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Is thyroid autoimmunity (TAI) associated with the decline of ovarian reserve in euthyroid women?Case-control study. Data from 4302 euthyroid women with normal ovarian reserve (NOR) and low ovarian reserve (LOR), including biochemical premature ovarian insufficiency (POI) and overt POI, were retrospectively analysed. The prevalence and effect of TAI on ovarian reserve was evaluated between women with NOR and LOR. Status of ovarian insufficiency and TSH levels was further stratified for analysis. The correlation between anti-thyroid peroxidase antibody (TPOAb), anti-thyroglobulin antibody (TgAb) titres and ovarian reserve markers was also determined.The prevalence of positive TAI and TgAb was equally distributed between women with NOR and LOR (P = 0.080, P = 0.172); the prevalence of TPOAb positivity was higher in the LOR group (P = 0.005). After stratifying ovarian reserve and TSH, positive TAI, TPOAb and TGAb were significantly associated with overt POI when TSH was2.5 µIU/ml (all P0.001); no association was observed with biochemical POI or overt POI when TSH was ≤2.5 µIU/ml. No correlation was found between TPOAb, TGAb titres and AMH (P = 0.218, P = 0.368, respectively), and bilateral AFC (P = 0.184, P = 0.315, respectively) in patients with LOR; only TPOAb titre was positively correlated with FSH (P = 0.039).Among the whole population of euthyroid women, TAI was not associated with low ovarian reserve but was significantly associated with overt POI in women with TSH2.5 µIU/ml. Further basic studies on underlying mechanisms are needed.

Endothelial cell senescence is the main risk factor contributing to vascular dysfunction and the progression of aging-related cardiovascular diseases. However, the relationship between endothelial cell metabolism and endothelial senescence remains unclear. The present study provides novel insight into fatty acid metabolism in the regulation of endothelial senescence. In the replicative senescence model and H2O2-induced premature senescence model of primary cultured human umbilical vein endothelial cells (HUVECs), fatty acid oxidation (FAO) was suppressed and fatty acid profile was disturbed, accompanied by downregulation of proteins associated with fatty acid uptake and mitochondrial entry, in particular the FAO rate-limiting enzyme carnitine palmitoyl transferase 1A (CPT1A). Impairment of fatty acid metabolism by silencing CPT1A or CPT1A inhibitor etomoxir facilitated the development of endothelial senescence, as implied by the increase of p53, p21, and senescence-associated β-galactosidase, as well as the decrease of EdU-positive proliferating cells. In the contrary, rescue of FAO by overexpression of CPT1A or supplement of short chain fatty acids (SCFAs) acetate and propionate ameliorated endothelial senescence. In vivo, treatment of acetate for 4 weeks lowered the blood pressure and alleviated the senescence-related phenotypes in aortas of Ang II-infused mice. Mechanistically, fatty acid metabolism regulates endothelial senescence via acetyl-coenzyme A (acetyl-CoA), as implied by the observations that suppression of acetyl-CoA production using the inhibitor of ATP citrate lyase NDI-091143 accelerated senescence of HUVECs and that supplementation of acetyl-CoA prevented H2O2-induced endothelial senescence. Deficiency of acetyl-CoA resulted in alteration of acetylated protein profiles which are associated with cell metabolism and cell cycle. These findings thus suggest that improvement of fatty acid metabolism might ameliorate endothelial senescence-associated cardiovascular diseases.

Type 2 diabetes mellitus (T2DM) is associated with brain damage and cognitive decline. Despite the fact that the thalamus involves aspects of cognition and is typically affected in T2DM, existing knowledge of subregion-level thalamic damage and its associations with cognitive performance in T2DM patients is limited. The thalamus was subdivided into 8 subregions in each hemisphere. Resting-state functional and structural MRI data were collected to calculate resting-state functional connectivity (rsFC) and gray matter volume (GMV) of each thalamic subregion in 62 T2DM patients and 50 healthy controls. Compared with controls, T2DM patients showed increased rsFC of the medial pre-frontal thalamus, posterior parietal thalamus, and occipital thalamus with multiple cortical regions. Moreover, these thalamic functional hyperconnectivity were associated with better cognitive performance and lower glucose variability in T2DM patients. However, there were no group differences in GMV for any thalamic subregions. These findings suggest a possible neural compensation mechanism whereby selective thalamocortical functional hyperconnectivity facilitated by better glycemic control help to preserve cognitive ability in T2DM patients, which may ultimately inform intervention and prevention of T2DM-related cognitive decline in real-world clinical settings.

In familial cortical myoclonic tremor with epilepsy, photic stimulation can trigger visual-related symptoms and induce a photoparoxysmal response on electroencephalography. This is known as photosensitivity. To explore the mechanism of prominent visual-related symptoms and photosensitivity in patients with genetically confirmed familial cortical myoclonic tremor with epilepsy type 1, resting-state functional magnetic resonance imaging data and electroencephalography data were collected from 31 patients carrying the heterozygous pathogenic intronic pentanucleotide (TTTCA)n insertion in the sterile alpha motif domain-containing 12 gene and from 52 age- and sex-matched healthy controls. Results: (1) Both regional homogeneity and degree centrality values in the bilateral calcarine sulcus were significantly increased in patients compared with HCs. (2) When the calcarine sulcus area with increased regional homogeneity was taken as a seed, increased functional connectivity values were observed in the right precentral gyrus, while decreased functional connectivity values were observed in the right superior frontal gyrus and right inferior parietal lobule. (3) independent component analysis showed increased connectivity in the left calcarine sulcus inside the medial visual network. (4) Correlation analysis revealed significant positive correlation between regional homogeneity values and frequency of seizure, and photoparoxysmal response grades were positively correlated with the severity of cortical tremor and duration of epilepsy. The findings provide strong evidence for the interpretation of visual-related symptoms and photosensitivity in familial cortical myoclonic tremor with epilepsy and may also relate to other epilepsy syndromes with photosensitivity. We speculate the significant functional change in primary visual cortex probably an imaging biomarker for the disease.

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.

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This study compared the overall survival (OS) of patients with early-stage primary non-small-cell lung cancer (NSCLC) treated with radiofrequency ablation (RFA) versus surgery.A systematic search was performed in MEDLINE, Embase, Cochrane Central Register, and all available Chinese databases to identify relevant publications from inception to April 2019. This meta-analysis compared hazard ratios (HRs) for OS. A multivariate fixed effects model was used to perform a meta-analysis to compare survival between treatments.Six retrospective studies were included in the quantitative synthesis. Compared with surgery, RFA was associated with a similar long-term OS. The HRs and 95% confidence intervals (CIs) for 2-, 3- and 5-year OS were 1.74 [0.82, 3.71], 1.15 [0.65, 2.02] and 2.69 [0.41, 17.47], respectively, while those of the pooled data were 1.47 [0.94, 2.32] in patients with early-stage primary NSCLC.RFA did not differ significantly from surgery in terms of the 5-year OS in patients with early-stage primary NSCLC. Randomized, controlled clinical trials are warranted to compare these two treatments.

Ischemic diseases are life-threatening, and the incidence increases as people's lifestyles change. Medications and surgical intervention offer limited benefit, and stem cell therapy has emerged as a potential approach for treating ischemic diseases. The exosomes secreted by stem cells have attracted more attention because they do not trigger the immune response and can be used as drug carriers. The non-coding RNA (ncRNA) carried by exosomes plays a key role in mediating exosome's beneficial effect, which can be further enhanced when combined with nanomaterials to improve its retention time. Here, we review the downstream target molecules and signal pathways of ncRNA and summarize recent advances of some nanomaterials used to encapsulate exosomes and promote ischemic tissue repair. We highlight the imprinting of exosomes from parent cells and discuss how the inflammasome pathway may be targeted for the development of novel therapy for ischemic diseases.

Multiphoton microscopy (MPM), a high-resolution laser scanning technique, has been shown to provide detailed real-time information on fibrosis assessment in animal models. But the value of MPM in human histology, especially in heart tissue, has not been fully explored. We aimed to evaluate the association between myocardial fibrosis measured by MPM and that measured by histological staining in the transplanted human heart. One hundred and twenty samples of heart tissue were obtained from 20 patients consisting of 10 dilated cardiomyopathies (DCM) and 10 ischemic cardiomyopathies (ICM). MPM and picrosirius red staining were performed to quantify collagen volume fraction (CVF) in explanted hearts postoperatively. Cardiomyocyte and myocardial fibrosis could be clearly visualized by MPM. Although patients with ICM had significantly greater MPM-derived CVF than patients with DCM (25.33 ± 12.65 % vs. 19.82 ± 8.62 %, p = 0.006), there was a substantial overlap of CVF values between them. MPM-derived CVF was comparable to that derived from picrosirius red staining based on all samples (22.58 ± 11.13% vs. 21.19 ± 11.79%, p = 0.348), as well as in DCM samples and ICM samples. MPM-derived CVF was correlated strongly with the magnitude of staining-derived CVF in both all samples and DCM samples and ICM samples (r = 0.972, r = 0.963, r = 0.973, respectively; all p

Background: Accurate electrode targeting was essential for the efficacy of deep brain stimulation (DBS). There is ongoing debate about the necessary of microelectrode recording (MER) in subthalamic nucleus (STN)-DBS surgery for accurate targeting. Objective: This study aimed to analyze the accuracy of imaging-guided awake DBS with MER in STN for Parkinson’s disease in a single center. Methods: The authors performed a retrospective analysis of 161 Parkinson’s disease patients undergoing STN-DBS at our center from March 2013 to June 2021. The implantation was performed by preoperative magnetic resonance imaging (MRI)-based direct targeting with intraoperative MER and macrostimulation testing. 285 electrode tracks with preoperative and postoperative coordinates were included to calculate the placement error in STN targeting. Results: 85.9% of electrodes guided by preoperative MRI were implanted without intraoperative adjustment. 31 (10.2%) and 12 (3.9%) electrodes underwent intraoperative adjustment due to MER and intraoperative testing, respectively. We found 86.2% (245/285) of electrodes with trajectory error ≤2 mm. The MER physiological signals length 2 mm in 38.0% and 8.8% of electrodes, respectively. Compared to non-adjustment electrodes, the final positioning of MER-adjusted electrodes deviated from the center of STN. Conclusion: The preoperative MRI guided STN targeting results in approximately 14% cases that require electrode repositioning. MER physiological signals length

Previous studies have reported evidence supporting structural and functional alterations in the brains of methamphetamine (MA) users. The aim of the present study was to extend current knowledge regarding brain function(s) in MA users by examining regional homogeneity (ReHo). Chronic MA users (51 male, 46 female), who were undergoing supervised abstinence for 12 to 621 days, and 79 healthy controls (43 male, 36 female) underwent resting-state functional brain magnetic resonance imaging. Voxel-wise whole-brain scale group differences in ReHo were examined. The mean ReHo values of significant clusters were extracted, and linear regression was used to identify factors that contributed to these mean ReHo values. MA users exhibited lower ReHo values in the left orbital part of the inferior frontal gyrus extending to the left insula and left temporal pole, left amygdala, and left fusiform gyrus. MA users also exhibited greater ReHo values in the bilateral pre- and postcentral gyri and right cerebellum. Characteristics of MA use, including duration, duration of abstinence from MA, and age at onset of MA use, demonstrated no reliable contribution to ReHo of the significant clusters. Findings of the present study demonstrated that chronic MA use was associated with regional specific disruption of ReHo, which is relatively independent of structural and functional alterations and, apparently, does not recover after relatively long-term abstinence. This disruption may underlie overall neurocognitive deficits in MA users, which is difficult to recover.

Colchicine is an ancient anti-inflammatory drug. In recent years, an increasing number of studies have shown that colchicine improves the prognosis of patients with coronary artery disease (CAD), while other studies have reported the opposite. The aim of this study was to evaluate the relative efficacy and safety of colchicine in treating CAD.PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were searched from inception to 20 October 2020 for randomized controlled trials (RCTs) comparing colchicine and placebo in patients with CAD. The primary outcomes were the primary composite outcomes of cardiovascular death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization after colchicine administration. The secondary outcomes were cardiovascular death, death from any cause, noncardiac death, MI, ischemic stroke, coronary revascularization, gastrointestinal (GI) symptoms, and the different effects of colchicine in acute and chronic CAD. We assessed the pooled odds ratio (OR) of all-cause and cardiovascular mortality for CAD in fixed-effects models, the pooled risk ratio (RR) of the primary composite outcomes, MI, ischemic stroke, and ischemia-driven coronary revascularization in fixed-effects models and the pooled RR of GI symptoms in random-effects models. The Cochrane risk of bias tool was used to assess the risk of bias in the included RCTs.Eleven of the 894 identified studies (n = 12,899 patients) were included (6501 subjects in the colchicine group; 6389 subjects in the control group). The colchicine group had significantly lower pooled RRs of the primary composite outcomes (0.73, 95% confidence interval (CI) 0.64-0.84, P 0.0001), MI (0.77, 95% CI 0.64-0.92, P = 0.004), ischemic stroke (0.47, 95% CI 0.30-0.76, P = 0.002), and ischemia-driven coronary revascularization (0.77, 95% CI 0.66-0.89, P = 0.0007), while the pooled RR of adverse GI events (2.15 95% CI 1.40-3.31, P = 0.0005) was significantly higher. Colchicine had a lower pooled RR of ischemic stroke (0.28, 95% CI 0.12-0.65, P = 0.003) for patients with acute compared with chronic CAD.Colchicine treatment significantly decreased the risk of primary cardiovascular composite outcomes, MI, ischemic stroke, and ischemia-driven coronary revascularization in CAD patients but increased adverse GI events. There was no significant difference in all-cause mortality, cardiovascular mortality, and non-cardiovascular death between the colchicine and control groups. Colchicine performs better in acute CAD patients with ischemic stroke than chronic CAD patients. Colchicine might be a new treatment for patients with CAD.

To explore the efficacy of uterine artery embolization (UAE) in the treatment of uterine fibroid and share the experience of transvaginal fibroid expulsion (FE) after UAE.We retrospectively analyzed the changes in uterine and fibroid volume in 152 patients with symptomatic uterine fibroid after UAE at Fujian Provincial Hospital and Fujian Longyan People Hospital from March 2014 to March 2020. After a 12-month follow-up, the improvement in postoperative clinical symptoms and the incidence of complications were evaluated. We also shared the clinical features and imaging findings of four patients with FE after UAE.All 152 patients successfully underwent UAE. After a 12-month follow-up, the postoperative volumes of the uterus and fibroid at 3, 6, and 12 months were significantly reduced or disappeared compared to those before surgery (P 0.05). Clinical symptoms, such as menorrhagia, dysmenorrhea, prolonged menstrual period, anemia, increased leucorrhea, pelvic discomfort, and urinary tract compression, were significantly improved after UAE. Among the 152 patients, the incidences of postoperative fever, nausea, vomiting, lower abdominal pain, and increased vaginal secretion were 7.89%, 7.24%, 3.95%, 19.08%, and 4.61%, respectively. Additionally, there were six cases of FE, with an incidence of 3.95%. Three cases of fibroid specimens and pathological images of fibroid biopsy, which were expelled through the vagina, were also provided.UAE is a satisfactory alternative surgical method for symptomatic uterine fibroid with definitive efficacy and high safety. However, it is necessary to guard against the occurrence of postoperative complications such as FE.

Purpose To address whether Curcumin has synergistic effect with cytarabine (Ara-C) in treating acute myeloid leukemia (AML). Methods A xenograft AML mouse model was established by injecting HL-60 cells into tail vein of mice to assess the function of Curcumin. Mononuclear cells (MNCs) isolated from AML mice and AML cell lines were used to examine the effect of Curcumin. Metagenomics and metabolomics were used to evaluate the alteration of intestinal microbiota and the change of metabolites in MNCs. Results Curcumin treatment sensitized response to Ara-C in MNCs of AML mice, but had no direct effect on AML cell lines. Metagenomics revealed an alteration of intestinal microbiota with Curcumin treatment, which contributes to sensitized response to Ara-C. Curcumin treatment led to enhanced intestinal intact to sensitize response to Ara-C in AML mice, through reducing mucus degrading bacteria. Metabolomics demonstrated that Curcumin treatment led to decreased cholesterol in MNCs of AML mice. Further study proved that Curcumin treatment resulted in inhibition of SQLE, a key enzyme of cholesterol biosynthesis, to increase sensitivity to Ara-C. Conclusion Curcumin sensitizes response to Ara-C through regulating microbiota, highlighting the importance of intestinal intact strengthening in chemoresistant therapy. Moreover, aiming at cholesterol synthesis is promising in AML treatment.

Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis. Supplementary Information The online version contains supplementary material available at 10.1007/s12265-021-10147-3.

Purpose The etiology of premature ovarian insufficiency (POI) is heterogeneous, and genetic factors account for 20–25% of the patients. The primordial follicle pool is determined by the meiosis process, which is initiated by programmed DNA double strand breaks (DSB) and homologous recombination. The objective of the study is to explore the role of DSB formation genes in POI pathogenesis. Methods Variants in DSB formation genes were analyzed from a database of exome sequencing in 1,030 patients with POI. The pathogenic effects of the potentially causative variants were verified by further functional studies. Results Three pathogenic heterozygous variants in PRDM9 and two in ANKRD31 were identified in seven patients. Functional studies showed the variants in PRDM9 impaired its methyltransferase activity, and the ANKRD31 variations disturbed its interaction with another DSB formation factor REC114 by haploinsufficiency effect, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent. Conclusion Our study identified pathogenic variants of PRDM9 and ANKRD31 in POI patients, shedding new light on the contribution of meiotic DSB formation genes in ovarian development, further expanding the genetic architecture of POI.

Mutations in presenilin 1 (PSEN1) are the most common known genetic cause of early-onset Alzheimer’s disease. Patients with PSEN1 mutations exhibit broad phenotypes. Here, we report clinical, neuroimaging and genetic findings in a patient with a de novo mutation in PSEN1 (c.697A > G, p.M233V) presenting with early-onset parkinsonism as the initial and primary symptom. We recruited a family with one affected patient with early-onset parkinsonism. The patient underwent comprehensive neurological examination and imaging evaluation. Whole genome sequencing was performed for the proband. The patient presented with parkinsonism and mild cognitive impairment. He had a good response to levodopa. Brain MRI evaluation showed atrophy of the bilateral frontotemporal lobe and hippocampus. 18F-fluorodeoxyglucose-positron emission tomography (PET) and 11C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane-PET showed decreased metabolism and dopamine transporter distribution in the bilateral putamen and caudate nucleus. 11C-Pittsburgh compound B -PET showed β-amyloid protein deposition. Genetic analysis identified a heterozygous de novo variant in PSEN1 (c.697A > G, p.M233V). Screening for PSEN1 variations should be considered in patients with levodopa-responsive early-onset parkinsonism.

BACKGROUND AND PURPOSE The GGC repeat expansion in the NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). Recently, this repeat expansion was also reported to be associated with essential tremor (ET). However, some patients with this repeat expansion, initially diagnosed with ET, were eventually diagnosed with NIID. Therefore, controversy remains regarding the clinical diagnosis of these expansion-positive patients presenting with tremor-dominant symptoms. This study aimed to clarify the clinical phenotype in tremor-dominant patients who have the GGC repeat expansion in the NOTCH2NLC gene. METHODS We screened for pathogenic GGC repeat expansions in 602 patients initially diagnosed with ET and systematically re-evaluated the clinical features of the expansion-positive probands and their family members. RESULTS Pathogenic GGC repeat expansion in the NOTCH2NLC gene was detected in 10 probands (1.66%). Seven of these probands were re-evaluated and found to have systemic areflexia, cognitive impairment, and abnormal nerve conduction, which prompted a change of diagnosis from ET to NIID. Three of the probands had typical hyperintensity in the corticomedullary junction on diffusion-weighted imaging. Intranuclear inclusions were detected in all four probands who underwent skin biopsy. CONCLUSIONS The NIID tremor-dominant subtype can be easily misdiagnosed as ET. We should take NIID into account for differential diagnosis of ET. Systemic areflexia could be an important clinical clue suggesting that cranial magnetic resonance imaging examination, or even further genetic testing and skin biopsy examination, should be used to confirm the diagnosis of NIID.

Background Massive hemoptysis due to aspergilloma is a rare but life-threatening complication. Bronchial artery embolization is recommended as a definitive treatment for massive hemoptysis. Polyvinyl alcohol is widely used in bronchial artery embolization. A very small number of studies have reported disrupted polyvinyl alcohol, which may cause ectopic embolism. Case presentation This case highlights an unusual phenomenon in which polyvinyl alcohol fragments appeared on pathological examination in a 61-year-old man, ethnic Han, with massive hemoptysis caused by aspergilloma for whom bronchial artery embolization failed. Lobectomy was carried out successfully. Hematoxylin and eosin stain provides clear images of polyvinyl alcohol fragments, while alpha-smooth muscle cell actin and cluster of differentiation-34 immunohistochemistry revealed their localization in bronchioles. Conclusion Thus far, only two cases of polyvinyl alcohol fragments in the lung have been reported, and the mechanism has not been elucidated. These two cases revealed no counter-indication for the use of polyvinyl alcohol. However, in some cases of off-target embolization causing fatal complications, such as stroke, paraplegia, and myocardial, polyvinyl alcohol fragmentation needs to be taken into consideration.

Background TGF-β superfamily signaling is indispensable for bone homeostasis. However, the global expression profiles of all the genes that make up this signaling module in bone and bone-related diseases have not yet been well characterized. Methods Transcriptomic datasets from human bone marrows, bone marrow-derived mesenchymal stem cells (MSCs) and MSCs of primary osteoporotic patients were used for expression profile analyses. Protein treatments, gene quantification, reporter assay and signaling dissection in MSC lines were used to clarify the interactive regulations and feedback mechanisms between TGF-β superfamily ligands and antagonists. Ingenuity Pathway Analysis was used for network construction. Results We identified TGFB1 in the ligand group that carries out SMAD2/3 signaling and BMP8A, BMP8B and BMP2 in the ligand group that conducts SMAD1/5/8 signaling have relatively high expression levels in normal bone marrows and MSCs. Among 16 antagonist genes, the dominantly expressed TGF-β superfamily ligands induced only NOG, GREM1 and GREM2 via different SMAD pathways in MSCs. These induced antagonist proteins further showed distinct antagonisms to the treated ligands and thus would make up complicated negative feedback networks in bone. We further identified TGF-β superfamily signaling is enriched in MSCs of primary osteoporosis. Enhanced expression of the genes mediating TGF-β-mediated SMAD3 signaling and the genes encoding TGF-β superfamily antagonists served as significant features to osteoporosis. Conclusion Our data for the first time unveiled the transcription landscape of all the genes that make up TGF-β superfamily signaling module in bone. The feedback mechanisms and regulatory network prediction of antagonists provided novel hints to treat osteoporosis.

BackgroundMelanoma, as one of the most aggressive and malignant cancers, ranks first in the lethality rate of skin cancers. Cuproptosis has been shown to paly a role in tumorigenesis, However, the role of cuproptosis in melanoma metastasis are not clear. Studying the correlation beteen the molecular subtypes of cuproptosis-related genes (CRGs) and metastasis of melanoma may provide some guidance for the prognosis of melanoma.MethodsWe collected 1085 melanoma samples in The Cancer Genome Atlas(TCGA) and Gene Expression Omnibus(GEO) databases, constructed CRGs molecular subtypes and gene subtypes according to clinical characteristics, and investigated the role of CRGs in melanoma metastasis. We randomly divide the samples into train set and validation set according to the ratio of 1:1. A prognostic model was constructed using data from the train set and then validated on the validation set. We performed tumor microenvironment analysis and drug sensitivity analyses for high and low risk groups based on the outcome of the prognostic model risk score. Finally, we established a metastatic model of melanoma.ResultsAccording to the expression levels of 12 cuproptosis-related genes, we obtained three subtypes of A1, B1, and C1. Among them, C1 subtype had the best survival outcome. Based on the differentially expressed genes shared by A1, B1, and C1 genotypes, we obtained the results of three gene subtypes of A2, B2, and C2. Among them, the B2 group had the best survival outcome. Then, we constructed a prognostic model consisting of 6 key variable genes, which could more accurately predict the 1-, 3-, and 5-year overall survival rates of melanoma patients. Besides, 98 drugs were screened out. Finally, we explored the role of cuproptosis-related genes in melanoma metastasis and established a metastasis model using seven key genes.ConclusionsIn conclusion, CRGs play a role in the metastasis and prognosis of melanoma, and also provide new insights into the underlying pathogenesis of melanoma.

Background Antibiotic-impregnated calcium sulfate has excellent curative efficacy in chronic osteomyelitis. However, its curative efficacy in pediatric hematogenous osteomyelitis has not been sufficiently studied. The purpose of this study was to evaluate the curative effects of antibiotic-impregnated calcium sulfate in the treatment of pediatric hematogenous osteomyelitis. Methods Overall, twenty-one pediatric patients with hematogenous osteomyelitis treated at our hospital between 2013 and 2018 were included for assessment. The clinical history, clinical manifestation, infection recurrence rate, sinus leakage, incision leakage, pathological fractures, bone growth and surgical procedures were analyzed. Results The infection recurrence rate was 0% (0/21) at a minimum of 31 months (range 31 to 91 months) of follow-up. Postoperative incision leakage was found in one pediatric patient. Osteolysis was found in one pediatric patient. Acceleration of bone growth occurred in one pediatric patient. Retardation of bone growth occurred in one pediatric patient. Genu valgus deformity occurred in one pediatric patient. Conclusions Although noninfectious complications occurred, the curative effect of antibiotic-impregnated calcium sulfate in pediatric hematogenous osteomyelitis was satisfactory.

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BackgroundThe major histocompatibility complex (MHC) and the killer cell immunoglobulin-like receptors (KIR) are key regulators of immune responses. The cynomolgus macaque, an Old World monkey species, can be applied as an important preclinical model for studying human diseases, including coronavirus disease 2019 (COVID-19). Several MHC-KIR combinations have been associated with either a poor or good prognosis. Therefore, macaques with a well-characterized immunogenetic profile may improve drug evaluation and speed up vaccine development. At present, a complete overview of the MHC and KIR haplotype organizations in cynomolgus macaques is lacking, and characterization by conventional techniques is hampered by the extensive expansion of the macaque MHC-B region that complicates the discrimination between genes and alleles.MethodsWe assembled complete MHC and KIR genomic regions of cynomolgus macaque using third-generation long-read sequencing approach. We identified functionalMafa-Bloci at the transcriptome level using locus-specific amplification in a cohort of 33 Vietnamese cynomolgus macaques.ResultsThis is the first physical mapping of completeMHCandKIRgene regions in a Vietnamese cynomolgus macaque. Furthermore, we identified four functionalMafa-Bloci (B2,B3,B5, andB6) and showed that alleles of theMafa-I*01,-B*056,-B*034, and-B*001functional lineages, respectively, are highly frequent in the Vietnamese cynomolgus macaque population.ConclusionThe insights into the MHC and KIR haplotype organizations and the level of diversity may refine the selection of animals with specific genetic markers for future medical research.

Background Previous articles have focused on the diagnosis and treatment of acute hematogenous osteomyelitis. Here, we present a case of chronic hematogenous osteomyelitis in a 2-month-old girl. The diagnostic procedure was unusual and difficult due to negative culture results. Case presentation A girl aged 2 months and 23 days had fever and swelling in her right lower leg for 7 days. On the basis of her medical history, physical, and histological examination results; and radiologic and magnetic resonance imaging findings, a diagnosis of chronic osteomyelitis was made. The patient underwent surgical treatment and was discharged successfully. The patient showed good recovery and no sequelae at the 12-month follow-up. Conclusion Hematogenous osteomyelitis in babyhood is different from that at any other age. Hematogenous osteomyelitis-related bone destruction in babyhood is more serious and occurs faster. The transition from acute hematogenous osteomyelitis to chronic hematogenous osteomyelitis takes only 7 days. To the best of our knowledge, this chronic hematogenous osteomyelitis patient is the youngest ever reported.

Ion channels are ubiquitously expressed in almost all living cells, and are the third-largest category of drug targets, following enzymes and receptors. The transient receptor potential melastatin (TRPM) subfamily of ion channels are important to cell function and survival. Studies have shown upregulation of the TRPM family of ion channels in various brain tumours. Gliomas are the most prevalent form of primary malignant brain tumours with no effective treatment; thus, drug development is eagerly needed. TRPM2 is an essential ion channel for cell function and has important roles in oxidative stress and inflammation. In response to oxidative stress, ADP-ribose (ADPR) is produced, and in turn activates TRPM2 by binding to the NUDT9-H domain on the C-terminal. TRPM2 has been implicated in various cancers and is significantly upregulated in brain tumours. This article reviews the current understanding of TRPM2 in the context of brain tumours and overviews the effects of potential drug therapies targeting TRPM2 including hydrogen peroxide (H2O2), curcumin, docetaxel and selenium, paclitaxel and resveratrol, and botulinum toxin. It is long withstanding knowledge that gliomas are difficult to treat effectively, therefore investigating TRPM2 as a potential therapeutic target for brain tumours may be of considerable interest in the fields of ion channels and pharmacology. The role of TRPM2 in the pathways of various inhibitors and activators. (a) A schematic illustration of the TRPM2 channel which includes 4 N-terminal MHR domains, six transmembrane helices labelled S1–S6, a TRP domain, a coiled-coil domain and NUDT9-H domain. (b) BTX increases mitochondrial ROS leading to increased caspase 9 and 3. (c) The pathway of TNF-α, increasing ROS, activating the caspase 8 cascade, increasing ROS in the mitochondria, finally leading to increased PARP. PARP converts NAD+ to ADPR, activating TRPM2 at the NUDT9-H domain, in turn allowing for Ca2+ influx. (d) Resveratrol as an adjuvant therapy with paclitaxel heightens the apoptotic affects of paclitaxel via activation of the caspase 9 and 3 cascades while increasing PARP for downstream effects as previously described . (d) Curcumin inhibits TRPM2 via inhibition of the PARP1. (f) Selenium increases the apoptotic ability of docetaxel via activation of TRPM2 channels, increasing PARP and ROS in the mitochondria, for increased ADPR production. (g) H2O2 and ROS increase ROS and increase PARP, augmenting ADPR expression and TRPM2 activation.

In recent years, there is a growing incidence of granulomatous lobular mastitis (GLM), but studies about the coexistence of erythema nodosum (EN) and GLM are rare. In this study, we assess the clinical characteristics and predictive factors of EN in GLM.A total of 303 patients diagnosed with GLM were enrolled from January 2012 to October 2018 at the second affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, including 78 patients with EN. Follow-up data included: lesion site, lesion size, therapy approaches, course of GLM, course of EN, the recurrence of disease, possible causes. All patients had pathologic confirmation of GLM based on core needle biopsy (CNB) or surgical excision.Fever in the EN group was significantly more common compared to the non-EN group (44.87% vs 12.89%, P 0.001). The proportion of lesion range2 quadrants in the EN group was significantly higher than that in the non-EN group (42.31% vs 16.00%, P 0.001). The course of the disease was longer in the EN group compared to the non-EN group (10.32 moths vs 8.74 moths, P 0.001). Patients with EN had a trend towards a higher risk of recurrence (5.13% vs 1.33%, P = 0.055).EN is more likely to be found in GLM patients with breast lesion range2 quadrants. The presence of EN in GLM indicates that the condition becomes more severe and the course of GLM also becomes longer.

Background Bipolar disorder is a common psychiatric disorder characterized by insufficient or ineffective connections associated with white-matter (WM) abnormalities. Previous studies have detected the structural attributes of WM using magnetic resonance imaging (MRI) or diffusion tensor imaging, however, they failed to disentangle the dysfunctional organization within the WM. Methods This study aimed to uncover the WM functional connectivity (FC) in 45 bipolar disorder patients during depressive episodes (BDD) and 45 healthy controls based on resting-state functional MRI. Eight WM functional networks were identified by using a clustering analysis of voxel-based correlation profiles, which were further classified into superficial, middle and deep layers of networks. Results Group comparisons on the FCs among 8 WM networks showed that the superficial tempofrontal network (TFN) in BDD patients had increased FC with the superficial cerebellar network (CN) and with the superficial pre/post-central network (PCN). Further, support vector regression prediction analysis results revealed that the increased FCs of CN-TFN and PCN-TFN could be served as features to predict the numbers of depressive episode in BDD patients. Conclusions The current study extended our knowledge about the impaired WM functional connections associated with emotional and sensory-motor perception processing in BDD, which may facilitate the interpretation of the pathophysiology mechanisms underlying BDD.

The polarization of tumor-associated macrophages (TAMs) plays a key role in tumor development and immunotherapy in colorectal cancer (CRC) patients. However, the impact of apoptosis on TAM polarization and immunotherapy efficacy in patients with different mismatch repair statuses (MMR) remains unclear. Here, we constructed an atlas of macrophage and found a higher rate of infiltration of M2-like TAM subpopulation in pMMR CRC tumor tissues compared with that in dMMR CRC tumor tissues. Importantly, a lower infiltration rate of M2c-like TAMs was associated with immunotherapy response. The M2 polarization trajectory revealed the apoptosis of M2c-like TAMs in dMMR while the differentiation of M2c-like TAMs in pMMR, implying a higher polarization level of M2 in pMMR. Furthermore, we found that a high expression of S100A6 induces the apoptosis of M2c-like TAMs in dMMR. In conclusion, we identified apoptotic TAM subpopulations in the M2 polarization trajectory and found that apoptosis caused by the high expression of S100A6 reduces their infiltration in tumors as well as the level of M2 polarization and contributes to a favorable immunotherapy response. These findings provide new insights into the potential role of apoptosis in suppressing tumors and enhancing immunotherapeutic efficacy.

Di-2-ethylhexyl phthalate (DEHP) has been proven to boost miR-155-5p level in trophoblasts, but how DEHP-induced miR-155-5p regulates trophoblastic functions is unclear. For in vivo experiments, DEHP was administered to pregnant Sprague-Dawley (SD) rats at various dosages. After birth, the development of rat fetuses was evaluated. The morphology of the placentae was evaluated using HE staining. miR-155-5p level in placentae was measured utilizing RT-qPCR. Placental cAMP/PKA pathway activation and lipid metabolism levels were assessed using WB, RT-qPCR, and ELISA. For in vitro experiments, DEHP, miR-155-5p inhibitor, or cAMP/PKA inhibitor were applied to treat HTR-8/Svneo cells. Cell viability and functions were investigated utilizing WB, RT-qPCR, CCK-8, transwell assay, plate colony formation assay, and flow cytometry. Besides, the cAMP/PKA pathway activation and lipid metabolism levels in HTR-8/Svneo cells were detected via ELISA, WB, and RT-qPCR. DEHP resulted in fetal malformations and abnormal placental histopathology. DEHP also promoted placental miR-155-5p expression, the cAMP/PKA inactivation, and lipid metabolism in placentae. miR-155-5p knockdown abrogated DEHP-induced proliferative, migrative, and invasive inhibition in HTR-8/Svneo cells. Moreover, miR-155-5p downregulation abolished DEHP-induced inactivation of the cAMP/PKA pathway and enhanced lipid metabolism. Additionally, DEHP-induced miR-155-5p facilitated lipid metabolism by inhibiting the cAMP/PKA signaling pathway in HTR-8/Svneo cells. The current study reveals that miR-155-5p plays an indispensable role in DEHP-induced trophoblastic toxicity by promoting lipid metabolism via inhibiting the cAMP/PKA signaling pathway, indicating miR-155-5p might be a promising therapeutic target for DEHP exposure during pregnancy.

ObjectiveTo establish a predictive scoring system for proximal junctional kyphosis (PJK) after posterior internal fixation in elderly patients with chronic osteoporotic vertebral fracture (COVF).Materials and methodsThe medical records of 88 patients who were diagnosed with COVF and underwent posterior internal fixation in our hospital from January 2013 to December 2017 were retrospectively analyzed. The included patients were divided into two groups according to whether they suffered PJK after surgery, namely, the PJK group (25 cases) and non-PJK group (63 cases). The following clinical characteristics were recorded and analyzed: age, gender, body mass index (BMI), bone mineral density (BMD), smoking history, fracture segment, proximal junction angle, sagittal vertebral axis, pelvic incidence (PI)–lumbar lordosis (LL), pelvic tilt (PT), sacral slope (SS), posterior ligamentous complex (PLC) injury, upper instrumented vertebra, lower instrumented vertebra, and the number of fixed segments. The prevalence of these clinical characteristics in the PJK group was evaluated, and the scoring system was established using logistic regression analysis. The performance of the scoring system was also prospectively validated.ResultsThe predictive scoring system was established based on five clinical characteristics confirmed as significant predictors of PJK, namely, age > 70 years, BMI > 28 kg/m2, BMD < −3.5 SD, preoperative PI-LL > 20°, and PLC injury. PJK showed a significantly higher score than non-PJK (7.80 points vs. 2.83 points, t=9.556, PConclusionThe predictive scoring system was confirmed with satisfactory sensitivity and specificity in predicting PJK after posterior internal fixation in elderly COVF patients. The risk of postoperative PJK in patients with a score of 6–11 is high, while the score of 0–5 is low.

Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of SLC12A3 encoding thiazide-sensitive Na-Cl cotransporter, which leads to disturbance of sodium and chlorine reabsorption in renal distal convoluted tubules, resulting in phenotypes such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. In this study, two GS families with proteinuria or Hashimoto’s thyroiditis were analyzed for genetic-phenotypic association. Sanger sequencing revealed that two probands carried SLC12A3 compound heterozygous mutations, and proband A carried two pathogenic mutations: missense mutation Arg83Gln, splicing mutation, or frameshift mutation NC_000016.10:g.56872655_56872667 (gcggacatttttg>accgaaaatttt) in exon 8. Proband B carries two missense mutations: novel Asp839Val and Arg904Gln. Both probands manifested hypokalemia, hypomagnesemia, hypocalcinuria, metabolic alkalosis, and RAAS activation; in addition, the proband A exhibited decreased urinary chloride, phosphorus, and increased magnesium ions excretion, complicated with Hashimoto’s Thyroiditis, while the proband B exhibited enhanced urine sodium excretion and proteinuria. The older sister of proband B with GS also had Hashimoto’s thyroiditis. Electron microscopy revealed swelling and vacuolar degeneration of glomerular epithelial cells, diffuse proliferation of mesangial cells and matrix, accompanied by a small amount of low-density electron-dense deposition, and segmental fusion of epithelial cell foot processes in proband B. Light microscopy showed mild mesangial hyperplasia in the focal segment of the glomerulus, hyperplasia, and hypertrophy of juxtaglomerular apparatus cells, mild renal tubulointerstitial lesions, and one glomerular sclerosis. So, long-term hypokalemia of GS can cause kidney damage and may also be susceptible to thyroid disease.

Background Pulmonary sequestration (PS) associated with massive hemoptysis, hemothorax, and elevated tumor markers or even lung malignancy has been reported in several studies. These clinical features combined with lung lesions on chest imaging are sometimes hard to differentiate from lung malignancies and often complicate the diagnostic procedure. Case presentation A 45-year-old man with PS presented with massive hemoptysis, hemothorax, and extremely elevated carcinoembryonic antigen (CEA) in pleural effusion was initially misdiagnosed with advanced lung carcinoma, but was ultimately diagnosed with PS with Aspergillus infection. Conclusions PS is rarely concurrent with lung cancer; most of the time, it is misdiagnosed as a malignancy, especially when presenting with a fungal infection, which could remarkably elevate CEA in pleural effusion.

Purpose Tumor and anatomical changes during radiotherapy have been observed in stage III non-small cell lung cancer (NSCLC) from many previous studies. We hypothesized that a routinely scheduled adaptive radiotherapy would have clinical important dose benefits to lower the risk of toxicities, without increasing the tumor recurrences. Methods We retrospectively reviewed 92 consecutive patients with inoperable stage III NSCLC between November 2017 and March 2019. All eligible patients should received simultaneously integrated boost (SIB) using intensity-modulated radiation therapy (IMRT). A mid-treatment CT simulation and a new adapted plan were routinely given after the first 20 fractions. The organs at risk (OARs) were delineated per RTOG 1106 atlas. Dose-volume histograms were quantitatively compared between the initial and composite adaptive plans. Logistic regression was applied to analyze the dose–response relationship. Clinical endpoints included acute symptomatic radiation pneumonitis (RP2) and esophagitis (RE2), local and regional tumor control, and progression-free survival (PFS). Results Sixty-four eligible patients received adaptive SIB-IMRT were consecutively included. The GTVs reduced by a median of −38.2% after 42 to 44 Gy in 20 fractions of radiotherapy. By adapting to tumor and anatomical changes, dosimetric parameters of OARs decreased significantly. The mean lung dose decreased by an average of −74.8 cGy, and mean esophagus dose was lower by 183.1 cGy. We found grade 2 or higher acute RP in 11 patients (17.2%), and RE2 in 28 patients (43.8%). Commonly used lung and esophagus dose metrics were significantly associated with RP2 and RE2. The adaptation could reduce RP2 probability by 3%, and RE2 risk by 5%. Subgroups with higher OARs dose or larger tumor shrinkage may get more dose and toxicities benefits. The estimated median PFS was 12.5 months from the start of radiotherapy. Conclusions We demonstrated that the routinely adaptive SIB-IMRT strategy could significantly reduce the dose to surrounding normal tissues, potentially lower the associated acute RP and RE, without increasing the risk of tumor recurrences.

NGF PLGA nanoparticles can exert a protective effect on hUCMSCs and promote the paracrine effects of hUCMSCs on angiogenesis and cardiomyocyte protection through TrkA-PI3K/Akt signaling pathway, the same with free NGF. The application of NGF PLGA nanoparticles in the hUCMSC fibrin cardiac patches can significantly improve the retention of transplanted hUCMSCs and enhance their ability to reduce myocardial apoptosis and promote angiogenesis in the mouse heart after MI.

To evaluate the performance of noninvasive prenatal screening (NIPS) for the fetal common aneuploidy screening in twin pregnancies.The data of 5469 women with twin pregnancies were collected in this retrospective observational study between January 2017 and December 2018. Patients underwent NIPS as first-line screening or after standard serum screening for fetal aneuploidy. The performance of NIPS was examined, and a regression analysis was performed to investigate testing failure in cases of low fetal fraction.In this study, 2231 (40.8%) patients opted for NIPS as the primary prenatal screening test, and 3238 (59.2%) opted for serum screening, including 440 patients who opted for NIPS after serum screening. Among the 2671 pregnancies with available NIPS outcomes, 11 cases of aneuploidy were identified, seven of trisomy 21 and four of sex chromosome aneuploidy (SCA). The sensitivity and specificity for trisomy 21 were 100% (95% CI, 56.1-100.0%) and 100% (95% CI, 99.8-100.0%), respectively. The positive predictive value (PPV) for SCA was 40.0% (95% CI, 13.7-72.6%). No false negatives were found, with a negative predictive value (NPV) of 100% (95% CI, 99.8-100.0%) in total. In 32 pregnancies who failed NIPS test without available NIPS outcomes due to low fetal fraction, the regression analysis demonstrated that increasing BMI and assisted reproductive technology treatment were significant independent predictors.NIPS is a high-performing routine primary prenatal screening test in twin pregnancies, with a high PPV and low false positive rate for detecting trisomy 21. It is also useful to identify common sex chromosome aneuploidies in twin pregnancies, with similar performance to that reported in singleton pregnancy.

As one of the most important weapons against infectious diseases, vaccines have saved countless lives since their first use in the late eighteenth century. Antibodies produced by effector B cells upon vaccination play a critical role in mediating protection. The past several decades of research have led to a revolution in our understanding of B cell response to vaccination. Vaccines against SARS-CoV-2 coronavirus were developed at an unprecedented speed to power our global fight against COVID-19 pandemic. Nevertheless, we still face many challenges in the development of vaccines against many other deadly viruses, such as human immunodeficiency virus (HIV) and influenza virus. In this review, we summarize the latest findings on B cell response to vaccination and pathogen infection. We also discuss the current challenges in the field and the potential strategies targeting B cell response to improve vaccine efficacy.Key abbreviations box: BCR: B cell receptor; bNAb: broadly neutralizing antibody; DC: dendritic cells; DZ: dark zone; EF response: extrafollicular response; FDC: follicular dendritic cell; GC: germinal center; HIV: human immunodeficiency virus; IC: immune complex; LLPC: long-lived plasma cell; LZ: light zone; MBC: memory B cell; SLPB: short-lived plasmablast; TFH: T follicular helper cells; TLR: Toll-like receptor.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract. In this study, we performed single‐cell RNA sequencing (RNA‐seq) on intra‐ and peri‐tumor tissues from GIST patients with the aim of discovering the heterogeneity of tumor cells in GIST and their interactions with other cells. We found four predominating cell types in GIST tumor tissue, including T cells, macrophages, tumor cells, and NK cells. Tumor cells could be clustered into two groups: one was highly proliferating and associated with high risk of metastasis, the other seemed “resting” and associated with low risk. Their clinical relevance and prognostic values were confirmed by RNA‐seq of 65 GIST samples. T cells were the largest cell type in our single‐cell data. Two groups of CD8+ effector memory (EM) cells were in the highest clonal expansion and performed the highest cytotoxicity but were also the most exhausted among all T cells. A group of macrophages were found polarized to possess both M1 and M2 signatures, and increased along with tumor progression. Cell‐to‐cell interaction analysis revealed that adipose endothelial cells had high interactions with tumor cells to facilitate their progression. Macrophages were at the center of the tumor microenvironment, recruiting immune cells to the tumor site and having most interactions with both tumor and nontumor cells. In conclusion, we obtained an overview of the GIST microenvironment and revealed the heterogeneity of each cell type and their relevance to risk classifications, which provided a novel theoretical basis for learning and curing GISTs., We performed single‐cell analysis on GISTs, obtained an overview of the GIST microenvironment, and revealed the heterogeneity of each cell type and their relevance to risk classifications according to bulk RNA sequencing cohorts. One subgroup of tumor cells was highly proliferating and associated with high risk of metastasis. A group of macrophages were found polarized to possess both M1 and M2 signatures, and increased along with tumor progression.

Background Germline mutations represent a high risk of hereditary cancers in population. The landscape and characteristics of germline mutations in genitourinary cancer are largely unknown, and their correlation with patient prognosis has not been defined. Methods Variant data and relevant clinical data of 10,389 cancer patients in The Cancer Genome Atlas (TCGA) database was downloaded. The subset of data of 206 genitourinary cancer patients containing bladder urothelial carcinoma (BLCA), kidney chromophobe carcinoma (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and prostate adenocarcinoma (PRAD) cancer with germline mutation information was filtered for further analysis. Variants were classified into pathogenic, likely pathogenic and non-pathogenic categories based on American College of Medical Genetics and Genomics (ACMG) guidelines. Genome Aggregation Database (gnomAD) database was used to assist risk analysis. Results There were 48, 7, 44, 45 and 62 patients with germline mutations identified in BLCA, KICH, KIRC, KIRP and PRAD, respectively. Pathogenic germline mutations from 26 genes and likely pathogenic mutations from 33 genes were revealed. GJB2, MET, MUTYH and VHL mutations ranked top in kidney cancers, and ATM and CHEK2 mutations ranked top for bladder cancer, while ATM and BRCA1 mutations ranked top for prostate cancer. Frameshift, stop gained and missense mutations were the predominant mutation types. BLCA exhibited the highest ratio of stop gained mutations (22/48 = 45.8%). No difference in patient age was found among pathogenic, likely pathogenic and non-pathogenic groups for all cancer types. The number of male patients far overweight female patients whether PRAD was included (P = 0) or excluded (P Conclusions The germline mutational status for genitourinary cancers has been comprehensively characterized. Pathogenic and likely pathogenic germline mutations increased the risk and indicated poor prognosis of genitourinary cancers.

Carbon quantum dots (CQDs) offer huge potential due to their enzymatic properties as compared to natural enzymes. Thus, discovery of CQDs-based nanozymes with low toxicity from natural resources, especially daily food, implies a promising direction for exploring treatment strategies for human diseases. Here, we report a CQDs-based biocompatible nanozyme prepared from chlorogenic acid (ChA), a major bioactive natural product from coffee. We found that ChA CQDs exhibited obvious GSH oxidase-like activities and subsequently promoted cancer cell ferroptosis by perturbation of GPX4-catalyzed lipid repair systems. In vivo, ChA CQDs dramatically suppressed the tumor growth in HepG2-tumor-bearing mice with negligible side toxicity. Particularly, in hepatoma H22-bearing mice, ChA CQDs recruited massive tumor-infiltrating immune cells including T cells, NK cells, and macrophages, thereby converting "cold" to "hot" tumors for activating systemic antitumor immune responses. Taken together, our study suggests that natural product-derived CQDs from coffee can serve as biologically safe nanozymes for anticancer therapeutics and may aid the development of nanotechnology-based immunotherapeutic.

As a common conditional pathogenic bacterium in nature

Fenton reaction-based chemodynamic therapy is hardly a self-sufficient cancer treatment, due to its stringent reaction conditions, limited substrate concentration, and negative feedback from the tumor microenvironment. Herein, we synthesized a novel two-dimensional (2D) vanadium-based nanosheets (Vanadene, V NSs) with polyvalent surfaces (VsupIV/sup/VsupV/sup), a very narrow band gap of 0.8 eV, and high biodegradability by a liquid-phase exfoliation strategy. The polyvalent surface endowed its multiple capabilities to modulate TME through GSH consumption and Osub2/subproduction via VsupV/supand to catalyze a Fenton-like reaction to produce ·OH under a mild condition via VsupIV/sup. In addition, efficient energy conversions including near-infrared (NIR)-thermal conversion (photothermal therapy, PTT) and NIR-electron conversion (photodynamic therapy, PDT) were ensured by the narrow band gap, in which NIR-thermal conversion enhanced the Fenton-like reaction activity through accelerating ionization while NIR-electron conversion catalyzed the conversion of Osub2/subto ·Osub2/subsup-/supfor further breaking redox homeostasis. Moreover, V NSs-based nanocatalyst can be slowly degraded into non-toxic species, enabling it to be innocuously eliminated from the body after completing tumor eradication by single drug injection and single NIR irradiation. Therefore, this study provides new insights into a universal nanoplatform for NIR-enhanced combination cancer therapy, highlighting the utility of 2D V NSs in the field of biomedicine.

PURPOSE Neoadjuvant chemotherapy (NAC) has been widely used in patients with breast cancer to minish tumor burden and increase resection rate of cancer. T-cell repertoire has been believed to be able to monitor antitumor immune responses. This study aimed to explore the dynamic change of T-cell repertoire and its clinical value in evaluating the tumor response in patients with breast cancer receiving NAC. MATERIALS AND METHODS Ninety-four patients who underwent NAC before surgery were recruited, and peripheral blood samples were collected at multiple time points during NAC. High-throughput T-cell receptor (TCR)-β sequencing was used to characterize the T-cell repertoire of every sample and analyzed the changes in circulating T-cell repertoire during NAC. RESULTS We found that the diversity of TCR repertoires was associated with age and clinical stage of the patients with breast cancer. The distribution of Vβ and Jβ genes in TCR repertoires was skewed in patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer. Vβ20.1 and Vβ30 expression levels before NAC correlate with tumor response after all cycles of NAC in HER2– and HER2+ patients, respectively. Some CDR3 motifs that correlated with clinical response in either HER2+ or HER2– patients were identified. Besides, TCR repertoire evolved during NAC and the diversity of TCR repertoire decreased more after two cycles of NAC in patients with good tumor response after all cycles of NAC (P = .0061). CONCLUSION Our results demonstrated that TCR repertoire correlated with the characteristics of the tumor, such as the expression status of HER2. Moreover, some characteristics of TCR repertoires that correlated with clinical response were identified and they might provide useful information to tailor therapeutic regimens at the early cycle of NAC., This study identified T-cell repertoires that correlated with clinical response in patients with breast cancer.

Background To comprehensively analyze the stemness characteristics related to prognosis and the immune microenvironment in lung adenocarcinoma (LUAD). Methods The OCLR machine learning method was used to calculate the stemness index (mRNAsi) of the LUAD samples. DEGs common between the low mRNAsi, normal, and high mRNAsi groups were screened and the immune-stemness genes were obtained. Then the PPI network was created and enrichment analyses were performed. Moreover, different subtypes based on immune-stemness genes associated with prognosis were identified, and the relationships between LUAD stemness and TIME variables were systematically analyzed, followed by TMB analysis. Results Patients in the high mRNAsi groups with poor prognosis were screened along with 144 immune-stemness genes. IL-6, FPR2, and RLN3 showed a higher degree in the PPI network. A total of 26 immune-stemness genes associated with prognosis were screened. Two clusters were obtained (cluster 1 and cluster 2). Survival analysis revealed that patients in cluster 2 had a poor prognosis. A total of 12 immune cell subpopulations exhibited significant differences between cluster 1 and cluster 2 (P P P Conclusion Immune-stemness genes, including L-6, FPR2, and RLN3, might play significant roles in LUAD development via cytokine–cytokine receptor interaction, neuroactive ligand‒receptor interaction, and the JAK‒STAT pathway. Immune-stemness genes were related to tumor-infiltrating immune cells, TMB, and expression of immune checkpoint gene.

Silicosis is a pulmonary fibrosis-associated disease caused by the inhalation of large amounts of free silicon dioxide (SiO2) that mainly manifests as early inflammation and late pulmonary fibrosis. As macrophage precursors, monocytes accumulate in the lung during early inflammation, but their role in the development of silicosis is unclear. Single-cell sequencing (cell numbers = 25,002), Western blotting, quantitative real-time PCR, ELISA and cell functional experiments were used to explore the specific effects of monocytes on fibroblasts. The CRISPR/Cas9 system was used to specifically knock down ZC3H4, a novel member of the CCCH zinc finger protein family, and was combined with pharmacological methods to explore the mechanism by which ZC3H4 affects chemokine and cytokine secretion. The results indicated that (1) SiO2 induced an infiltrating phenotype in monocytes; (2) infiltrating monocytes inhibited the activation, viability and migration of fibroblasts by regulating IL-10 but not IL-8; and (3) SiO2 downregulated IL-10 via ZC3H4-induced autophagy. This study revealed that ZC3H4 regulated the secretion function of monocytes, which, in turn, inhibited fibroblast function in early inflammation through autophagy signaling, thereby reducing pulmonary fibrosis. These findings provide a new idea for the clinical treatment of silicosis.

Our understanding of human hepatocellular carcinoma (HCC) development and progression has been hampered by the lack of in vivo models. We performed a genetic screen of 10 oncogenes and genetic mutations in Fah‐ablated immunodeficient mice in which primary human hepatocytes (PHHs) are used to reconstitute a functional human liver. We identified that MYC, TP53(R249S), and KRAS(G12D) are highly expressed in induced HCC (iHCC) samples. The overexpression of MYC and TP53(R249S) transform PHHs into iHCC in situ, though the addition of KRAS(G12D) significantly increases the tumorigenic efficiency. iHCC, which recapitulate the histological architecture and gene expression characteristics of clinical HCC samples, reconstituted HCC after serial transplantations. Transcriptomic analysis of iHCC and PHHs showed that MUC1 and FAP are expressed in iHCC but not in normal livers. Chimeric antigen receptor (CAR) T cells against these two surface markers efficiently lyse iHCC cells. The properties of iHCC model provide a biological basis for several clinical hallmarks of HCC, and iHCC may serve as a model to study HCC initiation and to identify diagnostic biomarkers and targets for cellular immunotherapy.

This study aimed to evaluate the efficacy and safety of intravenous combined with topical application of tranexamic acid (TXA) in reducing blood loss in opening wedge high tibial osteotomy (OWHTO).A total of 60 patients who underwent unilateral OWHTO between May 2018 and May 2019 were retrospectively reviewed. All the patients were then divided into one of the two groups (30 per group): the TXA group, patients receiving intravenous combined with topical application of TXA, and the control group, patients receiving no TXA. Outcome measures were drain volume, total blood loss, hidden blood loss, transfusion requirements, and incidence of complications.The mean follow-up of TXA group was 14.2 2.3 months (range, 13-16 months) and the mean follow-up for the control group was 14.4 2.1 months (range, 13-17 months). No significant difference was found for the follow-up of two groups (P=0.829). Drainage volume (143.3 65.4 ml vs 307.8 51.4 mL, P0.001), hidden blood loss (156.7 63.8 mL vs 286.4 79.1 mL, P0.001) and knee swelling (3.2 0.9 vs 6.5 2.1, P0.001) in the TXA group was clearly less than that in the control group, and there was no statistical significance with regard to hospitalization time (P=0.746), transfusion requirements (P=1.000), wound complications (P=0.386), deep venous thrombosis (P=1.000), postoperative Lysholm knee score (P=0.681) and Knee Injury and Osteoarthritis Outcome subscales pain (P=0.752), symptoms (P=0.673), activities of daily living (P=0.871), sport/recreation function (P=0.816), and knee-related quality of life (P=0.576) at 6 months postoperatively.This study has shown that administration of intravenous combined with topical TXA in OWHTO can effectively reduce perioperative blood loss without increasing the incidence of postoperative complications.Level III, Therapeutic Study.

Aberrant levels of reactive oxygen species (ROS) are potential mechanisms that contribute to both cancer therapy efficacy and the side effects of cancer treatment. Upregulation of the non-canonical redox-sensitive NF-kB family member, RelB, confers radioresistance in prostate cancer (PCa). We screened FDA-approved compounds and identified betamethasone (BET) as a drug that increases hydrogen peroxide levels in vitro and protects non-PCa tissues/cells while also enhancing radiation killing of PCa tissues/cells, both in vitro and in vivo. Significantly, BET increases ROS levels and exerts different effects on RelB expression in normal cells and PCa cells. BET induces protein expression of RelB and RelB target genes, including the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), in normal cells, while it suppresses protein expression of RelB and MnSOD in LNCaP cells and PC3 cells. RNA sequencing analysis identifies B-cell linker protein (BLNK) as a novel RelB complementary partner that BET differentially regulates in normal cells and PCa cells. RelB and BLNK are upregulated and correlate with the aggressiveness of PCa in human samples. The RelB-BLNK axis translocates to the nuclear compartment to activate MnSOD protein expression. BET promotes the RelB-BLNK axis in normal cells but suppresses the RelB-BLNK axis in PCa cells. Targeted disruptions of RelB-BLNK expressions mitigate the radioprotective effect of BET on normal cells and the radiosensitizing effect of BET on PCa cells. Our study identified a novel RelB complementary partner and reveals a complex redox-mediated mechanism showing that the RelB-BLNK axis, at least in part, triggers differential responses to the redox-active agent BET by stimulating adaptive responses in normal cells but pushing PCa cells into oxidative stress overload.

To improve the prevention and treatment of venomous snake bites by analyzing the epidemiological characteristics of venomous snake bite in Wuzhou City, Guangxi Zhuang Autonomous Region.A retrospective analysis was conducted. The medical records of 1 091 patients with venomous snake bites admitted to the department of snake wound of Wuzhou Hospital of Traditional Chinese Medicine from January 2014 to December 2020 were collected, including snake species, gender and age of patients, bite time, bite site and local symptom.The medical records of 952 patients with a definite clinical diagnosis of snake bite were enrolled. Among the 952 patients with venomous snake bites, the main bites were from Ovophis (32.98%), Trimeresurus (27.84%) and Naja (26.26%), followed by Bungarus multicinctus (6.51%), Ophiophagus Hannah (3.15%) and Agkistrodonhalys (1.58%), and few bites were from Rhabdophis subminiatus (0.73%), Bungarus fasciatus (0.42%), viper (0.32%) and Agkistrodon (0.21%). Of the 952 patients with venomous snake bites, there were almost twice as many males as females [647 cases (67.96%) vs. 305 cases (32.04%), with male to female ratio of 2.12:1]. The age of patients ranged from 0.8 to 87.0 years old, with 40-59 years old as the majority (42.44%), followed by ≥ 60 years old (27.31%). Snake bites mainly occurred from April to November (93.59%), with a peak in October (16.39%). The incidence time was mainly afternoon (12:00-17:59, 30.88%) and evening (18:00-23:59, 33.30%), followed by morning (06:00-11:59, 24.69%), and early in the morning (00:00-05:59, 11.13%). The incidence time of Ovophis and Bungarus multicinctus mainly concentrated in 18:00-23:59, the time of Trimeresurus was in 06:00-11:59, and that of Naja and Ophiophagus hannah was in 12:00-17:59. Most cases of snake bite were on limbs (98.53%), and mainly on the right limbs (53.57%). The lower limbs mainly were bitten by Ovophis, while the upper limbs mainly were bitten by Naja and by Ophiophagus hannah. The local symptoms of the bite of Ovophis and Trimeresurus were similar, mainly including pain, swelling, tenderness, high temperature of skin around the wound, bleeding and exudation, etc. And the local symptoms of the bite of Naja were pain, swelling, bruising, tenderness, bleeding and exudation, red skin, etc. Numbness and mild pain were the main symptoms of the bite of Bungarus multicinctus and Bungarus fasciatus, but other local characteristics were not obvious.The majority of venomous snake bite patients in Wuzhou City of Guangxi were middle-aged and elderly males, and the majority of venomous snakes were Ovophis, Trimeresurus, and Naja. Most venomous snake bite occurs from April to November, and the incidence time was concentrated between 12:00 and 23:59. The majority of venomous snake bite was limb bites. The local symptoms were pain, swelling, tenderness, high temperature of skin around the wound, bruising, etc. To reduce the incidence rate, disability rate and mortality of snake bite disease, a snake bite prevention system should be established, the education and publicity of snake bite prevention knowledge should be strengthened, the awareness of snake bite prevention should be improved, and clinical diagnosis and treatment should be assisted, based on the epidemiological characteristics of snake bite in Wuzhou area.