Elucidating Iron Metabolism through Molecular Imaging.

Iron is essential for many physiological processes, and the dysregulation of its metabolism is implicated in the pathogenesis of various diseases. Recent advances in iron metabolism research have revealed multiple complex pathways critical for maintaining iron homeostasis. Molecular imaging, an interdisciplinary imaging technique, has shown considerable promise in advancing research on iron metabolism. Here, we comprehensively review the multifaceted roles of iron at the cellular and systemic levels (along with the complex regulatory mechanisms of iron metabolism), elucidate appropriate imaging methods, and summarize their utility and fundamental principles in diagnosing and treating diseases related to iron metabolism. Utilizing molecular imaging technology to deeply understand the complexities of iron metabolism and its critical role in physiological and pathological processes offers new possibilities for early disease diagnosis, treatment monitoring, and the development of novel therapies. Despite technological limitations and the need to ensure the biological relevance and clinical applicability of imaging results, molecular imaging technology's potential to reveal the iron metabolic process is unparalleled, providing new insights into the link between iron metabolism abnormalities and various diseases.

Correlation between expression of Lin28B and C-myc in patients with laryngeal squamous cell carcinoma and clinicopathological features and prognosis. / Lin28B和C-mycè›‹ç™½åœ¨å–‰é³žç™Œä¸­çš„è¡¨è¾¾åŠå ¶ä¸Žä¸´åºŠç— ç†ç‰¹å¾å’Œé¢„åŽçš„ç›¸å ³æ€§.

OBJECTIVES: Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor of head and neck. Screening of target genes for malignant tumor therapy is one of the focuses of cancer research, with proto-oncogene and tumor suppressor gene as the breakthrough. It has become an urgent need to find the target gene related to the treatment and prognosis of LSCC.This study aims to explore the role of Lin28B and C-myc in LSCC by detecting the expressions of these two proteins and analyze the correlation between the expression of Lin28B and C-myc and clinicopathological features and prognosis of LSCC. METHODS: We detected the expression of Lin28B and C-myc proteins in 102 specimens of LSCC and 90 specimens of adjacent tissues by immunochemistry, and analyzed the correlation between Lin28B and C-myc protein expressions in LSCC as well as the correlation between the expressions of the two proteins and the clinicopathological features of LSCC. At the same time, the Kaplan-Meier method was used to analyze the relation between Lin28B and C-myc protein levels with the postoperative survival rate of LSCC patients. RESULTS: The protein levels of Lin28B and C-myc in the LSCC tissnes were significantly higher than those in the adjacent tissues (both P<0.05),and there was a positive correlation between the expression of Lin28B and C-myc in LSCC (r＝0.476, P<0.05). The expression of Lin28B protein was closely related to age, lymph node metastasis, clinical stage, tumor size, and pathological differentiation of LSCC patients (all P<0.05). while the expression of C-myc protein was closely related to lymph node metastasis, clinical stage, tumor size, and pathological differentiation of LSCC patients (all P<0.05). A relevant survival analysis showed that in patients with higher level of Lin28B (P＝0.001) or C-myc protein (P<0.001), the postoperative survival rate was relatively low. CONCLUSIONS: Lin28B and C-myc proteins are highly expressed in LSCC with a positive correlation. Furthermore, they are closely related to lymph node metastasis, clinical stage, tumor size, pathological differentiation and prognosis, suggesting that both Lin28B and C-myc might be involved in the occurrence and development of LSCC.

Sciatic nerve block downregulates the BDNF pathway to alleviate the neonatal incision-induced exaggeration of incisional pain via decreasing microglial activation.

Sciatic nerve block is under investigation as a possible therapeutic strategy for neonatal injury-induced exaggeration of pain responses to reinjury. Spinal microglial priming, brain-derived neurotrophic factor (BDNF) and Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) participate in exaggerated incisional pain induced by neonatal incision. However, effects of sciatic nerve block on exacerbated incisional pain and underlying mechanisms remain unclear. Here, we demonstrated that sciatic nerve block alleviates pain hypersensitivity and microglial activation in rats subjected to neonatal incision and adult incision (nIN-IN). Chemogenetic activation or inhibition of spinal microglia attenuates or mimics effects of sciatic nerve block on pain hypersensitivity, respectively. Moreover, α-amino-3-hydroxy- 5-methy- 4-isoxazole propionate (AMPA) receptor subunit GluA1 contributes to the exaggeration of incisional pain. The inhibition of BDNF or SHP2 blocks upregulations of downstream molecules in nIN-IN rats. Knockdown of SHP2 attenuates the increase of GluA1 induced by injection of BDNF in adult rats with only neonatal incision. The inhibition of microglia or ablation of microglial BDNF attenuates upregulations of SHP2 and GluA1. Additionally, sciatic nerve block downregulates the expression of these three molecules. Upregulation of BDNF, SHP2 or AMPA receptor attenuates sciatic nerve block-induced reductions of downstream molecules and pain hypersensitivity. Microglial activation abrogates reductions of these three molecules induced by sciatic nerve block. These results suggest that decreased activation of spinal microglia contributes to beneficial effects of sciatic nerve block on the neonatal incision-induced exaggeration of incisional pain via downregulating BDNF/SHP2/GluA1-containing AMPA receptor signaling. Thus, sciatic nerve block may be a promising therapy.

Adult Hippocampal Neurogenesis along the Dorsoventral Axis Contributes Differentially to Environmental Enrichment Combined with Voluntary Exercise in Alleviating Chronic Inflammatory Pain in Mice.

Cognitive behavioral therapy, such as environmental enrichment combined with voluntary exercise (EE-VEx), is under active investigation as an adjunct to pharmaceutical treatment for chronic pain. However, the effectiveness and underlying mechanisms of EE-VEx remain unclear. In mice with intraplantar injection of complete Freund's adjuvant, our results revealed that EE-VEx alleviated perceptual, affective, and cognitive dimensions of chronic inflammatory pain. These effects of EE-VEx on chronic pain were contingent on the occurrence of adult neurogenesis in the dentate gyrus in a functionally dissociated manner along the dorsoventral axis: neurogenesis in the ventral dentate gyrus participated in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas neurogenesis in the dorsal dentate gyrus was involved in EE-VEx's cognitive-enhancing effects. Chronic inflammatory pain was accompanied by decreased levels of brain-derived neurotrophic factor (BDNF) in the dentate gyrus, which were reversed by EE-VEx. Overexpression of BDNF in the dentate gyrus mimicked the effects of EE-VEx. Our results demonstrate distinct contribution of adult hippocampal neurogenesis along the dorsoventral axis to EE-VEx's beneficial effects on different dimensions of chronic pain.SIGNIFICANCE STATEMENT Environmental enrichment combined with voluntary exercise (EE-VEx) is under active investigation as an adjunct to pharmaceutical treatment for chronic pain, but its effectiveness and underlying mechanisms remain unclear. In a mouse model of inflammatory pain, the present study demonstrates that the beneficial effects of EE-VEx on chronic pain depend on adult neurogenesis with a dorsoventral dissociation along the hippocampal axis. Adult neurogenesis in the ventral dentate gyrus participates in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas that in the dorsal pole is involved in EE-VEx's cognitive-enhancing effects in chronic pain.

Increased expression of CaV3.2 T-type calcium channels in damaged DRG neurons contributes to neuropathic pain in rats with spared nerve injury.

Ion channels are very important in the peripheral sensitization in neuropathic pain. Our present study aims to investigate the possible contribution of CaV3.2 T-type calcium channels in damaged dorsal root ganglion neurons in neuropathic pain. We established a neuropathic pain model of rats with spared nerve injury. In these model rats, it was easy to distinguish damaged dorsal root ganglion neurons (of tibial nerve and common peroneal nerve) from intact dorsal root ganglion neurons (of sural nerves). Our results showed that CaV3.2 protein expression increased in medium-sized neurons from the damaged dorsal root ganglions but not in the intact ones. With whole cell patch clamp recording technique, it was found that after-depolarizing amplitudes of the damaged medium-sized dorsal root ganglion neurons increased significantly at membrane potentials of -85 mV and -95 mV. These results indicate a functional up-regulation of CaV3.2 T-type calcium channels in the damaged medium-sized neurons after spared nerve injury. Behaviorally, blockade of CaV3.2 with antisense oligodeoxynucleotides could significantly reverse mechanical allodynia. These results suggest that CaV3.2 T-type calcium channels in damaged medium-sized dorsal root ganglion neurons might contribute to neuropathic pain after peripheral nerve injury.

Anxiolytic effects of hippocampal neurosteroids in normal and neuropathic rats with spared nerve injury.

Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of GABAA receptors, which play a vital role in modulating hippocampal functions. Chronic pain is accompanied by increased neurosteroid production in the spinal cord and thalamus. We hypothesize that hippocampal neurosteroids participate in pain or pain-associated emotions, which we tested with high-performance liquid chromatography/tandem mass spectrometry and pharmacological behavioral tests. We observed increased levels of hippocampal neurosteroids (pregnenolone, progesterone, deoxycorticosterone, and allopregnanolone) in rats with chronic neuropathic pain (28 days after spared nerve injury). Meanwhile, the expression of the translocator protein, the upstream steroidogenesis rate-limiting enzyme, increased in the ventral but not dorsal hippocampus of neuropathic rats. In both naïve and neuropathic rats, in vivo stereotaxic microinjection of PK 11195, the translocator protein inhibitor, into the ventral hippocampus exacerbated anxiety-like behaviors. These results indicate anxiolytic effects of hippocampal neurosteroids in both normal and neuropathic rats. Neurosteroids could be considered as agents for treatment of general and pain-related anxiety disorders.

Characterizing heat-sensitization responses in suspended moxibustion with high-density EEG.

OBJECTIVE: We have reported "heat-sensitization" responses during suspended moxibustion, whose occurrence is associated with significantly better therapeutic effects. The present study aimed to characterize the electrophysiological features of this interesting phenomenon with high-density electroencephalography (EEG). METHODS: We performed EEG recording in a group of patients with chronic low back pain before, during, and after moxibustion treatment at DU3. RESULTS: 12 out of 25 subjects experienced strong heat-sensitization during moxibustion, which was accompanied by increased power spectral densities (PSDs) at the theta, alpha, and beta frequency bands. The scalp topographies of averaged power indicated that the theta and beta PSD changes were most obvious in fronto-central regions, whereas those of the alpha band were more global. In addition, nonsensitized and sensitized groups showed distinct activity patterns, with heat-sensitization inducing increased phase coherence at the theta and beta ranges. CONCLUSIONS: These data were the first objective evidence of heat-sensitization responses during suspended moxibustion, which were characterized by widespread oscillatory changes in scalp EEG.

Cardiac Arrhythmia Risk after Anti-Cancer Drug Exposure and Related Disease Molecular Imaging Outlook: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.

BACKGROUND: Chemotherapy is the main first-line treatment, but there is a problem of adverse reactions to systemic drugs. Chemotherapeutic agents may cause adverse effects on the body, influencing the prognosis. Whether the clinical application of anthracyclines is associated with an increased arrhythmic risk remains controversial. To evaluate the arrhythmic risk of anthracyclines as a class, and the comparative risk for each drug, we conducted a systematic review, meta-analysis, and network meta-analysis. METHODS: PubMed, Web of Science, EMBASE, and the Cochrane Library were searched, up to March 2022, for randomized controlled trials, cohort studies, and case-control studies that investigated the association between anthracyclines treatment and the risk of arrhythmia. We followed the PRISMA 2020 guidelines for data selection and extraction. Outcomes were pooled using fixed effects models in cohort studies and randomized controlled studies, and random models in single-arm studies. Direct and indirect comparisons in network meta-analysis were performed using frequentist methods. RESULTS: In total, 4 cohort studies, 8 RCTs, and 18 single-arm studies were included in our analysis. Anthracyclines' use was associated with a statistically significant 90% increase in the risk of arrhythmia (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.62-2.24) and a 114% increase in the risk of supraventricular arrhythmia (OR 2.14; 95% CI 1.18-3.89). And the single-arm studies also indicated that the incidence of arrhythmia rate is 20% and the 95% CI is 15/100-25/100. Epirubicin ranked most likely to have the highest risk of arrhythmia compared with non-anthracycline antineoplastic drugs in the analysis (OR 43.07 [95% CI 2.80-2105.83]) by network meta-analysis. CONCLUSIONS: Our findings show a significant association between anthracyclines' use and an increased risk of arrhythmia, especially supraventricular arrhythmia. Epirubicin ranked with the highest probability of arrhythmia. These results indicated that cardiac rhythm should be strictly monitored during the application of anthracyclines in clinical practice, and a possible therapy for anthracycline-associated arrhythmia should be explored. Molecular imaging technology is an important means to study the mechanism of drug action on cardiac electrophysiology in the future. By imaging molecular targets in cardiac cells, the effects of drugs on the electrophysiological properties of cardiac cells can be understood, which provides information for the development of safer and more effective drugs.

Enhanced TfR1 Recognition of Myocardial Injury after Acute Myocardial Infarction with Cardiac Fibrosis via Pre-Degrading Excess Fibrotic Collagen.

The fibrosis process after myocardial infarction (MI) results in a decline in cardiac function due to fibrotic collagen deposition and contrast agents' metabolic disorders, posing a significant challenge to conventional imaging strategies in making heart damage clear in the fibrosis microenvironment. To address this issue, we developed an imaging strategy. Specifically, we pretreated myocardial fibrotic collagen with collagenase I combined with human serum albumin (HSA-C) and subsequently visualized the site of cardiac injury by near-infrared (NIR) fluorescence imaging using an optical contrast agent (CI, CRT-indocyanine green) targeting transferrin receptor 1 peptides (CRT). The key point of this strategy is that pretreatment with HSA-C can reduce background signal interference in the fibrotic tissue while enhancing CI uptake at the heart lesion site, making the boundary between the injured heart tissue and the normal myocardium clearer. Our results showed that compared to that in the untargeted group, the normalized fluorescence intensity of cardiac damage detected by NIR in the targeted group increased 1.28-fold. The normalized fluorescence intensity increased 1.21-fold in the pretreatment group of the targeted groups. These data demonstrate the feasibility of applying pretreated fibrotic collagen and NIR contrast agents targeting TfR1 to identify ferroptosis at sites of cardiac injury, and its clinical value in the management of patients with MI needs further study.

Impaired neuronal macroautophagy in the prelimbic cortex contributes to comorbid anxiety-like behaviors in rats with chronic neuropathic pain.

A large proportion of patients with chronic pain experience co-morbid anxiety. The medial prefrontal cortex (mPFC) is proposed to underlie this comorbidity, but the molecular and neuronal mechanisms are not fully understood. Here, we reported that impaired neuronal macroautophagy in the prelimbic cortical (PrL) subregion of the mPFC paralleled the occurrence of anxiety-like behaviors in rats with chronic spared nerve injury (SNI). Intriguingly, such macroautophagy impairment was mainly observed in a FOS/c-Fos+ neuronal subpopulation in the PrL. Chemogenetic inactivation of this comorbid anxiety-related neuronal ensemble relieved pain-induced anxiety-like behaviors. Rescuing macroautophagy impairment in this neuronal ensemble relieved chronic pain-associated anxiety and mechanical allodynia and restored synaptic homeostasis at the molecular level. By contrast, artificial disruption of macroautophagy induced early-onset co-morbid anxiety in neuropathic rats, but not general anxiety in normal rats. Taken together, our work identifies causal linkage between PrL neuronal macroautophagy dysfunction and comorbid anxiety in neuropathic pain and provides novel insights into the role of PrL by differentiating its contribution in pain-induced comorbid anxiety from its modulation over general anxiety-like behaviors.Abbreviation: AAV: adeno-associated viruses; ACC: anterior cingulate cortex; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CNO: clozapine-N-oxide; CQ: chloroquine; DIA: data independent acquisition; DIO: double floxed inverse orf; DLG4/PSD-95: discs large MAGUK scaffold protein 4; Dox: doxycycline; GABA: γ-aminobutyric acid; GFP: green fluorescent protein; GO: gene ontology; Gi: inhibitory guanine nucleotide-binding proteins; HsCHRM4/M4D: human cholinergic receptor muscarinic 4; HsSYN: human synapsin; KEGG: Kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; LC3-II: PE conjugated microtubule-associated protein 1 light chain3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mPFC: medial prefrontal cortex; P2A: 2A self-cleaving peptide; PPI: protein-protein interaction networks; PrL: prelimbic cortex; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; rtTA: reverse tetracycline-transactivator; SDS-PAGE: sodium dodecylsulfate-polyacrylamide gel electrophoresis; SHANK3: SH3 and multiple ankyrin repeat domains 3; SLC1A1/EAAC1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, systemXag), member 1; SNAP23: synaptosomal-associated protein 23; SNI:spared nerve injury; SQSTM1/p62: sequestosome 1; SYT3: synaptotagmin 3; TRE: tetracycline-responsive element; TRE3G: third-generation tetracycline-responsive element.

Association between weight change and the predicted 10-year risk for atherosclerosis cardiovascular disease among U.S. older adults: data from National Health and Nutrition Examination Survey 1999-2018.

Background: It remains controversial regarding the association between weight change and cardiovascular disease risk in older adults (aged ≥60 years). This study aimed to evaluate the association between weight change and the predicted 10-year atherosclerotic cardiovascular disease (ASCVD) risks in older adults. Methods: This study used data from the National Health and Nutrition Examination Survey (NHANES). Older adults aged 60-79 years who were free of self-reported ASCVD at the time of the NHANES interview were included. Data were collected from January 1999 to December 2018 and analyzed in March 2022. We focused on the associations between weight change and the 10-year ASCVD risks with the percentage change in weight during short-term (1 year) and long-term (10 years), which categorized as moderate to high weight loss (≥10%), small weight loss (5.1-9.9%), stable weight (±5%), small weight gain (5.1-9.9%), and moderate to high weight gain (≥10%). Results: The number of participants was 1,867 (mean age 67.49 years; 42.10% female) for the long-term interval (10 years) in our analysis, and 1894 for the short-term interval (1 years). We only observed an inverse association between long-term weight loss and the 10-year ASCVD risk in fully adjusted model (loss ≥ 10%: ß = 2.52, 95%CI = 0.98, 4.05; loss 5.1% ~ 9.9%: ß = 2.99, 95% CI = 1.30, 4.68), but all intervals of weight gain ≥5% were not significant associated with higher risk than stable weight. However, in the subgroup analyses, the association between long-term weight loss and the 10-year ASCVD risk was not significant in old-old (aged 75-79), obesity (BMI ≥ 35 kg/m2), intentional weight loss, moderate physical activity and diabetics. Conclusion: Older adults (aged 60-79 years) with weight loss >5% over the past 10 years have excess predicted 10-year ASCVD risk. Our study supports the benefits of stable weight in promoting cardiovascular health in older adults.

Essential oils for treating anxiety: a systematic review of randomized controlled trials and network meta-analysis.

Background and purpose: The findings of clinical studies exploring essential oils (EOs) for anxiety remain disputed, and no studies have yet clarified the differences in the efficacy of EOs. The purpose of the study was to directly or indirectly compare the efficacy of different types of EOs on anxiety by pooling the results of randomized controlled trials (RCTs). Methods: PubMed, Cochrane Library, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception to November 2022. Only full texts of RCTs that investigated the effects of EOs on anxiety were included. The trial data were extracted and the risk of bias was assessed by two reviewers independently. Pairwise meta-analysis and network meta-analysis were performed by Stata 15.1 or R 4.1.2 software. Results: Forty-four RCTs (fifty study arms) involving 10 kinds of EOs and 3419 anxiety patients (1815 patients in EOs group and 1604 patients in control group) were included. Pairwise meta-analyses showed that EOs were effective in reducing State Anxiety Inventory scores (SAIS) [WMD = -6.63, 95% CI-8.17, -5.08] and Trait Anxiety Inventory scores (TAIS) [WMD = -4.97, 95% CI-6.73, -3.20]. Additionally, EOs could decrease systolic blood pressure (SBP) [WMD = -6.83, (95% CI -10.53, -3.12), P < 0.001] and heart rate (HR) [WMD = -3.43, (95% CI -5.51, -1.36), P < 0.001]. Network meta-analyses demonstrated that regarding the outcome of SAIS, Jasminum sambac (L.)Ait. (jasmine) was the most effective with a weighted mean difference (WMD) of-13.61 (95% CrI-24.79, -2.48). Followed by Citrus (citrus aurantium L.), which had a WMD of-9.62 (95% CrI-13.32, -5.93). Moderate effect sizes were observed for Rosa rugosa Thunb. (damask rose) (WMD = -6.78, 95% CrI-10.14, -3.49) and Lavandula angustifolia Mill. (lavender) (WMD = -5.41, 95% CrI-7.86, -2.98). Regarding the results of TAIS, citrus aurantium L. was the best ranked intervention with a WMD of-9.62 (95% CrI-15.62, -3.7). Moderate-to-large effect sizes were observed for Citrus limon (L.) Burm. F. (lemon) (WMD:-8.48; 95% CrI-16.67, -0.33) and lavender (WMD:-5.5; 95% CrI-8.7, -2.46). Conclusion: According to the comprehensive analysis, EOs are effective in reducing both state anxiety and trait anxiety, and citrus aurantium L. essential oil seems to be the most recommended type of EO for treating anxiety because of its significant effects in reducing SAIS and TAIS. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022331319.

Engineering the Staple Oil Crop Brassica napus Enriched with α-Linolenic Acid Using the Perilla FAD2-FAD3 Fusion Gene.

Modern people generally suffer from α-linolenic acid (ALA) deficiency, since most staple food oils are low in ALA content. Thus, the enhancement of ALA in staple oil crops is of importance. In this study, the FAD2 and FAD3 coding regions from the ALA-king species Perilla frutescens were fused using a newly designed double linker LP4-2A, driven by a seed-specific promoter PNAP, and engineered into a rapeseed elite cultivar ZS10 with canola quality background. The mean ALA content in the seed oil of PNAP:PfFAD2-PfFAD3 (N23) T5 lines was 3.34-fold that of the control (32.08 vs 9.59%), with the best line being up to 37.47%. There are no significant side effects of the engineered constructs on the background traits including oil content. In fatty acid biosynthesis pathways, the expression levels of structural genes as well as regulatory genes were significantly upregulated in N23 lines. On the other hand, the expression levels of genes encoding the positive regulators of flavonoid-proanthocyanidin biosynthesis but negative regulators of oil accumulation were significantly downregulated. Surprisingly, the ALA level in PfFAD2-PfFAD3 transgenic rapeseed lines driven by the constitutive promoter PD35S was not increased or even showed a slight decrease due to the lower level of foreign gene expression and downregulation of the endogenous orthologous genes BnFAD2 and BnFAD3.

Genetic profile identification and clinicopathologic characteristics analysis of the thyroid-like low-grade nasopharyngeal papillary adenocarcinoma.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare malignancy bearing histomorphological similarities to papillary thyroid carcinoma with good prognosis. It's important to distinguish TL-LGNPPA from other papillary tumors including nasopharyngeal papillary adenocarcinoma (NPPA), metastatic and ectopic papillary thyroid cancer, and metastasized adenocarcinomas, etc. To date, only 48 cases of TL-LGNPPA have been reported in the English literatures. Here, we reported the genomic characteristics of additional 4 cases and reviewed other reports to clarify the clinicopathological features of this tumor. In this study, 41 mutations were detected by whole-exome sequencing, but no typical driver mutations were found. Two sample with Copy Number Variations (CNV) were found (7 q22. 17 q12), of which the segment spanned the regions of RASA4, POLR2J2, SPDYE2, CCL3, CCL4, etc. Additionally, no MSI and HLA LOH were found. To our knowledge, we are the first to reveal the genetic underpinnings of this rare tumor. The clinicopathological features of TL-LGNPPA were characterized, shedding more light on the essential difference between TL-LGNPPA with other papillary tumors.

Association of body mass index trajectory and hypertension risk: A systematic review of cohort studies and network meta-analysis of 89,094 participants.

Introduction: Body mass index (BMI) trajectories, such as non-linear time trends and nonlinear changes in BMI with age, can provide information on the underlying temporal health patterns. The relationship between BMI trajectories and the risk of hypertension remains controversial. Methods: PubMed, Embase, Cochrane, Scopus, and Web of Science databases were searched from their inception to January 31, 2022. We categorized BMI trajectories as "Stable high," "table normal," "Stable low," "Fluctuated (sharp increase)," and "Fluctuated (elevated-decrease)." The main outcome was the relative risk for the prevalence of hypertension in the different BMI trajectories. Potential sources of heterogeneity were examined using meta-regression and subgroup analysis. A publication bias test and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach were also used. Results: The 18 cohort studies included 89,094 participants. Compared with the "Stable normal" trajectory, "Stable high," "Fluctuated (sharp increase)," and "Fluctuated (elevated-decrease)" trajectories were associated with an increased relative risk of hypertension: [RR (95% CI)]: 1.80 (1.29 2.50), p < 0.001; 1.53 (1.27 1.83), p < 0.001; 1.30 (1.24 1.37), p = 0.001, respectively. The "Stable low" trajectory was associated with a reduced risk of hypertension [0.83 (0.79 0.83), p < 0.001]. The "Stable high" trajectory (surface under the cumulative ranking curve = 88.1%) had the highest probability of developing hypertension in the population. The certainty of the evidence for direct comparisons of the incidence of hypertension between various BMI trajectories was generally very low. Conclusion: Our findings suggested that "Stable high," "Fluctuated (sharp increase)," and "Fluctuated (elevated-decrease)" trajectories were associated with an increased relative risk of hypertension, with the "Stable high" trajectory most likely associated with hypertension. Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=308575], identifier [CRD42022308575].

Growth factor for therapeutic angiogenesis in ischemic heart disease: A meta-analysis of randomized controlled trials.

Aim: This study was designed to systematically evaluate the effects of growth factor (GF) for therapeutic angiogenesis on ischemic heart disease (IHD) by pooling the results of randomized controlled trials (RCTs). Methods and Results: PubMed, EMBASE, and CENTRAL databases were searched from inception to October 2022. RCTs, investigating the effects of GF therapy on IHD, were included. The risk bias of included study was assessed according to Cochrane tool. Weighted mean difference (WMD), calculated with fixed effect model or random effect model, was used to evaluate the effects of GF therapy on left ventricular ejection fraction (LVEF) and Canadian Cardiovascular Society (CCS) angina class. Relative risk (RR) was used to evaluate the effects of GF therapy on all-cause mortality, major adverse cardiovascular events (MACE) and revascularization. Meta-analysis, meta-regression analysis and publication bias analysis were performed by RevMan 5.3 or Stata 15.1 software. Twenty-nine studies involving 2899 IHD patients (1,577 patients in GF group and 1,322 patients in control group) were included. Compared with the control group, GF therapy did not reduce all-cause mortality (RR: 0.82; 95% CI: 0.54-1.24; p = 0.341), MACE [(RR: 0.83; 95% CI: 0.61-1.12; p = 0.227), revascularization (RR: 1.27, 95% CI: 0.82-1.96, p = 0.290) and CCS angina class (WMD: -0.08, 95% CI: -0.36 to 0.20, p = 0.560). However, GF therapy could increase LVEF during short-term follow-up (<1 year). Conclusion: GF for therapeutic angiogenesis was beneficial for increasing LVEF during short-term follow-up (<1 year), however, the therapy was not efficacious in decreasing all-cause mortality, MACE and revascularization.

Isolated Diastolic Hypertension and Risk of Cardiovascular Events: A Systematic Review and Meta-Analysis of Cohort Studies With 489,814 Participants.

Background: The association between isolated diastolic hypertension (IDH) and cardiovascular events has been inconsistently reported. This meta-analysis of cohort studies was designed to investigate the effect of the 2018 European Society of Cardiology (ESC) definition of IDH on the risk of composite cardiovascular events, cardiovascular mortality, all-cause mortality, and all strokes including ischemic stroke (IS) and hemorrhagic stroke (HS). Methods: PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to July 6, 2021. Cohort studies that investigated the association between IDH and cardiovascular events risk, compared to normotension, were included. Pooled hazard ratios (HRs) and 95% CIs were calculated using a random-effects models and heterogeneity was evaluated using Q-test and I 2 statistic. The robustness of the associations was identified using sensitivity analysis. The methodological quality of the studies was assessed using the Newcastle-Ottawa scale. Publication bias was assessed using funnel plot, trim-and-fill method, Begg's test, and Egger's test. Results: A total of 15 cohort studies (13 articles) including 489,814 participants were included in this meta-analysis. The follow-up period ranged from 4.3 to 29 years. IDH was significantly associated with an increased risk of composite cardiovascular events (HR 1.28, 95% CI: 1.07-1.52, p = 0.006), cardiovascular mortality (HR 1.45, 95% CI: 1.07-1.95, p = 0.015), all strokes (HR 1.44, 95% CI: 1.04-2.01, p = 0.03), and HS (HR 1.64, 95% CI: 1.18-2.29, p = 0.164), but not associated with all-cause mortality (HR 1.20, 95% CI: 0.97-1.47, p = 0.087) and IS (HR 1.56, 95% CI: 0.87-2.81, p = 0.137). Subgroup analysis further indicated that IDH in the younger patients (mean age ≤ 55 years) and from Asia were significantly associated with an increased risk of composite cardiovascular events, while the elderly patients (mean age ≥ 55 years), Americans, and Europeans were not significantly associated with an increased risk of composite cardiovascular events. Conclusion: This meta-analysis provides evidence that IDH defined using the 2018 ESC criterion is significantly associated with an increased risk of composite cardiovascular events, cardiovascular mortality, all strokes and HS, but not significantly associated with all-cause death and IS. These findings also emphasize the importance for patients with IDH to have their blood pressure within normal, especially in the young adults and Asians. Trial Registration: PROSPERO, Identifier: CRD42021254108.

Overexpression of KIAA1199 is an independent prognostic marker in laryngeal squamous cell carcinoma.

BACKGROUND: KIAA1199 is a recently identified novel gene that is upregulated in various human cancers with poor survival, but its role and the underlying mechanisms in laryngeal squamous cell carcinoma (LSCC) remain unknown. Here, we collected tissues from 105 cases of LSCC to investigate the relationships between KIAA1199 protein expression and clinical factors. METHODS: Western blotting and real-time quantitative PCR (RT-PCR) were used for detect the protein and mRNA expression of KIAA1199 in LSCC tissue. Immunohistochemistry (IHC) staining was used to detect the expression of KIAA1199. Patient clinical information, for instance sex, age, pathological differentiation, clinical region, T stage, N stage, clinical stage, operation type, neck lymph dissection, smoking status, and drinking status were recorded. Kaplan-Meier survival analysis and Cox analysis were applied to identify the relationship between KIAA1199 and LSCC. RESULTS: Western blotting results showed KIAA1199 protein was significantly higher in tumor tissues vs. adjacent non-cancerous tissues (0.9385 ± 0.1363 vs. 1.838 ± 0.3209, P = 0.04). The KIAA1199 mRNA expression was considerably higher in tumor tissues (P < 0.001) than in adjacent non-cancerous tissues by RT-PCR. IHC results showed up-regulated KIAA1199 expression was related with some severe clinicopathological parameters: pathologic differentiation (P = 0.002), T stage (P < 0.001), N stage (P < 0.001), clinical stage (P < 0.001), survival time (P = 0.008) and survival status (P < 0.001). Kaplan-Meier survival analysis showed that patients with high KIAA1199 protein expression had poor overall survival (OS) (P < 0.05). Cox analysis suggested that the KIAA1199 protein expression constituted an independent prognostic marker for LSCC patients (P < 0.001). CONCLUSION: Our findings revealed that KIAA1199 protein expression may be used to predict LSCC patient outcome.

Development of a CRISPR-SaCas9 system for projection- and function-specific gene editing in the rat brain.

A genome editing technique based on the clustered regularly interspaced short palindromic repeats (CRISPR)-associated endonuclease Cas9 enables efficient modification of genes in various cell types, including neurons. However, neuronal ensembles even in the same brain region are not anatomically or functionally uniform but divide into distinct subpopulations. Such heterogeneity requires gene editing in specific neuronal populations. We developed a CRISPR-SaCas9 system-based technique, and its combined application with anterograde/retrograde AAV vectors and activity-dependent cell-labeling techniques achieved projection- and function-specific gene editing in the rat brain. As a proof-of-principle application, we knocked down the cbp (CREB-binding protein), a sample target gene, in specific neuronal subpopulations in the medial prefrontal cortex, and demonstrated the significance of the projection- and function-specific CRISPR-SaCas9 system in revealing neuronal and circuit basis of memory. The high efficiency and specificity of our projection- and function-specific CRISPR-SaCas9 system could be widely applied in neural circuitry studies.

Upregulation of Cav3.2 T-type calcium channels in adjacent intact L4 dorsal root ganglion neurons in neuropathic pain rats with L5 spinal nerve ligation.

Besides the injured peripheral dorsal root ganglion (DRG) neurons, the adjacent intact DRG neurons also have important roles in neuropathic pain. Ion channels including Cav3.2 T-type calcium channel in the DRG neurons are important in the development of neuropathic pain. In the present study, we aimed to examine the expression of Cav3.2 T-type calcium channels in the intact DRG neurons in neuropathic pain. A neuropathic pain model of rat with lumbar 5 (L5) spinal nerve ligation (SNL) was established, in which the L4 DRG was separated from the axotomized L5 DRG, and the molecular, morphological and electrophysiological changes of Cav3.2 T-type calcium channels in L4 DRG neurons were investigated. Western blotting showed that total and membrane protein levels of Cav3.2 in L4 DRG neurons increased, and voltage-dependent patch clamp recordings revealed an increased T-type current density with a curve shift to the left in steady-state activation in the acutely isolated L4 DRG neurons in neuropathic pain rats. Immunofluorescent staining further showed that the membrane expression of Cav3.2 increased in CGRP-, IB4-positive small neurons and NF200-positive large ones. In conclusion, the membrane expression and the function of Cav3.2 T-type calcium channels are increased in the intact L4 DRG neurons in neuropathic pain rats with peripheral nerve injury like SNL.