data were collected from the Surveillance, Epidemiology and End Results (SEER) database (year 2004-2014). Propensity-score matching (PSM) was used to match the demographic characteristic of the CHC versus hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A nomogram model was established to predict the prognosis in terms of cancer specific survival (CSS). The established nomogram was externally validated by a multicenter cohort.A total of 71,756 patients enrolled in our study including 62,877 HCC patients, 566 CHC patients, and 8303 ICC patients. The CHC, HCC, and ICC are not exactly similar in clinical characteristic. After PSM, the CSS of CHC was better than HCC but comparable to ICC. Tumor size, M stage, surgery, chemotherapy, and surgery were independently prognostic factors of CHC and were included in the establishment of novel nomogram. The c-index of the novel nomogram in SEER training set and multicenter validation was 0.779 and 0.780, respectively, which indicated that the model was with better discrimination power. In addition, decision curve analyses proved the favorable potential clinical effect of the predictive model. Lastly, a risk classification based on nomogram also verified the reliability of the model.CHC had better survival than HCC but was comparable to ICC. The nomogram was established based on tumor size, M stage, chemotherapy, surgery, and radiotherapy and well validated by external multicenter cohort.

Aims: The purpose was to investigate the correlation between calcification and outcome in metastatic colorectal cancer (mCRC) patients who received bevacizumab plus chemotherapy as the first-line treatment. Methods: A single retrospective cohort study was conducted with all diagnosed mCRC cases who received bevacizumab and chemotherapy as the first-line therapy. Results: Among all enrolled patients (n = 159), 31 had tumor calcification. The median overall survival and progression-free survival were significantly better in patients with tumor calcification than in those without calcification. A higher objective overall response rate was also observed in the tumor calcification group. On multivariate analysis, tumor calcification was independently associated with overall survival and progression-free survival. Conclusions: Tumor calcification was independently associated with improved survival in mCRC patients treated with bevacizumab plus chemotherapy.

ROS1 is a proto-oncogene encoding a receptor tyrosine protein kinase (RTK), homologous to the v - Ros sequence of University of Manchester tumours virus 2 (UR2) sarcoma virus, whose ligands are still being investigated. ROS1 fusion genes have been identified in various types of tumours. As an oncoprotein, it promotes cell proliferation, activation and cell cycle progression by activating downstream signalling pathways, accelerating the development and progression of non-small cell lung cancer (NSCLC). Studies have demonstrated that ROS1 inhibitors are effective in patients with ROS1-positive NSCLC and are used for first-line clinical treatment. These small molecule inhibitors provide a rational therapeutic option for the treatment of ROS1-positive patients. Inevitably, ROS1 inhibitor resistance mutations occur, leading to tumours recurrence or progression. Here, we comprehensively review the identified biological properties and Differential subcellular localisation of ROS1 fusion oncoprotein promotes tumours progression. We summarise recently completed and ongoing clinical trials of the classic and new ROS1 inhibitors. More importantly, we classify the complex evolving tumours cell resistance mechanisms. This review contributes to our understanding of the biological properties of ROS1 and current therapeutic advances and resistant tumours cells, and the future directions to develop ROS1 inhibitors with durable effects.

BACKGROUND There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. METHODS This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16-75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5-9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). FINDINGS Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p

Dehumanization is observed in adults across cultures and is thought to motivate human violence. The age of its first expression remains largely untested. This research demonstrates that diverse representations of humanness, including a novel one, readily elicit blatant dehumanization in adults (N = 482) and children (aged 5-12; N = 150). Dehumanizing responses in both age groups are associated with support for outgroup inferiority. Similar to the link previously observed in adults, dehumanization by children is associated with a willingness to punish outgroup transgressors. These findings suggest that exposure to cultural norms throughout adolescence and adulthood are not required for the development of outgroup dehumanization.

The heterogeneity of tumor microenvironment (TME) of hepatocellular carcinoma (HCC) may relate to cell-cell interaction event (CCE) dysregulation and would affect therapeutic responses and clinical outcomes. To reveal the differentiation of CCEs in the liver tissue from healthy donors (HD) to HCC, scRNA-seq data of ~62000 cells from HD, paracancerous nontumor tissue (NT), and HCC were analyzed. The microenvironmental CCE landscape was constructed. Dysregulated cell types and changed molecular functions were identified with CCE alterations in HCC. Dysregulated CCEs which function as pivotal roles in tumorigenesis and development of HCC included SPP1-CD44, MIF-TNFRSF14, and VEGFA-NRP1. A CCE-based immune regulatory network was extracted to illustrate the mechanism of TME dysregulation. A prognostic signature based on CCE genes was identified and validated in independent datasets. Our study provided insights into the characteristics of the cross-talk between tumor cells and microenvironment in HCC and established a workflow strategy for CCE analyses based on scRNA-seq data.

Specific locations of carbon-carbon double bonds (C═C) in lipids often play an essential role in biological processes, and there has been a booming development in C═C composition analysis by mass spectrometry. However, a universal derivatization and fragmentation pattern for the annotation of C═C positions in lipids is still challenging and attractive. To expand this field in lipidomics, a flexible and convenient

Brain functional connectivity (FC) networks derived from resting-state functional magnetic resonance imaging (rs-fMRI) have been widely applied to automated identification of brain disorders, such as Alzheimer's disease (AD) and attention deficit hyperactivity disorder (ADHD). To generate compact representations of FC networks, various thresholding strategies have been developed to analyze brain FC networks. However, existing studies usually employ predefined thresholds or percentages of connections to threshold FC networks, thus ignoring the diversity of temporal correlation (particularly strong associations) among brain regions in same/different subject groups. Also, it is usually challenging to decide the optimal threshold or connection percentage in practice. To this end, in this paper, we propose a distribution-guided network thresholding (DNT) method for functional connectivity analysis in brain disorder identification with rs-fMRI. Specifically, for each functional connectivity of a pair of brain regions, we proposed to compute its specific threshold based on the distribution of connection strength (i.e., temporal correlation) between subject groups (e.g., patients and normal controls). The proposed DNT can adaptively yield FC-specific threshold for each connection in brain networks, thus preserving the diversity of temporal correlation among brain regions. Experiment results on both ADNI and ADHD-200 datasets demonstrate the effectiveness of our proposed DNT method in fMRI-based identification of AD and ADHD.

BACKGROUND Transcutaneous auricular vagus nerve stimulation (taVNS) may modulate cardiac autonomic function. However, the response rate of the traditional tonic paradigm is low, and the results remain inconsistent. A recent pilot study presented a novel burst paradigm to activate the cardiac parasympathetic system, which might offer a new approach to treat cardiac autonomic function. The present study reassessed the effect of burst taVNS on modulating heart rate variability and explored the difference between burst and traditional tonic paradigms. MATERIALS AND METHODS Forty-two young adults were recruited for this study. Each participant underwent three types of taVNS with sham (30 sec of stimulation), tonic (25 Hz, 500 μsec), and burst (five pulses at 500 Hz every 200 msec) paradigms, respectively, with simultaneous electrocardiogram recording. One-way analysis of variance, multivariate analysis of variance, and linear regression were used for analysis. Multiple testing was performed using Bonferroni correction. RESULTS Both burst and tonic paradigms induced a significant decrease in heart rate, which continued until poststimulation, and increased cardiac parasympathetic activity. Moreover, two parasympathetic system indicators showed significant increase only in burst taVNS. The response rates during burst (35.7%) and tonic (38.1%) stimulations were both higher than that during sham stimulation (11.9%). The response to taVNS showed parameter specificity with few nonresponders to the tonic paradigm responding to the burst paradigm. The overall response rate increased from 38.1% in tonic taVNS to 54.8% in taVNS using both burst and tonic paradigms. For both burst and tonic responders, baseline cardiac parasympathetic activity was found to be significantly negatively correlated with changes during stimulation. CONCLUSION The burst parameter could be used as an alternative strategy for regulating cardiac parasympathetic function by taVNS, which has the potential to be used as a complementary paradigm to traditional tonic taVNS for promoting clinical treatment efficacy.

Recent studies revealed that long non-coding RNAs (lncRNAs) have significant roles in regulating the pathogenesis of ischemia stroke, and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cell apoptosis. Aberrant expression of NEAT1 was found after the injury of ischemia-reperfusion, but the mechanism was not fully understood.The expression of NEAT1 and Mfn2 were detected in BV-2 and N2a cell with or without OGD/R-induced by qRT-PCR. Inflammatory cytokines secretion was detected by enzyme-linked immunosorbent assay (ELISA). The oxidative stress was evaluated by the examination of ROS, MDA and SOD levels. Flow cytometry and apoptosis marker detection by western blot were performed to examined apoptosis.The expression of NEAT1 and Mfn2 were decreased in OGD/R-induced cell model. Overexpression of NEAT1 or Mfn2 reduced oxidative stress and apoptosis by OGD/R-induced in neuronal cells, while knockdown of Sirt3 reversed the protective effect of NEAT1 and Mfn2. NEAT1 stabilized Mfn2 mRNA via recruiting Nova. NEAT1 alleviates the oxidative stress and apoptosis by OGD/R-induced via activating Sirt3.LncRNA NEAT1 stabilizes Mfn2 mRNA via recruiting Nova, therefore increase the expression of Mfn2 and alleviates ischemia-reperfusion induced oxidative stress and apoptosis via Mfn2/Sirt3 pathway.

Circ-Memo1 has been proved to be upregulated in ischemia-reperfusion induced acute injury of kidney tissues. However, the potential role of circ-Memo1 in cerebral hypoxia/reoxygenation (H/R) injury is still unclear.Blood samples were collected from 25 ischemic stroke patients and 25 healthy controls. To construct the H/R model, human brain microvascular endothelial cells (HBMVECs) were cultured under the hypoxic condition, followed by reoxygenation. Cell viability was analyzed by MTT assay. Flow cytometry was carried out to examine cell apoptosis. The level of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured by MDA and SOD assay kits, respectively. The levels of TNF-α, IL-1β, and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter gene detection was employed to verify the binding relationships between circ-Memo1, miR-17-5p, and SOS1.Circ-Memo1 and SOS1 expressions were increased, and miR-17-5p expression was reduced in ischemic stroke patients. Circ-Memo1 silencing promoted cell viability, inhibited the activation of ERK/NF-κB signaling pathway, reduced oxidative stress and inflammatory response, and inhibited cell apoptosis. Moreover, miR-17-5p functioned as the sponge of circ-Memo1, and SOS1 was identified as the target of miR-17-5p. The protective effect of circ-Memo1 knockdown on cell injury after H/R treatment was weakened by miR-17-5p inhibition.Knockdown of circ-Memo1 alleviated H/R injury of HBMVEC cells by regulating the miR-17-5p/SOS1 axis, indicating that circ-Memo1 might be a potential treatment target for cerebral H/R injury.

Purpose: Immune-related pneumonitis (IRP) has attracted extensive attention, owing to its increased mortality rate. Conventional chemotherapy (C) has been considered as an immunosuppressive agent and may thus reduce IRP’s risk when used in combination with PD-1/L1 inhibitors. This study aimed to assess the risk of IRP with PD-1/L1 inhibitors plus chemotherapy (I+C) versus PD-1/L1 inhibitors alone (I) in solid cancer treatment. Method: Multiple databases were searched for RCTs before January 2021. This NMA was performed among I+C, I, and C to investigate IRP’s risk. Subgroup analysis was carried out on the basis of different PD-1/L1 inhibitors and cancer types. Results: Thirty-one RCTs (19,624 patients) were included. The I+C group exhibited a lower risk of IRP in any grade (RR, 0.60; 95% CI, 0.38–0.95) and in grade 3–5 (RR, 0.44; 95% CI, 0.21–0.92) as opposed to the I group. The risk of any grade IRP with PD-1 plus chemotherapy was lower than that with PD-1 monotherapy (RR, 0.50; 95% CI, 0.28–0.89), although grade 3–5 IRP was similar. There was no statistically meaningful difference in the risk of any grade IRP between PD-L1 plus chemotherapy and PD-L1 inhibitors monotherapy (RR, 0.95; 95% CI, 0.43–2.09) or grade 3–5 IRP (RR, 0.71;95% CI, 0.24–2.07). In addition, compared with the I group, the I+C group was correlated with a decreased risk in IRP regardless of cancer type, while a substantial difference was only observed in NSCLC patients for grade 3–5 IRP (RR, 0.39; 95% CI, 0.15–0.98). Conclusion: In comparison to PD-1/L1 inhibitor treatment alone, combining chemotherapy with PD-1/L1 inhibitors might reduce the risk of IRP in the general population. Furthermore, PD-1 inhibitors in combination with chemotherapy were correlated with a decreased risk of IRP compared to PD-1 inhibitor treatment alone. In contrast to the I group, the I+C group exhibited a lower risk of IRP, especially for NSCLC patients.

Appending of ferrocene (Fc) to biologically-active organic backbones can generate novel multi-functional species for targeting bacteria and cancer. In this work Fc was linked to coumarin and anthraquinone with the goal of harnessing the redox-active Fc centre to generate new compounds that exhibit cytoxicity through the generation of toxic reactive oxygen species (ROS). A Cu(I)-catalyzed azide-alkyne cycloaddition "click" reaction was used to connect the organic and Fc components

Background The overall survival rate of osteosarcoma (OS) patients has not been improved for 30 years, and the diagnosis and treatment of OS is still a critical issue. To improve OS treatment and prognosis, novel kinds of theranostic modalities are required. Molecular optical imaging and phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), are promising strategies for cancer theranostics that exhibit high imaging sensitivity as well as favorable therapeutic efficacy with minimal side effect. In this study, semiconducting polymer nanoparticles (SPN-PT) for OS-targeted PTT/PDT are designed and prepared, using a semiconducting polymer (PCPDTBT), providing fluorescent emission in the second near-infrared window (NIR-II, 1000 - 1700 nm) and photoacoustic (PA) signal in the first near-infrared window (NIR-I, 650 - 900 nm), served as the photosensitizer, and a polyethylene glycolylated (PEGylated) peptide PT, providing targeting ability to OS. Results The results showed that SPN-PT nanoparticles significantly accelerated OS-specific cellular uptake and enhanced therapeutic efficiency of PTT and PDT effects in OS cell lines and xenograft mouse models. SPN-PT carried out significant anti-tumor activities against OS both in vitro and in vivo. Conclusions Peptide-based semiconducting polymer nanoparticles permit efficient NIR-II fluorescence/NIR-I PA dual-modal imaging and targeted PTT/PDT for OS. Graphic Abstract

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

Implant-related infections are a primary reason for implant failures that affect millions of patients. It is of paramount importance to develop novel implants that possess the dual functions of osteogenesis-promotion and antibacterial activity. The objectives of this study were to: (1) develop novel dual-functional titanium (Ti) implants by combining oxygen non-thermal plasma and covalent bonding of antibacterial organosilicon quaternary ammonium monomers; (2) investigate the physicochemical properties, bioactivity and antibacterial effects of the modified implants for the first time.Surface characteristics of the modified Ti surfaces were tested. Adherence and viability of rat bone marrow-derived stem cells (rBMSCs) on the surface were evaluated. Metabolic activity of biofilm on the surfaces were measured. The stability of the dual-function after 5000 thermal cycles was also evaluated.The presence of chemical bonding between Ti and organosilicon monomers demonstrated covalent immobilization of the antibacterial agents. The water contact angle of the treated Ti surfaces decreased from 70.98 ± 3.68° to 59.86 ± 4.91°. The adhesion and proliferation of rBMSCs on the modified Ti were increased by 40%, compared to control group (P 0.05). The metabolic level of biofilms on modified Ti were reduced by more than half, compared to control (P 0.05). The modified Ti implants exhibited cell-promotion and antibacterial stability after thermal cycles.The new dual-functional Ti implant is promising to promote osteogenesis while simultaneously preventing infections. Furthermore, the novel surface modification and processing methods have applicability to enhancing a wide range of other implants to improve bioactivity and combat infections.

Background Vascular embolism is a serious complication of hyaluronic acid (HA) filler cosmetic injection, and hyaluronidase injection has been proposed as the treatment. Until now, there has been a lack of adequate clinical evidence regarding the benefits of treatment for HA filler-induced vascular embolism by percutaneous facial or supratrochlear arterial hyaluronidase injection. Objectives The authors sough to evaluate the efficacy of percutaneous facial or supratrochlear arterial hyaluronidase injection as a rescue treatment for HA filler-induced vascular embolism. Methods We included 17 patients with vascular embolism after facial HA filler injection. Intraarterial injection of 1500 units hyaluronidase was performed via facial artery for 13 cases with skin necrosis and via supratrochlear arterial for 4 cases with severe ptosis and skin necrosis but no visual impairment. Simultaneously, general symptomatic treatment and nutritional therapy were performed. Results After hyaluronidase injection, facial skin necrosis in all cases was restored and ptosis in the 4 cases was also significantly relieved. Patients were subsequently followed-up for 1 month to 1 year. The skin necrosis in 16 patients completely healed, and only 1 patient had small superficial scars. Conclusions It is effective to alleviate skin necrosis and ptosis resulting from HA filler embolism via percutaneous facial or supratrochlear arterial hyaluronidase injection. Level of Evidence: 4

Amyloid-β (Aβ) accumulating is considered as a causative factor for formation of senile plaque in Alzheimer’s disease (AD), but its mechanism is still elusive. The Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2), a key redox cofactor for energy metabolism, is reduced in AD. Accumulative evidence has shown that the decrease of α-secretase activity, a disintegrin and metalloprotease domain 10 (ADAM10), is responsible for the increase of Aβ productions in AD patient’s brain. Here, we observe that the activity of α-secretase ADAM10 and levels of Nmnat2 are significantly decreased, meanwhile there is a simultaneous elevation of Aβ in Tg2576 mice. Over-expression of Nmnat2 increases the mRNA expression of α-secretase ADAM10 and its activity and inhibits Aβ production in N2a/APPswe cells, which can be abolished by Compound C, an AMPK antagonist, suggesting that AMPK is involved in over-expression of Nmnat2 against Aβ production. The further assays demonstrate that Nmnat2 activates AMPK by up-regulating the ratio of NAD+/NADH, moreover AMPK agonist AICAR can also increase ADAM10 activity and reduces Aβ1-40/1-42. Taken together, Nmnat2 suppresses Aβ production and up-regulates ADAM10 in AMPK activity-dependent manner, suggesting that Nmnat2 may serve as a new potential target in arresting AD.

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by the pathogenic mutation of PKD1 or PKD2 gene and usually affects bilateral kidneys. Synonymous mutations are generally assumed to be neutral as they do not alter amino acids. Herein, we described an extremely rare ADPKD child caused by a heterozygous synonymous mutation of PKD2 gene accompanied by massive proteinuria and congenital solitary kidney. Clinical characteristics of the patients were summarized. Whole-exome sequencing was performed to screen the disease-causing gene mutation, and reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing were applied to analyze the impact of the identified mutation on gene transcription and splicing. Polycystic changes were found in the solitary kidney of a girl initially presented with nephrotic-range proteinuria. Thereafter her mother and 2 other family members were diagnosed to be ADPKD. Whole-exome sequencing of the proband identified a heterozygous synonymous mutation (c.1716G>A, p.Lys572=) located in the splicing site of exon 7 in PKD2 gene, which was co-segregated with the PKD phenotype in the family. RT-PCR and direct sequencing of amplified products revealed that this heterozygous synonymous mutation led to exon7 skipping in PKD2 gene. We reported an extremely rare child case of ADPKD2 in combination with solitary kidney and nephrotic-range proteinuria, and firstly confirmed the pathogenicity of a heterozygous synonymous mutation (c.1716G>A) in PKD2 gene. The results indicate that synonymous mutations should not be excluded from disease-causing if they are located in splicing site of an exon.

Continuous renal replacement therapy (CRRT) was currently demonstrated to be an effective way to induce fast hypothermia and had proective effects on cardiac dysfunction and brain damage after cardiac pulmonary resuscitation (CPR). In the present study, we aimed to investigate the influence of extracorporeal circuit cooling using CRRT on renal and intestinal damage after CPR based on a porcine model.32 pigs were subjected to ventricular fibrillation for 8 min, followed by CPR for 5 min before defibrillation. All were randomized to receive extracorporeal circuit cooling using CRRT (CRRT, n = 9), surface cooling (SC, n = 9), normothermia (NT, n = 9) or sham control (n = 5) at 5 min post resuscitation. Pigs in the CRRT group were cooled by 8-h CRRT cooling with the infusion line initially submerged in 4 °C of ice water and 16-h SC, while in the SC group by a 24-h SC. Temperatures were maintained at a normal range in the other two groups. Biomarkers in serum were measured at baseline and 1, 3, 6, 12, 24 and 30 h post resuscitation to assess organ functions. Additionally, tissues of kidney and intestine were harvested, from which the degree of tissue inflammation, oxidative stress, and apoptosis levels were analyzed.The blood temperature decreased faster by extracorporeal circuit cooling using CRRT than SC (9.8 ± 1.6 vs. 1.5 ± 0.4 °C/h, P0.01). Post-resuscitation renal and intestinal injury were significantly improved in the 2 hypothermic groups compared to the NT group. And the improvement was significantly greater in animals received extracorporeal circuit cooling than those received surface cooling, from both the results of biomarkers in serum and pathological evidence.Fast hypothermia induced by extracorporeal circuit cooling was superior to. surface cooling in mitigating renal and intestinal injury post resuscitation.

Congenital generalized lipodystrophy (CGL) is an extremely rare genetic disease mainly characterized by absence of whole-body adipose tissue and metabolic dysfunctions such as insulin resistance, diabetes mellitus, hypertriglyceridemia, hepatic steatosis, and acanthosis nigricans. In this study, we reported a novel case of a young woman patient with CGL. The patient came to the hospital for early-onset lipodystrophy and diabetes. She was 19-year-old with a height of 160 cm, a weight of 46 kg, BMI of 17.9 kg/m先天性全身性脂肪萎缩(congenital generalized lipodystrophy,CGL)是一种极端罕见的常染色体隐性遗传病,表现为明显的全身脂肪极度缺失,肌肉感明显,并伴有一系列的代谢指标异常,包括严重的胰岛素抵抗,高血糖,高脂血症,脂肪肝以及黑棘皮等。本文针对1例CGL患者及其家系进行研究。先证者为19岁年轻女性,自幼皮下脂肪缺如,血清瘦素水平仅0.14 μg/L。对患者及其亲属(父母、弟弟)进行全基因组检测,显示该患者BSCL2基因5号外显子存在复合杂合突变(c.560AG和c.565GT),c.560AG突变导致对应编码的187位的氨基酸由酪氨酸突变为半胱氨酸(p.Y187C),从而引起BSCL2编码的SEIPIN蛋白发生错义突变;c.565 GT突变引起对应编码的189位氨基酸转为终止密码子(p.E189X),产生蛋白截短突变。经Sanger测序验证,患者父亲携带c.565GT杂合突变,患者母亲携带c.560AG杂合突变,患者弟弟未携带BSCL2基因致病性突变。本研究通过转染突变p.Y187C质粒至HEK293细胞,观察到SEIPIN蛋白量及与甘油-3-磷酸酰基转移酶(glycerol-3-phosphate acyltransferase, GPAT3)互作减少;原代培养的患者皮肤成纤维细胞体外功能实验表明,患者的SEIPIN蛋白量明显低于正常健康人,加入组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACis)可部分挽救SEIPIN蛋白表达。此外,油酸刺激下患者皮肤成纤维细胞脂滴小于正常健康人。本文同时综述国内外既往文献中报道的BSCL2基因突变位点,丰富了CGL的临床表型谱和致病基因突变谱,有助于提高临床医生对CGL的临床诊治和致病机制的理解。.

Congenital hyperinsulinemia (CHI) is a disease phenotype characterized by persistent or recurrent hypoglycemia due to abnormal secretion of insulin by β cells of the pancreas. CHI induced by activation mutation of a single allele of glucokinase (GCK) is the rarest type. In this paper, the clinical data of a patient with hypoglycemia of unknown cause were collected without obvious clinical symptoms. And a heterozygous missense mutation (c.295TC:p.W99R) was detected in exon 3 of the GCK gene. The mutation was found in both the son and daughter of the proband, and the blood glucose level was low, while the others were normal. By summarizing and analyzing the characteristics of this case and the genetic pedigree of the family, the possibility of congenital hyperinsulinemia caused by a single gene mutation should be considered for hypoglycemia whose etiology is difficult to be determined clinically. This case also provides new clinical data for subsequent genetic studies of the disease.先天性高胰岛素血症(congenital hyperinsulinism, CHI)是由于胰腺β细胞分泌胰岛素失调引起持续性、反复性低血糖发生的病症,其中葡萄糖激酶(glucokinase, GCK)单个等位基因激活突变所致的CHI为最罕见类型。本文收集一例不明原因低血糖症的临床资料,该患者无明显临床症状,在GCK基因3号外显子上检测到1个杂合错义突变(c.295TC:p.W99R)。3代家系验证发现其儿子、女儿均可见该变异,血糖水平检测偏低,其他人则表现正常。通过总结分析该例病例特点及其家系遗传规律,对于临床上难以明确病因的低血糖症,建议考虑单基因突变致先天性高胰岛素血症致低血糖的可能。该病例也为该疾病后续的遗传学研究提供新的临床资料。.

BACKGROUNDMetabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis.METHODSWe examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1,773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African-American Study of Kidney Disease and Hypertension (AASK), and 5,305 participants of the Atherosclerosis Risk in Communities (ARIC) study.RESULTSIn CRIC, more than half of the measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully adjusted models in CRIC; 3 of these metabolites were also significant in fully adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also highlight N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC.CONCLUSIONOur findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.FUNDINGThis study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, and R01 DK124399).

PurposeTo investigate the trends of myopia among primary and junior school students in the post-COVID-19 epidemic period.MethodA prospective of cross-sectional study using spot photoscreenings in 123,538 children among primary and junior school students from 2019 to 2021 was conducted to evaluate the development of myopia in Xuzhou, China in the post-COVID-19 epidemic period. Equivalent refraction and the prevalence of myopia were recorded.ResultsThe spherical equivalent refraction of myopia decreased across all grades except grade 1 (0.23 ± 0.56 D in 2019, 0.24 ± 0.63 D in 2020) from 2019 to 2020. However, refraction exhibited a hyperopic shift in 2021 compared to 2020 for grades 1–5 (no significant decreased for grade 4). The prevalence of myopia in all grades increased in 2020 compared to 2019, and the most dramatic changes were observed from grades 2–5 and grades 7–8 (P < 0.05). The changes in myopia prevalence in grades 1–4 were mild, and the reduction in myopia for Grade 5 is significant from 2020 to 2021. Nevertheless, students in grades 6 and 9 exhibited the greatest growth in myopia prevalence (P < 0.01). All grades had higher myopia prevalence in 2021 compared with 2019, except grade 1 (P = 0.25). The prevalence of myopia in girls was higher compared with boys, and the urban myopia prevalence was higher than in rural areas over the 3 years except in 2019 (P = 0.18).ConclusionsThe prevalence of myopia increased during the COVID-19 epidemic. However, the spherical equivalent refraction of lower grade children drifted to hyperopia and the trends of myopia development remained stable in the post-COVID-19 epidemic period. We should be more concerned about the prevalence of myopia in graduating for the primary or junior grades in the future.

The rapid global spread of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has introduced various challenges in global public health systems. The poor applicability and sensitivity of the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and antigen-based tests, as well as the persistent emergence of SARS-CoV-2 variants with different mutations hinder satisfactory epidemic prevention and control. Therefore, there is an urgent need for diagnostic technologies capable of distinguishing SARS-CoV-2 variants with high sensitivity and low (or no) equipment dependence. Diagnosis based on clustered regularly interspaced short palindromic repeats (CRISPR) has low equipment requirements and is programmable, sensitive, and easy to use. Various nucleic acid detection tools with great clinical potential have been developed for the diagnosis of infectious diseases. Therefore, this review focuses on the reported state-of-the-art CRISPR diagnostic technologies developed for the detection and differentiation of SARS-CoV-2 variants, summarizes their characteristics and provides an outlook for their development.

ObjectiveThe aim of this study was to evaluate the diagnostic accuracy of different olfactory evaluation tools in congenital hypogonadotropic hypogonadism (CHH) patients.MethodsSeventy-one CHH patients were prospectively recruited at Peking Union Medical College Hospital between November 2020 and July 2021. The Chinese Olfactory Function Test (COFT) and Self-reported Olfactory Scale (SROS) were adapted as the subjective tools for the evaluation of olfactory function, and magnetic resonance imaging of olfactory apparatus (MRI-OA) was the objective tool. The olfactory bulb volume (OBV) and the olfactory sulcus depth (OSD) were quantified.ResultsBased on the COFT, 36 patients were categorized as having normosmic CHH (nCHH), and the other 35 patients were categorized as having Kallmann syndrome (KS). Among nCHH patients, 35 patients were classified as having normal olfaction and 1 patient had abnormal olfaction by SROS. For KS patients, there were 30 patients grouped into abnormal olfaction, while 5 patients had normal olfaction by SROS. For MRI-OA, 67% (18/27) of nCHH patients showed normal olfactory apparatus, and 33% (9/27) showed bilateral or unilateral olfactory bulb aplasia or hypoplasia. Among KS patients, 96% (27/28) of patients showed bilateral olfactory bulb hypoplasia or aplasia, and 4% (1/28) of patients showed normal olfactory apparatus. All six patients with unilateral olfactory bulb aplasia and three patients with bilateral olfactory bulb aplasia showed normal olfactory function. The accuracy of the SROS in the diagnosis of nCHH and KS was 91.5%, with a sensitivity of 0.857 and a specificity of 0.972, while the accuracy of MRI-OA is 92.7%, with a sensitivity of 0.964 and a specificity of 0.889.ConclusionSROS and MRI-OA both showed high accuracy to distinguish between KS and nCHH. The abnormal structure of the olfactory apparatus was relatively common in nCHH patients. CHH patients with unilateral olfactory bulb aplasia dysplasia usually had normal olfaction. Normal olfaction without apparent olfactory bulbs is rare but occurred in male CHH patients.

Peritoneal carcinomatosis (PC) is an advanced malignancy that is not sensitive to systemic conventional chemotherapy. Treatment options for PC are usually palliative rather than curative. Cytoreductive surgery and hyperthermic intraperitoneal (IP) chemotherapy are associated with limited efficacy in patients with PC. However, the peritoneum can produce effective immunity by inducing T-lymphocyte recruitment and proliferation, and the unique immune environment of the peritoneum provides the rationale for IP immunotherapy in PC.The authors retrieved relevant documents of IP immunotherapy for PC from PubMed and Medline. This review elaborates on the knowledge of the peritoneal immune microenvironment and IP immunotherapy for PC covering immune stimulators, radioimmunotherapy, catumaxomab, cancer vaccines, chimeric antigen receptor (CAR)-T cells, and immune checkpoint inhibitors.The prognosis of PC is poor. However, the peritoneal cavity is a unique immune compartment with abundant immune cells which can produce effective immunity. IP immunotherapy may be a promising strategy in patients with PC.

A direct evaluation of insulin sensitivity on pituitary response to gonadotropin relasing hormone (GnRH) has not been shown in congenital hypogonadotropic hypogonadism (CHH), despite a growing body of evidence in the association of testosterone concentrations with insulin sensitiviy. The objective of the study was to explore whether increased testosterone concentrations in men with CHH improve insulin sensitivity, or vice versa.A retrospective study at a tertiary centre.Series of male CHH patients were included from Jannuary 2014 to December 2019.Insulin sensitivity indices calculated from oral glucose tolerance test and steroid hormone levels were examined in 52 patients with newly diagnosed CHH and 22 healthy controls. Thirty-two of the 52 CHH patients received pulsatile GnRH therapy with follow-up every 3-6 months.Compared to healthy controls, CHH patients had elevated 2 h post-load glucose, HbA1c, fasting insulin, HOMA of insulin resistance (HOMA-IR) and decreased Matsuda index and testosterone (p ≤ .01). The median follow-up for patients (n = 32) who received pulsatile GnRH therapy was 13.5 (11.3-24) months (432 person-months in total). GnRH therapy increased testosterone and Matsuda index (p ≤ .0001), whilst decreased platelet count (p = .04), leptin (p = .04), fasting glucose (p = .01) and HOMA-IR (p lt; .0001) compared with baseline. The median treatment duration first time to reach the lower limit of normal testosterone concentrations of patients with high and low baseline insulin sensitivity was 15 (95% CI: 8.1-21.9) and 30 months (21.2-38.8), respectively. Correspondingly, after GnRH therapy, luteinizing hormone responsiveness to GnRH provocative test was more vigorous in patients with high insulin sensitivity than those with low insulin sensitivity [17.0 (9.5-25.9) vs. 8.2 (3.3-13.0), p = .01].Pulsatile GnRH therapy elevated testosterone levels in male CHH patients, ameliorated impaired insulin sensitivity and attenuated subclinical inflammatory response, increased insulin sensitivity, in turn, may benefit the efficacy of pulsatile GnRH therapy.

Objectives: Three-dimensional radiological anatomic characteristics of condyle trabeculae was obtained quantitatively based on a volume-of-interest (VOI) analysis. Methods: Nine human mandibular condyle specimens were scanned by micro-computed tomography (micro-CT). A total of 34 VOIs were selected from each condyle specimen, which were divided into six layers and four parts to analyze the morphological characteristics of trabeculae based on cylindrical VOIs with a diameter and height of 2 mm. One-way analysis of variance was used to compare the regional differences of morphological parameters among each layer and part. Results: Values for bone mineral density, bone volume/total volume, trabecular thickness, and trabecular bone number were greater in the anterior part compared with the posterior part; and the lateral part was larger than the medial part in the first, second, and third layers, while the medial part was larger in the fourth and fifth layers; these values in the first and sixth layers were much larger, while those in the third and fourth layers were smaller. Bone surface area/bone volume, trabecular spacing, and trabecular bone pattern factor were larger in the posterior part than in the anterior part; and the lateral part was larger than the medial part in the fourth and fifth layers, while the medial part was larger in the first and second layers. Conclusions: The morphological distribution of VOIs was anisotropic within trabecular bone of human mandibular condyles. The upper and lower ends of trabecular bone were much more compact, with higher bone density, trabecular thickness, and trabecular number than in the middle layers.

As exemplified by the Ebbinghaus illusion, the perceived size of an object can be significantly biased by its surrounding context. The phenomenon is experienced by humans as well as other species, hence likely evolutionarily adaptive. Here, we examined the heritability of the Ebbinghaus illusion using a combination of the classic twin method and multichannel functional near-infrared spectroscopy. Results show that genes account for over 50% of the variance in the strength of the experienced illusion. Interestingly, activations evoked by the Ebbinghaus stimuli in the early visual cortex are explained by genetic factors whereas those in the posterior temporal cortex are explained by environmental factors. In parallel, the feedforward functional connectivity between the occipital cortex and the temporal cortex is modulated by genetic effects whereas the feedback functional connectivity is entirely shaped by environment, despite both being significantly correlated with the strength of the experienced illusion. These findings demonstrate that genetic and environmental factors work in tandem to shape the context-dependent visual size illusion, and shed new light on the links among genes, environment, brain, and subjective experience.

Elevated fibroblast growth factor 23 (FGF23) levels are markers and potential mediators, of adverse outcomes in acute kidney injury (AKI). We recently identified glycerol-3-phosphate (G-3-P), a glycolysis byproduct, as a kidney-derived factor that circulates to bone and bone marrow and triggers FGF23 production in ischemic AKI. This kidney-to-bone signaling axis was further shown to require the conversion of G-3-P to lysophosphatidic acid (LPA) in bone marrow, followed by LPA signaling through the LPAR1 receptor. These findings highlight discrete steps potentially amenable to therapeutic targeting in conditions of FGF23 excess, although more work is required to determine the specificity and safety of targeting specific enzyme and receptor isoforms. Importantly, the initial metabolomic screen that identified a strong correlation between renal vein G-3-P and circulating FGF23 was conducted in human subjects undergoing elective catheterization, none with AKI. This raises the question of whether G-3-P might also modulate FGF23 homeostasis in patients with more mild or chronic decrements in kidney function, or under normal physiologic conditions – a question that is reinforced by a growing body of literature highlighting functional roles for a range of circulating metabolites traditionally thought to function exclusively inside cells.

Background COVID-19 has resulted in significant morbidity and mortality worldwide. Lateral flow assays can detect anti-Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) antibodies to monitor transmission. However, standardized evaluation of their accuracy and tools to aid in interpreting results are needed. Methods We evaluated 20 IgG and IgM assays selected from available tests in April 2020. We evaluated the assays’ performance using 56 pre-pandemic negative and 56 SARS-CoV-2-positive plasma samples, collected 10–40 days after symptom onset, confirmed by a molecular test and analyzed by an ultra-sensitive immunoassay. Finally, we developed a user-friendly web app to extrapolate the positive predictive values based on their accuracy and local prevalence. Results Combined IgG + IgM sensitivities ranged from 33.9 to 94.6%, while combined specificities ranged from 92.6 to 100%. The highest sensitivities were detected in Lumiquick for IgG (98.2%), BioHit for both IgM (96.4%), and combined IgG + IgM sensitivity (94.6%). Furthermore, 11 LFAs and 8 LFAs showed perfect specificity for IgG and IgM, respectively, with 15 LFAs showing perfect combined IgG + IgM specificity. Lumiquick had the lowest estimated limit-of-detection (LOD) (0.1 μg/mL), followed by a similar LOD of 1.5 μg/mL for CareHealth, Cellex, KHB, and Vivachek. Conclusion We provide a public resource of the accuracy of select lateral flow assays with potential for home testing. The cost-effectiveness, scalable manufacturing process, and suitability for self-testing makes LFAs an attractive option for monitoring disease prevalence and assessing vaccine responsiveness. Our web tool provides an easy-to-use interface to demonstrate the impact of prevalence and test accuracy on the positive predictive values.

PURPOSE: To analyze the optical consequences of epithelial remodeling in irregular corneas and their impact on the choice of different surface ablation techniques. METHODS: Anterior corneal and stromal surface topographies and epithelial thickness maps were analyzed in 24 eyes with irregular corneal optics. On two of the eyes, four different surface ablation techniques were simulated: (1) conventional anterior topography-guided photorefractive keratectomy (PRK), (2) transepithelial phototherapeutic keratectomy (PTK), (3) transepithelial anterior topography-guided PRK, and (4) stromal topography-guided PRK. RESULTS: Stromal surface topographies showed higher keratometric values, astigmatism, asphericity, and corneal higher order aberrations compared to topographies of anterior corneas covered by epithelium. Transepithelial anterior topography-guided PRK and stromal topography-guided PRK both resulted in regularized stromal surface, transepithelial PTK achieved partial regularization corresponding to the smoothing effect of the epithelial remodeling, and conventional anterior topography-guided PRK delivered after epithelial removal resulted in residual stromal surface irregularities. CONCLUSIONS: The difference in optical landscapes between the stromal and anterior surfaces in irregular corneas will represent a source of error when anterior topography-guided treatments are delivered on the deepithelialized stroma, as in conventional PRK. In contrast, anterior topography-guided ablations performed as transepithelial PRK and stromal topography-guided PRK delivered after epithelial removal address the full stromal irregularity, whereas transepithelial PTK alone may be used when topography-guided treatments are not possible. The authors conclude topography-guided PRK of irregular corneas should lead to significantly improved regularization only if it includes the effect of epithelial remodeling. [ J Refract Surg . 2022;38(8):529–537.]

Whether amino acids act on cellular insulin signaling remains unclear, given that increased circulating amino acid levels are associated with the onset of type 2 diabetes (T2D). Here, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or phenylalanine-producing aspartame or overexpressing human phenylalanyl-tRNA synthetase (hFARS) develop insulin resistance and T2D symptoms. Mechanistically, FARS phenylalanylate lysine 1057/1079 of IRβ (F-K1057/1079), inactivating IRβ and preventing insulin from promoting glucose uptake by cells. SIRT1 reverse F-K1057/1079 and counteract the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels in white blood cells from T2D patients are positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitizes insulin signaling and relieves T2D symptoms in hFARS-transgenic and db/db mice. These findings shed light on the activation of insulin signaling and T2D progression through inhibition of phenylalanylation.

Metabolites in the tumor microenvironment are a critical factor for tumor progression. However, the lack of knowledge about the metabolic profile in the bone marrow (BM) microenvironment of multiple myeloma (MM) limits our understanding of MM progression. Here, we show that the glycine concentration in the BM microenvironment is elevated due to bone collagen degradation mediated by MM cell-secreted matrix metallopeptidase 13 (MMP13), while the elevated glycine level is linked to MM progression. MM cells utilize the channel protein solute carrier family 6 member 9 (SLC6A9) to absorb extrinsic glycine subsequently involved in the synthesis of glutathione (GSH) and purines. Inhibiting glycine utilization via SLC6A9 knockdown or the treatment with betaine suppresses MM cell proliferation and enhances the effects of bortezomib on MM cells. Together, we identify glycine as a key metabolic regulator of MM, unveil molecular mechanisms governing MM progression, and provide a promising therapeutic strategy for MM treatment.

To investigate the effects of paclitaxel, quizartinib and their combination on proliferation, apoptosis and FLT3/STAT5 pathway of human leukemia cell line MV4-11 (FLT3-ITD+).MV4-11 cells were treated with paclitaxel and quizartinib at different concentrations for 24 h, 48 h and 72 h, respectively, and then the two drugs were combined at 48 h to compare the inhibition of proliferation, the apoptosis rate was detected by flow cytometry, the expression of FLT3 and STAT5 mRNA was determined by fluorescence quantitative PCR, and the protein expression of FLT3, p-FLT3, STAT5 and p-STAT5 was determined by Western blot.Different combination groups of paclitaxel and quizartinib had synergistic inhibitory effect. The cell survival rate in the combination group was significantly lower than that in the single drug group (P0.05). The cell apoptosis rate in the combination group was significantly higher than that in the single drug group (P0.001). The expression of FLT3 mRNA in combination group was significantly higher than that in two single drugs (P0.01). The expression of STAT5 mRNA in combination group was significantly higher than that in quizartinib group (P0.001); increased compared with paclitaxel group, but there was no statistical significance. The expression level of p-FLT3、p-STAT5 protein in the combination group was significantly lower than that in the single drug group (P0.05, P0.05).Paclitaxel combined with quizartinib can synergistically inhibit the proliferation of MV4-11 cell line and promote the apoptosis of MV4-11 cell line by inhibiting the activity of FLT3/STAT5 pathway.紫杉醇和奎扎替尼单药及其联用对AML细胞株MV4-11及其STAT5信号通路的作用.探讨紫杉醇、奎扎替尼单药及二者联合对人白血病细胞株MV4-11（FLT3-ITD+）增殖、凋亡的影响，以及对FLT3/STAT5通路的作用.分别用不同浓度紫杉醇、奎扎替尼单药作用于MV4-11细胞24、48、72 h，在48 h时间点两种药物分别选取两种浓度联合使用，比较细胞增殖抑制情况；选用一种药物浓度组合用流式细胞术检测细胞凋亡率，荧光定量PCR法测定FLT3、STAT5 mRNA表达水平，Western blot法测定FLT3、p-FLT3、STAT5、p-STAT5蛋白的表达水平.不同的紫杉醇、奎扎替尼联合用药组均有协同抑制作用，联合用药组的细胞存活率明显低于单药组(P0.05)，联合用药组细胞的凋亡率均明显高于单药组(P0.001)。联合用药组FLT3 mRNA的表达量均显著高于单药组(P0.001)； 联合用药组STAT5 mRNA的表达量高于奎扎替尼单药组(P0.01)，但与紫杉醇单药组比较差异无统计学意义。联合用药组p-FLT3、p-STAT5蛋白的表达水平均显著低于单药组(P005，P0.05).紫杉醇联合奎扎替尼可以协同抑制MV4-11细胞株的增殖，可能通过抑制FLT3/STAT5通路活性促进MV4-11细胞株凋亡.

p53 mutations that result in loss of transcriptional activity are commonly found in numerous types of cancer. While the majority of these are missense mutations that map within the central DNA-binding domain, truncations and/or frameshift mutations can also occur due to various nucleotide substitutions, insertions, or deletions. These changes result in mRNAs containing premature stop codons that are translated into a diverse group of C-terminally truncated proteins. Here we characterized three p53 frameshift mutant proteins expressed from the endogenous TP53 locus in U2OS osteosarcoma and HCT116 colorectal cancer cell lines. These mutants retain intact DNA-binding domains but display altered oligomerization properties. Despite their abnormally high expression levels, they are mostly transcriptionally inactive and unable to initiate a stimuli-induced transcriptional program characteristic of wild-type p53. However, one of these variant p53 proteins, I332fs*14, which resembles naturally expressed TAp53 isoforms β and γ, retains some residual antiproliferative activity and can induce cellular senescence in HCT116 cells. Cells expressing this mutant also display decreased motility in migration assays. Hence, this p53 variant exhibits a combination of loss-of-gain and gain-of-function characteristics, distinguishing it from both wild type p53 and p53 loss. Implications: p53 frameshift mutants display a mixture of residual antiproliferative and neomorphic functions that may be differentially exploited for targeted therapy.

Purpose Hypoxic microenvironment plays a vital role in myocardial ischemia injury, generally leading to the resistance of chemotherapeutic drugs. This induces an intriguing study on mechanism exploration and prodrug design to overcome the hypoxia induced drug resistance.Methods In this study, we hypothesized that the overexpression of carbonic anhydrase 9 (CAIX) in myocardial cells is closely related to the drug resistance. Herein, bioinformatics analysis, gene knockdown and overexpression assay certificated the correlation between CAIX overexpression and hypoxia. An original aspirin-containing CAIX inhibitor AcAs has been developed.Results Based on the downregulation of CAIX level, both in vitro and in vivo, AcAs can overcome the acquired resistance, and more effectively attenuate myocardial ischemia and hypoxia injury than that of aspirin. CAIX inhibitor is believed to recover the extracellular pH value so as to ensure the stable effect of aspirin.Conclusion Results indicate great potential of CAIX inhibitor for further application in myocardial hypoxia injury therapy.

PURPOSE: To evaluate the influence of coma on manifest refractive cylinder (MRC) in eyes with coma-dominated corneal optics and suggest alternative guidelines for surgical planning of astigmatism correction in topography-guided ablation and toric intraocular lens (IOL) exchange surgery. METHODS: Twelve eyes with coma-dominant corneal optics and low lenticular astigmatism were selected. The astigmatism remaining after subtraction of total corneal astigmatism (TCA) and lenticular astigmatism from MRC, termed discrepant astigmatism, was calculated and correlated to corneal coma at the anterior surface. Refractive and topography data were then used to simulate topography-guided refractive surgery (topography-guided group) in 7 eyes and lenticular exchange surgery with toric intraocular lens (IOL) implantation (toric IOL group) in 5 eyes. The estimated postoperative MRC after correction of TCA or MRC for each group was compared. RESULTS: The axis and amplitude of discrepant astigmatism correlated strongly with the axis and amplitude of coma. In the topography-guided group, where topography-guided ablation eliminated corneal higher order aberrations (HOAs), TCA-based correction led to less estimated postoperative manifest astigmatism than MRC-based correction. In the toric IOL group, where removal of the crystalline lens did not affect corneal HOAs, MRC-based correction via toric IOL implantation led to less estimated postoperative astigmatism than TCA-based correction. CONCLUSIONS: Discrepant astigmatism in eyes with coma-dominant corneal optics correlates with coma. In such eyes, treating TCA, along with corneal HOAs, instead of MRC, seems appropriate in topography-guided treatments, whereas treating MRC may be a better choice in lenticular exchange surgery with toric IOL implantation, where corneal HOAs are not treated. [ J Refract Surg . 2021;37(4):274–282.]

Bone marrow stromal cells (BMSCs) have been implicated in multiple myeloma (MM) progression. However, the underlying mechanisms remain largely elusive. Therefore, we aimed to explore key factors in BMSCs that contribute to MM development. RNA-sequencing was used to perform gene expression profiling in BMSCs. Enzyme-linked immunosorbent assays (ELISAs) were performed to determine the concentrations of PGE2 and TNFα in sera and conditioned media (CM). Western blotting, qRT-PCR and IHC were used to examine the expression of cyclooxygenase 2 (COX2) in BMSCs and to analyze the regulation of TNFα by COX2. Cell growth and adhesion assays were employed to explore the function of COX2 in vitro. A 5T33MMvt-KaLwRij mouse model was used to study the effects of COX2 inhibition in vivo. COX2 was found to be upregulated in MM patient-derived BMSCs and to play a critical role in BMSC-induced MM cell proliferation and adhesion. Administration of PGE2 to CM derived from BMSCs promoted MM cell proliferation and adhesion. Conversely, inhibition of COX2 in BMSCs greatly compromised BMSC-induced MM cell proliferation and adhesion. PCR array-based analysis of inflammatory cytokines indicated that COX2 upregulates the expression of TNFα. Subsequent rescue assays showed that an anti-TNFα monoclonal antibody could antagonize COX2-mediated MM cell proliferation and adhesion. Administration of NS398, a specific COX2 inhibitor, inhibited in vivo tumor growth and improved the survival of 5TMM mice. Our results indicate that COX2 contributes to BMSC-induced MM proliferation and adhesion by increasing the secretion of PGE2 and TNFα. Targeting COX2 in BMSCs may serve as a potential therapeutic approach of treating MM.

Background & Aims The association between cellular senescence and Helicobacter pylori–induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori–induced atrophic gastritis and the underlying mechanism. Methods C57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using senescence-associated beta-galactosidase, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro. Results Gastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-κB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori–infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression. Conclusions Our study showed a new mechanism of H pylori–induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori–induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556., Graphical abstract

Background: Multiple myeloma (MM) is incurable in spite of recent treatment improvements, highlighting the development of new therapies. Chimeric antigen receptor (CAR) T-cell therapy has dramatically changed the therapeutic effectiveness in high-risk B-cell malignancies. For relapsed/refractory multiple myeloma (RRMM), preclinical evaluations of CAR-T therapy have shown promising efficacy, thus various active clinical trials are under way. Herein, we conducted this review to summarize efficacy and safety of CAR-T therapy and provide more evidence to guide clinical treatments. Method: We systematically searched literature based on databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials), and conference abstracts reported from American Society of Hematology (ASH), European Hematology Association (EHA) and American Society of Clinical Oncology (ASCO), in addition to other sources (www.clinicaltrials.gov, article citations). Data assessed efficacy and safety of CAR-T therapy in patients with RRMM were extracted and evaluated, and then systematically analyzed by Comprehensive Meta-analysis 3.0 (CMA 3.0). Results: A total of 23 studies including 350 participants from different countries, diagnosed as RRMM and treated with CAR-T therapy (containing 7 antigens targeted by CARs) were combined. In summary, we discovered the pooled overall response rate (77%), complete response rate (37%) and minimal residual disease (MRD) negativity rate within responders (78%). Furthermore, the pooled relapse rate of responders was 38% and median progression-free survival was 8 months. The pooled survival rate was 87% at last follow-up (median, 12 months). In addition, the pooled grade 3-4 rates of cytokine release syndrome (CRS) and neurologic toxicities (NT) were 14% and 13%, respectively. Conclusion: Our study suggests that CAR-T therapy has demonstrated efficacy and safety in RRMM patients. BCMA-targeted CAR-T and anti-BCMA contained regimen have shown better efficacy.

Glioma is the most prevalent and lethal primary brain tumour. Abundant long non‐coding RNAs ( lncRNAs) are aberrant and play crucial roles in the oncogenesis of glioma. The exact functions of linc00475 in glioma remain blurred. Here, we analysed the expression levels of linc00475 by qRT‐PCR and discovered that linc00475 was up‐regulated in glioma and predicted a poor prognosis in patients with glioma. Besides, inhibiting linc00475 restrained the progression of glioma in vitro and in vivo. Further experiments confirmed that linc00475 regulated the progression of glioma by acting as a sponge for miR‐141‐3p. Moreover, we detected the binding sites of linc00475 and miR‐141‐3p, the YAP1‐ 3′UTR and miR‐141‐3p by luciferase reporters. The rescue assays confirmed that inhibiting linc00475 restrained the progression of glioma through the miR‐141‐3p/YAP1 pathway. Collectively, our research demonstrates the key roles of linc00475 in glioma, which could be a promising therapeutic target.

With Western therapeutic techniques prevailing in Chinese therapies, some techniques that include Chinese traditional cultural features are required since some cultural factors are not considered in the Western method. Our study introduced a new technique, the moving to emptiness technique (MET), which combines Western structural progress and core factors of Chinese culture. Seventeen therapists treated 107 clients with the MET. Clients reported their target symptoms initially, and therapists helped them transfer invisible symptoms to perceivable stuff and remove their jarring stuff using the psychological emptiness area. At the end of the consultations, we found that MET could eliminate symptoms immediately. By grouping target symptoms according to their frequency, the results showed that clients in the high-frequency symptom group had higher rehabilitation rates than those in the low-frequency symptom group. Additionally, the results of the bereavement group were better than those of the non-bereavement group, indicating that the MET can significantly alleviate clients' target symptoms. In future studies, the replication and stability of the MET can be assessed by integrating questionnaires, experimental designs, and neurological equipment.

Liver cancer is the sixth most common malignant tumor in the world. Hepatocellular carcinoma (HCC) accounts for 85%-90% of all patients with liver cancer. It possesses the characteristics of insidious onset, rapid progression, early recurrence, easy drug resistance, and poor prognosis. NIMA related kinase 2 (NEK2) is a cell cycle regulating kinases, which regulates cell cycle in mitosis. Cellular senescence is a complex heterogeneous process, and is a stable form of cell cycle arrest that limits the proliferative potential of cells. This study aims to investigate the relationship between the expression level of NEK2 and the senescence in hepatoma cells, and to explore the effect of NEK2 expression on hepatoma cell senescence and the underlying molecular mechanism.A total of 581 senescence-relevant genes were obtained from the GenAge website. The gene expression data of tumor tissues of 370 HCC patients were downloaded from the Cancer Genome Atlas database. The co-expression of NEK2 and aging-related genes was analyzed by R-package. KEGG was used to analyze the significant gene enrichment pathway of differentially expressed genes in NEK2 overexpression HEK293. The stable transfected cell lines with overexpression and knockdown of NEK2 were constructed in hepatoma cell line SMMC-7721 and HepG2, and senescence-associated β-galactosidase (SA-β-gal) staining was used to detect senescence, the cell proliferation was detected by CCK-8 method and clone formation experiment, the cell cycle was analyzed by flow cytometry, and the expression of proteins related to p53/p21, p16/Rb, and phosphatase and tensin homolog deleted on chromosome ten (PTEN)/Akt signal transduction pathway was detected by Western blotting.There were 320 senescence related genes co-expressed with NEK2. KEGG analysis showed that the senescence signaling pathway was significantly enriched in HEK293 cells with overexpression of NEK2.Compared with SMMC-7721 or HepG2 without knockdown of NEK2, the senescent cells of SMMC-7721 and HepG2 with knockdown of NEK2 were increased, cell proliferation and clone formation were decreased significantly, the percentage of cells in GNEK2 may mediate the anti-aging effect of hepatoma cells through p16/Rb and PTEN/Akt signal transduction pathways, which provides a new theoretical basis for NEK2 to promote the progress of liver cancer and a new idea for the targeting treatment for liver cancer.

To observe the efficacy and complications of one-stage tumor resection to treat primary sacral neurogenic tumors and to discuss some details in the clinically relevant anatomy.A retrospective analysis of 26 patients with neurogenic turors of the sacral spine who were surgically treated from January 2001 to January 2018, including 16 males and 10 females, aged from 21 to 69 years old with an average age of (39.3±10.9) years old. The courses of diseases ranged from 3 to 56 months with an average of (17.9±10.1) months. The diameters of presacral components ranged from 3.3 to 19.6 cm with an average of (8.7±4.1) cm. The proximal margin of presacral lesions was above the LTotal excision was achieved in all 26 patients, with an operation time of (160.4±35.3) mins and an intraoperative blood loss of (1 092.3±568.8) ml. Tumors have been removed via a posterior-only approach in 21 cases and via combined anterior/posterior approaches in 5 cases. The diameter of presacral masses components ranged from 11.3 to 19.6 cm with an average of (15.1±3.2) cm in patients with combined anterior/posterior approaches, and ranged from 3.3 to 10.9 cm with an average of (7.2±2.4) cm in patients with a posterior-only approach. Five of the six patients whose proximal margin of presacral masses was above the LThe posterior approach can directly expose the lesions, and it is also convenient to deal with nerve roots and blood vessels. The operation time, intraoperative blood loss, degree of symptom relief, complication rate, and recurrence and metastasis rate can be controlled at an appropriate level. It is a safe and effective surgical approach. When the upper edge of the presacral mass is higher than the L

Varicella-Zoster virus (VZV) causes chickenpox and shingles. Although the infection is associated with severe morbidity in some individuals, molecular mechanisms that determine innate immune responses remain poorly defined. We found that the cGAS/STING DNA sensing pathway was required for type I interferon (IFN) induction during VZV infection and that recognition of VZV by cGAS restricted its replication. Screening of a VZV ORF expression library identified the essential VZV tegument protein ORF9 as a cGAS antagonist. Ectopically or virally expressed ORF9 bound to endogenous cGAS leading to reduced type I IFN responses to transfected DNA. Confocal microscopy revealed co-localisation of cGAS and ORF9. ORF9 and cGAS also interacted directly in a cell-free system and phase-separated together with DNA. Furthermore, ORF9 inhibited cGAMP production by cGAS. Taken together, these results reveal the importance of the cGAS/STING DNA sensing pathway for VZV recognition and identify a VZV immune antagonist that partially but directly interferes with DNA sensing via cGAS.